This creates a vicious cycle and helps convert DIC from the “non-overt” into an “overt” phase. Similarly, inhibitors have anti-inflammatory reactions so the loss of inhibitors and generation of activated coagulation factors and activation of platelets all serve to exacerbate the inflammatory state, which then, in turn, accelerates and promotes activation of hemostasis. Note, that DIC fuels or perpetuates its own fire…inflammation is one of the main inciting causes of DIC and activated coagulation factors can induce an inflammatory response, including via activation of complement. At this stage of DIC, laboratory tests will be abnormal, facilitating the diagnosis of DIC. Eventually, platelets and coagulation factors become depleted and fibrinolysis may dominate, such that the animal enters the hypocoagulable phase or hemorrhagic phenotype of DIC, in which clots do not form sufficiently, so bleeding dominates the clinical picture and is readily detectable (this occurs particularly in dogs).
DIC LAB FINDINGS SERIAL
Again, this phase is challenging to diagnose, but serial testing of hemostasis may reveal worsening (decreasing activity of inhibitors, progressive increase in clotting times, decreasing platelet count, increasing D-dimer) or abnormal test results (various combinations of thrombocytopenia, prolonged APTT, prolonged PT, decreased antithrombin activity). The animal is still hypercoagulable (prothrombotic) and is now in the thrombotic phase of “overt” DIC, particularly if fibrinolysis is inhibited. During this stage, microvascular thrombi are forming, and platelets and coagulation factors are being consumed in clot formation. DIC has now become “uncontrolled” and is in the “overt” stage, where thrombosis is occurring and platelets and coagulation factors are being consumed (but not excessively enough to always result in hemorrhage). Thrombin generation then proceeds unchecked and is in the maintenance or perpetuation phase. cell-free DNA), injure other tissues and upregulate TF (e.g. These DAMPs can activate coagulation (e.g. Over time (and depending on the nature of the initiating disease), spatial and temporal control over hemostasis is lost as inhibitors are overwhelmed, downregulated or inhibited, the endothelium becomes dysfunctional or injured, inflammation is stimulated and tissues are injured, with release of damage-associated molecular patterns (DAMPs), including extracellular or cell-free DNA, histones and nucleosomes (DNA-histone complexes), neutrophil proteases (elastase, myeloperoxidase) and other molecules (such as α-defensins, which act a DAMPs) and inflammatory nuclear-based cytokines (such as high mobility group box protein 1 or HMGB1). The tests that may be abnormal are markers of thrombin generation, of which only D-dimer is readily available in animals. This stage is very difficult to diagnose because we lack suitable assays for detecting hypercoagulability (most screening assays of hemostasis are normal) and microvascular thrombi are difficult to detect clinically. thrombosis may be occurring in this stage of DIC.
The affected animal is considered “hypercoagulable” (defined as excess generation of thrombin) or at risk of thrombosis and may actually be suffering from thrombosis, i.e. Initially, thrombin generation is contained or restricted by inhibitors and at this stage, DIC is called “compensated” or is in the “non-overt” stage. Thrombin amplifies its own formation (amplification phase) on the negatively charged surface of cells and cell-derived extracellular vesicles (EVs) bearing phosphatidylserine (PS) or extruded DNA. The disorder is not a simple syndrome, but is rather a continuum of hemostasis activation, beginning with a trigger (initiation phase) that activates coagulation, generating thrombin.
As coagulation factors and platelets are consumed, inhibited or cleaved, hemorrhage can ensue. Disseminated intravascular coagulation (DIC) is the abnormal (excessive) activation of hemostasis, with subsequent generation of excess thrombin and formation of microvascular thrombi (arterioles, venules, capillaries).
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