Hemorrhagic diathesis. Basic syndromes, diagnostic criteria. Trombocytopenia.Hemophilia.
Definition of the “hemorrhagic syndrome“ and “hemorrhagic diathesis.”
Bleeding from a platelet disorder is usually localized to superficial sites such as the skin and mucous membranes, comes on immediately after trauma or surgery, and is readily controlled by local measures. In contrast, bleeding from secondary hemostatic or plasma coagulation defects occurs hours or days after injury and is unaffected by local therapy. Such bleeding most often occurs in deep subcutaneous tissues, muscles, joints, or body cavities. A careful and thorough history may establish the presence of a hemostatic disorder and guide initial laboratory testing.
Current classification of hemorrhagic diathesis. Etiology, pathogenesis of hemorrhagic diathesis in the patients with disorders of coagulation, platelet and vessel wall.
Patients with platelet or vessel wall disorders usually bleed into superficial sites such as the skin, mucous membranes, or genitourinary or gastrointestinal tract. Bleeding begins immediately after trauma and either responds to simple measures such as pressure and packing or requires systemic therapy with glucocorticoids, desmopressin [1-desamino-8-D-arginine vasopressin (DDAVP)], plasma fractions, or platelet concentrates. The most common platelet/vessel wall disorders are (1) various forms of thrombocytopenia, (2) von Willebrand’s disease (vWD), and (3) drug-induced platelet dysfunction.
PLATELET DISORDERS
Platelets arise from the fragmentation of megakaryocytes, which are very large, polyploid bone marrow cells produced by the process of endomitosis. They undergo from three to five cycles of chromosomal duplication without cytoplasmic division. After leaving the marrow space, about one-third of the platelets are sequestered in the spleen, while the other two-thirds circulate for 7 to 10 days. Normally, only a small fraction of the platelet mass is consumed in the process of hemostasis, so most platelets circulate until they become senescent and are removed by phagocytic cells. The normal blood platelet count is 150,000 to 450,000/ul. A decrease in platelet count stimulates an increase in the number, size, and ploidy of megakaryocytes, releasing additional platelets into the circulation. This process is regulated by thrombopoietin (TPO) binding to its megakaryocyte receptor, a proto-oncogene c-mpl. TPO (c-mpl ligand) is secreted continuously at a low level and binds tightly to circulating platelets. A reduction in platelet count increases the level of free TPO and thereby stimulates megakaryocyte and platelet production.
The platelet count varies during the menstrual cycle, rising following ovulation and falling at the onset of menses. It is also influenced by the patient’s nutritional state and can be decreased in severe iron, folic acid, or vitamin B12 deficiency. Platelets are acute-phase reactants, and patients with systemic inflammation, tumors, bleeding, and mild iron deficiency may have an increased platelet count, a benign condition called secondary or reactive thrombocytosis. The cytokines interleukin (IL)-3, IL-6, and IL-11 may stimulate platelet production in acute inflammation. In contrast, the increase in platelet count that is characteristic of the myeloproliferative disorders such as polycythemia vera, chronic myelogenous leukemia, myeloid metaplasia, and essential thrombocytosis can cause either severe bleeding or thrombosis. In these patients, unregulated platelet production is secondary to a clonal stem cell abnormality affecting all the bone marrow progenitors.
THROMBOCYTOPENIA
Thrombocytopenia is caused by one of three mechanisms-decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. In order to determine the etiology of thrombocytopenia, each patient should have a careful examination of the peripheral blood film, an assessment of marrow morphology by examination of an aspirate or biopsy, and an estimate of splenic size by bedside palpation supplemented, if necessary, by ultrasonography or computed tomographic (CT) scan. Occasional patients have “pseudothrombocytopenia,” a benign condition in which platelets agglutinate or adhere to leukocytes when blood is collected with EDTA as anticoagulant. This is a laboratory artifact, and the actual platelet count in vivo is normal.
Impaired Production Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. They usually affect multiple hematopoietic cell lines so that thrombocytopenia is accompanied by varying degrees of anemia and leukopenia. Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate or biopsy, which should show a reduced number of megakaryocytes. The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration with malignant cells, all of which produce highly characteristic marrow abnormalities. Occasionally, thrombocytopenia is the presenting laboratory abnormality in these disorders. Cytotoxic drugs impair megakaryocyte proliferation and maturation and frequently cause thrombocytopenia. Rare marrow disorders such as congenital amegakaryocytic hypoplasia and thrombocytopenia with absent radii (TAR syndrome), produce a selective decrease in megakaryocyte production.
Splenic Sequestration Since one-third of the platelet mass is normally sequestered in the spleen, splenectomy will increase the platelet count by 30%. Postsplenectomy thrombocytosis is a benign self-limited condition that does not require specific therapy. In contrast, when the spleen enlarges, the fraction of sequestered platelets increases, lowering the platelet count. The most common causes of splenomegaly are portal hypertension secondary to liver disease and splenic infiltration with tumor cells in myeloproliferative or lymphoproliferative disorders. Isolated splenomegaly is rare, and in most patients it is accompanied by other clinical manifestations of an underlying disease. Many patients with leukemia, lymphoma, or a myeloproliferative syndrome have both marrow infiltration and splenomegaly and develop thrombocytopenia from a combination of impaired marrow production and splenic sequestration of platelets.
Accelerated Destruction Abnormal vessels, fibrin thrombi, and intravascular prostheses can all shorten platelet survival and cause nonimmunologic thrombocytopenia. Thrombocytopenia is common in patients with vasculitis, the hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or as a manifestation of disseminated intravascular coagulation (DIC). In addition, platelets coated with antibody, immune complexes, or complement are rapidly cleared by mononuclear phagocytes in the spleen or other tissues, inducing immunologic thrombocytopenia. The most common causes of immunologic thrombocytopenia are viral or bacterial infections, drugs, and a chronic autoimmune disorder referred to asidiopathic thrombocytopenic purpura (ITP). Patients with immunologic thrombocytopenia do not usually have splenomegaly and have an increased number of bone marrow megakaryocytes.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
The immunologic thrombocytopenias can be classified on the basis of the pathologic mechanism, the inciting agent, or the duration of the illness. The explosive onset of severe thrombocytopenia following recovery from a viral exanthem or upper respiratory illness (acute ITP) is common in children and accounts for 90% of the pediatric cases of immunologic thrombocytopenia. Of these patients, 60% recover in 4 to 6 weeks and >90% recover within 3 to 6 months. Transient immunologic thrombocytopenia also complicates some cases of infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus infection and can be part of the prodromal phase of viral hepatitis and initial infection with HIV. Acute ITP is rare in adults and accounts for <10% of postpubertal patients with immune thrombocytopenia. Acute ITP is caused by immune complexes containing viral antigens that bind to platelet Fc receptors or by antibodies produced against viral antigens that cross-react with the platelet. In addition to these viral disorders, the differential diagnosis includes atypical presentations of aplastic anemia, acute leukemias, or metastatic tumor. A bone marrow examination is essential to exclude these disorders, which can occasionally mimic acute ITP.
Most adults present with a more indolent form of thrombocytopenia that may persist for many years and is referred to as chronic ITP. Women age 20 to 40 are afflicted most commonly and outnumber men by a ratio of 3:1. They may present with an abrupt fall in platelet count and bleeding similar to patients with acute ITP. More often they have a prior history of easy bruising or menometrorrhagia. These patients have an autoimmune disorder with antibodies directed against target antigens on the glycoprotein IIb-IIIa or glycoprotein Ib-IX complex. Although most antibodies function as opsonins and accelerate platelet clearance by phagocytic cells, occasional antibodies bind to epitopes on critical regions of these glycoproteins and impair platelet function. Platelet-associated IgG can be measured but specificity is a problem. High “background” level of IgG oormal platelets and elevations in plasma immunoglobulin levels or in circulating immune complexes will nonspecifically increase platelet-associated IgG. Few clinical situations require platelet-associated IgG testing.
A low platelet count may be the initial manifestation of systemic lupus erythematosus (SLE) or the first sign of a primary hematologic disorder. Thus, patients with chronic ITP should have a bone marrow examination and an antinuclear antibody determination. In addition, patients with hepatic or splenic enlargement, lymphadenopathy, or atypical lymphocytes should have serologic studies for hepatitis viruses, cytomegalovirus, Epstein-Barr virus, toxoplasma, and HIV. HIV infection is a common cause of immunologic thrombocytopenia. Thrombocytopenia can be the initial symptom of HIV infection or a complication of fully developed clinical AIDS.
Patients with congenital plasma coagulation defects characteristically bleed into muscles, joints, and body cavities hours or days after an injury. Most of the inherited plasma coagulation disorders are due to defects in single coagulation proteins, with the two X-linked disorders, factors VIII and IX deficiency, accounting for the majority. These patients may have severe bleeding and chronic disability and require specialized medical therapy. With rare exceptions, the known disorders prolong either the prothrombin time (PT), partial thromboplastin time (PTT), or both. If they are abnormal, quantitative assays of specific coagulation proteins are then carried out using the PT or PTT tests with plasma from congenitally deficient individuals as substrate. The corrective effect of varying concentrations of patient plasma is measured and expressed as a percentage of a normal pooled plasma standard. The interval range for most coagulation factors is from 50 to 150% of this average value, and the minimal level of most individual factors needed for adequate hemostasis is 25%.
Acquired coagulation disorders are both more frequent and more complex, arising from deficiencies of multiple coagulation proteins and simultaneously affecting both primary and secondary hemostasis. The most common acquired hemorrhagic disorders are (1) disseminated intravascular coagulation (DIC), (2) the hemorrhagic diathesis of liver disease, and (3) vitamin K deficiency and complications of anticoagulant therapy.
Platelet Disorders
The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the cytoplasmic fragmentation of megakaryocytes in the bone marrow and circulate in blood as disk-shaped anucleate particles.
Under normal circumstances, the resistance of the endothelial cell lining to interactions with platelets and coagulation factors prevents thrombosis. When endothelial continuity is disrupted and the underlying matrix is exposed, a coordinated series of events are set in motion to seal the defect (primary hemostasis). Platelets play a primary role in this process, interacting with subendothelium-bound von Willebrand factor (vWf) via the membrane glycoprotein Ib complex. This initial interaction (platelet adhesion) sets the stage for other adhesive reactions that allow the platelets to interact with each other to form an aggregate (see Pict. 4).
Pict. 4. Normal hemostasis
The platelet glycoprotein (glycoprotein IIb/IIIa) complex mediates platelet–to–platelet interactions (platelet aggregation). On resting platelets, glycoprotein IIb/IIIa is unable to bind fibrinogen or vWf. Platelet activation allows binding of these proteins, which bridges adjacent platelets. Morphologically, the platelets change dramatically from disks to spiny spheres in a process called shape change.
Platelets contain 2 unique types of granules, the alpha granules and the dense granules. The alpha granules contain hemostatic proteins such as fibrinogen, vWf, and growth factors (eg, platelet-derived growth factor). The dense granules contain proaggregatory factors such as adenosine 5′-diphosphate (ADP), calcium, and 5-hydroxytryptamine (serotonin). During activation, the granules are centralized and their contents are discharged into the lumen of the open canalicular system, from which they are then released to the exterior (the release reaction).
Following activation, platelets have 2 major mechanisms to recruit additional platelets to the growing hemostatic plug. They release proaggregatory materials (eg, ADP) by the release reaction, and they synthesize thromboxane A2 from arachidonic acid. Thus, the release reaction and prostaglandin synthesis act to consolidate the initial hemostatic plug by promoting the participation of other platelets in the growing hemostatic plug. In addition, when platelets are activated, negatively charged phospholipids move from the inner to the outer leaflet of the membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system, resulting in the formation of a clot (secondary hemostasis).
Pathophysiology: Platelet disorders lead to defects in primary hemostasis and have signs and symptoms different from coagulation factor deficiencies (disorders of secondary hemostasis). The body’s reaction to vessel wall injury is rapid adhesion of platelet subendothelium. The initial hemostatic plug, composed primarily of platelets, is stabilized further by a fibrin mesh generated in secondary hemostasis. The arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively results from the primary hemostatic plug.
Hence, primary hemostatic disorders are characterized by prolonged bleeding time, and the characteristic physical examination findings are petechiae and purpura. In comparison, defects in secondary hemostasis exhibit delayed deep bleeding (eg, muscles and joints) and the characteristic physical examination finding is hemarthrosis. Hemarthrosis and muscle hematomas are not present in primary hemostatic disorders.
Autoimmune thrombocytopenias
Immune thrombocytopenic purpura
Immune thrombocytopenic purpura (ITP) is one of the most common autoimmune disorders. It occurs in 2 distinct clinical types, an acute self-limiting form observed almost exclusively in children (5 cases per 100,000 persons), and a chronic form, observed mostly in adults (3-5 cases per 100,000 persons) and rarely in children.
This disease is caused by autoantibodies to platelets. The antigenic target in most patients appears to be the platelet glycoprotein IIb/IIIa complex. Platelets with antibodies on their surface are trapped in the spleen, where they are efficiently removed by splenic macrophages. The mechanism of origin of these antibodies is not known. These antibodies may be directed towards the viral antigens and then cross-react with platelet antigens. They persist because of the failure of immune surveillance mechanisms to repress these antibodies. These antibodies can also react with the developing megakaryocytes in bone marrow, leading to decreased protection of platelets (ineffective thrombopoiesis).
ITP occurs commonly in otherwise healthy individuals and only rarely as the initial manifestation of lupus and other autoimmune disorders. HIV infection is often associated with immune thrombocytopenia in both adults and children.
Chronic ITP
This is typically observed in adults aged 20-40 years. It has an insidious onset, and a history of an antecedent infectioeed not be present. Unlike childhood ITP, chronic ITP is more common in females than in males. As in childhood ITP, the bleeding manifestations depend on the platelet count.
The diagnosis of ITP is established by the exclusion of other causes of thrombocythemia. The peripheral blood film should be examined to rule out thrombotic thrombocytopenic purpura (TTP) (fragments) or spurious thrombocytopenia resulting from clumping. Often, the smear shows giant platelets, which is a reflection of the increased thrombopoietin-induced stimulation of bone marrow. Bone marrow examination, which is not always necessary, shows increased megakaryocytes.
Alloimmune thrombocytopenia
Posttransfusion purpura
Platelet glycoprotein IIb/IIIa is a major antigen in platelets and is polymorphic. Most individuals have leucine at position 33 (phospholipase A1 [PLA1]/PLA1 or human platelet alloantigen [HPA]–1a). A small number of individuals, approximately 1-3% of random populations, have proline at position 33. Homozygotes with proline are termed phospholipase-negative (or HPA-1b, PLA2/PLA2), and, when they receive blood products from HPA-1a–positive individuals, they produce an antibody reactive against HPA-1a. This alloantibody destroys the transfused platelets and the patient’s own platelets, leading to a severe form of thrombocytopenia that lasts for several weeks and, sometimes, several months.
Posttransfusion purpura typically occurs 10 days following a transfusion. This syndrome can be induced by a small amount of platelets contaminating a red blood cell transfusion or, occasionally, following fresh frozen plasma transfusion. The thrombocytopenia responds to intravenous immunoglobulin (IVIG). Other platelet alloantigens are occasionally implicated in posttransfusion purpura.
Drug-induced thrombocytopenia
Drugs can induce thrombocytopenia by a number of mechanisms. In addition to the cytotoxic drugs, thiazide diuretics, interferon, and alcohol can cause thrombocytopenia by inhibiting platelet production in the bone marrow. More commonly, drug-induced thrombocytopenia results from the immunological destruction of platelets. Drugs can induce antibodies to platelets, either acting as a hapten or as an innocent bystander. Also, drugs such as gold salts and interferon can induce an ITP-like disorder.
Common drugs associated with thrombocytopenia include quinidine, amiodarone, gold, captopril, sulfonamides, glibenclamide, carbamazepine, ibuprofen, cimetidine, tamoxifen, ranitidine, phenytoin, vancomycin, and piperacillin.
The diagnosis of drug-induced thrombocytopenia is often empirical. A temporal relationship must be present between the administration of the drug and the development of thrombocytopenia, with no other explanations for the thrombocytopenia. Recurrent thrombocytopenia following reexposure to the drug confirms the drug as the cause of thrombocytopenia. Identifying the drug that is causing severe thrombocytopenia in an acutely ill patient who is taking multiple drugs is often challenging.
Heparin causes a unique situation among drug-induced thrombocytopenias in that the antibodies also activate platelets and induce a hypercoagulable state.
Thrombotic thrombocytopenic purpura
TTP is a rare but serious disorder that was initially described as a pentad of thrombocytopenia (with purpura), red blood cell fragmentation, renal failure, neurological dysfunction, and fever. Recent evidence indicates that this disorder results from the abnormal presence of unusually large multimers of von Willebrand protein. These ultra-large precursors, normally synthesized in the endothelial cells, are processed by a plasma enzyme to normal-sized multimers. This enzyme is now identified as ADAMTS13, a metalloproteinase synthesized in the liver.
The sporadic forms of TTP are caused by an antibody or toxin inhibiting the activity of ADAMTS13. The chronic, recurrent form of TTP may result from a congenital deficiency of the enzyme. The ultra-large multimers are thought to induce the aggregation of platelets, causing platelet consumption. Occlusion of microvasculature by the platelets in the brain, kidney, and other organs leads to myriad symptoms. A TTP-like syndrome has been associated with lupus, pregnancy, HIV infection, and certain drugs (eg, quinine, ticlopidine, clopidogrel, cyclosporine, chemotherapeutic agents).
TTP is often associated with an episode of flulike illness 2-3 weeks before presentation. Most patients with TTP do not have the classic pentad. The most common presentation is petechiae and neurological symptoms. The neurologic symptoms can range from headache and confusion to seizures and coma. Fever is present in slightly more than half the patients.
Hemolytic uremic syndrome
Patients with hemolytic uremic syndrome (HUS) have vascular lesions indistinguishable from those observed in patients with TTP, but the renal vasculature endures the most lesions, with minimal neurological dysfunction. This is a catastrophic illness that predominantly affects children aged 4-12 months, sometimes affects older children, and rarely affects adults. It follows an upper respiratory tract infection. In the tropics, epidemics of HUS are frequent and resemble an infectious disease; however, no causative organism has been identified. In
Disorders of platelet function
Functional disorders of platelets are relatively rare, and most of these disorders are mild and may not be recognized early in life.
von Willebrand disease
von Willebrand disease is the most common inherited bleeding disorder. It is autosomal dominant, and its prevalence is estimated to be as high as 1 case per 1000 individuals.
The hallmark of von Willebrand disease is defective platelet adhesion to subendothelial components caused by a deficiency of the plasma protein vWf. This factor is a large, multimeric protein synthesized, processed, and stored in the Weibel-Palade bodies of the endothelial cells, and it is secreted constitutively following stimulation. vWf has a major role in primary hemostasis as mediator of the initial shear-stress–induced interaction of the platelet to the subendothelium via the glycoprotein Ib complex. In addition, von Willebrand protein acts as a carrier and stabilizer of coagulation factor VIII by forming a complex in the circulation. In the absence of vWf, the factor VIII level is low. In classic hemophilia A, the factor VIII level is low because of a deficiency of factor VIII itself, whereas in von Willebrand disease, the factor VIII level is low because of a deficiency in its carrier protein.
von Willebrand disease is a relatively mild bleeding disorder, except in the occasional patient who is homozygous for the defect and who has severe bleeding often indistinguishable from classic hemophilia. The bleeding manifestations are predominantly skin-related and mucocutaneous (ie, easy bruising, epistaxis, GI hemorrhage). Most bleeding episodes occur following trauma or surgery. In women, menorrhagia is common, often exacerbated by the concurrent administration of cyclooxygenase inhibitors. Pregnant patients with this disease usually do not have problems.
Bleeding time is prolonged in persons with von Willebrand disease. Because the von Willebrand protein is phase-reactant (ie, increased synthesis in the presence of inflammation, infection, tissue injury, and pregnancy), a mild prolonged bleeding time may be normalized, resulting in difficulty in diagnosis.
In addition to the prolonged bleeding time, characteristic abnormalities in platelet aggregation tests occur. In patients with von Willebrand disease, platelets aggregate normally to all agonists except ristocetin. The antibiotic ristocetin induces binding of the von Willebrand protein to platelets, similar to what happens with platelets following vessel wall injury in vivo. Ristocetin-induced platelet aggregation correlates with the platelet-aggregating activity of the von Willebrand protein. Levels of coagulation factor VIII are also low, resulting from a decrease in vWf.
Platelet dysfunction in uremia
Abnormal bleeding is common in patients with uremia. The bleeding has the characteristics of a platelet disorder, and GI tract bleeding is the most frequent symptom.
Platelet Disorders
Bleeding time is generally very prolonged in patients with uremia, signifying a major defect in platelet function, which improves after dialysis. A number of dialyzable platelet-inhibitory factors have been shown to inhibit platelet function. Furthermore, uremic platelets synthesize less thromboxane A2, and the blood vessels taken from patients with uremia produce greater quantities of platelet-inhibitory prostaglandin. Nitric oxide produced by the endothelial cells inhibits platelet function. Because the prolonged bleeding time and the hemostatic abnormalities are partly corrected by red blood cell transfusion or erythropoietin therapy, the failure of hemoglobin to quench excess nitric oxide synthesis has been suggested as partly responsible for the platelet dysfunction.
Frequency:
· In the
Sex:
· Unlike hemophilia, most inherited disorders of platelets are not X-linked and are equally distributed in both sexes.
· Chronic autoimmune thrombocytopenia is more common in females than in males.
· Acute ITP is observed equally in both sexes.
History:
· History and physical examination findings help distinguish between primary and secondary hemostatic disorders and whether the disorder is inherited or acquired.
· Epistaxis is common in individuals with primary hemostatic disorders, but it is also common in healthy individuals. Details about the frequency, duration, packing requirement, and prior treatment (cautery or transfusion) are helpful for assessing the severity of bleeding.
· Bleeding gums is a common symptom in persons with primary disorders of hemostasis. Bleeding could be spontaneous or could be associated with brushing or flossing.
· Bleeding from tooth extractions is possible. A molar tooth extraction is a traumatic procedure. Uneventful extraction of a molar is unlikely in a patient with a severe bleeding disorder.
· Hemoptysis, hematemesis, hematuria, hematochezia, and melena are rarely the initial symptoms of a bleeding disorder. However, these may be exacerbated by an underlying bleeding disorder.
· Menstrual history is important. Metromenorrhagia is often observed in individuals with primary hemostatic disorders. This is especially common in patients with von Willebrand disease and is often exacerbated by the NSAIDs used to treat dysmenorrhea.
· Bleeding after childbirth may be the first manifestation of a mild bleeding disorder.
· Bleeding in the joints is the hallmark of hemophilia and other secondary hemostatic disorders.
· Details of previous surgery, including the amount of blood transfused, if any, are helpful.
· In males, excessive bleeding following circumcision is often the initial manifestation of a congenital bleeding disorder.
· Delayed bleeding from the umbilical stump is characteristic of a factor XIII deficiency.
· Defective wound healing is observed in individuals with a factor XIII deficiency and abnormal fibrinogens.
· Medication history findings may be helpful because aspirin often accentuates a preexisting bleeding disorder. A history of previous iron therapy for anemia may be useful.
Physical:
· A careful physical examination often reveals signs of a hemostatic disorder (see Pic. 5).
Pic. 5. Purpuric spots
· Bruising is common in individuals with a platelet disorder.
· Petechiae are pinpoint hemorrhages (<
· Splenomegaly is not observed in the typical patient with ITP. The spleen can engulf platelets and be several times normal size without becoming palpably enlarged.
· Hemarthrosis and deep muscle hematomas are unusual in patients with primary hemostatic disorders.
Causes:
· Platelet defects can be considered either as a decreased number of platelets (thrombocytopenia) or as defective platelets. Platelet aggregation tests are useful in differentiating various disorders of platelet function. Spurious thrombocytopenia can occur due to aggregates forming in the specimen. Also, dilutional thrombocytopenia may occur in situations of fluid replacement or blood component replacement without platelet support. In all cases of thrombocytopenia, the peripheral blood smear must be reviewed to confirm the thrombocytopenia. This review is crucial.
· Thrombocytopenia can be further divided into increased destruction or decreased production. Thrombocytopenia resulting from increased destruction occurs either by an immune mechanism or increased consumption. Platelets are consumed intravascularly by the activation of the coagulation process (diffuse intravascular coagulation [DIC]) or by deposition on damaged endothelial cells (microangiopathy). Production defects result from those diseases that cause bone marrow failure, such as aplastic anemia, infiltration by leukemia or another malignancy, fibrosis or granulomatous disorders, or tuberculosis.
· Functional disorders of platelets can be inherited (rare) or acquired (common).
· Causes of thrombocytopenia related to increased destruction include (1) immune thrombocytopenias (eg, autoimmune, alloimmune, drug-induced) and (2) increased consumption (eg, DIC, TTP).
· Causes of thrombocytopenia related to decreased production include bone marrow depression.
· Disorders of platelet function are as follows:
o Disorders of platelet adhesion (von Willebrand disease, Bernard-Soulier syndrome)
o Disorders of aggregation (Glanzmann thrombasthenia)
o Disorders of secretion
o Disorders of thromboxane synthesis
o Acquired disorders of platelet function (drugs, eg, aspirin, NSAIDs, alcohol)
o Uremia
o Paraproteins
o Fibrin degradation products
o Myelodysplasia or a myeloproliferative syndrome
Lab Studies:
· Peripheral smear
o Careful examination of the peripheral smear is essential in a patient with thrombocytopenia.
o Spurious thrombocytopenia due to platelet clumping or platelets adhering to neutrophils (platelet satellitism) can be seen in the smear (see Pic. 6).
Pic. 6. Spurious thrombocytopenia. Peripheral smear of a patient reported to have platelet counts of 10,000-150,000/mL on various occasions. The smear shows clumping of the platelets and satellitism involving neutrophils and platelets
o Giant platelets are often seen in persons with ITP (see Pic. 7).
Pic. 8. Peripheral smear of a patient with Bernard-Soulier syndrome showing giant platelets. These platelets are not counted as platelets in most particle counters.
o In TTP, a striking degree of red blood cell fragmentation is seen in addition to thrombocytopenia (see Pic. 9 ).
· Platelet-associated immunoglobulin G
o The autoantibodies responsible for autoimmune thrombocytopenia do not induce complement-mediated lysis. Furthermore, when platelets are destroyed in the circulation, they internalize plasma proteins, including immunoglobulin. Platelets also have low affinity to the crystallizable fragment (Fc) receptor, FcgRIIa, that binds immunoglobulin.
o In patients with autoimmune thrombocytopenia, the larger platelets have proportionately more membrane surface than the Fc receptor.
· Test of primary hemostasis bleeding time
o This is a valuable test for disorders of primary hemostasis.
o It is performed by measuring the duration required for bleeding to stop from a fresh superficial cut (
o Under these conditions, the cessation of bleeding results from the formation of a primary hemostatic plug. A fairly linear correlation exists between bleeding time and platelet counts of 10,000-100,000/mL.
o A prolonged bleeding time with a normal platelet count is very significant and indicates a qualitative platelet disorder.
o In disorders of secondary hemostasis (eg, hemophilia A and B), bleeding time is almost invariably normal.
o Bleeding time is prolonged when platelet counts indicate fewer than 75,000/mL and do not provide any further information.
o This test should not be performed on patients with thrombocytopenia.
o This test is highly operator-dependent and is not recommended as a routine screening test.
· Platelet aggregation
o Platelet aggregation is measured by turbidimetric methods.
o When platelets aggregate, the opalescent suspension of platelet-rich plasma becomes clearer and allows more light transmission. The extent of aggregation is determined by measuring the increase in light transmission.
o Small doses of ADP (<1 mmol) induce a reversible form of platelet aggregation (primary wave), unaccompanied by thromboxane synthesis or release of intraplatelet ADP. However, with increasing doses of ADP, sufficient stimulation of platelets occurs and leads to the release of intraplatelet ADP and the synthesis of thromboxane A2 from arachidonic acid, thus resulting in more pronounced irreversible aggregation (secondary wave).
o Ristocetin induces platelet aggregation by inducing von Willebrand protein binding to the platelet glycoprotein Ib complex.
o Platelet aggregation tests are useful in distinguishing different disorders of platelet function. They are also particularly useful in the diagnosis of von Willebrand disease, in which ristocetin-induced platelet aggregation is defective.
Imaging Studies:
· Imaging studies are not necessary to diagnose uncomplicated ITPs.
· Rarely, platelet survival studies may be necessary to document decreased platelet survival before splenectomy in a patient with possible bone marrow hypofunction. Typically, the platelet half-life is decreased from the normal 5-7 days. A normal platelet survival curve is not consistent with increased splenic destruction.
· In a patient who has relapsed following splenectomy, an indium-labeled platelet imaging study is sometimes useful for localizing an accessory spleen.
Other Tests:
· Bone marrow examination is not necessary in most cases of platelet disorders. The isolated presence of large platelets in the peripheral blood, in the absence of any other signs of bone marrow dysfunction, is very suggestive of normal marrow activity.
· Bone marrow examination is necessary in patients who have an atypical course, have splenomegaly, or will undergo splenectomy.
Bone marrow examination in patients with ITP shows megakaryocytic hyperplasia (see Pic.10). Quantifying the megakaryocytes in the bone marrow is technically difficult. Usually, 2-3 megakaryocytes are present in each spicule in typical marrow. Clusters of immature megakaryocytes are often observed in patients with ITP.
Pic. 10. Bone marrow in immune thrombocytopenic purpura. Bone marrow examination reveals an increased number of megakaryocytes.
Medical Care:
· Treatment of chronic ITP in adults
o No consensus has been reached regarding when to start steroid therapy for chronic ITP in adults and how long to treat it.
o Most physicians elect to not treat patients unless their platelet count is below 50,000/mL or bleeding manifestations are present.
o A course of steroid therapy is often administered upon the initial diagnosis in an effort to induce a sustained remission. The treatment of choice is oral prednisone, usually administered in a dose of 1 mg/kg. Approximately two thirds of patients can be expected to show a therapeutic response with steroid therapy.
o Steroids are usually continued until the platelet count reaches normal or over 50,000, and then they are gradually tapered in 4-6 weeks.
o Methylprednisone (30 mg/kg IV days 1-3, tapered every third day to 1 mg/kg) has also been used with similar results.
o In a more recent study, a 4-day course of high-dose dexamethasone (40 mg/d) has been reported as an effective initial therapy for adults with ITP, with 50% of patients showing sustained platelet count of over 50,000.
o In general, only 15-25% of patients are expected to have lasting remission; the remainder have disease characterized by frequent relapses and remissions.
o Unlike in children, IVIG does not induce an early rise in platelet counts in adults and does not have an advantage over steroids as an initial therapy.
o Even if the platelet count normalizes, many patients can maintain platelet counts of more than 20,000-30,000/mL with lower doses of steroids during times of relapse. However, in approximately one third of patients with chronic ITP, steroids are not effective, either because of a failure in response or a steroid requirement that leads to unacceptable adverse effects (eg, glucose intolerance, GI bleeding).
o The second line of treatment for the management of steroid failures is splenectomy. Splenectomy is considered for any patient who does not respond to steroids (or who cannot receive steroids) and has clinically significant bleeding manifestations.
o The appropriate time to perform the splenectomy is controversial. Most physicians wait for 3-6 months before recommending splenectomy because sometimes ITP goes into spontaneous remission, especially in younger patients. Often, other clinical considerations (eg, coexistence of diabetes or peptic ulcer disease) may influence the decision for earlier splenectomy.
o Splenectomy is effective because it removes the major site of destruction and the major source of antiplatelet antibody synthesis.
o Before splenectomy, patients should receive a pneumococcal vaccine.
o Even if complete remission is not achieved, the platelet count will be higher after splenectomy.
o Intravenous IgG (1 g/kg/d for 1-2 d) induces a short-term increase in the platelet count, starting within several days and lasting approximately 2-3 weeks, both in patients who have undergone splenectomy and in those who have not. No clear evidence indicates that repeated infusions induce a lasting remission. Significant adverse effects include hypotension and renal failure.
o Anti-D immunoglobulin (WinRho, 50-75 mcg/kg IV) is also as effective as intravenous immunoglobulin in Rh positive adults with an intact spleen. Rarely, massive intravascular hemolysis with disseminated intravascular coagulation and occasional death has occurred with use of anti-D immunoglobulin.
o Both intravenous IgG and anti-D immunoglobulin are relatively expensive therapy for adults compared with steroids and is primarily used to on an interim basis during a crisis (eg, before splenectomy or major surgery).
o Approximately 10-20% of patients who undergo splenectomy remain thrombocytopenic and continue to have a bleeding risk that requires continued treatment. Both steroid therapy and splenectomy are considered failures in these patients, and the patients are challenging to treat. An accessory spleen should be excluded as the cause of treatment failure after splenectomy.
o Limited benefit may be observed using immunosuppression with cytotoxic agents. Azathioprine (150 mg/d) or cyclophosphamide (50-100 mg/d) has been used with some success. These cytotoxic drugs can cause myelosuppression, alopecia, hemorrhagic cystitis (cyclophosphamide [Cytoxan]), sterility, and secondary malignancy. These drugs are given for a minimum duration and are withdrawn as soon as remission is achieved. Blood counts must be monitored during therapy.
o Vincristine infusion (0.02 mg/kg) with a maximum dose of 2 mg every week for 3 weeks has also been shown to induce remission.
o Rituximab, a monoclonal antibody directed against the lymphocyte antigen, has been reported to induce remission in refractory ITP.
o Recently, several studies have reported improved platelet counts in patients with Helicobacter pylori–positive ITP following standard H pylori eradication therapy, with cohorts from Japan and Italy reporting higher response rates. Several explanations, such as molecular and immunomodulation by macrolides, have been provided.
o A number of treatments have been proposed for splenectomy and steroid failures. Most of them are not based on placebo-controlled studies, and evaluating the efficacy of these treatments in a disease associated with spontaneous remissions and relapse is difficult. The anabolic steroid danazol (400-800 mg/d) has been shown to induce remission in certain patients. Cyclosporine and alfa-interferon have also been used. Plasmapheresis and extracorporeal protein A adsorption have been tried in desperate situations. The autoantibodies responsible for ITP are primarily IgG, and plasmapheresis is of limited value because more than half of the normal IgG pool is in the extravascular space.
o Refractory ITP has also been treated with combination chemotherapy used for low grade non-Hodgkin lymphoma (6 cycles of cytoxan, vincristine, and prednisone with some success). Other evolving therapies for refractory ITP include autologous hematopoietic stem cell transplantation and anticytokine therapy with etanercept.
· Severe thrombocytopenia with bleeding
o A bleeding patient with a very low platelet count is a medical emergency.
o The presence of hemorrhagic bullae in the buccal mucosa and retinal hemorrhages are harbingers of internal and intracranial bleeding.
o Diseases that cause such severe thrombocytopenia are ITP, TTP, posttransfusion purpura, drug-induced thrombocytopenia, and aplastic anemia. Differentiating TTP from ITP is very important because platelet transfusions are contraindicated in patients with TTP and plasma exchange therapy should be initiated as soon as possible in patients with TTP.
o Careful examination of the peripheral smear helps differentiate ITP from TTP. Furthermore, the presence of neurological signs, renal failure, fever, and a high LDH level also helps in the diagnosis of TTP.
o The patient’s medication history should be reviewed, and drug-induced thrombocytopenia should be considered if a temporal relationship exists between thrombocytopenia and drug exposure.
o Patients with liver disease and those who abuse alcohol often present with severe thrombocytopenia following binge drinking. These patients may have severe thrombocytopenia resulting from splenomegaly, alcohol-induced suppression of platelet production, folate deficiency, and DIC from active liver disease.
o Aplastic anemia is associated with pancytopenia, and the smear examination findings help differentiate it from ITP.
o Once the diagnosis of ITP with clinically significant bleeding is established, treatment with steroids (intravenous methylprednisolone at 30 mg/kg) and IVIG should be started immediately.
o Platelet transfusions are administered to patients with severe clinical bleeding, and a sustained increase in platelet counts is sometimes observed in those with ITP.
o Currently, emergency splenectomy is rarely necessary and is only considered prior to an emergency operation such as evacuation of an intracranial hematoma.
Drug Category: Corticosteroids — Inhibit macrophage-induced platelet phagocytosis and have immunosuppressive effects on antiplatelet antibody production by lymphocytes.
Drug Category: Intravenous immunoglobulins — Impair clearance of platelets by macrophages.
Drug Category: Anabolic steroids — Suppress macrophage-mediated platelet destruction and inhibit platelet antibody production.
Drug Category: Chemotherapeutic agents — Vincristine strongly binds to platelets. Phagocytosis of platelet-bound vincristine by macrophages in ITP delivers drug in high concentration and leads to macrophage dysfunction.
Drug Category: Synthetic hormones — Used to improve platelet function in qualitative disorders.
Drug Category: Immunosuppressive agents — Benefit observed with immunosuppression. Given for minimum duration and withdrawn as soon as remission achieved. Blood counts must be monitored.
Drug Category: Antihemorrhagics — For use in patients with blood-product deficiencies.
Drug Category: Antithrombotic agents — Thrombin, the end product of the coagulation mechanism, initiates transformation of fibrinogen to a fibrin clot and activates platelets.
Prognosis:
· ITP is generally a benign disorder. Severe ITP with a platelet count of fewer than 5000/mL is occasionally associated with fatal hemorrhages in the brain or internal organs. Patients who are elderly, those whose disease is refractory to treatment who have a prior history of hemorrhage, and patients with concomitant bleeding disorders (hemophilia and uremia) are at higher risk for serious life-threatening hemorrhage.
· TTP is a very serious disorder. With the introduction of plasma exchange therapy, the prognosis is better but mortality rates remain approximately 20%.
· Among congenital bleeding disorders involving platelets, type III von Willebrand disease and type I Glanzmann thrombasthenia are severe diseases associated with life-long hemorrhages. Most other platelet disorders are mild bleeding disorders.
Immune thrombocytopenic purpura (ITP)
Immune thrombocytopenic purpura (ITP) is a clinical syndrome in which a decreased number of circulating platelets (thrombocytopenia) manifests as a bleeding tendency, easy bruising (purpura), or extravasation of blood from capillaries into skin and mucous membranes (petechiae).
In persons with ITP, platelets are coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased platelet count.
To establish a diagnosis of ITP, exclude other causes of thrombocytopenia, such as leukemia, myelophthisic marrow infiltration, myelodysplasia, aplastic anemia, or adverse drug reactions. Pseudothrombocytopenia due to platelet clumping is also a diagnostic consideration.
No single laboratory result or clinical finding establishes a diagnosis of ITP; it is a diagnosis of exclusion.
Pathophysiology: An abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for 1 or more platelet membrane glycoproteins (GPs), binds to circulating platelet membranes.
Autoantibody-coated platelets induce Fc receptor–mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. The spleen is the key organ in the pathophysiology of ITP not only because platelet autoantibodies are formed in the white pulp but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets.
If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.
Mortality/Morbidity:
· Hemorrhage: The primary cause of long-term morbidity and mortality is hemorrhage.
· Intracranial hemorrhage: The most frequent cause of death in association with ITP is spontaneous or accidental trauma-induced intracranial bleeding in patients whose platelet counts are less than 10 X 109/L (<10 X 103/mL). This situation occurs in less than 1% of patients.
· Treatment-related morbidity: To maintain a platelet count in a safe range in patients with chronic treatment-resistant ITP, a long-term course of corticosteroids, other immunosuppressive medications, or splenectomy may be required. In patients with this disease, morbidity and mortality can be related to treatment, reflecting the complications of therapy with corticosteroids or splenectomy.
Sex:
· In children, the prevalence is the same among boys and girls.
· In adults, women are affected approximately 3 times more frequently than men.
Age:
· Children may be affected at any age, but the prevalence peaks in children aged 3-5 years.
· Adults may be affected at any age, but most cases are diagnosed in women aged 30-40 years.
· Onset in a patient older than 60 years is uncommon, and a search for other causes of thrombocytopenia is warranted. The most likely causes in these persons are myelodysplastic syndromes, acute leukemia, and marrow infiltration (myelophthisis).
Clinical picture
History:
Ø The medical history should focus on (1) factors that suggest another disease for which thrombocytopenia is a complication and (2) signs and symptoms that differentiate mild, moderate, and severe bleeding tendencies.
Ø Other systemic illnesses
Ø In adults, thrombocytopenic purpura may be a manifestation of systemic lupus erythematosus or acute or chronic leukemia.
Ø Thrombocytopenic purpura may be a manifestation of a myelodysplastic syndrome, particularly in patients older than 60 years.
Ø In young children, ITP may manifest as a primary immune deficiency syndrome.
Ø Postviral illness
Ø In children, most cases of ITP are acute, and onset seems to occur within a few weeks of recovery from a viral illness. The severity of symptoms of the viral illness is not correlated with the degree of thrombocytopenia.
Ø Thrombocytopenia is a recognized complication after infection with Ebstein–Barr virus, varicella virus, cytomegalovirus, rubella virus, or hepatitis virus (A, B, or C); thought the most typical association is a vaguely defined, viral, upper respiratory infection or gastroenteritis.
Ø Transient thrombocytopenia often follows recent immunization with attenuated live-virus vaccines.
Ø HIV infection
Ø Thrombocytopenia may occur during the acute retroviral syndrome coincident with fever, rash, and sore throat.
Ø Thrombocytopenia may be a manifestation of AIDS, occurring late in the course of HIV infection.
Ø Thrombocytopenia not uncommonly marks the onset of symptomatic HIV infection, particularly in people who abuse drugs.
Ø Drug-induced thrombocytopenia
Ø Regard any medication taken by a person who develops thrombocytopenia as a potential causative agent. A history of all prescription and over-the-counter medications is required to exclude drug-related thrombocytopenia.
Ø Persons who have been sensitized (by previous exposure) to quinidine or quinine may develop immune-mediated drug purpura within hours to days of subsequent exposure. To exclude drug purpura in a person previously treated with quinidine or quinine, the history must include questions about possible exposure to over-the-counter medications, tonic water in cocktails, or bitter lemon beverages.
Ø Investigate the records of patients who have been hospitalized and who develop acute thrombocytopenias for all of their medications that are listed and not listed iursing charts. For example, people who are at risk for heparin-induced thrombocytopenia because of current or recent treatment with heparin may be receiving the heparin with the routine flushing of intravenous (IV) catheters, and this exposure may not be listed on the nursing medication sheet. Many catheters are also heparin impregnated, and unless checked, they can be a hidden cause of heparin-induced thrombocytopenia.
Ø Other drugs associated with drug purpura include antibiotics (eg, cephalothins, rifampicin), gold salts, analgesics, neuroleptics, diuretics, antihypertensives, eptifibatide (Integrilin), and abciximab (ReoPro), which is a Fab fragment of the chimeric human–murine monoclonal antibody 7E3 directed against the platelet GPIIb/IIIa receptor.
Ø Acute and chronic alcohol consumption also may be associated with thrombocytopenia. In persons with chronic liver disease, hypersplenism with secondary thrombocytopenia is not uncommon.
Physical: Similar to the medical history, focus the physical examination on (1) findings that suggest another disease for which thrombocytopenia is a complication and (2) physical signs that suggest serious internal bleeding.
Ø General health
Ø ITP is a primary illness occurring in an otherwise healthy person.
Ø Signs of chronic disease, infection, wasting, or poor nutrition indicate that the patient has another illness.
Ø Vital signs: Hypertension and bradycardia may be signs of increased intracranial pressure and evidence of an undiagnosed intracranial hemorrhage.
Ø Skin and mucous membranes
Ø An initial impression of the severity of ITP is formed by examining the skin and mucous membranes.
Ø Widespread petechiae and ecchymoses, oozing from a venipuncture site, gingival bleeding, and hemorrhagic bullae indicate that the patient is at risk for a serious bleeding complication. If the patient’s blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated. Suction-type ECG leads may similarly induce petechiae.
Ø Mild thrombocytopenia and a relatively low risk for a serious bleeding complication may manifest as petechiae over the ankles in patients who are ambulatory or on the back in patients who are bedridden.
Ø Cardiovascular system: Distant low-amplitude heart sounds accompanied by jugular venous distension may be evidence of hemopericardium.
Ø Abdomen
Ø In an adult, hepatosplenomegaly is also atypical for ITP and may indicate chronic liver and other diseases. In fact, splenomegaly excludes the diagnosis of ITP.
Ø Nervous system
Ø Any asymmetrical finding of recent onset can indicate an intracranial hemorrhage.
Ø Pupils should be equal in size and have intact extraocular muscles and symmetrical eye movements.
Ø Balance and gait should be intact.
Ø Funduscopic examination reveals whether the margins of the optic disc are blurred. Examine the patient for the presence of retinal hemorrhages and other evidence of increased intracranial pressure.
Causes:
In adults, most cases of ITP are chronic, manifesting with an insidious onset, typically in middle-aged women. These clinical presentations suggest that the triggering events may be different. However, in both children and adults, the cause of thrombocytopenia (destruction of [antibody-coated] immunoglobulin-coated platelets by mononuclear macrophages) appears to be similar.
· Autoantibody stimulation
Ø In persons with chronic ITP, membrane GPs on the surface of platelets become immunogenic, stimulating the production of platelet autoantibodies.
Ø In persons with acute ITP, the stimulus for autoantibody production is also unknown. Platelet membrane cryptantigens may become exposed by the stress of infection, or pseudoantigens may be formed by the passive adsorption of pathogens on platelet surfaces.
Ø Autoantibody specificity
Ø In persons with chronic ITP, approximately 75% of autoantibodies are directed against platelet GPIIb/IIIa or GPIb/IX GP complexes.
Ø Presumably, the remaining 25% are directed against other membrane epitopes, including GPV, GPIa/IIa, or GPIV.
· Role of the spleen
Ø The spleen is the site of autoantibody production (white pulp).
Ø It is also the site of phagocytosis of autoantibody-coated platelets (red pulp).
Ø The slow passage of platelets through splenic sinusoids with a high local concentration of antibodies and Fc-gamma receptors on splenic macrophages lend to the uniqueness of the spleen as a site of platelet destruction.
Ø Low-affinity macrophage receptors, Fc gamma RIIA and Fc gamma RIIIA bind immune-complexed IgG and are the key mediators of platelet clearance.
– Platelet destruction
Ø The mononuclear macrophage system of the spleen is responsible for removing platelets in ITP because splenectomy results in prompt restoration of normal platelet counts in most patients with ITP.
Ø Platelets are sequestered and destroyed by mononuclear macrophages, which are neither reticular nor endothelial in origin. Therefore, the former designation of reticuloendothelial system is considered imprecise.
Ø Immune destruction of immunoglobulin–coated platelets is mediated by macrophage IgG Fc (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) and complement receptors (CR1, CR3).
Lab Studies:
· Determination of CBC
o The hallmark of ITP is isolated thrombocytopenia.
o Anemia and/or neutropenia may indicate other diseases.
Ø Peripheral blood smear
o The morphology of RBCs and leukocytes is normal.
o The morphology of platelets is typically normal, with varying numbers of large platelets. Some persons with acute ITP may have megathrombocytes or stress platelets, reflecting the early release of megakaryocytic fragments into the circulation.
o If most of the platelets are large, approximating the diameter of RBCs, or if they lack granules or have an abnormal color, consider an inherited platelet disorder.
o Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid–anticoagulated blood are evidence of pseudothrombocytopenia. The diagnosis of this type of pseudothrombocytopenia is established if the platelet count is normal when repeated on a sample from heparin-anticoagulated or citrate-anticoagulated blood.
Ø Test for antibodies to HIV
o In patients who have risk factors for HIV infection, a blood sample should be tested with an enzyme immunoassay for anti-HIV.
o During the acute HIV retroviral syndrome, the results of the anti-HIV assay may be negative. In this situation, a polymerase chain reaction for HIV DNA is more reliable than the anti-HIV assay.
Ø Test for antiplatelet antibodies
o Assays for platelet antigen–specific antibodies, platelet-associated immunoglobulin, or other antiplatelet antibodies are available in some medical centers and certain mail-in reference laboratories.
o The reliability of the results of a platelet antibody test is highly specific to the laboratory used. A negative antiplatelet antibody assay result does not exclude the diagnosis of ITP, and this test should not be considered part of the routine evaluation.
o This test is not required to diagnose ITP.
Ø Test for antinuclear antibodies
o In selected women, the medical history may suggest a chronic, recurrent, multisystemic illness with vague, generalized signs or symptoms, such as recurrent, multiple, painful, tender, or swollen joints.
o In such cases, a negative antinuclear antibody result is useful in diagnosing ITP if the patient’s thrombocytopenia becomes chronic and resistant to treatment.
Ø Direct antiglobulin test: If anemia and thrombocytopenia are present, a positive direct antiglobulin (Coombs) test result may help establish a diagnosis of Evans syndrome.
Ø Helicobacter pylori testing
o Studies from Italy and Japan indicate that many persons with ITP have H pylori gastric infections and that eradication of H pylori results in increased platelet counts.
o In the United States and Spain, the prevalence of H pylori infections does not appear to be increased in persons with ITP and eradication of H pylori has not increased platelet counts.
o Therefore, routine testing for H pylori infections in adults and children with ITP is not recommended.
Imaging Studies:
Ø CT scanning and MRI are relatively benign and useful noninvasive imaging studies that can be used to rule out other causes of thrombocytopenia. However, they are not part of the routine evaluation of patients who may have ITP.
Ø Promptly perform CT or MRI when the medical history or physical findings suggest serious internal bleeding.
Histologic Findings:
Bone marrow aspirate
The cellularity of the aspirate and the morphology of erythroid and myeloid precursors should be normal. The number of megakaryocytes may be increased. Because the peripheral destruction of platelets is increased, megakaryocytes may be large and immature, although in many cases the megakaryocyte morphology is normal. Older patients require a careful examination of megakaryocyte morphology to exclude an early myelodysplastic syndrome.
Bone marrow biopsy
Sections of a needle biopsy specimen or marrow clot should reveal normal marrow cellularity, without evidence of hypoplasia or increased fibrosis.
Splenic evaluation
The spleen reveals no specific findings. In adults, the microscopic finding of extramedullary hematopoiesis is atypical and indicates myeloid metaplasia. Carefully examine spleens removed from patients with ITP for a primary splenic lymphoma or granuloma or other signs of an undiagnosed infectious disease.
Treatment
Medical Care:
Ø The goal of medical care is to increase the platelet count to a safe level, permitting patients with ITP to live normal lives while awaiting spontaneous or treatment-induced remission. ITP has no cure, and relapses may occur years after seemingly successful medical or surgical management.
Ø Corticosteroids (ie, oral prednisone, IV methylprednisolone) are the drugs of choice (DOCs) for the initial management of ITP. Treatment with corticosteroids may change marrow morphology. Therefore, bone marrow aspiration should be performed to confirm the diagnosis if the clinical presentation or other findings are atypical for acute ITP before the patient is treated with corticosteroids.
Ø IV immunoglobulin (IVIG) has been the drug of second choice (after corticosteroids) for many years. However, recent data indicate that, for Rh(D)-positive patients with ITP, IV Rho immunoglobulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG.
Ø The limitation of using IV RhIG is the lack of efficacy in Rh(D)-negative or splenectomized patients. Also, IV RhIG induces immune hemolysis in Rh(D)-positive persons and should not be used when the hemoglobin concentration is less than 8 g/dL.
Ø Most children with acute ITP do not require treatment, and thrombocytopenia resolves spontaneously.
Ø If bone marrow aspiration is unacceptable to parents and if the diagnosis of acute ITP is equivocal, IV RhIG is an effective treatment for ITP that avoids the problem of a misdiagnosis of acute leukemia because of steroid-related changes in the marrow.
Ø In adults, the initial treatment for ITP is similar to that in children, except that additional precautions are required for persons with hypertension, peptic ulcers, recent aspirin ingestion, or other risk factors for increased bleeding.
o Adults whose platelet counts are greater than (50 X 109/L (>50 X 103/mL) typically have minimal purpura, and the risk of a severe hemorrhage is low. They may be treated without a specific medication.
o Platelet transfusions may be required to control bleeding but are not recommended for prophylaxis. Transfused platelets also have decreased circulation, and repeated platelet transfusions may lead to platelet alloimmunization.
Ø Pregnant women require special consideration for delivery.
o If the platelet count is greater than 50 X 109/L (>50 X 103/mL), the risk of serious hemorrhage is low, but beginning oral prednisone a week before delivery is a reasonable precaution.
o If the platelet count is less than 50 X 109/L (50 X 103/mL) before delivery, treatment with oral prednisone and IVIG is recommended.
o The standard dose of IV RhIG for ITP contains approximately 10-fold the concentration of anti-D that is in the standard antepartum dose of intramuscular RhIG for Rh immunoprophylaxis. While the effects on an Rh(D)-positive fetus are unknown, avoiding the use of IV RhIG in this situation until safety data are available is advisable.
Ø Among the treatment options after corticosteroids, IV RhIG, IVIG, and rituximab are cyclophosphamide, azathioprine, and danazol.
Ø Interventions with decreased certain efficacy and with conflicting reports in the literature include vinblastine, vincristine, ascorbic acid, colchicine, and interferon alfa.
Surgical Care:
Ø In persons with acute ITP, splenectomy usually results in rapid, complete, and lifelong clinical remission.
Ø In persons with chronic ITP, the results of splenectomy are typically less predictable than they are in patients with acute ITP. Platelet counts may not fully revert to normal values, and relapses are not uncommon.
Ø Laparoscopic splenectomy is an interventional approach less invasive than traditional splenectomy and offers the promise of decreased postoperative morbidity and shorter recovery. However, the ultimate role for laparoscopic splenectomy in ITP depends on long-term follow-up to determine whether this approach is as effective as conventional splenectomy for visual scrutiny of the abdominal cavity to identify accessory spleens.
Ø Splenectomy results in a lifelong increased risk of sepsis from infection by encapsulated bacteria.
o In adults, this risk is estimated to be approximately 1%, with a fatal outcome in approximately 1 per 1500 patient-years
o In children, the risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many pediatricians recommend delaying splenectomy until children are aged 5 years.
o These estimates are presumably based on early data and may be inflated, given the increased alertness to the importance of early treatment, availability of more effective antibiotics, and availability of vaccines for prophylactic immunization against specific encapsulated bacteria.
o Before one concludes that medical management and splenectomy have failed and that treatment with alternative options is needed, perform an imaging study to ensure that the problem is not associated with an accessory spleen.
Ø If elective splenectomy is planned for a child or an adult, initiate immunization with Haemophilus influenzae type b vaccine at least 14 days before surgery.
Ø Immunize adults and children older than 2 years with polyvalent Streptococcus pneumoniae vaccine and quadrivalent meningococcal polysaccharide vaccine.
Ø Evaluate patients who have a relapse after having an initially satisfactory response to splenectomy for the possible presence of an accessory spleen.
o An accessory spleen is strongly indicated if Howell-Jolly bodies appeared on the peripheral smear after splenectomy and are no longer present. However, the continued presence of Howell-Jolly bodies does not exclude an accessory spleen.
o Imaging techniques using radionucleotide-labeled sulfur colloid, heat-damaged RBCs, or, preferably, autologous platelets provide more useful information than standard imaging with CT or MRI.
Ø Complications:
Ø Inform patients who have undergone splenectomy that their natural defense against acute bacterial infection is decreased.
o Any fever, particularly with signs or symptoms that suggest something more serious than the common cold, requires prompt medical attention and, possibly, early antibiotic treatment.
o Children with a fever (temperature of
Ø Prognosis:
Ø Adults
o Approximately 60-90% of adults with ITP respond with an increased platelet count after treatment with prednisone or prednisone and IV RhIG or IVIG.
o Of those adults who do not maintain an increased platelet count and require splenectomy, approximately two thirds have a sustained response and 10-15% have a partial response.
FACTOR VIII DEFICIENCY–HEMOPHILIA A
Pathogenesis and Clinical Manifestations The antihemophilic factor (AHF), or factor VIII coagulant protein, is a large (265-kDa), single-chain protein that regulates the activation of factor X by proteases generated in the intrinsic coagulation pathway. It is synthesized in liver and circulates complexed to the von Willebrand factor (vWF) protein. Factor VIII molecule is present in low concentration (10 ug/L) and is susceptible to proteolysis. The gene for factor VIII is on the X chromosome, and carrier detection and prenatal diagnosis are well established.
One in 10,000 males is born with deficiency or dysfunction of the factor VIII molecule. The resulting disorder, hemophilia A, is characterized by bleeding into soft tissues, muscles, and weight-bearing joints. Symptomatic patients usually have factor VIII levels <5%, with a close correlation between the clinical severity of hemophilia and plasma AHF level. Patients with <1% factor VIII activity have severe disease; they bleed frequently even without discernible trauma. Patients with levels of 1 to 5% have moderate disease with less frequent bleeding episodes. Those with levels >5% have mild disease with infrequent bleeding that is usually secondary to trauma. Occasional patients with factor VIII levels as high as 25% are discovered when they bleed after major trauma or surgery. The majority of patients with hemophilia A have factor VIII levels below <5%.
Hemophilic bleeding occurs hours or days after injury, can involve any organ, and, if untreated, may continue for days or weeks. This can result in large collections of partially clotted blood putting pressure on adjacent normal tissues and can cause necrosis of muscle (compartment syndromes), venous congestion (pseudophlebitis), or ischemic damage to nerves. Patients with hemophilia often develop femoral neuropathy due to pressure from an unsuspected retroperitoneal hematoma. They can also develop large calcified masses of blood and inflammatory tissue that are mistaken for cancers (pseudotumor syndrome).
Patients with severe hemophilia are usually diagnosed shortly after birth because of an extensive cephalhematoma or profuse bleeding at circumcision. However, young children with moderate disease may not bleed until they begin to walk or crawl, and individuals with mild hemophilia may not be diagnosed until they are adolescents or young adults. Typically, a hemophilia patient presents with pain followed by swelling in a weight-bearing joint, such as the hip, knee, or ankle. The presence of blood in the joint (hemarthrosis) causes synovial inflammation, and repetitive bleeding erodes articular cartilage and causes osteoarthritis, articular fibrosis, joint ankylosis, and eventually muscle atrophy. Bleeding may occur into any joint, but after a joint has been damaged, it may become a site for subsequent bleeding episodes.
Hematuria, without any genitourinary pathology, is also common. It is usually self-limited and may not require specific therapy. The most feared complications of hemophilia are oropharyngeal and central nervous system bleeding. Patients with oropharyngeal bleeding may require emergency intubation to maintain an adequate airway. Central nervous system bleeding can occur without antecedent trauma or without evidence of a specific lesion.
Patients suspected of having hemophilia should have a platelet count, bleeding time, PT, and PTT. Typically, the patient will have a prolonged PTT with all other tests normal. Because of the clinical similarity of factor VIII deficiency and factor IX deficiency, any male with an appropriate bleeding history and a prolonged PTT should have specific assays for factor VIII and factor IX.
FACTOR IX DEFICIENCY–HEMOPHILIA B
Factor IX is a single-chain, 55-kDa proenzyme that is converted to an active protease (IXa) by factor XIa or by the tissue factor-VIIa complex. Factor IXa then activates factor X in conjunction with activated factor VIII. Factor IX is one of six proteins synthesized in the liver that require vitamin K for biologic activity. Vitamin K is a cofactor for a unique posttranslational modification that inserts a second carboxyl group onto certain glutamic acid residues on factor IX. This modification permits calcium binding and adsorption onto phospholipid surfaces. Factor IX gene is on the X chromosome.
Factor IX deficiency or dysfunction (hemophilia B, Christmas disease) occurs in
FACTOR XI DEFICIENCY
Factor XI is a 160-kDa dimeric protein activated to an active protease (XIa) by factor XIIa, in conjunction with high-molecular-weight kininogen and kallikrein. Factor XI deficiency is inherited as an autosomal recessive trait and is especially common in Ashkenazi Jews. In contrast to deficiency in factors VIII and IX, the correlation between factor level and propensity to bleed is not as precise, spontaneous bleeding is less, and hemarthroses are rare. Many patients with factor XI deficiency present with posttraumatic bleeding or with bleeding in the perioperative period, and occasional factor XI-deficient women have menorrhagia. Daily infusions of fresh-frozen plasma are sufficient, since the half-life of factor XI is approximately 24 h. The majority of defective factor XI alleles were accounted for by a limited number of mutations.
Hemophilia
Hemophilia A (HA) is considered the classic form of hemophilia, and hemophilia B (HB) is termed Christmas disease. HA is a consequence of a congenital deficiency of factor VIII (FVIII), and HB is a consequence of a congenital deficiency of factor IX (FIX). This deficiency results in insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade. For more information on factor deficiencies, see Factor XIII and Factor IX.
The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels, which are the most widely used criteria. Persons with less than 1% normal factor (<0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to <0.40 IU/mL) are considered to have mild hemophilia. Clinical bleeding symptom criteria have been used because patients with FVIII or FIX levels less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.
Frequency:
· In the US: The annual incidence of HA in Europe and North America is approximately 1 case per 5000 male births. The incidence of HB is estimated to be approximately 1 case per 30,000 male births. In the United States, the prevalence of HA is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. The prevalence of HB is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.
History:
· Ask about the patient’s family history and bleeding symptoms.
o Male patients with severe hemophilia present at circumcision.
o Easy bruising may occur at the start of ambulation or primary dentition.
o The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues.
o A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia. Physiologically low levels of all vitamin K–dependent procoagulant factors may complicate the early diagnosis of HB.
· The principal sites of bleeding in patients with hemophilia are as follows:
o For joints, weight-bearing joints and other joints are affected.
o Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.
o In the genitourinary tract, gross hematuria may occur in as many as 90% of patients.
o In the GI tract, bleeding may complicate common GI disorders.
o Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.
Physical:
· Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues.
· Observe the patient’s stature.
· Examine the weight-bearing joints and, in general, the large joints for deformities or ankylosis.
· Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted.
Causes:
· HA and HB are a consequence of a congenital deficit of FVIII and FIX, respectively.
· The defect results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade.
· This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding.
Lab Studies:
· The plasma concentration of FVIII or FIX determines the severity of hemophilia.
o Levels of these factors are assayed against a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII or FIX 1 U/mL. Values in patients are 50-150% of normal.
o Aging, pregnancy, contraceptives, and estrogen replacement therapies are associated with increased levels.
o In term and healthy premature neonates, FIX values are lowered (20-50% of the normal level) and rise to normal levels after 6 months (hepatic immaturity). FVIII levels are normal during that period of life.
o Spontaneous bleeding complications are severe in individuals with undetectable activity (<0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.
· HA and HB protein deficiencies of the intrinsic pathway result in abnormal whole-blood clotting times, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs).
o FVIII and FIX activities are usually determined by using the 1-stage assay based on the aPTT.
o Chromogenic assays or 2-stage assays have also been used to determine FVIII levels.
· Differentiation of HA from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia.
· Laboratory confirmation of a FVIII or FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode.
o For autoantibody and alloantibody inhibitors, obtain a repeat measurement of the patient’s prolonged aPTT after incubating the patient’s plasma with normal plasma at
o If the prolonged aPTT is not corrected, use the Bethesda method to titrate the inhibitor biologic concentration. By convention, more than 0.6 BU is considered a positive result for an inhibitor, less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer.
Imaging Studies:
· Radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progress with subchondral bone cyst formation, which may occur in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages.
· Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage.
· MRI is useful in the evaluation of the cartilage, synovium, and joint space.
Procedures:
· Specific orthopedic procedures may be required in chronic, neglected cases with irreversible joint or muscular deformities.
· Patients with portal hypertension due to hepatic cirrhosis secondary to chronic hepatitis have undergone portocaval shunt procedures or variceal sclerotherapy, with good palliative results.
Histologic Findings: Recurrent joint bleeds result in synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage.
Staging: Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to stage 5, which consists of advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.
Medical Care: Before a patient with hemophilia is treated, the following information should be obtained: (1) the type and severity of factor deficiency, (2) the nature of the hemorrhage or the planned procedure, (3) the patient’s previous treatments with blood products, (4) the presence and possible titers of inhibitors, and (5) the patient’s previous history of desmopressin acetate (DDAVP) use (eg, in mild HA only) with the degree of response and clinical outcome.
Various FVIII and FIX concentrates are now available to treat HA and HB. Reductions in infectious complications and improved purity are the main advantages of these concentrates. During production, a specific viral-inactivation stage, either solvent-detergent treatment or liquid-phase heat treatment, is implemented to inactivate viruses, such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a problem.
Recombinant FVIII and FIX are now commercially available. They have lowered the risk of viral contamination.
General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
|
Indication or Site of Bleeding |
Factor Level Desired (%) |
FVIII Dose, IU/kg* |
FIX Dose, IU/kg* |
Comment |
|
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
10-25 |
20-50 |
Consider aminocaproic acid (Amicar), 1-2 d |
|
Joint (hip or groin) |
40 |
20 |
40 |
Repeat transfusion in 24-48 h |
|
Soft tissue or muscle |
20-40 |
10-20 |
40 |
No therapy if site small and not enlarging (transfuse if enlarging) |
|
Muscle (calf and forearm) |
30-40 |
15-20 |
40 |
None |
|
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
20-30 |
40-60 |
Transfuse, repeat at 24 h, then as needed |
|
Neck or throat |
50-80 |
25-40 |
50-80 |
None |
|
Hematuria |
40 |
20 |
40 |
Transfuse to 40% then rest and hydration |
|
Laceration |
40 |
20 |
40 |
Transfuse until wound healed |
|
GI or retroperitoneal bleeding |
60-80 |
30-40 |
60-80 |
None |
|
Head trauma (no evidence of CNS bleeding) |
50 |
25 |
50 |
None |
|
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
50 |
100 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
|
Trauma with bleeding, surgery† |
80-100 |
50 |
100 |
10-14 d |
Source.—Dimitrios P. Agaliotis, MD, PhD, FACP.
*Dosing intervals are based on a half-life for FVIII of 8-12 h (2-3 doses/d) and half-life of FIX of 18-24 h (1-2 doses/d). Maintenance doses of one half the initial dose may be given at these intervals.
†Continuous factor infusions may be administered. After the initial loading dose, continuous infusion at a dose of 3 IU/h is given. Subsequent doses are calculated according to the plasma factor levels.
· For dosage calculations, these general guidelines may be applied:
o FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours.
o FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.
· Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels.
o Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an HA factor level of 30% and an HB factor level of 20%.
o Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an HA factor level of 50% and an HB factor level of 40%.
o Life-threatening bleeds (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an HA factor level of 80-90% and an HB factor level of 60-80%. Plasma levels are maintained higher than 40-50% for a minimum of 7-10 days.
· Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.
· In dental procedures, antifibrinolytic drugs and local hemostatic techniques, such as topical thrombin and cellulose bandaging, may be useful.
· Substantial progress has recently been made in the development of gene therapy for HA and HB. This advancement reflects technical improvements of existing vector systems and the development of new delivery methods.
o Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. The induction of neutralizing antibodies often precludes stable phenotypic correction.
o On the contrary, certain promoters are prone to transcriptional inactivation in vivo, resulting in failure of long-term FVIII or FIX expression. Several phase I trials of gene therapy are ongoing in patients with severe hemophilia. Some individuals report fewer bleeding episodes than before, and low levels of clotting factor activity are occasionally detected.
· Pain medications are used for acute bleeding or chronic arthritis.
o Safe analgesics include acetaminophen, oxycodone, propoxyphene, and pentazocine.
o Avoid all aspirin products.
· The treatment of patients with inhibitors of FVIII is difficult.
o Attempts to overwhelm the inhibitor with large doses of human FVIII have been tried.
o Porcine FVIII, which has low cross-reactivity with human factor VIII antibody, has also been administered.
o FVIII-bypassing agents, including FIX complex and activated FVII has also been used.
Activity:
· Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously.
· Any physical activity may trigger bleeding in soft tissues.
· Prophylactic factor replacement early in life may help prevent bleeding, as well as chronic arthritic and muscular damage and deformity.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.
Recombinant activated FVIIa
Recombinant activated FVIIa (Eptacog Alfa or Novo Seven) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa. It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.
Recombinant FVIIa is effective and well tolerated in patients with HA and HB with inhibitors, in those with acquired hemophilia, or in those with Glanzmann thrombasthenia. Recombinant FVIIa (Eptacog Alfa) is the treatment of choice in patients with HB with high-responding inhibitors and in patients with FVII deficiency.
To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with inhibitors for FVIII or FIX; when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding.
In summary, recombinant activated FVIIa is a valuable treatment choice in patients with hemophilia with inhibitors, in those with platelet-refractory Glanzmann thrombasthenia, or in those with congenital FVII deficiency.
Immune tolerance induction
In immune tolerance induction (ITI), a person is rendered tolerant to FVIII or FIX by means of repeated daily exposure to FVIII or FIX over several months to years.
First described by Backmann in 1977, ITI has been used, with variations in the dosing schedule for FVIII and in the presence or absence of immunosuppressive therapy. A characteristic of most recent protocols that use FVIII alone has been the avoidance of immunosuppression (steroids, cyclophosphamide) because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia.
The success of rituximab in eliminating refractory FVIII inhibitors may be a valid subject of further investigation. Reports describe durable complete responses with a brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to >200 BU.
The overall likelihood of success with ITI is 70% ± 10%.
An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high dose-ITI.
Drug Category: Posterior pituitary hormones — These agents raise endogenous FVIII levels in mild HA. Increases as much as 3-fold from the baseline are observed, with peak responses at 30-60 minutes after infusion.
Drug Category: Antifibrinolytic agents — These agents are used in oral surgery or bleeding. Their use should be avoided in cases of genitourinary bleeding (ie, obstructive uropathy) and in combination with prothrombin complex concentrate (PCC).
Further Inpatient Care:
· Hospitalizing patients with internal bleeding, with uncontrollable bleeding, and before elective surgery or other invasive procedures is advised.
Further Outpatient Care:
· Monitor patients with hemophilia in an outpatient setting for bleeding episode frequency, use of home-administered replacement factors, dental status, and joint and muscle problems.
· If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient’s CD4 count, observed them for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.
Deterrence/Prevention:
· Prophylactic replacement of FVIII or FIX is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and breaking the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.
o This goal is achieved by administering factor 2-3 times a week.
o The National Hemophilia Foundation has recently recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.
· Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia.
o Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia.
o Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned, or replacement therapy can be scheduled for the perinatal period.
o Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages.
· Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.
o The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used.
o This technique circumvents pregnancy termination.
· In summary, data suggest that genetic correction of the hemophilias is feasible.
o Future prospects for RNA repair, use of gene-modified endothelial progenitors, and gene-modified stem-cell therapy are being investigated.
o Patients report decreasing bleeding episodes; this observation suggests that reasonable factor levels can be reached and encourage further research in this type of hemophilia treatment.
o Gene transfer for the treatment of hemophilia requires a combination of vector delivery systems, animal models, and clinical models and/or studies to prove its practical utility.
Complications:
· Infection is the most important complication of hemophilia therapy.
o As many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate.
o The preferred source of factor are recombinant preparations, which do pose a risk of transmitting infectious disease, which is still theoretically possible with plasma-derived concentrates.
o Virally attenuated products have reduced the risk of hepatitis observed in most patients receiving early-developed products.
o Products that are not heat treated result in 90% positivity rates for hepatitis B surface antibody and hepatitis C virus. Therefore, their use is not recommended (or generally available) for routine management.
o More than 50% of patients with severe hemophilia who have used older products have elevations in liver enzyme levels.
o Outbreaks of hepatitis A infection in Europe and the United States have prompted more vigorous monitoring of product safety than before.
o HIV infection has been the most serious complication of hemophilia to date. In the United States, as many as 90% of adults with severe hemophilia are HIV-positive. HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.
· Allergic reactions are occasionally reported with the use of cryoprecipitate, fresh-frozen plasma (FFP), and factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.
· Thrombosis or even acute myocardial infarctions have been encountered in patients using PCC products, especially patients with concurrent liver disease or those taking multiple doses, as during surgery. A highly purified FIX product that is preferred.
· The cost of treatment of an average adult patient is more than $100,000 per year.
o Costs are increased for the treatment of patients with inhibitors.
o The use of prophylactic factor has resulted in short-term increases in cost, though the long-term economic benefit of reducing the incidence of joint disease is expected to outweigh the initial expense.
Prognosis:
· Prophylactic use of antihemophilic factors and early treatment with replacement therapy with factors that are safe from infections have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia.
· Factor concentrates have made home-replacement therapy possible, improving patients’ quality of life.
o In addition, dramatic gains in life expectancy occurred during the era of replacement therapy.
o The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to more than 50-60 years by the early 1980s.
o Viral complications occurred during the factor replacement era..
· Intracranial hemorrhages and hemorrhages of the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications.
o The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement.
o The life expectancy of patients receiving inhibitors may be slightly shorter than that of patients not receiving inhibitors.
o Approximately one quarter of children and adolescents with severe hemophilia aged 6-18 years have below-normal motor skills and academic performance.
Hemophilia A (HA)
The hemostatic system, consisting of the blood vessels and their content, blood, plays a crucial role in human survival. The importance of the plasma coagulation system in protecting life by preventing further blood loss following transection of a blood vessel is well recognized. Blood is usually maintained in a fluid state, without evidence of bleeding or clotting. The presence of an X-linked pattern of inheritance of a bleeding diathesis in families, referred to as hemophilia, has been recognized for hundreds of years
That the disorder was due to a deficiency of a factor (F) in the blood was proven in 1840 by correction of the bleeding defect by transfusion of whole blood; this was followed in 1911 by the demonstration that normal plasma could shorten the whole blood clotting time of hemophilic blood. Finally, in
Further progress was achieved in the 1950s with the development of cryoprecipitate and plasma concentrates to treat hemophilia A. The clinical and therapeutic observation that clotting time was corrected after transfusion of blood from one hemophilic patient to another was followed by the description of “plasma thromboplastin component” or FIX deficiency. This second type of deficiency was referred to as hemophilia B to differentiate it from hemophilia A.
Clarification of the structure and function of the FVIII molecule (FVIII-C, an X-linked gene product) noncovalently bound to von Willebrand factor (vWF, an autosomal 12p gene product) in plasma clarified the separate roles of FVIII-C and vWF proteins. This led to an understanding of the role of the different components of the FVIII molecule in the physiology of normal hemostasis and to a recognition that hemophilia A and von Willebrand (vW) disease were caused by a deficiency of different proteins in the FVIII complex.
An understanding of the reasons for the development of FVIII inhibitors in persons with hemophilia or in persons with previously normal hemostasis (referred to as acquired hemophilia) expanded understanding of the antigenic structure of the FVIII molecule. Cloning of the FVIII gene was followed by the preparation of recombinantly derived FVIII (rFVIII) as replacement therapy for the missing factor. Several different vectors have now been used to correct FVIII deficiency in humans, with many questions still to be resolved (Kazazian, 1995; Reitsma, 2001). The potential role of increased levels of FVIII in thrombophilic states is continuing to be explored.
Pathophysiology: FVIII-C is an essential part of the hemostatic mechanism, participating as a cofactor in the second burst of thrombin generation, which leads to clot formation. An isolated deficiency of FVIII-C is associated with a significant bleeding diathesis, demonstrating the importance of FVIII in hemostasis.
· Internationally: Hemophilia A is found in all ethnic groups in the world. Alloantibodies and autoantibodies to FVIII (FVIII inhibitors) have been reported from many parts of the world. The inherited combined FV and FVIII deficiency has been reported in patients from Europe, Tunisia, the Middle East, Iran, and, more recently, India.
Mortality/Morbidity: Intracranial bleeding was the major cause of death in individuals with hemophilia until the AIDS epidemic, which, from the late 1970s into the 1990s, became the major cause of death in this population. Significant morbidity is experienced from frequent joint and other bleeding episodes. Hepatitis remains a major cause of morbidity and mortality because of its progression to chronic liver disease (Lauer, 2001); chronic fatigue is caused by the ongoing active viral illness and/or is related to antiviral therapy. Portal hypertension, variceal bleeding, ascites, and upper GI hemorrhage occur as liver disease progresses. Hepatocellular carcinoma can develop as a consequence of chronic hepatitis. Emerging pathogens potentially transmitted by blood or blood products (eg, prions) will change the pattern of morbidity and mortality in the future.
The development of an alloantibody further complicates an already burdensome disease.
Acquired FVIII inhibitors (autoantibodies) are associated with significant morbidity and at least a 20% mortality rate at present, but higher mortality rates prevailed earlier when currently available products to treat inhibitor patients were unavailable.
The tremendous physical, psychological, and financial burden borne by patients and their families because of the restraints imposed by recurrent bleeding must be dealt with intensively. In this setting, HIV infection adds another layer of burden (Treisman, 2001). Therefore, the drug addiction and abuse in this population is not surprising. All of these issues require close, coordinated care delivered by a multidisciplinary team.
Patients with combined FV and FVIII deficiency develop all of the complications known to develop in patients with hemophilia A, due to the necessity of frequent blood or blood product replacement. The absence of a safer source of FV, such as purified FV concentrate, to correct the FV deficiency requires the repeated use of fresh frozen plasma (FFP), with its potential for transmitting illnesses.
Sex: Otherwise healthy males with a single copy of the abnormal gene in their only X chromosome have bleeding manifestations. The severity of bleeding generally depends on their basal level of FVIII-C but is also influenced by the co-inheritance of other bleeding or thrombophilic mutations.
Carrier females, usually asymptomatic, have one affected and one normal X chromosome; lower levels of FVIII-C than that expected with a carrier state have been found in such females (see Pict.). One explanation is that an unbalanced inactivation of the normal X chromosome during early embryonal development results in a preponderance of the abnormal X chromosome, thus leading to a lower basal level of FVIII-C. A combination of this unbalanced inactivation with a new FVIII gene mutation has been shown to result in severely reduced FVIII levels in a female (severe female hemophilia) (Favier, 2000).
Recent data cast doubt on a correlation between the pattern of X chromosome inactivation and the wide variation in levels of FVIII or FIX found in carriers of hemophilia A or B because researchers did not find a skewed pattern of inactivation of the appropriate X chromosome in carriers with either low or high levels of FVIII or FIX (Orstavik, 2000). Lower basal levels of FVIII-C in carriers is associated with a bleeding disorder, although less severe than that observed in the corresponding hemophilic male, due to the presence of higher basal levels of FVIII or FIX in the clinically symptomatic carrier.
Females with hemophilia, although rare, can arise from the union of a male with hemophilia and a carrier female, in females with X-chromosomal abnormalities such as Turner syndrome (XO), X-autosome translocation involving a breakpoint in the FVIII gene, or due to uniparental isodisomy in which the affected female inherits 2 copies of the mutated X chromosome (and all other X chromosomal genes) from her mother. Apparently, this last example may be incompatible with life. Interestingly, isodisomy was the documented cause of male-to-male transmission of hemophilia A in one case, in which the affected male passed his abnormal X chromosome and his Y chromosome to his son, with no contribution of an X chromosome from his mother (Kazazian, 1995).
Acquired FVIII inhibitors develop in either sex.
Age: Prenatal diagnosis of hemophilia A can be made using markers for restriction fragment length polymorphisms, by chromosomal analysis of cells obtained by amniocentesis at approximately 16 weeks’ gestation, or by chorionic villus sampling at approximately 10 weeks’ gestation.
Postnatal evaluation is triggered by a history of bleeding, which can start immediately after birth (eg, intracranial bleeding) or may be delayed in those with mild hemophilia. Oral bleeding starts with teething and cuts and abrasions to the lips, tongue, and frenulum, followed by joint and muscle bleeding with the start of ambulation. In a single-center study, the age at which bleeding starts was found to vary. Approximately 44% bled within the first year, while others did not experience their first bleeding episode until age 4 years. Recurrent episodes of joint bleeding usually started approximately 6 months after the first bleeding episode; half the patients had their first bleeding episode by age 1.22 years, while the mean age for the first joint bleed was 1.91 years. These data support the concept that primary prophylaxis need not begin at the same age in all patients (Pollmann, 1999).
Because of the increasing safety of recombinant FVIII concentrates, advances in therapy, home treatment, and the long-term physical and psychological benefits of being able to lead a normal life style, the Medical Advisory and Safety Committee of the National Hemophilia Foundation has endorsed the use of recombinant products wherever feasible. As early as 1994, the committee recommended prophylactic treatment as the optimal approach to hemophilic care.
A survey of written guidelines and practices of obstetricians, hematologists, and neonatologists at medical centers in the United States for the management of pregnant carriers, newborns with hemophilia, and infants with intracranial hemorrhage showed that more than 94% of these major facilities had no written guidelines. As a result of data obtained from this survey, it has been suggested that vacuum devices and fetal scalp monitors not be used in the vaginal delivery of known carriers of hemophilia and that all infants with intracranial hemorrhage and women with postpartum hemorrhage be evaluated for a bleeding disorder. A national registry of these cases would provide the type of informatioecessary to develop rational national guidelines to help improve care for pregnant women with bleeding disorders (Kulkarni, 1999; Kulkarni, 2001).
Acquired FVIII deficiency is observed in older populations, generally those older than 60 years. Inhibitors that develop in patients with hemophilia now are likely to be found in a younger age group, due to the recent practice of starting prophylactic replacement therapy at a younger age.
Bleeding in patients with a combined deficiency of FV and FVIII starts in childhood as the child starts ambulating, with the earliest possible evidence at the time of circumcision after birth.
Clinical picture
History: Recurrent spontaneous or minor injury–induced episodes of joint bleeding are common in persons with severe and moderately severe hemophilia, causing severe pain and limitation of joint movement. The repeated presence of blood in the joint leads to synovial hypertrophy, with a tendency for recurrent joint bleeding, which finally results in a destructive chronic synovitis with destruction of synovium, cartilage, and bone. This leads to chronic pain, arthritis, joint stiffness, and limitation of movement due to progressive and permanent severe joint damage with progressive muscle wasting (see Pict. 14-21).
Pict. 14. Teenage boy with bleeding into his right thigh, knees, and ankles
Pict. 15. An older man with a chronically fused extended knee following open drainage of right knee bleeding that occurred many years previously
Pict. 16. Severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint in an attempt to aspirate recent bleeding aggravated bleeding
Pict. 17. Chronic severe arthritis, fusion, loss of cartilage, and joint space deformities of the knee joint. Advanced hemophilic arthropathy
Pict. 18. Chronic severe arthritis, fusion, loss of cartilage, and joint space deformities of the elbow. Advanced hemophilic arthropathy
Pict. 19 .Hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required
Pict. 20. Large amount of vascular synovium removed at surgery
Pict. 21. Microscopic appearance of synovial proliferation and high vascularity; if stained with iron, it would show diffuse deposits; iron-laden macrophages present
· Intramuscular hemorrhage, the second most common bleeding event, also leads to acute severe and recurring pain, swelling, and limitation of movement. The hematoma may dissect down into the fascial planes and result ieuropathies due to nerve compression, such as with psoas bleeding; large retroperitoneal bleeding can lead to hypotension.
· Mucous membranes can be the site of bleeding, manifesting as epistaxis, oropharyngeal, or retropharyngeal bleeding, which can lead to acute respiratory obstruction. The GI tract may be a source of bleeding in approximately one fifth of patients, with an increasing frequency due to the consequences of cirrhosis and the use of readily available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for relief of arthritic pain. Peptic ulcer disease is approximately 5 times more common in individuals with hemophilia than in the general population.
· CNS hemorrhage (~3-14%) was the major cause of death in persons with hemophilia prior to the widespread availability and use of factor replacement to prevent bleeding and prior to the AIDS epidemic (Ludlam, 2000). Approximately one third of CNS bleeding episodes lead to death, and at least half result in major, long-term sequelae. Bleeding is usually preceded by head trauma in children, whereas adults may develop CNS bleeding without obvious trauma. Symptoms are typical of any CNS event, with a variety of symptoms such as headaches, seizures, vomiting, and focal neurologic defects. Findings depend on the sites of bleeding.
· Spontaneous hematuria can be seen in those with severe hemophilia. The use of NSAIDs, protease inhibitors, or over-the-counter drugs; trauma; exercise; or exertion may precipitate genitourinary (GU) bleeding. Associated clots in the GU system causing acute hydronephrosis may be a complication of the use of fibrinolytic inhibitors concomitantly with factor replacement in patients with hematuria. Underlying pathology, such as nephrolithiasis, tumors, or infections, should be excluded when persistent bleeding is present. Indinavir (Crixivan) may be associated with crystalluria or calculi in HIV-infected patients.
· Acute and chronic viral illnesses have been transmitted by the less pure products, which were the only ones available to treat bleeding in the past. HIV-related illnesses and AIDS; repeated viral, fungal, and bacterial illnesses due to AIDS; malignancies, such as Kaposi sarcoma; and the aggressive AIDS-associated lymphomas are life-threatening complications (Evatt, 2000). Despite these problems, plasma-derived products remain a valuable resource without which many persons with hemophilia throughout the world would experience the painful consequences of recurrent bleeding.
· The availability of newer recombinant products (with no risk of transmission of HIV and hepatitis) for use in home care and in-hospital treatment means that those unexposed to plasma-derived products could conceivably achieve a normal life span.
· Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs. Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are frequently involved locations for a pseudotumor (see Pic. 22-28).
Pict. 22. Large pseudocyst involving the left proximal femur.
Pict. 23. Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb) showing the black-brown old blood, residual muscle, and bone
Pict. 24. Dissection of a pseudocyst.
Pict. 25. Transected pseudocyst with chocolate brown-black old blood
Pict. 26. Patient presenting with a slowly expanding abdominal and flank mass with increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Pict. 27. Plain x-ray film of the pelvis showing a large lytic area
Pict. 28. Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst
· Delayed bleeding develops after dental extractions; therefore, patients require appropriate presurgical and postsurgical management. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, face, or dissecting neck hematomas or other serious bleeding.
· Co-inheritance of thrombophilic mutations has been suggested as a reason for reduction in the severity of bleeding in some individuals with severe hemophilia. A recent study of the correlation between concentrate utilization, incidence of bleeding episodes per year, and prevalence of hemophilic arthropathy in those with severe hemophilia with and without the FV Leiden mutation (a known thrombophilic mutation in the white population) showed that indeed FV Leiden carriers had fewer bleeding episodes, but the authors of this study do suggest, appropriately, the need to study this issue in a larger cohort with additional testing (Nichols, 1996; Lee, 2000; Escuriola Ettingshausen, 2001).
· The development of alloantibodies in persons with hemophilia is a serious complication that leads to increased bleeding and a lack of response to usual therapy, which can be fatal (see Pict. 29-30).
Pict. 29. Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor
Pict. 30. Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
· Acquired FVIII inhibitors (ie, acquired hemophilia due to an autoantibody in previously hemostatically normal individuals) are a cause of significant morbidity and are associated with a mortality rate of at least 20% because they affect elderly people who have comorbid conditions. Patients present with extensive bleeding, often life-threatening, before it is recognized.
o In contrast to persons with severe inherited FVIII deficiency (hemophilia A), in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, GU, GI, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venepuncture. Bleeding can develop at any site.
o Postpartum inhibitors usually come to attention several months after delivery (2-5 mo), when bleeding symptoms supervene; rarely, the inhibitor may develop during pregnancy.
o Because of the unusual characteristics of these autoantibodies, patients may present with significant bleeding despite the presence of detectable amounts of plasma FVIII-C activity in vitro; this residual FVIII activity in a patient with active bleeding can mislead the clinician about the seriousness of the FVIII deficiency.
· Bleeding manifestations in homozygous patients with the combined FV and FVIII deficiency include variable bleeding after circumcision, ranging from severe to less-than-severe. Epistaxis can occur, as can gingival bleeding and easy bruising, starting with mild trauma, as occurs during normal childhood activities. Menorrhagia can start at menarche. Hemarthrosis has been reported in approximately 20% of patients; therefore, joint bleeding is less common in this group than in patients with severe hemophilia A or B.
o Confusion with joint bleeding may arise when bleeding occurs in a bursa surrounding a joint. For example, bleeding in the olecranon bursa may be misinterpreted as bleeding into the elbow joint.
o In the absence of appropriate factor replacement, dental extractions or other surgeries precipitate bleeding. Intracranial bleeding can develop, even after minor trauma to the head.
o Due to higher basal levels of FV and FVIII than those found in homozygotes with combined FV and FVIII deficiency, only a few heterozygotes manifest excessive bleeding (Roberts and Hoffman, 2001).
Physical:
· Severe pain in the target joint(s); bogginess around the involved joint(s) due to an inflamed synovium and the presence of blood and fluid; fullness of joint space and/or surrounding bursa; and varying degrees of limitation of joint mobility
· Deep muscle hematomas, with pain, tenderness, and limitation of movement
· Delayed onset of bleeding from sites of trauma and/or surgery
· Blood in the urine
· Blood in the stool or upper GI bleeding
· Changes ieurological function, eg, headache, focal neurologic deficits
· Signs of jaundice, spider angiomas, hepatomegaly accompanied by tenderness, and splenomegaly related to chronic hepatitis or cirrhosis
· Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C
· Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS syndrome
· Possible development of anaphylaxis after the start of FVIII infusions in severely deficient children (although frequency is greater in patients with severe FIX deficiency)
Lab Studies:
Preliminary identification of the coagulation disorder: Tests include activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count, and bleeding time
A prolonged aPTT and a normal PT indicate an abnormality in the early part of the intrinsic coagulation pathway. However, a normal aPTT does not exclude mild hemophilia A because the aPTT may not be sufficiently sensitive to detect slightly reduced levels of FVIII-C in the approximate 20-30% range, as occurs in persons with mild hemophilia or in carriers. If the clinical history warrants it, then a specific FVIII-C level should be obtained.
Prolongation of the PT alone, or both the PT and aPTT, is not consistent with hemophilia A alone; this kind of coagulopathy may be due to the superimposition of other causes, such as liver disease, overdose of heparin or warfarin sodium, or DIC.
Thrombocytopenia or platelet dysfunction is not consistent with hemophilia A alone.
The nature and severity of bleeding are assessed using a CBC count with differential, stool analysis for blood, and urinalysis for hematuria.
Confirmatory tests and specific coagulation factor assays
A mixing test in which the patient’s plasma is mixed with normal pooled plasma, incubated at
Correction of the aPTT in this test implies a deficiency, whereas persistence of an abnormally prolonged aPTT suggests the presence of an inhibitor.
Imaging Studies:
MRI, CT scan, and ultrasound have all been used to localize, quantify, and serially follow the response of bleeding to specific therapy. The depth, location, and size of the hematoma guide the choice of diagnostic test. A simple test, if adequate, is more appropriate for serial follow-up of the size of the hematoma during therapy. MRI and CT scan are better for diagnosing and localizing pseudotumors. Other tests should be performed as needed to diagnose renal calculi and tumors.
Histologic Findings: Synovial proliferation is caused by repeated bleeding into the joint. This results in damage to joint structures, leading to limitation of movement and deformity. The presence of excess iron in these tissues is evident microscopically. See Pict. 21 for histologic features.
The gross and microscopic findings of a pseudocyst with chocolate-colored inspissated material are shown in Pic. 22-25.
Treatment
Home-care programs have made patients self-sufficient in infusing product, with guidance and supervision from personnel at a hemophilia center or a knowledgeable physician in the local community. This has also improved quality of life by minimizing the time spent in hospital emergency departments, providing rapid and early therapy for acute bleeding, achieving a prompt reduction in pain due to early specific correction of the factor deficiency and joint immobilization, and allowing concomitant provision of appropriate narcotic and nonnarcotic analgesics. Joint integrity can be preserved with the start of early prophylactic home-care programs in childhood (maintain a minimum of 1-2% FVIII-C at all times by infusing replacement product at home 3 times/wk).
All of these allow a patient to participate in more of life’s activities. The specific dose and duration of factor replacement therapy is determined by the location of the bleeding, severity of the bleeding, and known actual response to prior therapy.
Intermediate- or high-purity plasma-derived products are still available for use in patients who have previously used such products. Monoclonal antibody purified plasma–derived products are usually free of some viral contaminants. In children who are starting therapy for the first time or in persons with hemophilia who are negative for HIV, recombinant products are used whenever possible because of their presumed higher viral safety. Importantly, be aware that approximately 25% of the lots of human albumin containing first-generation recombinant FVIII concentrates have been found to be positive for transfusion-transmitted (TT) virus from contaminated human serum albumin. All second-generation recombinant FVIII preparations (free from human albumin) have beeegative for the virus.
Monitoring actual levels of FVIII-C is necessary to confirm the presence of adequate amounts of FVIII in vivo to correct hemostasis when (1) a patient is first treated, (2) a new product is being used, (2) the onset of an inhibitor is suggested, (4) active ongoing bleeding is present, or (5) persistence or inadequate correction of bleeding has been encountered with previously adequate doses.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated because these may aggravate the bleeding.
Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use higher dosing initially, followed by a gradual lowering of the dose after bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding. Acute joint bleeding and expanding, large hematomas require adequate replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeding frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.
Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and save approximately 30% of expensive product usage (Hathaway, 1984; Batorova, 2000).
For serious bleeding events, continue replacement for at least 7-10 days because of the potential risk of recurrent bleeding. A multiple-bolus drug dosing regimen model has been developed to better estimate loading and maintenance dose requirements to allow maintenance of a minimum trough level of FVIII at all times (Dedik, 2000). In patients who may have an intracranial hemorrhage, administer a full dose of factor concentrate before the patient is sent for any diagnostic radiologic procedures in order to avoid delays in bleeding control. Surgically drain intracranial bleeding promptly, as clinically dictated, following replacement therapy.
Patients with combined FV and FVIII deficiency require combined replacement with FVIII concentrates and FFP for FV, which also supplies a small amount of FVIII. Deamino-8-D-arginine vasopressin (DDAVP) to raise FVIII (without concomitant FVIII concentrate) in combination with FFP as a source of FV has been used successfully in the perioperative management of an older Italian man who was undergoing surgical repair of massive bilateral inguinal hernias (McKenna, 1987). In current practice, pooled solvent-detergent–treated plasma (PLAS+ SD) is safer than standard FFP because the lipid enveloped viruses are removed.
Collaboration with an infectious disease consultant is a major need in caring for patients with HIV/AIDS or hepatitis. The serious psychiatric issues present in the management of patients infected with HIV may require the assistance of a psychiatrist (Treisman, 2001).
Simple immediate ancillary measures of ice, pressure, elastic bandage (ACE) wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.
The benefits of prophylaxis in the management of hemophilia A should be emphasized (Hoots and Nugent, 2006). There are clear advantages of prophylaxis for patients with hemophilia A compared to on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. Sadly, there is a heavier economic burden with increased factor use.
Prophylactic factor replacement
Secondary prophylaxis thus far has been undertaken mainly in patients with target joint–related recurrent bleeding in a biweekly or triweekly intravenous dose of FVIII of 25-40 U/kg to maintain trough FVIII-C levels in the range of 3-5%. Recent data clearly show that in order to preserve joint function, primary prophylaxis must be started early in childhood, after the child experiences the first few episodes of bleeding into a joint.
Surgical Care:
· Preoperative evaluation of the aPTT, along with a mixing test that includes prolonged incubation of a patient’s plasma with normal pooled plasma to exclude an inhibitor, is very important. Most individuals with hemophilia are routinely tested when examined by a physician with expertise in this area. The patient must receive the proper dose of FVIII before and serially after surgery to achieve and maintain an adequate level of FVIII-C to permit maintenance of good hemostasis. Following bone and joint surgery, prolonged replacement for several weeks is necessary not only to allow healing at the surgical site but also to prevent bleeding during the necessary intensive postoperative physical therapy, which allows for maximum joint mobility to develop (Aznar, 2000).
· Procedures such as endoscopies, although considered routine for unaffected people, require preprocedural product replacement in persons with hemophilia so that they do not bleed either during or following a needed biopsy. Postbiopsy replacement with FVIII must continue until the biopsy site has healed.
· Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, along with Amicar. A standard approach to dental extractions has been proposed based on a case-control study, which proved the validity of the tested approach (Zanon, 2000). In this study, patients received a single dose of AMCA of 20 mg/kg, along with a single infusion of FVIII, to achieve a peak level of approximately 30% prior to dental extraction. No significant differences in bleeding rates occurred when compared with controls, with a cost reduction due to outpatient management. Routine practice is to continue therapy with antifibrinolytics in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.
General Guidelines for Management With FVIII Concentrates for Intermittent Bolus Dosing
|
Type of Hemorrhage |
Desired |
Dose and Duration of Therapy |
|
Minor |
20-30 |
10-15 U/kg IV q12-24h for 1-2 d |
|
Moderate |
25-50 |
15-25 U/kg IV q12-24h for 3-7 d |
|
*Dental extraction(s) |
50-100 |
25-50 U/kg IV q12h for 2-5 d |
|
Major |
~50-100 until bleeding is controlled; then gradually decrease dosage to minimal required to prevent rebleeding |
25-50 U/kg IV q12h for 5-10 d |
*Concomitant administration of EACA or AMCA (both inhibitors of fibrinolysis) can help reduce the dose of concentrate required to treat such bleeding. Approximately 50% of the initial dose is given as the second dose approximately 8 hours after the first; all subsequent doses are given every 12 hours.
For dental extractions, a single preoperative dose of FVIII of 15 U/kg and oral or intravenous Amicar at
Continuous infusion of FVIII can be used for treating patients after joint replacements or CNS bleeding, in which a continuous, steady level is desired. This can be achieved by an initial bolus dose, as discussed, followed by a maintenance infusion of 150 U/h, with monitoring of levels for adequacy.
DDAVP in a dose of 0.3 mcg/kg intravenously can be given for several doses every 12 hours to raise FVIII levels in patients with mild hemophilia perioperatively for minor procedures, such as dental extractions and even uncomplicated cholecystectomies. Prior proof of adequate response to DDAVP is ideal for elective procedures. Tachyphylaxis will develop. DDAVP may be combined with Amicar to inhibit fibrinolysis.
The duration of therapy varies depending on site, size, and severity of the bleeding episode. In orthopedic procedures, replacement may be needed for weeks until physical therapy has been completed.
Products available for FVIII replacement therapy in patients with hemophilia A
· Intermediate-purity products – Plasma-derived (FVIII-specific activity of 1-10 U/mg)
o Humate-P – Heat-treated
o Profilate – Solvent-detergent–treated
· High-purity products – Plasma-derived (FVIII-specific activity of 50-100 U/mg)
o Alphanate – Solvent-detergent–treated
o Koate HP – Solvent-detergent–treated
· Ultra–high-purity products – Monoclonal-antibody–purified (FVIII-specific activity of >3000 U/mg)
o Hemophil M – Solvent-detergent–treated
o Monoclate P – Pasteurized
· Ultra–high-purity products – Recombinant (FVIII-specific activity of >3000 U/mg)
o Bioclate – Heat-treated, solvent-detergent–treated
o Helixate – Heat-treated
o Kogenate – Heat-treated, baby hamster kidney cells
o Recombinate – Heat-treated, solvent-detergent–treated, Chinese hamster ovary cells
o ReFacto – Chinese hamster ovary cells, B domain deleted
Products available to treat FVIII inhibitors
· Human FVIII concentrates – Loading dose of 10,000 units followed by 1000 U/h depending on FVIII levels achieved and maintained
· Feiba VH – Dose of 25-100 U/kg at least every 12 hours, usually more often; not to exceed 200 U/kg/d
· Autoplex-T – Dose of 25-100 U/kg at least every 12 hours
· Porcine FVIII – Dosage based on inhibitor titer and absence of in vitro cross-reactivity to the patient’s inhibitor; initial dose of 50-100 U/kg repeated at 8- to 12-hours intervals
· rFVIIa – Initial dose of 30 mcg/kg, up to 90 mcg/kg intravenously, repeated every 2-3 hours
Advantages and disadvantages of products used to treat patients with FVIII inhibitors
Human FVIII concentrates may be in very limited supply. The needs of a single inhibitor patient may exhaust all product available at several hospitals in a city because of the large doses needed, even in low-titer inhibitor patients.
Porcine FVIII is expensive. It is effective when insignificant or no cross-reactivity occurs between porcine FVIII and the patient’s inhibitor, with a cross-reactivity titer of below 10 BU (cross-reactivity in approximately 15%, only 2% had total cross-reactivity). Good venous access is required.
rFVIIa is the most expensive of the products discussed. Monitoring for DIC is optimal. Drawbacks include possible thrombotic complications, the need for good venous access, and the frequency of intravenous doses needed. rFVIIa is effective and has markedly increased viral safety when compared with human plasma–derived products; no viral illnesses are thought to be transmitted by this product. Hemostasis is usually localized to the site of injury, with no anamnestic rise in antibody titer. It has proven safety even with home therapy.
Activated prothrombin-complex concentrates have a poorly defined mode of action, an unpredictable hemostatic response, are derived from pooled plasma (thereby posing a high risk of transmission of virally induced illnesses), and require good access and frequent administration. They have a greater failure rate, induce an anamnestic rise in antibody titer, and cannot be used at home.
ITI regimens can be associated with a nephrotic syndrome, which would require discontinuation of the product.
Deterrence/Prevention:
· Hepatitis A and B vaccination is appropriate for all nonimmune patients.
· Avoiding high-risk activities (eg, boxing, motorbike riding) and NSAIDs reduces the frequency of bleeding. Avoiding alcohol intake helps protect liver function in patients with hepatitis.
· Use of barrier contraception is important to protect sexual partners of HIV-positive patients.
Complications:
· FVIII inhibitors in patients with hemophilia A (alloantibodies)
o Approximately 20% of individuals with severe hemophilia develop inhibitors to FVIII-C, with an overall prevalence rate of 5-10% in all persons with hemophilia; 95% of inhibitors develop in patients with FVIII-C levels of less than 5%. The development of an inhibitor is a serious complication, adding to morbidity and mortality. Inhibitor development depends on the specific genetic defect, the type of FVIII replacement product used, and the patient’s immune system. It has been suggested that persons with severe hemophilia who were exposed to and had an induction of immune tolerance to FVIII in utero by exposure to maternal FVIII as a consequence of maternal-fetal hemorrhage were less likely to develop inhibitors following replacement therapy.
o Approximately 70-75% of patients with large deletions or non-sense mutations involving the A3 domain developed inhibitors, whereas non-sense mutations in the C1 or C2 domain were associated with inhibitors in approximately 25% of patients. Non-sense mutations in the heavy chain are associated with a low frequency of inhibitor formation (~8%). Patients with gross deletions (>2 kb) have 5 times the incidence of inhibitors compared with patients without deletions, based on Southern blot analysis (Millar, 1990).
o Use of rFVIII has been associated with a rate of inhibitor development of up to 29%, with a median of 10 days of exposure to the recombinant product prior to the development of an inhibitor. However, one third of these were low-titer transient inhibitors, and these patients remained responsive to FVIII replacement therapy. Inhibitors developing in patients with mild hemophilia follow this pattern, and when replacement product is withheld, the inhibitor tends to disappear spontaneously in 1-3 months and may not reappear with subsequent reexposure to product. A recent study suggests that the A2 domain and light chain of FVIII confer greater immunogenicity towards the development of an inhibitor (Scandella, 2001).
o Patients with low-titer inhibitors (3-5 BU) may be further classified as low responders (25%) or high responders (75%), based on the lack of or a rise in their inhibitor titer following reexposure to products containing FVIII. The former may disappear, but the latter may persist for years once they are formed, even in the absence of reexposure to FVIII. Inhibitors appear to be more common in African American and Hispanic individuals.
o A rather unique FVIII alloantibody developed in 2 unrelated individuals with mild hemophilia who had a mutation in the C1 domain of FVIII; both patients had significant residual FVIII activity in their plasma coexisting with anti-FVIII antibodies. One inhibitor was examined in detail and showed the ability to neutralize wild-type but not self-FVIII and behaved like a type II inhibitor. It was able to differentiate between the mutated FVIII that the patient had and wild-type FVIII because of its epitope specificity (Peerlinck, 1999).
o Thus, patients who see infused, external normal FVIII as a novel antigen or an altered antigen because they have been acclimated only to their own, internal, immunologically altered protein (and not to the normal wild-type protein) are the ones likely to develop an inhibitor.
· Acquired spontaneously developing FVIII inhibitors (autoantibodies)
Prognosis:
· Prognosis depends on the type of complications a patient develops; it also depends on the type of product replacement the patient receives and the viral infections the patient accumulates over the years.
· Newly diagnosed patients must receive recombinant products that ensure maximum safety.
· Primary prophylaxis may be the best way to preserve joint function. Joint replacement is likely in the older patients with severe arthropathy. Patients with inhibitors are now able to undergo orthopedic procedures.
· Early and complete genetic testing may help patients prepare for possible inhibitor development.
· Blockade of T-cell activation may reduce the anamnestic rise in inhibitor titers.
· Gene therapy is still in its infancy, but it is the best long-term solution.
Special Concerns:
· Patients with hemophilia should undergo genetic testing so that the type of defect in the family is known; that information would then be available to carriers for use in prenatal testing. Carriers with a sibling with hemophilia or those who have seen other members in the family with this disease are more likely to undergo prenatal testing. A woman who has given birth to a child with hemophilia is more likely to have fewer children than women who have undergone prenatal testing.
· Manage pregnancy, labor, and delivery based on the FVIII level and bleeding. Ensure prompt therapy (ie, hydration, epinephrine, antihistaminics) for allergic reactions. Awareness of the possible development of thrombotic complications during product replacement and need for anticoagulants is important.
· The author gratefully acknowledges the provision of several photographs used in this article and in Factor IX by a dedicated colleague from Chicago, Margaret Telfer, MD. The author would also like to acknowledge Professor K.N. Subramanian (Department of Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure and mutation of the FVIII gene.
References.
- A –
Main : - 1. Davidson’s Principles and practice of medicine (21st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.
- 2.
Harrison ’s principles of internal medicine (18th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p. - 3. The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.
- 4. Web -sites:
- a) http://emedicine.medscape.com/
- b) http://meded.ucsd.edu/clinicalmed/introduction.htm
- B – Optional:
- a. Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.
- b. On Line Resources:
- i. http://image.bloodline.net/category.html
- ii. http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_deficient_erythropoiesis/decreased_erythropoiesis.html
- iii. http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_hemolysis/overview_of_hemolytic_anemia.html?qt=&sc=&alt=
- iv. http://bestpractice.bmj.com/best–practice/monograph/94/treatment/guidelines.html
