PATHOPHYSIOLOGY OF HEMOSTASIS

 Plan

1.     Hypocoagulation

    – Thrombocytopenia

    – Thrombocytopathy

    – Angiopathy

    – Coagulopathy

2.     Hypercoagulation

         – DIC- syndrome

 

The hemostasis violations are classificated acording to: etiology, direction of variations and the mechanism of progressing. The directivity of variations there are hypocogulation and hypercoagulation, acording to the mechanism of violations progressing there are vessel-platelets hemostasis disorder and  coagulative  hemostasis  disorder. Hypocogulation is characterized by the reduced of blood capacity to coagulate. All reasons of  hypocoagulation are united in four groups:

·        Thrombocytopenia

·        Thrombocytopathy

·        Angiopathy

·        Coagulopathy

HYPOCOAGULATION

Thrombocytopenia

Thrombocytopenia includes a diseases group, which are characterized by the decrease of thrombocytes blood level less than 150×10⁹/l. There are the congenital and acquired forms of thrombocytopenias. The congenital thrombocytopenias are mostly followed by the changes ofthrombocytes functional properties that make it possible to refer these illnesses to thrombocytopathies group.

The aquired thrombocytopenias are the result of immune and mechanical damages, the depression of thrombocytes forming, and increased  thrombocytes using. There are four groups of immune thrombocytopenias: a) alloimmune–thrombocytes distruction is the result of noncompatibility at one of blood group systems; b) transimmune – thrombocytes damage can be carried out by mother autoantibodies, who suffers from autoimmunal thrombocytopenia, and these immunoglobulins penetrate through placenta and cause the thrombocytes amount decrease in infant; c) heteroimmune-thrombocytes damage is the result of their injury by antigenic pattern under the influence of viruses or the appearance of a new antigene or gapten; d) autoimmune-thrombocytes destruction of is a result antibodies synthesis against ownthrombocytic antigene.

Heteroimmune thrombocytopenia is mostly common for children’s age, and autoimmune one – for adult. Werlhof’s disease (so-called idiopathic purpura) is the one example of the autoimmune thrombocytopenia, the main reason of it is the decrease of immune tolerance to own antigenes. T-suppressors deficit predetermines B-lymphocytes activation and autoimmune process beginning. The reason of suppression function lymphocytes failure at the idiopathic autoimmune thrombocytopenia isn’t know so far may be this is T-suppressors genetic trouble.

The possible mechanism provoking autoagression is the alteration of thrombocytes antigene under the influence of drugss, viruses, and bacterias. In some cases the bacterial antigenes, probably, have similarity with the  thrombocytic antigens determinants. Macrophages of the spleen plays the main role in pathogenesis of autoimmune thrombocytopenias, they kill of thrombocytes and decrease their number. At heteroimmune thrombocytopenias, the antibodies are synthesized against alien antigene, which are fixed on thrombocytes surface and which have stipulated the alteration of antigenic pattern (this antigene there can be medicines: quinidine, digitoxinum, sulfonilamid drugs, rifampicinum, hypothiazidum, viruses of rubella, chickenpox, influenza and adenoviral infection, vaccine). Thrombocytopenia is dangerous with progressing hematencephalons, gastrointestinal tract bleedings, and hematuria.

Thrombocytopathia

Thrombocytopathies is characterized by hemostasis disorder in the result of platelets dysfunction. The first group is congenital desaggregative thrombocytopathies without any failures of reaction of granules release. This group consists of Glantsman’s thrombasthenia (absence of thrombocytes glycoproteins 2а and 3b complex in shells, which are indispensable components of thrombocytes adhesion stimulators and fibrinogen interaction), essential athrombia, May-Heglin’s anomaly, and partial desaggregative thrombocytopathies. Signs of this group disease are the petechias, frequent nose bleedings, menorrhagia, and hematencephalon.

The second group is characterized by the failure of granules release, which leads to absence of thrombocytes aggregation during their contact with collagen fibers of basal membrane and the absence of the second surge aggregation, and as the result thromboxan А₂ synthesis, ADP, serotonin, adrenaline, Са²⁺  disengagement is violated. The key role in the pathogeny of this defect is played by cyclogenase and thromboxan-synthetase deficit, decrease of membrane phospholypase activity. Clinical signs are petechias, mild appearance of  ecchymoses; nose and gem bleedings are possible.

The third group are the result of thrombocytes disability to store and to select granules content (ADP, serotonin, adrenaline, factor IV) athemostasis. One of examples is the Herdimansky’s-Pudlac’s disease, which is characterized by not dangerous bleeding. Another example is TAR-syndrome (pathology of megacaryocytic-thrombocytes with bones anomalies).

The fourth group of thrombocytopathies are caused by failures of adhesive and agregational thrombocytes (different variants ofWillebrand’s and Willebrand’s-Urgens‘ diseases – thrombocytes disfunction is the result of Willebrand’s factor deficit; Bernar’s-Syle’s syndrome, which is the result of  megacaryocytes and thrombocytes anomaly, such as the increase blood platelets sizes, the absence of glycoprotein 1 in megacaryocytes and thrombocytes cytoplasmic membrane, that being indispensable for the interaction with Willebrand’s, V and XI factors. Severe danger even of mild of this disease arises during sexual maturation of the girl (juvenile menorrhagias arise) and atlabours.

The fifth group is caused by the deficit and the decrease accessibility of factor III (Boye’s and Oven’s thrombocytopathies). Thethrombocytes pathology is characterized by the deficit of membrane phospholipids, which activate of factor III, so normal structural modification of membranes doesn’t take place during adhesion and aggregation of thrombocytes.

Wiscott-Oldridge’s syndrome is the example of the sixth group thrombocytopathies. A reason of thrombocytes pathology is the low content of dense and alpha granules, the small conservation of ATP, ADP, serotonin and reductants of alpha granules, decrease of thrombocytes adhesive properties.

The prognosis for life thus is unfavorable. The majority of the aquired thrombocytopathies are characterized by the complication of pathogeny. Only some medicines and toxins (conditioned by aspirin) have legible and stable functional marker. Aquired thrombocytopathies arise at acute leucosis (blastal surrounding provokes disorder of thrombocytes maturation). Thrombocytes dysfunction and hemorrhagic syndrome can be immune inhibition. Immune thrombocytopathies are coused by the capacity of antibodies to damage cytoplasmic membrane and to lock up the receptors. The В₁₂-deficient anemia is also called thrombocytopathy, which is characterized by the disorders of granules release reaction. Thrombocytopathies can arise at uremia, diseases of the liver. Very often the applying of medical drugs can be the reason of the  thrombocytes functions disorder. However the mechanism of many medicines action is well studied and this enables to distinguish the following links of pathogeny of thrombocytes activity disorders: 1) suppression of thromboxan А₂ synthesis, such operating mechanism is characterized for phospholypase inhibitors, which violate the arachidonic acid synthesis (сhinacrinum, glucocorticoids), for cyclogenase inhibitors (acetylsalycilic  acid,  indomethacinum,  butadionum,  ibuprofenum, naproxenum), for thromboxan-synthetase inhibitors (prostacyclinum,  imidazole); 2) the decrease of thrombocytes cAMP level, such mechanism of action is characterized for stimulators adenilatcyclase  (prostacyclinum, prostaglandinum Е), for inhibitors of phosphodieterase, which conduce the cAMP degradation (dipiridamolum,  papaverine, euphilinum,  flavonoids), for stimulators of prostocycline synthesis, (anabolic steroids, niacin); 3) infringement of Ca²⁺ transportation (verapamilum, corinfarum).

Vassopathies (angiopathies)

Vassopathies (angiopathies) are the diseases, which are characterized by the bleeding in the result of vascular wall pathology. All congenital vassopathies, despite their variety, are united by the same pathology – congenital inferiority and improper development of the connective tissue, including vessels subendothelium. Congenital angiopathies are presented by heritable hemorrhagical teleangioectazias, diffusal trunk angiokeratoma, heritable thrombocytopenic microangiomatosis etc.

Bleeding is the basic performance of this disease and is conditioned by the low resistance and easy vunurability of a vascular wall, by very gentle stimulation in these adhesion sections by both the thrombocytes aggregation and blood coagulation. Most often bleedings nose start, however possible are profuse and sometimes fatal bleedings from teleangioectazias of bronchi and gastrointestinal truck, sometimes brain and internal organs hemorrhages are registered.

The group of acquired (secondary) angiopathies (vascular purpuras) includes mostly dermal bleedings, which arise in the result ofexogenic or endogenic vessels injuries. There are idiopathic, stagnant (orthostatic), atrophic (dystrophic), neurogenic, mechanical and other acquired vassopathies. The etiology of idiopathic angiopathies is not known (example is the idiopathic hemorrhagic Caposhi’s sarcoma-reticulihystiocytic system malignant tumor with skin bleeding in the result of vessels hemostasis failure). The stagnant angiopathies can be caused by chronic heart failure, local venous insufficiency (Klots‘ haemostatic dermatitis, Favr-Racusho’s dermatitis) and are the result of long-time tissues hypoxia and vassal dystrophy.

Steroid purpura is the example of atrophic-dystrophic angiopathies; it arises after the durable treatment by glucocorticoids, which suppress the fibroblasts proliferation, decrease the collagen and mucopolysaccharides synthesis that predetermine the dot hemorrhages.

Vessels dystrophy and the following bleeding can be the result of vascular walls damage by immune complexes (Shanline-Genokh’s hemorrhagical  vasculitis). The vitamin C deficit (scorbutus) also promotes the infringement of collagen fibres synthesis (they ensure the continuity of capillary endothelial covering) and is the reason of bleeding in pericappilar spaces (in fascia,  aponeurosis, fatty tissue, muscles, joint cavities, in very severe cases the  hemothorax and hemopericardium can develops.

Coagulopathy

Coagulopathy is the example of hypocoagulation in the result of  coagulative  blood system pathology development. There are primary (hereditary) and secondary (aquired).

The primary coagulopathies are divided on such group as: 1) failure of internal  mechanisms prothrobinase activity forming (hemophilia A – procoagulant  unit of factor-VIII deficit, hemophilia B – factor-IX deficit and  hemophilia  C –  factor-XI deficit, Willebradn’s disease, Hageman’s defect –  factor-XII deficit), 2) failure of external mechanisms prothrombinase activity forming (hypoproconvertinaemia – factor – VII deficit), 3) the combined failure of external and internal mechanisms prothrombinase activity forming (parahemophilia  – factor-V deficit), 4) failure of final stage blood coagulation (hypofibrinogenemia,  dysfibrinogenemia). The patients’ number, which suffer hemophilia A, B, C and Willebrand’s disease occur more often in clinical practice. The  hemophilia A is the result of heritable deficit or molecular anomaly of VIII-factors’  procoagulative part, and is characterized by the  coagulative  hemostasis  failure. Normally factor-VIII circulates in blood in the large molecular protein form and consists of a subunits series: glucoprotein having procoagulative property (VШ:К); glucoprotein with property to cause of thrombocytes adhesion (Willebrand’s factor – VШ:W), ristomicine-cofactor (VIII:R-cоf.), and also antigenic markers of VIII:K and VIII:R-cof.. Activity of both factor VIII:K and VШ:W is being decreased at the decrease of complex structure mass. Synthesis of factor-VIII all components is controlled by X-chromosome. The gene of hemophilia is recessive, thus men are suffered mostly (woman, having the second normal X-chromosome, as a rule, don’t suffer from bleeding, but the VIII-factor activity is reduced in twice and this fact should be taken into consideration surgical operations referring to mothers, sisters and especially daughters the person,  which is ill with hemophilia.

Table. Components of 8-th coagulative factor

 

The hemophilia A сan be caused by poor synthesis of VIII:K factor, thus it’s antigen isn’t discovered in patients plasma (so-called antigeegative hemophilia or hemophilia A^–). In other cases antigen activity of VIII:K factor prevails the activity of this component, as the result of abnormal VIII:K factor synthesis (so-called antigen positive hemophiliaA or hemophilia A).

Clinically the hemophilia A is manifested by hemorrhages in major joints of finitenesses, deep hypodermic, intermuscular and intramuscular hematomas, massive and prolonged posttraumatic bleedings. Man, who have cariotype 46,Х^hУ and women, who have cariotype 46,Х^hХ^h  or 45,Х^hО suffer with hemophilia A, but woman, who have cariotype 46,ХХ^h are the carriers only.

The Willebrand’s disease is the example of autosomal heritable coagulopathy. This is not single disease, but a group of related of hemorrhagic diathesises, which are caused by the infringement of synthesis or the quality anomalies of VIII:W factor. The great number of Willebrand’s disease variations is the proof of factor-VIII structure complication. The patients frequently have hypodermic hematomas, parent bleedings with women can be last 15-25 days, are hardly treated, the hemorrhages in large joints are possible.

The heritable factor-IX deficit is called hemophilia B or Cristmas’ disease; it is inherited by the recessive type and is joined with X-chromosome, however the structural gene of the factor-IX is localized in the other end of this chromosome and isn’t connected with the gene of VIII: K factor.

Hemophilia B is antigene positive (hemophilia B⁺) and antigene negative one (hemophilia B^–). Such patients have caryotypes 46,X^hY, 46,Х^hХ^h, 45,Х^hО or 46,XX/45,X^hO).Hemophilia B is identical to hemophilia A by clinical developments, by gravity and complications. These hemophilias are distinguished only by the results of laboratory studies. The hemophilia C is the example of autosomal heritablecoagulopathies, which caused by the factor-XI deficit.

The acquired coagulopathies, as a rule, are caused by the complex infringement in the coagulative system and have much more complicated pathogeny, than the heritable ones. The insulated deficit of the some coagulation factors occurs not often (amiloidosis provokes factor-X deficit; factor-VIII deficit may be result of its immune inhibition at the antigenic noncompatibility of the mother and the fetus. The simultaneous deficit of several factors is frequent in clinical practice. Hemorrhagic syndrome, as a result of of K-vitamin dependent coagulation factors deficit, is characterized by the disorder of synthesis in hepatocytes and the decrease of factors VII, X, IX and II blood concentrations. Reasons of hemostasis violations and poor vitamin K synthesis can be  dysbacteriosis, profusal diarrhea, enteropathies, failures of this  liposoluble vitamin suction at bile deficit (mechanical icterus), failure of the final stage vitamin-K dependent coagulation factors synthesis (process of their decarboxilation) due to displacement of vitamin K from the metabolism by competitive antagonists anticoagulants of the indirect action, dangerous liver destructions. The depression of the VII, X, IX, XII factors activity arises thus in succession, this depends on the different lifetime of these factors in blood. The medical drugs using can be complicated by coagulopathies. This happens if the drugs have the anthithrombical activity and are overdosed (heparin especially).

HYPERCOAGULATION. DIC-SYNDROME

Hypercoagulation is the organism state characterized by excessive activation of  coagulative blood systems. The examples are thrombosis and  dessiminative intravascular blood coagulation syndrome (DIC-syndrome). Most often DIC-syndrome arises at the development of infections (especially generalized one); at septic states coused by bacteriemia or virusemia, including at abortions, after labors, at a long-term vessels catheterization; at shock (traumatic, hemorrhagical, anaphylactic, cardiogenic, septic, in conditions of septic shock the acute DIC-sindrome is registered in 100 % of cases); at traumatic surgical operations; at long-term usage of an artificial blood circulation apparatus; at all terminal states the DIC-syndrome (in 100 % of cases); at acute hemolysis; at anticipatory flaking-off of placenta, at thermal and chemical burns, at immune diseases, at allergic reactions.

The main DIC-syndrome mechanisms are the following:

1) the activation of thrombocytic and coagulative hemostasis components by the endogenenic factors – tissues thromboplastin, factors of tissues and blood cells disintegration, leukocytic proteases, factors of endothelium injured;

2) the  activation of hemostasis system by such exogenic factors as bacterias, viruses, medicines, snake poisons;

3) the  injure of vascular endothelium, followed by the decrease its  antithrombical potential;

4) the  dissipated intravascular blood coagulation, thrombocytes and erythrocytes aggregation with the formation of many microclots and the block of microcirculation;

5) deep dystrophic failures in organs-targets, the failures of their function;

6) circulatory disturbances which predetermine tissues hypoxia,  hemocoagulational   shock, acidosis, microcirculation failure caused by the disability of the organism to promote the capillary hemodilution process, and stop blood flow;

7) the development of the consumption coagulopathy followed by complete disability of blood to coagulate, the exhaustion ofanticoagulative  mechanisms (deficit of antithrombin III and protein С), component of fibrinolytic and calicrein-kinin systems;

8) the  secondary high-gravity endogene intoxication by toxic substances of proteolysis and tissues destruction. The key role in apathogeny of a DIC-syndrome is given to the increase of thrombinum concentrationin (hypethrombinemia), to the exhaustion ofhemocoagulational potential.

The main initiator of the coagulation process is the tissues thromboplastin that comes into the blood from the injured tissues and endothelium. Activated monocytes provoke to produce tissues thromboplastin and this mechanism plays an important role in DIC-syndromepathogeny at virusemia, at  endotoxemia, at immune diseases (activated monocytes start to produce partially activated such factors as VII, X, IX, II. The thrombocytes aggregation and their using for the thromb forming is the obligatory component of DIC-syndrome pathogeny. The erythrocytes at DIC-syndrome are injured, their lifetime in blood is shortened and the intravascular hemolysis appears. This process activates the blood coagulation because much ADP and other agents from injured erythrocytes came into the blood, promotes thrombocytes aggregation, conduces the DIC-syndrome progressing, and microcirculation disorder in tissues. The very important pathogenetic link of this pathology is the activatioot only the system of blood coagulation, but also of such plasma proteolytic systems, as  fibrinolytic,  calicrein-kinin and complement ones. There of the imagination about the acute DIC-syndrome as about the “humoral protease detonating” was developed in the result of which the patients’ blood is filled up with the great amount of proteins disintegration metabolites. These substances can damage a vascular wall; promote bleeding and secondarily strendhen blood coagulation. DIC-syndrome progressing provokes the decrease of anticoagulants concentration, especially antithrombin III, which is the coagulation enzyme factors inhibitor and protein C, which is the not enzyme factors (f.-VIII and f.-V) inhibitor. Similarly the fibrinolytic components (precallicrein, kininogene) are utilized.

The hemorrhagic syndrome at these conditions is the result of  coagulative  blood properties failure, namely; 1) the anticoagulative action of toxic substances, 2) usage of the factors VIII and V; 3) failure of  thrombocytic hemostasis in the result of hypoxia; 4) toxic influence on a vascular wall of proteolysis products; 5) the decrease in blood of the most active thrombocytes and their block by the fibrin dissociation products. Thrombocytopenia and thrombocytopathy, which arise at this condition, is the important bleeding factor.

Gravity of DIC-syndrome depends on infringement of microcirculation in organs. Constant satellites of DIC-syndrome are shock lung, acute renal insufficiency and other organ failures. Their development is the result of massive capillary block by fibrin clots and blood cells aggregates. Hematocrite capillary blood index increases until 0,45 – 0,55 l/l at DIC-syndrome. The indicated failure and microvessels thrombosis plays the key role in the development of stasis, hypoxia and organs dystrophy. The current of DIC-syndrome can be acute, lingering, the relapsing, chronic, and latent. Stages of DIC-syndrome are following: the first stage – hypercoagulation and thrombocytes aggregation; the second stage – consumption coagulopathy and thrombocytopathia; the third stage –hypocoagulation; the fourth stage – recovery or consequences and complications (at the unfavorable current the death of the patient is possible). By the gravity of the current DIC-syndrome may be acute, subacute and chronic.

The main signs of DIC-syndrome are hemocoagulative or mixed shock (at acute form), failure of hemostasis (thrombosis andhemorrhagia), hypovolemia, anemia, disfunction and dystrophy of organs, metabolic disorders. Hemocoagulative shock is the result of microcirculation violations in organs and tissuel hypoxia, the formation of proteolysis toxic substances. This is characterized by the decrease of arterial and central venous pressure, by organs microcirculation violations and acute organs functional insufficiency (acute renal or hepatorenal insufficiency, shock lung). The development of profusal bleeding promotes the transformation of hemocoagulative shock into the hemorrhagic one.

There are different phases at hemostasis failure – from hypercoagulation up to hypocoagulation (at first we can observe massive thrombogenesis, but then thrombogenesis depression and bleeding). The thrombocytopenia and  thrombocytopathy in this condition is the result of great number microthrombuses forming, of the thrombocytes injury and returning to circulation of degranulated thrombocytes. Hemorrhagic syndrome (bleeding) mostly arises at acute DIC-syndrome in hypocoagulation stage. The main  pathogenetic mechanisms of bleeding are pathological influence on vessels of toxic proteolysis substances, the failure of thrombocytes angiothrophical function, thrombocytopenia, thrombocytopathy of consumption, fibrinolytic system activation.

The microcirculation block predetermines the disfunction and dystrophy of organs. The organs-targets (lung, kidneys, intestine) suffer mostly. The combined forms of organ violations are more difficult, for example, the combination of pulmonary and renal insufficiencies. The stomach and intestine also belong to the group of organs, which are frequently damaged at a DIC-syndrome. Microcirculation violations provoke mucous membrane dystrophy and profusal bleedings. In complicated cases the failures of cerebral circulation, of paranephroses, of pituitary body, and liver are possible.

Disseminated intravascular coagulation (DIC), also known as disseminated intravascular coagulopathy or less commonly asconsumptive coagulopathy, is a pathological activation of coagulation (blood clotting) mechanisms that happens in response to a variety of diseases. 

Under homeostatic conditions, the body is maintained in a finely tuned balance of coagulation and fibrinolysis. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called fibrin degradation products (FDPs) or fibrin split products (FSPs). In a state of homeostasis, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis.

In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein called tissue factor (TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumor necrosis factor, and endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors which then triggers the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) to promote coagulation.

The release of endotoxin is the mechanism by which Gram-negative sepsisprovokes DIC. In acute promyelocytic leukemia, treatment causes the destruction of leukemic granulocyte precursors, resulting in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may enhance the expression of various oncogenes that result in the release of TF and plasminogen activator inhibitor-1 (PAI-1), which prevents fibrinolysis.

Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.

Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a feedback system develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs and this has been attributed to the entrapment and consumption of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC.

Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in excess amounts of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock, hypotension, and increased vascular permeability. The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high mortality rate.

There has been a recent challenge however to the basic assumptions and interpretations of the pathophysiology of DIC. A study of sepsis and DIC in animal models has shown that a highly-expressed receptor on the surface of hepatocytes, termed the Ashwell-Morell receptor, is responsible for thrombocytopenia in bacteremia and sepsis due to streptococcal pneumoniae (SPN) and possibly other pathogens. The thrombocytopenia observed in SPN sepsis was not due to increased consumption of coagulation factors such as platelets, but instead was the result of this receptor’s activity enabling hepatocytes to ingest and rapidly clear platelets from circulation. By removing pro-thrombotic components before they participate in the coagulopathy of DIC, the Ashwell-Morell receptor lessens the severity of DIC, reducing thrombosis and tissue necrosis, and promoting survival. The hemorrhage observed in DIC and among some tissues lacking this receptor may thereby be secondary to increased thrombosis with loss of the mechanical vascular barrier. This discovery has possible significant clinical implications in devising new approaches to reducing the pathophysiology of DIC.

DIC can occur in the following conditions:

·             Cancers of lung, pancreas, prostate and stomach, as well as acute myeloid leukemia (particularly APL)

·             Obstetric: abruptio placentae, pre-eclampsia, amniotic fluid embolism, retained intrauterine fetal demise, abortion

·             Massive tissue injury: Trauma, burns, Hyperthermia, Rhabdomyolysis, extensive surgery

·             Bacterial, Protazoa and Fungal infections: Gram-negative sepsis, T. B. Gambiense (WASS) Neisseria meningitidis, Streptococcus pneumoniae, malaria, histoplasmosis, aspergillosis, Rocky mountain spotted fever

·             Viral infections: Arenaviruses causing Argentine hemorrhagic fever or Bolivian Hemorrhagic Fever among others.

·             Miscellaneous: Liver disease, snake bite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, serotonin syndrome.