DIC

 
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DIC continuum

The DIC continuum

Disseminated intravascular coagulation (DIC) is the abnormal (excessive) activation of hemostasis, with subsequent generation of excess thrombin and formation of vascular thrombi. DIC is not a simple syndrome, but is rather a continuum of hemostasis activation, beginning with a trigger (initiation phase) that activates coagulation, generating thrombin. Thrombin amplifies its own formation (amplification phase) on the surface of cells bearing phosphatidylserine (PS). Initially, thrombin generation is contained or restricted to a local site by inhibitors and at this stage, DIC is called “compensated” or is in the “non-overt” stage. 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. thrombosis may be occurring in this stage of DIC. 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. The tests that may be abnormal are markers of thrombin generation, of which only D-dimer is readily available. Over time (and depending on the nature of the initiating disease), spatial and temporal control over hemostasis is lost as inhibitors are overwhelmed or inhibited, and thrombin generation proceeds unimpeded and disseminates through the vasculature (progression/dissemination phase). Dissemination of coagulation is facilitated by the shedding of procoagulant PS-expressing membrane-derived microparticles from various cells. DIC has now become “uncontrolled” and is in the “overt” stage. During this stage, microvascular thrombi are forming, and platelets and coagulation factors are being consumed in excessive clot formation. The animal is still hypercoagulable (prothrombotic) and is now in the thrombotic phase of “overt” DIC. Again, this phase is challenging to diagnose, but serial testing of hemostasis may reveal worsening (decreased activity of inhibitors, prolonged clotting times from consumption of coagulation factors, decreasing platelet count, increasing D-dimer) or abnormal test results (prolonged APTT, prolonged PT, thrombocytopenia, decreased antithrombin activity). Eventually, platelets and coagulation factors become depleted and 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). At this stage of DIC, laboratory tests will be abnormal, facilitating the diagnosis of DIC. Note, that DIC fuels or perpetuates its own fire…inflammation is one of the main inciting causes of DIC and activated coagulation factors actually induce an inflammatory response. 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. This creates a vicious cycle and helps convert DIC from the “non-overt” into an “overt” phase. Note that non-overt DIC does not always naturally segue into overt DIC. For instance, massive head trauma may immediately result in overt DIC from release of tissue factor in the brain, whereas low-grade inflammation may incite a more slow-burning controlled process (non-overt DIC) that may not progress. Although hemorrhage is the most apparent clinical manifestation of DIC, microthrombi have far more serious sequelae, due to the effects of hypoxic injury on end-organ function. It is usually end-organ injury or failure that results in the demise of the patient and DIC should be thought of first as a thrombotic syndrome and second as a hemorrhagic one. Which phase of DIC dominates depends on the initiating cause and species. Dogs have robust fibrinolysis so the hemorrhagic phenotype of DIC dominates. In contrast, hemorrhage is uncommon in cats or horses with this disorder, suggesting suffer more from the thrombotic phenotype of DIC. Indeed, the disorder has been called “sub-clinical” in these species (which is really a misnomer, because thrombi are having clinical consequences, just ones that are hard to definitively ascribe to thrombosis, e.g. ischemic injury will contribute or cause azotemia, dyspnea, hepatic injury, etc).

Phases of DIC

Over the past decade, our understanding of DIC has evolved from recognition of a severe hemorrhagic disorder to appreciation of DIC as a disease continuum. The process is initiated by inappropriate activation of hemostasis, at first kept in check by natural inhibitors. If regulatory mechanisms become overwhelmed, DIC progresses to a full-blown decompensated disorder characterized by systemic thrombosis and ultimately, a consumptive coagulopathy, the most readily recognized form of DIC in the clinical situation. For ease of understanding, the complex process that is DIC, can be broken down into the phases of initiation, amplification and progression (includes dissemination and potentiation). Although there is always an initiating phase, the amplification and progression phases, can proceed simultaneously depending on the underlying cause.

Initiation

An important aspect of DIC is that it is never a primary disease. It is always initiated or triggered by another disease process. Diseases that can induce DIC are given in the table below, along with potential mechanisms by which those diseases can trigger DIC. The most common diseases associated with DIC are moderate to severe inflammation, neoplasia, bacterial sepsis, and massive endothelial injury. DIC has been documented in most domestic animals, with the exception of camelids. In dogs and cats, neoplasia and systemic inflammation (e.g. sepsis, pancreatitis, IMHA, heat stroke) are the most common initiating diseases. Endotoxemia (secondary to gastrointestinal disorders) and sepsis are the main causes of DIC in adult horses and neonatal foals, respectively. Similarly, DIC is primarily due to endotoxemia or sepsis in ruminants. DIC is thought to be initiated in these diseases primarily by the excessive exposure of extravascular tissue factor (through massive endothelial injury) or aberrant expression of tissue factor on cells within the vasculature, e.g. monocytes, endothelial cells, cancer cells. Inflammatory cytokines have been shown to upregulate tissue factor on monocytes and possibly endothelial cells. Cancer cells, and their shed exosomes and membrane-derived microvesicles, can constitutively express tissue factor. There are also tissue factor-independent ways by which hemostasis could be activated in conditions associated with DIC. This includes the expression of proteases, such as a factor X-activating enzyme, on cancer cells. New evidence also suggests that factor XII and kallikrein (of the contact pathway) can also promote activation of FIX and prothrombin, in a FXI-independent manner, in the presence of long-chain polyphosphates, such as those found in bacteria (Puy et al 2013). In addition, activated neutrophils and other cell types (e.g. cancer cells, dying cells) can release nuclear material (DNA, histones, high mobility box proteins), which is procoagulant and antifibrinolytic. For instance, cell free DNA, by virtue of its negative charge, can activate FXII of the intrinsic pathway. Histones can directly activate prothrombin to thrombin and also activate platelets (Gould et al 2015). This could be an additional mechanism of DIC initiation in disorders, such as bacterial sepsis, severe acute inflammation and cancer (Gould et al 2015Liaw et al 2015).
Diseases with associated potential mechanisms of initiation of DIC
Disease Potential mechanism of DIC initiation
Infectious agents: Bacterial sepsis (gram positive and negative bacteria), viruses (e.g. Feline infectious peritonitis virus), protozoa (Babesia canis), parasites (e.g. Angiostrongylus vasorum), rickettsia (e.g. Rocky Mountain Spotted Fever) Cytokine-induced tissue factor (TF) expression: On monocytes and (likely) endothelial cells. Cytokine-induced downregulation of inhibitors: Thrombomodulin, antithrombin, protein C. Activation of factor XII (FXII; contact pathway): In the presence of long chain bacterial polyphosphates, FXII can activate factor IX and prothrombin directly (Puy et al 2013). Extracellular or cell free DNA or nuclear material can also activate FXII and initiate coagulation via the intrinsic pathway. This DNA material is released in abundance by neutrophils in response to bacteria and activated platelets and is called netosis (Liaw et al 2015). Endothelial injury: Exposure of extravascular TF on fibroblasts and smooth muscle cells, induction of TF on endothelial cells, release of nuclear material (histone release can cause a vicious cycle by causing endothelial cytotoxicity).
Cancer: Particularly metastatic tumors, but also hemangiosarcoma and hematopoietic (lymphoma, acute leukemia) neoplasia Expression of TF on cancer cells: Constitutive or induced by hypoxia, cytokines, or apoptosis. Induction of TF expression: Tumor-secreted cytokines act on monocytes, fibroblasts, and endothelial cells. Shedding of procoagulant membrane-derived microparticles: TF- and phosphatidylserine (PS)-bearing microparticles from tumor cells, hematopoietic cells, other cell types. Expression/secretion of procoagulants: Cancer procoagulant (a vitamin K-dependent cysteine protease), mucin can activate coagulation factors, released polyphosphate and extracellular nuclear material can activate FXII. Chemotherapy-induced changes: Tumor lysis (upregulation TF, expression of PS, shedding of microparticles, release of procoagulant factors, such as cell free DNA), may be exacerbated by myelotoxicity (thrombocytopenia).
 Inflammation/necrosis: Trauma, immune-mediated hemolytic anemia (IMHA; dogs), pancreatitis, heat stroke, hepatitis, vasculitis, gastric dilatation-volvulus (dogs), strangulating obstructions and inflammatory gastrointestinal disorders (horses) Inflammatory cytokines: See infectious agents above. Endothelial injury: See infectious agents above. Tissue injury/necrosis/apoptosis: Exposure of TF; activation of FXII via cell free DNA and other factors, shedding of PS-enriched microparticles by apoptotic cells. Release of procoagulants: See above. Enzymes released from tissues (e.g. trypsin from the pancreas in pancreatitis) can also activate and cleave factors, including inhibitors and fibrin.
Intravascular hemolysis: IMHA, acute transfusion reactions, insect/snake bites, oxidant injury (e.g. red maple leaf toxicity in horses) Endothelial injury: See infectious agents above. Erythrocyte procoagulant activity: RBC membrane-associated elastase, shedding of PS-enriched MPs. Release of other procoagulants: NETosis by activated neutrophils, DNA release from injured or dying cells
Envenomation Snake venom proteases: Direct activation of coagulation factors (e.g. factor X) and cleavage of fibrinogen, phospholipase-induced tissue injury/cell lysis.

Amplification

Thrombin amplifies its own production by activating the following:
  • Factor XI of the intrinsic pathway of coagulation. This then cleaves and activates factor IX. Release of polyphosphates from activated platelets promote the activation of FXI by thrombin.
  • Factor VIII: The intrinsic pathway cofactor for activated FIX (part of the intrinsic “tenase” complex). Activated FVIII markedly accelerates activation of factor X on the surface of PS-expressing cells.
  • Factor V: The common pathway cofactor for activated FX (part of the “prothrombinase” complex). Like FVIIIa, FVa markedly accelerates thrombin generation by FXa on the surface of cells, producing bursts of thrombin, that can cleave fibrinogen to fibrin. Polyphosphates promote factor V activation (Smith et al 2006).
  • Platelets: Thrombin binds to protease-activated receptors (PAR) on platelets. Activated platelets recruit additional platelets, release polyphosphates and other agonists (e.g. ADP), and flip their membranes, expressing PS on their outer membrane leaflet, thus providing a scaffold and localizing area for coagulation factor assembly. PS also positions coagulation factors in an optimal conformation so coagulation factor activation is accelerated (along with thrombin generation). Activated platelets also shed PS-expressing microparticles, which are strongly procoagulant (more than the platelet itself) and vastly increases the surface area on which thrombin generation proceeds. Although platelets are considered the main source of PS and surface membranes that support thrombin generation, activated leukocytes and RBC also provide PS-bearing membranes and shed microparticles and likely play a major role in DIC. For instance, histones have been shown to cause PS expression on RBCs, turning them into procoagulant molecules, and are also platelet agonists (Gould et al 2015).
Thrombin not only amplifies its own generation, but it also creates a fibrin clot, by first cleaving fibrinogen to form soluble fibrin and then activating factor XIII, which crosslinks soluble fibrin to insoluble fibrin. At the same time that thrombin is promoting clot formation, it is also inhibiting clot breakdown, by activating an inhibitor of fibrinolysis (thrombin-activatable fibrinolytic inhibitor or TAFI). The activity of TFPI is enhanced by polyphosphates, which also increase fibrin clot strength making the fibrin clot more resistant to lysis (Smith and Morrissey 2008). In early DIC, as in physiologic hemostasis, thrombin’s generation and its actions are opposed by the plasma anticoagulants, antithrombin (AT) and protein C, and the endothelial cell surface receptor, thrombomodulin (which activates protein C). This phase of systemically activated coagulation restrained by natural anticoagulants is referred to as “non-overt” DIC, a state of stressed, but compensated hemostasis. As indicated previously, patients with non-overt DIC are hypercoagulable, i.e. at risk for widespread microvascular fibrin deposition.
DIC sepsis

DIC progression in bacterial sepsis

Progression

The development of DIC depends not only on the location and severity of the inciting stimulus, but on the ability of naturally occurring inhibitors to regulate the procoagulant hemostatic response. These inhibitors hold the breaks on hemostasis. Effective inhibition or containment results in the non-overt or compensated stage of DIC and DIC may never progress beyond that point. However, depending on the primary disease, severity of the process and extent of hemostasis activation, DIC can progress from the non-overt to overt phase. Overt DIC is marked by:
  • Loss of control or inhibition: Inhibitors become overwhelmed, are inactivated or are consumed in trying to stop the excessively activated hemostatic system.
    • Tissue factor pathway inhibitor (TFPI):  Under physiologic hemostasis, the TF-FVIIa-FXa complex is rapidly neutralized by TFPI. TFPI is primarily expressed on endothelial cells, with its activity enhanced by cell-surface heparin and heparin-like glycosaminoglycans. In the process of DIC, TFPI is rendered ineffective through a number of mechanisms, including cleavage of TFPI by granulocytic elastases (whose activity are promoted by cell free DNA), cytokine-mediated suppression of TFPI expression, decreased protein S (a cofactor for TFPI, see below), and generation of excess TF-FVIIa that overwhelms TFPI’s inhibitory capacity. 
    • Antithrombin: Inflammatory cytokines down regulate production in hepatocytes (this does not appear to occur in cats). Antithrombin is also consumed by binding to thrombin, forming thrombin-antithrombin (TAT) complexes. Increased numbers of TAT complexes are proof of excessive production of thrombin and a hypercoagulable state. Downregulation of heparin-like glycosaminoglycans on endothelial cells also decrease the activity of antithrombin. As for TFPI, neutrophil and other proteases can degrade antithrombin.
    • Protein C: Protein C is produced in the liver and its production is downregulated by inflammatory cytokines. Protein C is activated by thrombin binding to a receptor on endothelial cells, called thrombomodulin. Inflammatory cytokines also decrease endothelial expression of thrombomodulin, decreasing activation of protein C in DIC. Histones released from the nucleus of cells (cancer cells, dying cells, neutrophils) can bind to both thrombomodulin and protein C, decreasing protein C activation (Gould et al 2015). Decreased levels of protein S, a co-factor for protein C, (see below), also contribute to decreased activity. Neutrophil proteases (and other proteases, such as trypsin or plasmin) can potentially degrade protein C.A protein C inhibitor binds to activated protein C and facilitates its clearance, which is increased in DIC.
    • Protein S: This vitamin K dependent protein produced in the liver is a co-factor for protein C and TFPI. It is found in free and complexed form to C4-binding protein. C4-binding protein is an acute phase reactant and increased levels in inflammation decrease the amounts of free protein S that can behave as a cofactor for other inhibitors. As for other inhibitors, proteases can degrade protein S.
  • Dissemination: This is where there is loss of spatial localization of hemostasis. Instead of being restricted to a specific site of injury, it occurs throughout the vasculature. This is facilitated by the release of procoagulant microparticles, which provide the surface on which coagulation proceeds. Such microparticles are derived from platelets, cancer cells, apoptotic cells, endothelial cells, activated leukocytes and even erythrocytes. Due to their small size, microparticles are slowly cleared from the circulation and thus persist and promote systemic thrombin generation. The unchecked and systemic generation of thrombin produces diffuse microvascular fibrin thrombi, the hallmark of overt DIC. With time, coagulation factors and platelets become consumed and hemorrhage may ensue. Thus, DIC is characterized first and foremost by thrombosis and, only in some species, by hemorrhage.
  • Perpetuation of an activated coagulation system: A self-perpetuating cycle develops in DIC triggered by sepsis or non-septic inflammation. Inflammation initiates coagulation via tissue injury, induced TF expression, and platelet and leukocyte activation and microvesiculation. Inflammation also promotes dissemination through downregulation or inactivation of inhibitors. Coagulation, in turn, fuels inflammation, through the pro-inflammatory properties of active coagulation factors (e.g. thrombin, FXa, FVIIa). This vicious cycle would help progression of DIC into an overt phase.  Other factors can also promote DIC progression. The release of vasoactive peptides (e.g. bradykinin, endothelin) from damaged or thrombin-stimulated cells induces hemodynamic changes that often decrease tissue perfusion thereby contributing to hypoxic injury. Ischemic and necrotic tissue injury, in turn, promotes inflammation and coagulation. Secondary acidosis inhibits platelet function and coagulation factor activity, furthering development of hemorrhagic DIC. Endothelial dysfunction (due to the primary disease or hypoxia) causes a loss of inhibition and a gain of pro-inflammatory and procoagulant properties. Healthy endothelial cells secrete potent platelet inhibitors (e.g. prostacyclin) and express receptors that modulate coagulation and inflammation. Upon injury, these functions are lost and endothelial cells may secrete inflammatory cytokines and platelet activating compounds and upregulate adhesion molecules, facilitating inflammation and perpetuating coagulation activation and progression. 

Diagnosis of DIC

Every animal with an inciting primary disease should be considered at risk for developing DIC. Confirmation of DIC is challenging because animals may be examined at any point of the DIC continuum, clinical signs may be subtle or nonspecific, and individual laboratory tests are variably sensitive and none are specific for this syndrome. Histopathologic evidence of fibrin thrombi throughout the microvasculature in biopsy or necropsy specimens represents a “gold standard” test. Unfortunately, this test modality has low diagnostic utility because biopsy specimens are inconsistently obtained antemortem, and fibrin thrombi often lyse rapidly after death. The table below summarizes the differences between non-overt and overt stages of DIC.

Non-overt DIC

As described above, non-overt DIC is characterized by an activated, but not overwhelmed, hemostatic system. Non-overt DIC also applies to the clinical designation of hypercoagulability or “chronic DIC” reflecting continuous low grade, but compensated, activation of coagulation (see table below).
  • Clinical signs: Affected animals should have an underlying disease predisposing them to DIC. Since this phase is dominated by thrombosis (if occurring at all), it is difficult to impossible to detect clinically, particularly when thrombi occur internally or in small vessels (the majority of thrombi with DIC). Doppler ultrasonography may be useful in detecting larger thrombi. Blood gas analysis can detect ventilation:perfusion mismatch in patients with dyspnea and support pulmonary thromboembolism. Deteriorating organ function, e.g. worsening azotemia, increasing liver leakage enzymes, could also be due to hypoxic injury to major organs.
  • Laboratory tests: Routine coagulation screening tests, such as the APTT and PT, are insensitive to this phase because they detect coagulation factor deficiencies, rather than accelerated coagulation or hypercoagulability. This phase is marked by excessive thrombin generation and tests geared towards detection of excessive thrombin are useful for detection of this phase. This might include measurement of TAT complexes, D-dimer, and sophisticated assays that measure the kinetics and rate of thrombin generation, e.g. thrombin potential assays. Unfortunately, with the exception of D-dimer (which is not specific for DIC), these tests are not widely available for routine clinical diagnosis. It was hoped that viscoelastographic techniques, which monitor and record the rate of fibrin formation in whole blood, would be useful for detecting this phase of DIC, but they are yet to demonstrate this promise and are, unfortunately affected by other variables (e.g. hypercoagulable tracings are present in dogs and horses with lower hematocrits), which are frequently present in dogs with DIC (e.g. anemia). There are several human schemes to help diagnosis of non-overt DIC. All rely on documentation of an underlying disease and various combinations of routine test results. The most optimal technique may be serial measurement of coagulation assays to document a worsening, stable or improving hemostatic system. Worsening of hemostatic dysfunction (progressive prolongation of APTT, decreasing platelet count) even in the absence of test abnormalities (APTT and platelet count may still be within reference intervals) would support non-overt DIC and potential progression to overt DIC in a patient with an associated primary disease process.

Overt DIC

Overt DIC means that the disorder has manifested clinically, i.e. thrombosis is definitely occuring and some animals may be suffering from hemorrhage. This is important because it is the thrombosis and not the hemorrhage, that results in death in DIC and has given DIC the moniker, “death is coming”. Widespread microvascular thrombosis decreases blood flow to vital tissues causing hypoxic injury, cell death, and organ failure. These factors which are ultimately responsible for the high morbidity and mortality of DIC. Although severe signs at presentation often prompt laboratory investigation, screening tests to detect overt DIC should be performed in all patients with primary inciting disorders. There is no single diagnostic test for overt DIC, rather we rely on a constellation of test abnormalities, along with associated clinical signs and documentation of a primary disease.
  • Clinical signs: Affected animals should have an underlying disease predisposing them to DIC. Depending on the species, this phase can be dominated by thrombosis (thrombotic phenotype), which is difficult to detect, or hemorrhage, which is far readily apparent clinically.  Hemorrhagic DIC develops frequently in dogs, but appears to be uncommon in horses and cats. This could be due to the robust fibrinolysis in dogs (they have high tissue plasminogen activator activity) and perhaps, inhibition of fibrinolysis (by upregulation of plasminogen activator inhibitor, as occurs in humans) in other species. Regardless, in all species, fibrin thrombosis is occurring in this phase of DIC, so DIC should be thought of first and foremost as a thrombotic and not a hemorrhagic disorder. When bleeding occurs, it manifests as any (and more than one) of the following: epistaxis, petechiae, bruising, prolonged bleeding after venipuncture or minor surgical procedures, and spontaneous hematoma formation and body cavity hemorrhage.
  • Laboratory tests: Diagnosis of overt DIC relies upon identifying abnormalities in multiple tests, rather than a single pathognomonic sign or laboratory finding. Traditional criteria for diagnosis of overt DIC in animals include a combination of 2 or more test abnormalities, specifically abnormalities in all pathways of hemostasis (primary, secondary, fibrinolysis, inhibitors)
    • Primary hemostasis: Mild to moderate thrombocytopenia is a consistent finding in dogs with overt DIC (75-100% sensitivity, i.e. some animals will not be thrombocytopenic), but not in cats or horses (0-64% sensitivity in published reports). Overt DIC is therefore unlikely in dogs having sequential platelet counts that remain within reference intervals but should be suspected in dogs with a normal platelet count that is progressively declining with serial measurement. In rare cases, some animals with overt DIC can have high platelet counts (if the underlying disease process is concurrently stimulating thrombopoiesis). Overt DIC is suspected in the latter animals if other assays on a DIC panel are abnormal (e.g. prolonged APTT, high D-dimer, low AT activity) and the animal has a disease process that could trigger DIC (of course). High concentrations of fibrin(ogen) degradation products may inhibit platelet function, so bleeding symptoms associated with primary hemostatic disorders (e.g. mucosal hemorrhage, petechiae) may occur even when the platelet count is not critically low (<30,000/uL).
    • Secondary hemostasis: Prolonged coagulation times (PT, APTT, TCT) and hypofibrinogenemia may occur in DIC due to consumption of coagulation factors, including fibrinogen. Plasmin and other proteases may also cleave (inactivate) coagulation factors. The TCT may be additionally prolonged by high concentration of fibrin(ogen) degradation products which inhibit fibrin polymerization in the test. Remember, a low fibrinogen (<50 mg/dL in the dog and <90 mg/dL in other species) will prolong the PT and APTT, regardless of other coagulation factor deficits. The apparent diagnostic utility of these tests varies depending on species and stage at presentation. Of the routine coagulation screening tests, the APTT appears to be more sensitive for detecting DIC in animals than the PT or TCT. Hypofibrinogenemia is generally an insensitive indicator of DIC because fibrinogen is an acute phase reactant protein and likely to be upregulated secondary to underlying inflammatory disorders. Indeed, the finding of normal fibrinogen values in a patient with active inflammation suggests ongoing consumption of fibrinogen in a DIC process.
    • Fibrinolysis: High fibrin(ogen) degradation product (FDPs) or D-dimer are characteristic of DIC in most species. Even though fibrinolysis may be inhibited to some extent in DIC, it is still occurring, resulting in high values of these degradation products. In most diagnostic laboratories, D-dimer assays have replaced FDP testing for detecting fibrinolysis in DIC. D-dimer is a sensitive test for DIC in dogs (75-100%) but is less sensitive in horses (50%). D-dimer has not been adequately evaluated in cats, however internal studies show that D-dimer may only be increased in about 50% of cats with diseases predisposing them to DIC (pancreatitis, feline infectious peritonitis virus infection, cancer).
    • Decreased inhibitors: Low activity of inhibitors (AT and protein C) would be expected in overt DIC for the reasons given above. Low AT activity is one of the more sensitive tests for diagnosis of DIC in dogs (77-90%) and horses (89-93% in published studies). In cats with DIC, AT activities may acutely decrease, however values rarely fall below reference intervals and may actually be high in some patients.
    • Red blood cell fragments: Additional tests sometimes used to characterize DIC include blood smear examination for erythrocyte fragments (schistocytes, acanthocytes, keratocytes - these are of most use in the dog). The presence of fragments with concurrent thrombocytopenia in a sick dog should raise a clinical suspicion for DIC. However, the absence of these fragments never rules out DIC as these RBC changes only occur in low numbers of animals (around 20% of cases in one study). RBC fragments are very non-specific for DIC in cats, being seen more with various types of liver disease, including lipidosis (many of these cats are not in DIC). Similarly, fragments are not specific for DIC in dogs either and can occur with any other cause of blood turbulence causing shearing of RBC (e.g. portosystemic shunts, mitral valve disease), mechanical fragility of RBC (e.g. iron deficiency) and oxidant injury to RBC. RBC fragments are also rarely reported in horses and ruminants with DIC, although we have seen fragments in isolated cases of DIC in these species.
    • Other tests: Other tests that have been performed in dogs are measurement of soluble fibrin monomer and individual coagulation factor activities (e.g. factor V). Thromboelastography has also been performed in dogs with DIC and shows that hypercoagulable and hypocoagulable tracings in dogs with DIC. However, hypercoagulable tracings could be a direct consequence of anemia or high fibrinogen in affected dogs and hypocoagulable tracings will occur in thrombocytopenic animals, which is an inevitable consequence of DIC in dogs. Thus, it is unclear if thromboelastography provides any real additional information on hemostatic status in animals with DIC.
Distinguishing between overt and nonovert DIC
Overt Non-overt
Alternate name Uncompensated, acute, fulminant, consumptive coagulopathy, thrombotic phase = hypercoagulable, hemorrhagic phase - hypocoagulable Compensated, chronic, subclinical, pre-DIC, hypercoagulable
Pathophysiology Decompensated hemostasis with fibrin deposition throughout the microvasculature. Platelet and factor depletion develop over time. Procoagulant excess opposed by coagulation inhibitors, partial compensation modulates fibrin deposition (thrombi may or may not be forming)
Clinical features Primary inciting disease, thrombotic phenotype (systemic thrombosis, pulmonary thromboembolism, multiple organ dysfunction), hemorrhage from multiple sites (bleeding features of primary or secondary hemostasis)  Primary inciting disease, subclinical or tissue thrombosis (may not be clinically evident)
Screening test abnormalities Thrombotic phase: Worsening test results or abnormal test results (see hemorrhagic phase). Hemorrhagic phase: Some or all of the following: Thrombocytopenia, prolonged clotting times (aPTT, PT, TCT), hypofibrinogenemia, low AT, high FDP & D-dimer (tests vary in sensitivity and specificity depending on the species) No screening test abnormalities and/or progressive fall in platelet count and increase in clotting times, high FDP & D-dimer, high fibrinogen (hypercoagulable)
 

Treatment of DIC

Affected animals should always be treated for their primary disease with the goal of breaking the DIC cycle. Supportive care aimed at alleviating metabolic/hemodynamic sequelae of DIC (shock, hypoperfusion and acidosis) helps minimize organ damage, inflammation, and continued activation of hemostasis. Effective treatment modalities beyond primary disease-specific and supportive care remain unproven. General treatment options include transfusion therapy and anticoagulant and anti-inflammatory drug therapy. Treatment recommendations are generally derived from the human literature and should only be used with the knowledge that they may not be suitable for animals, due to species-specific differences in hemostasis and drug pharmacokinetics and efficacy (i.e. they may hurt). Randomized, controlled clinical trials on DIC treatment are needed in veterinary medicine to identify safe and cost-effective DIC treatment strategies.
  • Transfusion therapy: The fear that transfusions “fuel the fire” of DIC is largely unfounded, however transfusion therapy is generally restricted to actively bleeding patients in human studies. Component therapy, rather than whole blood, generally provides the most effective means of restoring adequate levels of factors or platelets to support hemostasis. Fresh frozen plasma provides all coagulation factors and platelet concentrates can provide platelets in an emergency situation (acutely bleeding dog).
  • Anticoagulants: Although thrombosis underlies the morbidity and mortality of DIC, anticoagulant therapy, particularly heparin therapy, has not been proven to be a consistently effective therapy of overt DIC in people or animals. Anticoagulants, such as heparin, should used with caution for treating DIC in animals, with recommendations for unfractionated and low molecular weight heparin (LMWH) therapy being adopted from humans. Platelet inhibitors, such as aspirin or clopidogrel, are generally not used to treat DIC (platelets may be dysfunctional from high concentrations of FDPs).
  • Inhibitors and anti-inflammatory drugs: Since inhibitors, particularly activated protein C, has anti-inflammatory effects and contain hemostasis, provision of inhibitors, in concept, should be beneficial in treating DIC. However, inhibitor concentrates or recombinant proteins are unavailable in animals and can only be provided from blood components. Since inflammation drives hemostasis activation, finding suitable anti-inflammatory drugs to treat affected animals would be beneficial (corticosteroids should be avoided as they may inhibit fibrinolysis and promote thrombosis; non-steroidal anti-inflammatory drugs, particularly COX-1 inhibitors, can inhibit platelet function).
 
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