Disseminated Intravascular Coagulation
Disseminated intravascular coagulation () is the most common hemostatic dysfunction in the horse. disseminated intravascular coagulation is an acquired process in which activation of coagulation causes widespread fibrin deposition in the microcirculation resulting in ischemic damage to tissues. Hemorrhagic diathesis occurs as a result of consumption of procoagulants or hyperactivity of fibrinolysis. In normal coagulation, thrombin activates the conversion of plasma soluble fibrinogen to the insoluble fibrin, which forms a clot. Simultaneously, the fibrinolytic system is activated to prevent tissue ischemia that would occur from persistent fibrin clots. The fibrinolytic protein that is primarily responsible for limiting fibrin clot formation and providing a mechanism for clot removal is plasmin. Antithrombin III and protein C also minimize clot formation by inhibiting the actions of thrombin and as well as some of the other clotting factors. In disseminated intravascular coagulation, antithrombin III and protein C become depleted as a result of overzealous activation of coagulation. This results in excessive, unchecked thrombin and clot formation, which in turn activates plasmin. FDPs are formed when plasmin degrades fibrin. As the FDPs begin to accumulate in the circulation, they contribute to the coagulopathy by inhibiting thrombin activity and by causing platelet dysfunction. The end result is the dynamic combination of disseminated thrombosis at the same time that clotting factor consumption and fibrinolysis potentiate bleeding.
Disseminated intravascular coagulation is not a primary disease; it occurs in conjunction with diseases that generate excessive procoagulant activity in the blood. Diseases related to the gastrointestinal system (e.g., strangulating obstruction, colitis, enteritis), sepsis, renal disease, hemolytic anemia, and neoplasia are the most common primary diseases associated with disseminated intravascular coagulation. In one study, 96% of the horses that developed disseminated intravascular coagulation over a 5-year period were diagnosed with colic that required surgical intervention. Horses with devitalized intestine that required resection and anastomosis were more likely to develop disseminated intravascular coagulation than those horses in which resection and anastomosis was not required. Because endotoxin is a prominent feature of ischemic or inflammatory disease of the equine gastrointestinal tract, it is a logical conclusion that endotoxemia is the underlying pathophysiologic event that most commonly triggers disseminated intravascular coagulation. Endotoxin can initiate disseminated intravascular coagulation by several mechanisms: (1) direct damage to the endothelium, thereby releasing tissue factor; (2) induction of tissue factor expression and cytokine synthesis by mononuclear phagocytes; (3) direct activation of factor XII; (4) stimulation of thromboxane A2 synthesis by platelets which promotes irreversible platelet aggregation; and (5) inhibition of fibrinolysis by increasing production of plasminogen activator inhibitor.
Clinical signs of disseminated intravascular coagulation range from mild thrombosis and ischemic organ failure to petechiae and hemorrhage. In contrast to humans, frank hemorrhage associated with disseminated intravascular coagulation is rare. Petechial or ecchymotic hemorrhages of the mucous membranes or sclerae, epistaxis, hyphema, and melena can occur. Hypoperfusion and microvascular thrombosis lead to focal or widespread tissue damage and culminates in colic; laminitis; and signs of renal, pulmonary, and cerebral disease. Peripheral veins are susceptible to spontaneous thrombosis as well as increased thrombus formation after catheterization or simple venipuncture. Clinical signs of the primary underlying disease may overshadow the initial signs of disseminated intravascular coagulation.
A single test cannot confirm disseminated intravascular coagulation. The presence of clinical signs — thrombocytopenia, prolonged APTT and PT, and an increase in FDP concentration (>40 fig/ml) — is consistent with disseminated intravascular coagulation. In the early stages of disseminated intravascular coagulation, FDPs may not be increased. Monitoring changes over time can help decipher difficult cases, as thrombocytopenia and prolongation of the PT are frequently the only abnormalities initially detected. Hypofibrinogenemia is an uncommon finding in the horse; in fact, fibrinogen concentration may be increased, depending on the duration of the underlying primary disease. Reduced antithrombin III activity (<80% normal) also supports a diagnosis of disseminated intravascular coagulation.
Treatment and Prognosis
Determining the correct therapy for disseminated intravascular coagulation is difficult and controversial. Identification and treatment of the underlying disease process is paramount. Intravenous fluid therapy is necessary to maintain tissue perfusion and combat shock. If a septic process is present, antimicrobials are indicated. If a strangulating intestinal obstruction is present, immediate surgical correction is warranted. Minimizing the effects of endotoxemia may attenuate the disease process (see Chapter 3.7: “Endotoxemia”). Flunixin meglumine (0.25 mg/kg IV q8h) will mitigate the detrimental effects of eicosanoids. Corticosteroids are contraindicated because they potentiate the vasoconstrictive effect of catecholamines and reduce the activity of the mononuclear phagocyte system, which exacerbates coagulopathy by enabling FDPs to accumulate.
Fresh plasma therapy (15-30 ml/kg of body weight) is indicated with severe hemorrhage. It should be noted that administration of plasma could exacerbate thrombosis by supplying more clotting factors to “fuel the fire.” Fresh whole blood can be given if anemia is present from blood loss. Although its use remains controversial, administration of heparin (20 to 100 U/kg SQ q8-12h) in conjunction with fresh plasma may minimize clot formation by potentiating the anticoagulative effects of antithrombin III. Thus if heparin therapy is to be used, adequate antithrombin III must be present. Heparin can cause thrombocytopenia, hemorrhage, and reversible erythrocyte agglutination. If heparin is used, the packed cell volume should be closely monitored for a sudden decline. Low-molecular-weight heparin (Fragmin, Kabi Pharmacia AB; Stockholm, Sweden; 50 U/kg SQ ql2h) does not cause agglutination of equine erythrocytes, but its use may be cost-prohibitive. The prognosis for disseminated intravascular coagulation depends on the severity of the underlying disease and the response to therapy. In general, the prognosis is guarded to poor. In humans, the mortality rate is 96% when the antithrombin III activity falls below 60%.
Warfarin and Sweet Clover Toxicosis
Horses may develop hemorrhagic diathesis after consuming warfarin for therapeutic reasons, rodenticides, or moldy sweet clover (Melilotus spp.). Warfarin has been used for treatment of thrombophlebitis and navicular disease. Combination of warfarin with other protein-bound drugs, such as phenylbutazone, results in toxic accumulation in the plasma. Sweet clover hay or silage that is improperly cured can contain dicumarol. The toxin is not present in the living plant. The pathogeneses of warfarin and sweet clover toxicosis are identical. Dicumarol and warfarin competitively inhibit vitamin K, which is necessary for the production of clotting factors II, VII, IX, X.
The clinical signs of warfarin or dicumarol toxicosis include hematomas, hematuria, epistaxis, and ecchymoses of the mucous membranes. Absence of petechial hemorrhages can distinguish warfarin and dicumarol toxicity from disseminated intravascular coagulation. The diagnosis is made based on history of exposure and laboratory data. Clinical pathology reflects prolonged PT first because the plasma half-life of factor VII is shorter than the other clotting factors. The APTT becomes prolonged, but the platelet count remains normal.
Treatment for warfarin toxicity may only require discontinuation of the drug. If accidental exposure to rodenticides or dicumarol occurs, treatment with vitamin K, (0.5 to 1 mg/kg of body weight SQ q6h) 3 to 5 days is recommended. Therapy should be guided by measuring PT. Vitamin K3 causes acute renal failure and should not be given to horses. In an acute crisis, plasma or a whole blood transfusion may be indicated.