Benjamin M. Brainard, VMD, DACVAA, DACVECC
Disseminated intravascular coagulation (DIC) is both a consumptive coagulopathy and a thrombohemorrhagic state. Some patients suffer from thrombotic tendencies, others a bleeding diathesis, and in others, the two occur simultaneously. DIC starts as a procoagulant condition, but as platelets and coagulation factors are used up in micro- and macrothromboses, patients develop a hemorrhagic phenotype. Identification of and therapy for the underlying trigger is necessary for successful management of DIC.
Many causes of DIC are associated with systemic inflammation, either due to organic disease or infection. Initiation of coagulation and the production of thrombin promote both clot formation and inflammation, through interaction with protease-activated receptors (PARs) on white blood cells (WBC). WBC PAR activation stimulates proinflammatory cytokine production. In health, the procoagulant and proinflammatory actions of coagulation are balanced by endogenous anticoagulant factors that limit the effects of the coagulation cascade and can be anti-inflammatory as well. DIC develops when the inflammation and coagulation axis is not balanced by anticoagulant or anti-inflammatory factors. Changes in endothelial cell topography induced by systemic inflammation can promote a procoagulant phenotype that can drive DIC. In addition, microthrombosis in organs can interrupt blood flow and oxygen delivery and promote further inflammation.
Once clots have formed, plasminogen is activated by tissue plasminogen activator into plasmin, which breaks down the fibrin meshwork of the clot. The products of fibrinolysis that are released as microthromboses are broken down during DIC may be detected as circulating fibrin degradation products (FDP) or (more specifically) d-dimers.
Diagnosis of DIC
Most animals that develop DIC have diseases that result in systemic inflammation, and so the physical examination findings of patients that are likely to have or develop DIC will be consistent with the systemic inflammatory response syndrome (SIRS). The veterinary definition of SIRS requires patients to display at least 3 of the cardinal signs, including hyper- or hypothermia, tachycardia (or bradycardia in cats), tachypnea or hypoventilation, and a circulating WBC count of < 5 or > 18 x 109/L, or more than 10% immature (band) neutrophils. Other findings on physical examination may be brick-red mucous membranes with a rapid capillary refill time, indicative of distributive shock.
Underlying diseases associated with the development of DIC in companion animals include severe infection that results in sepsis or septic shock. The infection may be bacterial, fungal, protozoal, or parasitic, and may be localized (e.g., pyometra, hepatic abscess, endocarditis) or systemic (e.g., septicemia, babesiosis). Other inflammatory diseases that can trigger DIC in dogs are not associated with infection and include pancreatitis, severe trauma, neoplasia, splenic or liver lobe torsion, immune-mediated hemolytic anemia, zinc toxicosis, gastric dilatation-volvulus, hemorrhage and massive transfusion, and snake envenomation. In cats, processes such as neoplasia, infections (e.g., cytauxzoonosis, sepsis, feline infectious peritonitis, toxoplasmosis), pancreatitis, hepatic lipidosis, uroperitoneum, and trauma have been associated with the development of DIC.
Because DIC is a consumptive process with regards to coagulation factors, most of the bedside diagnostics are focused on the demonstration of consumption of platelets and coagulation factors, or on the discovery of elevated products of fibrinolysis and clot breakdown (e.g., FDP, d-dimers). The key approach to diagnosing DIC is to have a high index of suspicion in animals that have SIRS and to continually monitor these patients for the elements of a consumptive coagulopathy.
Thrombocytopenia occurs secondary to increased consumption, destruction, sequestration, and decreased production of platelets. Thrombocytopenia from DIC or other consumptive causes frequently results in a platelet count between 40–100 x 109/L, while immune-mediated destruction of platelets usually results in a platelet count < 20 x 109/L. A drop in platelet count is one of the earliest signs of a consumptive coagulopathy, and clinicians treating patients at high risk for DIC should monitor platelet count frequently to catch the onset of the syndrome. Platelet count may be estimated using automated machines, but a blood smear should always be reviewed, especially in patients with severe inflammatory disease, as platelet clumping can result in erroneous machine-generated values. This is especially true in cats. Each platelet seen on a high power field (100x) of a blood smear represents approximately 15 x 109/L circulating platelets.
Coagulation Function Testing
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are measures of coagulation factor function. The prothrombin time (PT) monitors the tissue factor pathway (extrinsic) and common portions of the coagulation cascade. Activated partial thromboplastin time (aPTT) monitors the intrinsic and common pathways. The activated clotting time (ACT) is similar to the aPTT because it also interrogates the intrinsic coagulation pathway. Abnormalities of both PT and aPTT may be seen in dogs with consumptive coagulopathy, but in the early stages of DIC (prior to excessive clotting factor consumption), it is more common to see a mild to moderate prolongation of the aPTT and a normal PT. This may be because the main coagulation machinery for generating fibrin is the intrinsic pathway, so once coagulation is initiated, the majority of clot propagation is supported by this pathway.
Plasma fibrinogen levels may initially be elevated, consistent with the inflammatory state of the patient, but as DIC progresses, the concentration drops, and when a patient is in fulminant DIC, with a hemorrhagic phenotype, fibrinogen levels are very low, and it is difficult to form stable blood clots. Fibrin degradation products (FDP) are the breakdown products of both fibrin and fibrinogen, while d-dimers are generated only from breakdown of fibrin that has been crosslinked into a mature clot. Fibrin degradation products assays have largely been replaced by d-dimer measurement because of the increased specificity for crosslinked fibrin.
Identification of Macrothrombosis
The identification of macrothrombosis antemortem is difficult in veterinary medicine. Physical exam changes such as asymmetric edema or a decrease in pulses or temperature of extremities should raise concern for thrombotic complications. Pulmonary thromboembolism (PTE) and portal vein thrombosis are also common thrombotic complications of critical illness. Both are difficult to detect, but may be identified on imaging studies. PTE may be suspected based on the presence of new pulmonary hypertension detected using echocardiography, but computed-tomography (CT) angiography is the best available imaging modality for assessing the pulmonary vasculature. Portal vein thrombi are suspected with the appearance of ascites, abdominal discomfort and gastrointestinal signs, and may be identified using abdominal ultrasonography.
The identification of DIC early in the course of consumption is critical, as the process is more likely to be reversed before the systemic hypocoagulable state is seen. No single clinical sign or laboratory test has been identified that confirms the presence or absence of DIC, but the animal must be assessed as a whole with regards to the underlying disease, physical exam, oxygenation and perfusion parameters, and coagulation system. Scoring systems for DIC have been evaluated in humans and dogs.
DIC cannot be treated prior to identifying and treating the underlying inflammatory stimulus. This may include antimicrobial therapy and surgery in the case of abdominal sepsis or an abscess, or supportive care (maintenance of oxygenation and perfusion and provision of analgesia etc.) in the case of diseases that do not have a surgical solution. The maintenance of oxygen delivery to tissues will prevent tissue hypoxia and a second inflammatory 'hit' caused by the reperfusion of ischemic tissues.
Packed red blood cells (pRBC) are given to augment oxygen-carrying capacity and oxygen delivery to tissues, while crystalloid fluids (e.g., lactated Ringer's solution) are given to replace lost volume and artificial colloids (e.g., hetastarch or tetrastarch) may be used to maintain colloid oncotic pressure. pRBCs may be dosed at 5 to 10 mL/kg, or an increase in hematocrit of approximately 1% can be anticipated for each mL/kg of pRBCs infused, if a specific PCV goal is desired. If whole blood is used, dosing can be based on the donor hematocrit, or may be estimated as 2–3 mL/kg to result in a 1% increase in PCV. The clinician should always assess clinical signs of perfusion as well as other laboratory diagnostics (heart rate, lactate, urine output, etc.) to judge the need for additional transfusions.
Dogs are most commonly diagnosed with DIC when they are in a state of overt DIC and have evidence of a consumptive coagulopathy. Blood products are indicated when these patients exhibit spontaneous bleeding. Fresh frozen plasma (FFP) is generally used for replacement of consumed coagulation factors. Dogs and cats require a dose of at least 6 to 10 mL/kg (up to 20 mL/kg) for correction of bleeding from factor deficiency. Cryoprecipitate may also be used when a deficiency in fibrinogen is the primary disturbance, as cryoprecipitate contains factor VIII, von Willebrand factor, factor XIII, and fibrinogen. Fresh frozen plasma also contains these elements.
While plasma or other blood product transfusions can be lifesaving for veterinary patients, the complications associated with transfusions should be kept in mind. Although transfusion reactions are infrequently reported, all transfusions must be monitored closely. Type-specific blood products (DEA 1.1 +/-) should be administered when available. Transfusion reactions range from mild pruritis, facial swelling, or rash, to more severe ones such as fever, anaphylaxis, or death. Transfusion-related acute lung injury (TRALI) may also occur in animals; it is acute lung disease that occurs during or within 6 hours of a transfusion.
The use of antithrombotic medications for veterinary (and human) patients with DIC is controversial. Because it is very difficult to diagnose DIC in the initial hypercoagulable state, or because this initial diagnosis is frequently complicated by the need to perform invasive procedures such as surgery, there are few opportunities for anticoagulation of the DIC patient. In human medicine, anticoagulant medications are used in patients who have gross thrombosis or evidence of ischemic tissues due to a thromboembolic shower.
Although there are a number of drugs available to veterinary practitioners that inhibit platelet function, anti-platelet medications are not commonly used in patients with thrombocytopenias and have the added disadvantage of requiring oral administration, which is not always tolerated in critically ill patients. Although platelets are implicated in the pathogenesis of DIC, the use of anti-platelet medications in this condition have not been studied, and inhibition of platelet function in a patient with low platelet count may be more likely to result in hemorrhage.
For these reasons, the primary anticoagulant drug used for therapy of the procoagulant phase of DIC is heparin. The use of unfractionated heparin (UFH) in human and veterinary patients with DIC is also controversial. Heparin inhibits coagulation by binding to antithrombin (AT), which is one of the endogenous anti-inflammatory molecules. While potentially slowing the consumptive coagulopathy and minimizing formation of microthrombi, UFH may also mitigate some of the anti-inflammatory effects of AT. Patients with thrombocytopenia may be at increased risk of bleeding with UFH therapy.
Heparins are most accurately dosed by monitoring anti-Xa activity (aXa) values, but may also be dose-adjusted using the aPTT. The recommendation for therapeutic UFH (in human patients with a preexisting thrombus) is aXa levels between 0.35 to 0.7 U/mL and a prolongation of aPTT by 1.2–1.5 times the baseline. Prophylactic doses for UFH may be 10% of those therapeutic levels. Guidelines for low-molecular-weight heparin (LMWH) in humans targets a therapeutic aXa value of 0.5–1.0 U/mL and 0.1–0.3 U/mL for prophylaxis. It is difficult to determine which animals may benefit from prophylactic dosing.
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