Disseminated intravascular coagulation

Disseminated intravascular coagulation is a pathologic process in which coagulation and fibrinolysis are inappropriately initiated in the microvasculature, resulting in systemic generation of thrombin. Generation of thrombin produces widespread thrombosis (the earliest and often unrecognized manifestation of DIC) which eventually leads to hemorrhage (from consumption of platelets and consumption and cleavage of coagulation factors). Inhibitors such as antithrombin and protein C are depleted when the body attempts to limit the over-activated hemostatic system. Plasmin and other proteases (e.g. neutrophil elastase in sepsis-induced DIC) lyse the formed clots, liberating excessive amounts of FDPs and D-dimer. Fibrinolysis contributes to hemorrhage by clot lysis, plasmin-mediated cleavage of coagulation factors, and the anticoagulant effect of FDPs (FDPs bind to platelets and fibrin monomers [only when FDPs are in high concentration], inhibiting platelet function and fibrin polymerization). The consumption of inhibitors allows unchecked activation of coagulation. The main clinical manifestation of DIC is bleeding which is due to depletion of coagulation factors and platelets, fibrinolysis, and the anticoagulant effect of FDPs. However, every animal in DIC is also experiencing diffuse microvascular thrombosis which directly contributes to the high morbidity and mortality of DIC.

Disseminated intravascular coagulation is always a secondary hemostatic disorder, that is initiated by an underlying disease. Many conditions, including sepsis, heat stroke, intravascular hemolysis, burns, shock, pancreatitis, neoplasia, or trauma can initiate DIC. Most animals with acute or overt DIC are very ill and many show evidence of a long-standing, serious disease.

It is now believed that the main trigger for DIC in nearly all disease states is the pathologic exposure, expression, or release of tissue factor. In certain conditions, e.g. snake bites, pancreatitis (trypsin release) or certain neoplasms, the coagulation cascade can be activated directly. Tissue factor expression on monocytes/macrophages and possibly endothelial cells is upregulated by cytokines (particularly IL-6). Tissue factor initiates coagulation through the extrinsic pathway of coagulation, which is then amplified by excessive thrombin generation (as described in the section on secondary hemostasis). At the same time, tissue plasminogen activator is released from endothelial cells and initiates systemic fibrinolysis. Other factors (such as platelet hyperaggregability [e.g. from the release of ADP, a platelet agonist, in intravascular hemolysis] or hyperfibrinogenemia) facilitate the development of DIC. In some conditions, e.g. sepsis, the fibrinolytic pathway is actually downregulated by TNFA-mediated release of plasminogen activator inhibitor. This aggravates widespread thrombosis. Although DIC is not a primary event, if left unchecked it can cause death of the patient primarily due to hypoxic injury of vital organs because of thrombosis.

There is no single diagnostic test for DIC. The diagnosis of acute or overt DIC (the most commonly recognized form of DIC in animals) requires identification of an appropriate underlying disease, recognition of clinical signs of hemorrhage or thrombosis, and documentation of the constellation of laboratory abnormalities consistent with DIC.

  • Clinical signs: Overt DIC is most readily recognized in the dog, because this species demonstrates excessive hemorrhage, which is often clinically obvious and dramatic. In other species, such as horses and cats, clinical diagnosis of DIC is more difficult because they rarely manifest signs of excessive hemorrhage, but are suffering from diffuse thrombosis. In these patients (and in dogs with DIC that are not actively bleeding) DIC is often called "sub-clinical". This is not due to the fact that the disease is truly not clinical, but because thrombosis is so difficult to detect by clinical criteria and current imaging techniques.
  • Laboratory tests: In overt DIC, there are defects/abnormalities in all aspects of hemostasis, including platelets (especially number), factors/enzymes of the coagulation cascade, inhibitors and fibrinolytic components. Typical laboratory findings include thrombocytopenia (or a sequentially decreasing platelet count), prolonged APTT (and possibly ACT if factor deficiencies are severe enought) and PT, low fibrinogen, low antithrombin activity, and positive FDP and/or D-dimer results. Of these tests, a prolonged APTT, low antithrombin activity and high FDP/D-dimer results are the most sensitive for the diagnosis of DIC in dogs and horses. Fibrinogen concentrations are often normal or even high as fibrinogen acts as an acute phase reactant with increased production occurring secondary to the underlying disease. This increased production offsets or balances the increased consumption occurring in DIC. A normal PT does not rule out DIC, as for unknown reasons, this test is not as sensitive as the APTT for diagnosis of DIC in dogs or horses. Cats with DIC may have a prolonged aPTT and/or PT but may not have increased FDPs/D-dimer. They usually do not have low antithrombin activity or low fibrinogen concentrations.

Patients in non-overt (early) DIC are even more difficult to recognize. Patients more commonly have diffuse thrombosis rather than the acute fulminant life-threatening thrombosis/hemorrhage seen in acute overt DIC. These patients are often described as having "compensated" DIC, as increased production of coagulation factors and platelets by the liver and bone marrow result in normalization of many of the coagulation screening tests and the activated coagulation system is kept in check by inhibitors. Often the only routine laboratory test that is abnormal in non-overt DIC is a positive FDP/D-dimer result.

Therapy for DIC is quite controversial and no authors agree on appropriate treatment regimes. All authors agree, however, that treatment for DIC should primarily be centered on the identification and treatment of the underlying disease. Supportive therapy including intravenous fluids to maintain fluid volume and organ perfusion is vital. When it comes to treating the coagulation defects, opinions diverge. Currently, most authors recommend administration of heparin (especially low-molecular weight forms) in patients with evidence of thrombosis, although few controlled studies have been done to determine the benefit of such treatment. Aspirin is contra-indicated due to its effect on platelet function, as platelet function is inhibited in DIC by FDPs already and platelet hyperaggregability is not usually a cause for thrombosis in DIC. In hemorrhaging patients, most authors recommend the use of fresh or fresh frozen plasma or whole blood (for platelets) to replace depleted clotting factors. The early concept that such treatment will "fuel the fire" is now recognized as myth. Some authors have suggested that heparin be injected into bags of fresh or fresh frozen plasma (to activate antithrombin) prior to transfusion, however this approach has not been substantiated by well-controlled studies. Recent studies in human patients indicate that administration of inhibitors, particularly protein C, are beneficial in treating DIC in sepsis. However, this product is not available in animals.