Lecture 01. Hemorrhagic diatheses in the children
IDIOPATHIC (AUTOIMMUNE) THROMBOCYTOPENIC PURPURA
The most common cause of acute onset of thrombocytopenia in an otherwise well child is (autoimmune) idiopathic thrombocytopenic purpura (ITP).
The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of generalized petechiae and purpura. The parents often state that the child was fine yesterday and now is covered with bruises and purple dots. Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 x 109/L). There is a history of a preceding viral infection 1-4 wk before the onset of thrombocytopenia.
Findings on physical examination are normal, other than the finding of petechiae and purpura. Hemorrhagic rash: asymmetric, polymorphic, polychromic, places everywhere (on skin, on tunica mucosa), disappears without pigmentation.
Splenomegaly, lymphadenopathy, bone pain, and pallor are rare.
The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, or remarkable lymphadenopathy suggests other diagnoses (leukemia). When the onset is insidious, especially in an adolescent, chronic ITP or the possibility of a systemic illness, such as systemic lupus erythematosus (SLE), is more likely.
Laboratory Findings
Severe thrombocytopenia (platelet count <20 x 109/L) is common, and platelet size is normal or increased, reflective of increased platelet turnover (Fig. 478-3). In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should be normal. Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia. Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes. Some of the megakaryocytes may appear to be immature and are reflective of increased platelet turnover.
Indications for bone marrow aspiration/biopsy include an abnormal WBC count or differential or unexplained anemia as well as findings on history and physical examination suggestive of a bone marrow failure syndrome or malignancy.
Other laboratory tests should be performed as indicated by the history and physical examination. In adolescents with new-onset ITP, an antinuclear antibody test should be done to evaluate for SLE. HIV studies should be done in at-risk populations, especially sexually active teens. Platelet antibody testing is seldom useful in acute ITP. A direct antiglobulin test (Coombs) should be done if there is unexplained anemia to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia) or before instituting therapy with IV anti-D.
Treatment. There are no data showing that treatment affects either short- or long-term clinical outcome of ITP. Many patients with new-onset ITP have mild symptoms, with findings limited to petechiae and purpura on the skin, despite severe thrombocytopenia. Compared with untreated control subjects, treatment appears to be capable of inducing a more rapid rise in platelet count to the theoretically safe level of >20 х 109/L, although there are no data indicating that early therapy prevents intracranial hemorrhage. Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets. Thus, platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present. Initial approaches to the management of ITP include the following:
1. No therapy other than education and counseling of the family and patient for patients with minimal, mild, and moderate symptoms, as defined earlier. This approach emphasizes the usually benigature of ITP and avoids the therapeutic roller coaster that ensues once interventional therapy is begun. This approach is far less costly, and side effects are minimal.
2. Intravenous immunoglobulin (IVIG). IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days induces a rapid rise in platelet count (usually >20 х 109/L) in 95% of patients within 48 hr. IVIG appears to induce a response by downregulating Fc-mediated phagocytosis of antibody-coated platelets. IVIG therapy is both expensive and time-consuming to administer. Additionally, after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis.
3. Intravenous anti-D therapy. For Rh positive patients, IV anti-D causes a rise in platelet count to >20 х 109/L in 80-90% of patients within 48-72 hr. When given to Rh positive individuals, IV anti-D induces mild hemolytic anemia. RBC-antibody complexes bind to macrophage Fc receptors and interfere with platelet destruction, thereby causing a rise in platelet count. IV anti-D is ineffective in Rh negative patients. Rare life-threatening episodes of intravascular hemolysis have occurred in children and adults following infusion of IV anti-D.
4. Prednisone. Corticosteroid therapy has been used for many years to treat acute and chronic ITP in adults and children. Doses of prednisone of 1-4 mg/kg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP. Whether bone marrow examination should be performed to rule out other causes of thrombocytopenia, especially acute lymphoblastic leukemia, before institution of prednisone therapy in acute ITP is controversial. Corticosteroid therapy is usually continued for 2-3 wk or until a rise in platelet count to >20 ? 109/L has been achieved, with a rapid taper to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis.
Each of these medications may be used to treat ITP exacerbations, which commonly occur several weeks after an initial course of therapy. In the special case of intracranial hemorrhage, multiple modalities should be used, including platelet transfusion, IVIG, high-dose corticosteroids, and prompt consultation by neurosurgery and surgery.
There is no consensus regarding the management of acute childhood ITP, except that patients who are bleeding significantly should be treated, representing less than 5% of children with ITP. Intracranial hemorrhage remains rare, and there are no data showing that treatment actually reduces its incidence.
The role of splenectomy in ITP should be reserved for 1 of 2 circumstances. The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are not easily controlled with therapy is a candidate for splenectomy. Splenectomy must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids. Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms and the potential development of pulmonary hypertension in adulthood.
Factor VIII or Factor IX Deficiency (Hemophilia A or B)
Deficiencies of factors VIII and IX are the most common severe inherited bleeding disorders. Recombinant factor VIII and factor IX concentrates are available to treat patients with hemophilia and thereby avoid the infectious risk of plasma-derived transfusion-transmitted diseases.
Clinical Manifestations
Neither factor VIII nor factor IX crosses the placenta; bleeding symptoms may be present from birth or may occur in the fetus. Only 2% of neonates with hemophilia sustain intracranial hemorrhages, and 30% of male infants with hemophilia bleed with circumcision. Thus, in the absence of a positive family history (hemophilia has a high rate of spontaneous mutation), hemophilia may go undiagnosed in the newborn. Obvious symptoms such as easy bruising, intramuscular hematomas, and hemarthroses begin when the child begins to cruise. Bleeding from minor traumatic lacerations of the mouth (a torn frenulum) may persist for hours or days and may cause the parents to seek medical evaluation. Even in patients with severe hemophilia, only 90% have evidence of increased bleeding by 1 yr of age.
Although bleeding may occur in any area of the body, the hallmark of hemophilic bleeding is hemarthrosis. Bleeding into the joints may be induced by minor trauma; many hemarthroses are spontaneous. The earliest joint hemorrhages appear most commonly in the ankle. In the older child and adolescent, hemarthroses of the knees and elbows are also common. Whereas the child’s early joint hemorrhages are recognized only after major swelling and fluid accumulation in the joint space, older children are frequently able to recognize bleeding before the physician does. They complain of a warm, tingling sensation in the joint as the first sign of an early joint hemorrhage. Repeated bleeding episodes into the same joint in a patient with severe hemophilia may become a “target” joint. Recurrent bleeding may then become spontaneous because of the underlying pathologic changes in the joint.
Although most muscular hemorrhages are clinically evident owing to localized pain or swelling, bleeding into the iliopsoas muscle requires specific mention. A patient may lose large volumes of blood into the iliopsoas muscle, verging on hypovolemic shock, with only a vague area of referred pain in the groin. The hip is held in a flexed, internally rotated position owing to irritation of the iliopsoas. The diagnosis is made clinically from the inability to extend the hip but must be confirmed with ultrasonography or CT. Life-threatening bleeding in the patient with hemophilia is caused by bleeding into vital structures (central nervous system, upper airway) or by exsanguination (external trauma, gastrointestinal or iliopsoas hemorrhage). Prompt treatment with clotting factor concentrate for these life-threatening hemorrhages is imperative. If head trauma is of sufficient concern to suggest radiologic evaluation, factor replacement should precede radiologic evaluation. Simply put: “Treat first, image second!” Life-threatening hemorrhages require replacement therapy to achieve a level equal to that of normal plasma (100 IU/dL, or 100%).
Patients with mild hemophilia who have factor VIII or factor IX levels > 5 IU/dL usually do not have spontaneous hemorrhages. These individuals may experience prolonged bleeding after dental work, surgery, or injuries from moderate trauma.
Laboratory Findings and Diagnosis
The laboratory screening test that is affected by a reduced level of factor VIII or factor IX is PTT. In severe hemophilia, the PTT value is usually 2-3 times the upper limit of normal. Results of the other screening tests of the hemostatic mechanism (platelet count, bleeding time, prothrombin time, and thrombin time) are normal. Unless the patient has an inhibitor to factor VIII or IX, the mixing of normal plasma with patient plasma results in correction of PTT value. The specific assay for factors VIII and IX will confirm the diagnosis of hemophilia. If correction does not occur on mixing, an inhibitor may be present. In 25-35% of patients with hemophilia who receive infusions of factor VIII or factor IX, a factor-specific antibody may develop. These antibodies are directed against the active clotting site and are termed inhibitors. In such patients, the quantitative
Treatment
Early, appropriate therapy is the hallmark of excellent hemophilia care. When mild to moderate bleeding occurs, values of factor VIII or factor IX must be raised to hemostatic levels, in the 35-50% range. For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity.
TREATMENT OF HEMOPHILIA
|
TYPE OF HEMORRHAGE |
HEMOPHILIA A |
HEMOPHILIA B |
|
Hemarthrosis* |
50 IU/kg factor VIII concentrate on day 1; then 20IU/kg on days 2, 3, 5 until joint function is normal or back to baseline. Consider additional treatment every other day for 7-10 days. Consider prophylaxis. |
80-100 IU/kg on day 1; then 40 IU/kg on days 2, 4. Consider additional treatment every other day for 7-10 days. Consider prophylaxis. |
|
Muscle or significant subcutaneous hematoma |
50 IU/kg factor VIII concentrate; 20 IU/kg every-other-day treatment may be needed until resolved. |
80 IU/kg factor IX concentrate[‡]; treatment every 2-3 days may be needed until resolved. |
|
Mouth, deciduous tooth, or tooth extraction |
20 IU/kg factor VIII concentrate; antifibrinolytic therapy; remove loose deciduous tooth. |
40 IU/kg factor IX concentrate; antifibrinolytic therapy; remove loose deciduous tooth. |
|
Epistaxis |
Apply pressure for 15-20 min; pack with petrolatum gauze; give antifibrinolytic therapy; 20 IU/kg factor VIII concentrate if this treatment fails. |
Apply pressure for 15-20 min; pack with petrolatum gauze; antifibrinolytic therapy; 30 IU/kg factor IX concentrate if this treatment fails. |
|
Major surgery, life-threatening hemorrhage |
50-75 IU/kg factor VIII concentrate, then initiate continuous infusion of 2-4 IU/kg/hr to maintain factor VIII >100 IU/dL for 24 hr‘ then give 2-3 IU/kg/hr continuously for 5-7 days to maintain the level at >50 IU/dL and an additional 5-7 days to maintain the level at >30 IU/dL. |
120 IU/kg factor IX concentrate, then 50-60 IU/kg every 12-24 hr to maintain factor IX at >40 IU/dL for 5-7 days, and then at >30 IU/dL for 7 days. |
|
Iliopsoas hemorrhage |
50 IU/kg factor VIII concentrate, then 25 IU/kg every 12 hr until asymptomatic, then 20 IU/kg every other day for a total of 10-14 days.** |
120 IU/kg factor IX concentrate; then 50-60 IU/kg every 12-24 hr to maintain factor IX at >40 IU/dL until patient is asymptomatic; then 40-50 IU every other day for a total of 10-14 days.** |
|
Hematuria |
Bed rest; maintenance fluids; if not controlled in 1-2 days, 20 IU/kg factor VIII concentrate; if not controlled, give prednisone (unless patient is HIV-infected). |
Bed rest; maintenance fluids; if not controlled in 1-2 days, 40 IU/kg factor IX concentrate; if not controlled, give prednisone (unless patient is HIV-infected). |
|
Prophylaxis |
20-40 IU/kg factor VIII concentrate every other day to achieve a trough level ≥1%. |
30-50 IU/kg factor IX concentrateevery 2-3 days to achieve a trough level ≥1%. |
With the availability of recombinant replacement products, prophylaxis is the standard of care for most children with severe hemophilia, to prevent spontaneous bleeding and early joint deformities. A study comparing prophylaxis with aggressive episodic treatment provides evidence for the superiority of prophylaxis in preventing debilitating joint disease. If target joints develop, “secondary” prophylaxis is often initiated.
With mild factor VIII hemophilia, the patient’s endogenously produced factor VIII can be released by the administration of desmopressin acetate (DDAVP). In patients with moderate or severe factor VIII deficiency, the stored levels of factor VIII in the body are inadequate, and desmopressin treatment is ineffective. The risk of exposing the patient with mild hemophilia to transfusion-transmitted diseases and the cost of recombinant products warrant the use of desmopressin, if it is effective. A concentrated intranasal form of desmopressin acetate, not the enuresis or pituitary replacement dose, can also be used to treat patients with mild hemophilia A. Most centers administer a trial of desmopressin to determine the level of factor VIII achieved after its infusion. Desmopressin is not effective in the treatment of factor IX–deficient hemophilia.
Prophylaxis
Many patients are now given lifelong prophylaxis to prevent spontaneous joint bleeding. The National Hemophilia Foundation recommends that prophylaxis be considered optimal therapy for children with severe hemophilia. Usually, such programs are initiated with the first joint hemorrhage. Young children often require the insertion of a central catheter to ensure venous access. Such programs are expensive but are highly effective in preventing or greatly limiting the degree of joint pathology. Treatment is usually provided every 2-3 days to maintain a measurable plasma level of clotting factor (1-2%) when assayed just before the next infusion (trough level). Whether prophylaxis should be continued into adulthood has not yet been adequately studied. If moderate arthropathy develops, prevention of future bleeding will require higher plasma levels of clotting factors. In the older child who is not given primary prophylaxis, secondary prophylaxis is frequently initiated if a target joint develops.
von Willebrand Disease
The most common hereditary bleeding disorder is von Willebrand disease (VWD), and some reports suggest that it is present in 1-2% of the general population. VWD is inherited autosomally, but most centers report more affected women than men. Because menorrhagia is a major symptom, women may be more likely to seek treatment and thus to be diagnosed. VWD is classified on the basis of whether the protein is quantitatively reduced, but not absent (type 1); qualitatively abnormal (type 2); or absent (type 3). Mutations in different loci that code for different functional domains of the von Willebrand factor (VWF) protein cause the different variants of VWD.
Patients with VWD usually have symptoms of mucocutaneous hemorrhage, including excessive bruising, epistaxis, menorrhagia, and postoperative hemorrhage, particularly after mucosal surgery, such as tonsillectomy or wisdom tooth extraction. Because a teenager’s menstrual history is usually put in the context of other family members, excessive menstrual bleeding is not always recognized as being abnormal, because others in the family may be affected with the same disorder. If a menstruating female has iron deficiency, a detailed history of bruising and other bleeding symptoms should be elicited and further hemostatic evaluation undertaken.
Because VWF is an acute-phase protein, stress will increase its level. Thus, patients may not bleed with procedures that incur major stress, such as appendectomy and childbirth, but may bleed excessively at the time of cosmetic or mucosal surgery. Bruising symptoms may diminish during pregnancy, because VWF levels may physiologically double or triple as an acute phase response. Rarely, patients with VWD may have gastrointestinal telangiectasia. This combination results in major bleeding and accounts for numerous hospital admissions for patients with severe disease. In patients with type 3, or homozygous, VWD, bleeding symptoms are much more profound. These patients are usually diagnosed early in life and may have severe epistaxis or menorrhagia that results in major blood loss and possibly shock. Patients with severe type 3 VWD may have joint hemorrhages or spontaneous central nervous system hemorrhages.
Laboratory Findings
Although patients with VWD were described historically as having a long bleeding time and a long partial thromboplastin time, these findings are frequently normal in patients with type 1 VWD. Normal results on screening tests do not preclude the diagnosis of VWD. Because there is no single assay that has demonstrated the ability to rule out VWD, if the history is suggestive of a mucocutaneous bleeding disorder, VWD testing should be undertaken, including a quantitative assay for VWF antigen, testing for VWF activity (ristocetin cofactor activity), testing for plasma factor VIII activity, determination of VWF structure (VWF multimers), and a platelet count. Although the platelet count is usually normal in most patients, those with type 2B disease or platelet-type disease (pseudo-VWD) may have lifelong thrombocytopenia. Figure 471-1 lists the variants of VWD and summarizes their laboratory findings. Levels of VWF vary with blood type (type O < A < B < AB), which can confound the clinical diagnosis of hereditary VWD, but most clinicians feel bleeding is related to the plasma level of VWF. In addition, there is controversy regarding the clinical definition of “true” VWD. Molecular genetics may clarify the diagnosis of type 1 VWD, but other genetic modifiers may exist outside the gene for VWF and significantly influence the diagnosis. The milder the patient’s phenotype, the greater the difficulty in diagnosis.
Treatment
Treatment of VWD is directed toward increasing the plasma level of VWF and factor VIII. Because the gene for factor VIII is normal in patients with VWD, elevating the plasma concentration of VWF permits normal recovery and survival of endogenously produced factor VIII. The most common form of VWD is type
A small subset of children and adults, especially infants, do not release VWF in response to desmopressin. In these cases, replacement therapy must be used. Current replacement therapy uses plasma-derived VWF containing concentrates that also contain factor VIII. VWF distributes only to the intravascular space, because it is so large. During plasma fractionation, VWF multimers are altered to a variable extent. Therefore, 1 U/kg will increase the plasma level by 1.5%. The plasma half-life of both factor VIII and VWF is 12 hr, but the alteration of VWF during fractionation results in half-lives of 8-10 hr when concentrates are infused.
Purified or recombinant VWF concentrates (containing no factor VIII) may become available in the near future. These will be useful in prophylaxis or in presurgical management. However, when used for acute bleeding, these VWF concentrates may need to be supplemented by an infusion of recombinant factor VIII for the 1st infusion, as they contain little or no factor VIII. Both VWF and factor VIII are required for normal hemostasis. If only VWF is replaced, endogenous correction of the factor VIII level takes 12-24 hr.
Dental extractions and sometimes nosebleeds can be managed with both desmopressin and an antifibrinolytic agent, such as aminocaproic acid (Amicar).
Henoch-Schönlein purpura
The most common pediatric vasculitis is HSP, IgA immune complex–mediated small-vessel leukocytoclastic vasculitis that classically presents with the triad of nonthrombocytopenic palpable purpura, colicky abdominal pain, andarthritis.
The major cause of morbidity is renal involvement.
HSP is significantly more prevalent in young children, but cases in older mchildren and adults seem to have a higher propensity for causing significant renal damage. Symptomatic involvement of other organs is not common, although one study found that a large percentage of children with HSP had abnormalities of pulmonary diffusion capacity despite having no respiratory symptoms. In rare cases, CNS or respiratory lesions may lead to hemorrhagewith serious sequelae.
A wide variety of infections may trigger HSP. Group A streptococcus is the most common precipitant, demonstrable in up to one third of cases, but exposure to Bartonella, Haemophilus parainfluenza, and numerous vaccines and drugs may precede the development of HSP. Consistent with the contribution of infectious triggers in children, HSP seems to be slightly more common in boys than in girls, and it occurs more commonly during winter and spring than during warmer months. In adults, however, HSP is reported most frequently in the summer, suggesting different predisposing factors in these cases. Skin involvement in HSP may begin as urticaria, but in most cases it progresses to dramatic purple, nonblanching lesions. The disease seems to be mediated by activation of the alternate pathway of complement by large IgA-containing immune complexes. This association may explain the predilection of skin lesions for the lower legs and buttocks in ambulatory children and the sacrum, ears, and buttocks in infants, because gravity causes immune complexes to deposit and incite inflammation in dependent areas.
The arthritis of HSP is usually transient, and it does not cause chronic joint changes or permanent sequelae.
Gastrointestinal involvement ranges from colicky abdominal pain to profuse bleeding, intussusception (typically ilio-ilial, unlike intussusceptions associated with infections) and perforation. Pancreatitis, cholecystitis, and protein-losing enteropathy may also occur. Frequently, gastrointestinal symptoms follow the rash; when they occur first, distinguishing appendicitis or other abdominal catastrophes from HSP may be quite challenging.
In most cases, renal disease is observed early in the disease course, during
the first days or weeks. One series found that nephritis occurred within the first
3 months of the illness in 97% of patients. In this study, risk factors for renal involvement included age over 47 years, gastrointestinal bleeding, purpura of more than 1 month’s duration, factor XIII activity less than 80% of normal, and factor XIII concentrate treatment. HSP recurs in about one third of patients, especially those with nephritis. It usually recurs during the first 4 to 6 months of the disease. Recurrent episodes resemble the initial presentation, although they are generally less severe, and they do not adversely impact prognosis.
In general, long-term outcomes in HSP are quite good. The major exception is patients with significant kidney involvement, although some female patients with milder renal involvement nonetheless seem to develop hypertension and proteinuria during pregnancy. More generally, there is a correlation between the severity of urinary abnormalities and the chances of developing chronic renal disease, with patients demonstrating both nephritic and nephrotic changes at greatest risk. Renal biopsy is useful for confirming the extent and severity of nephritis and planning treatment: the higher the percentage of glomeruli with crescents, the more likely is development of end-stage renal disease.
Differential Diagnosis. HSP most commonly must be distinguished from two other purpuric conditions of childhood: acute hemorrhagic edema of infancy and hypersensitivity vasculitis. Acute hemorrhagic edema of infancy characteristically presents with fever, large purpuric lesions, and edema. It is a self-limited condition, but clinicians must exclude infectious and noninfectious causes of purpura before reassuring parents that the rash is likely to resolve within weeks.
Hypersensitivity vasculitis is an inflammatory condition of small vessels that
occurs after exposure to drugs or infections or may be idiopathic. Histologic evaluation shows leukocytoclastic vasculitis, primarily involving postcapillary venules. Immune complexes are usually present, and mononuclear or poly-morphonuclear cells may be present as well. Clinical features include fever, urticaria, lymphadenopathy, arthralgias, low serum complement levels, and elevated ESR. Low serum concentrations of C3 and C4 and the absence of IgA deposition in vessel walls help to distinguish this entity from HSP, in which serum complement levels are normal.
Therapy of HSP is primarily supportive, aiming for symptomatic relief of
arthritis and abdominal pain. Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) seem to be effective in most cases; there is no evidence that these agents increase the likelihood of gastrointestinal hemorrhage in HSP. Use of steroids in children who do not respond to NSAIDs or in those thought to be at highest risk of developing renal compromise continues to be controversial.
Prednisone, at a dose of 2 mg/kg/day, seems to relieve symptoms rapidly in most cases, but caregivers must avoid excessively rapid tapering of the steroids, because precipitate tapers commonly trigger a flare of symptoms. More potent immunosuppressive agents, such as cyclophosphamide or azathioprine, are re- served for children with biopsy-proven crescentic glomerulonephritis or other life-threatening complications such as cerebral or pulmonary hemorrhage.
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