Updates in anticoagulant therapy (Proceedings)

Coagulation abnormalities are commonly encountered in critical illness. Traditionally, clinically relevant coagulation disorders have consisted mostly of bleeding associated with advanced stages of disseminated intravascular coagulation or toxin ingestion. However, advances in critical care have highlighted hypercoagulability as a clinically relevant state that must be recognized and treated to optimize the chances of a positive outcome.

Systemic inflammation is a potent trigger of coagulation, mainly through cytokine-mediated tissue factor expression on the surface of both activated inflammatory cells and the damaged vascular endothelium. Endogenous anticoagulant systems such as protein C, antithrombin, and tissue factor pathway inhibitor are simultaneously activated to control coagulation but are ultimately overwhelmed when severe systemic inflammation predominates, leading to fibrin deposition in the microvasculature and reduced oxygen delivery to capillary beds. This clinically silent phenomenon may be identifiable by a mildly reduced platelet count on the CBC.

Diseases associated with severe inflammation include sepsis, pancreatitis, burn injury, polytrauma, and immune mediated hemolytic anemia In addition prolonged immobility, mechanical ventilation, and recent major surgery or episodes of cardiovascular instability also stimulate inflammation and can therefore be associated with a hypercoagulable tendency. In general, hypercoagulability should be suspected in any critically ill animal with mild thrombocytopenia. Due to the small time period making up the normal range for coagulation testing, a shortened PT and aPTT is not considered helpful for the diagnosis of hypercoagulability. Fibrin(ogen) degradation products detect the breakdown of both fibrin and fibrinogen, and are therefore not very sensitive indicators that coagulation has occurred. The D-dimer test, however, specifically detects the breakdown of crosslinked fibrin, and is superior to FDPs in suggesting that coagulation has been activated. In general, a hypercoagulable state is considered less likely if D-dimers are negative. A positive test, however, may or may not support excessive coagulation. Finally, thromboelastography is gaining popularity for the detection of hypercoagulability in veterinary medicine. Changes in thromboelastogram consistent with a hypercoagulable state include shortened R time, increased angle, and increased MA.

Evidence for thromboembolism in animals with naturally occurring disease is present in veterinary literature, mostly in the form of isolated case reports and retrospective studies. In a necropsy study of 29 dogs with pulmonary thromboembolism (PTE), neoplasia, systemic bacterial infection and immune mediated hemolytic anemia were the most common diagnoses associated with PTE. Thromboembolism was suspected in 11 of 17 dogs showing respiratory signs, because of the concurrent presence of a disease known to be associated with a hypercoagulable state. In this study, thrombosis was noted in organs other than the lung in 31% of cases. In another study, 54% of dogs with splenic vein thrombosis had neoplasia, while 43% were receiving exogenous corticosteroids. Other diseases associated with splenic thrombus formation included immune mediated disease, SIRS, pancreatitis, non-proteinuric renal failure, and protein losing nephropathy. Portal vein thrombosis is another common site of thrombus formation. A retrospective study of 6 cats found that all cats with PVT also had hepatic disease. Concurrent diseases associated with PVT included congenital portosystemic shunt formation, hepatic neoplasia, and acute pancreatitis. In one study of PVT in dogs, concurrent conditions included pancreatic necrosis, peritonitis, neoplasia, and exogenous corticosteroid administration. Ultimately, the awareness of thromboembolism as a complication of disease processes has evolved, and as a result clinicians are faced with the decision of whether or not to initiate anticoagulant therapy.

Anticoagulation

Anticoagulation is typically considered whenever a hypercoagulable state is suspected. Commonly used anticoagulants include unfractionated heparin administered subcutaneously either 3-4 times per day or as a continuous rate infusion, and low molecular weight heparin therapy administered subcutaneously once or twice daily. Alternatively, drugs targeting platelets including low dose aspirin or Clopidogrel may be selected.

Heparin

Heparin is a heterogeneous mixture of glycosaminoglycans with a molecular weight ranging from 1,800 to 30,000 daltons that. Heparin is a natural anticoagulant found in high concentrations in the liver, mast cell granules, basophils, and on endothelial surfaces. Commercial preparations of heparin are prepared from porcine intestinal mucosa and bovine lung. The anticoagulant action of heparin is based on binding and activation of antithrombin (a powerful protease inhibitor). Binding of heparin to antithrombin induces a conformational change the antithrombin molecule that greatly increases its anticoagulant activity (10,000 times!). The antithrombin – heparin complex then binds to and inactivates thrombin. The plasma half life of heparin is 1-2 hours. It is partly metabolized and degraded by reticuloendothelial cells and by heparinase in the liver. Unmetabolized heparin or its degradation products are excreted in the urine. The half life of heparin may be increased in liver and renal failure. Since heparin does not cross the placental barrier, it is the anticoagulant of choice during pregnancy.

Low molecular weight heparin (LMWH) consists of smaller molecules (1,800-5,000 daltons) whose anticoagulant effect is based more on inhibition of factor X than on binding antithrombin. Potential advantages include a longer half life and predictable clearance allowing for once a day dosing, as well as a more predictable anticoagulant response requiring less monitoring. The use of LMWH is associated with a higher cost. A common form of LMWH is Dalteparin (Fragmin).

Heparin is used clinically in situations of acute documented or impending thrombosis. Conditions leading to a hypercoagulable state include glomerulonephritis, immune mediated hemolytic anemia, hyperadrenocorticism, heartworm disease, sepsis, and disseminated intravascular coagulation (DIC). Heparin is also used in cats with cardiomyopathy with left atrial enlargement that are at risk for aortic thromboembolism. Heparin can be administered intravenously (as intermittent injections or as a continuous rate infusion), as well as subcutaneously, with one method of administration not clearly proven to be beneficial over the other. Due to lack of intestinal absorption and rapid inactivation by intestinal heparinase, oral administration is not effective. The anticoagulant effect of heparin is most often monitored using the activated partial thromboplastin time (aPTT) or the activated coagulation time (ACT), with prolongation of the aPTT by 1.5x the upper limit of normal considered indicative of appropriate anticoagulation. Alternatively, anti Xa levels can be used to monitor heparin therapy, with a target anti Xa level of 0.3-0.7 U/ml used to indicate adequate anticoagulation. A recent study of dogs with IMHA suggested that a heparin dose tailored to the anti Xa level may be more effective than a fixed dose regimen. The most common side effect of heparin use is hemorrhage. In people, an immune thrombocytopenia has been noted with heparin use, although this has not been described in dogs. Contraindications of heparin use include liver disease, coagulopathy, severe thrombocytopenia, and overt bleeding.

Platelet inhibitors

There is growing interest in the role of the platelet in naturally occurring disease processes. In addition to being a prominent feature of arterial thrombi, platelet activation has been documented in dogs with IMHA and is being explored in animals with a variety of disease processes. Platelet inhibitors inhibit platelet aggregation and adhesion. Following endothelial injury, platelets bind to the exposed subendothelial collagen. Platelet binding initiates platelet activation and further binding. Activation results in the release of ADP and serotonin that further assist in platelet activation/recruitment. The arachidonic acid cascade results in synthesis of inflammatory mediators (such as thromboxane A2). The platelet fibrinogen receptor glycoprotein (GP) IIb-IIIa becomes activated and crosslinks fibrinogen into a stable clot. There are 3 classes of antiplatelet drugs: cyclooxygenase inhibitors, thienopyridines (ADP receptor antagonists) and GP IIb-IIIa blockers.

Cyclooxygenase inhibitors

Non steroidal anti-inflammatory drugs are widely used in clinical practice. NSAIDS inhibit cyclooxygenase which synthesizes the endoperoxide precursors to prostaglandin and the thromboxanes. In clinical usage, the inhibition of thromboxanes (potent activators of platelet aggregation) is the notable effect. Aspirin causes acetylation of cyclooxygenase, leading to reduced platelet aggregation at the site of vascular injury. Since platelets cannot synthesize additional cyclooxygenase, this effect is irreversible and lasts for the lifespan of the platelet (7-10 days, until additional platelets are formed). This differs from other NSAIDS whose effects on platelet function are reversible (i.e. the effects last only as long as the drug is in circulation). The usefulness of aspirin for prevention of thromboembolism has been documented in humans when prophylactic aspirin was shown to decrease the risk of myocardial infarction. Aspirin has been used prophylactically to prevent embolism in dogs and cats with diseases such as heartworm or certain cardiac disorders. Due to the effects of NSAIDS on platelet aggregation, administration is generally discontinued several days prior to a surgical procedure to minimize the chances of bleeding complications. Long term administration of NSAIDS may result in gastrointestinal bleeding from gastric mucosal erosion. The GI ulceration and bleeding may be low grade (causing iron deficiency anemia), or severe enough to produce acute blood loss. Gastrointestinal ulceration is thought to be due to inhibition of COX-1, leading to reduced Prostaglandin E2 and ultimately disrupted bicarbonate and mucous production, and reduced mucosal blood flow.

Thienopyridines

Thienopyridines inhibit the binding of ADP to its platelet receptor (ADP2Y12). ADP receptor blockade leads to direct inhibition of fibrinogen binding to the GP IIb-IIIa receptor thus reducing platelet aggregability. Clopidogrel and ticlopidine are the 2 thienopyridines commercially available. These drugs have been poorly evaluated in dogs but have been evaluated in healthy cats. Ticlopidine effectively decreased platelet aggregation in cats but was associated with unacceptable side-effects (vomiting, anorexia) which precludes its clinical usefulness. Clopidogrel was evaluated in healthy cats and found to be well tolerated and significantly decreased platelet function. Although most studies have focused on the anticoagulant effect of clopidogrel in healthy animals, a recent study of dogs with IMHA suggested that clopidogrel is safe and effective either alone or in combination with other anticoagulants in this population. In general, clopidogrel (Plavix) is being used with greater frequency in cats with cardiomyopathy and in dogs with underlying hypercoagulability.

Gpiibiiia antagonists

These potent antiplatelet agents block platelet-fibrinogen binding, the final pathway for platelet aggregation. They are administered intravenously. Abciximab, Tirofiban, and Eptifibatide are all examples of GPIIbIIIa antagonists. Abciximab is used in canine and feline models of arterial injury, and does not have adverse effects in normal animals used in these clinical trials. Eptifibatide induces a toxic reaction in cats and is therefore contraindicated in this species.

Conclusion

The correlation between hypercoagulability and risk of thrombus formation has not been defined, and the decision to institute anticoagulation is disease and clinician dependant. The cost benefit ratio of anticoagulation for any disease process must also be considered. Ongoing research in coagulation and anticoagulation will undoubtedly provide additional insight to help clarify these dilemmas and specify anticoagulation guidelines for critically ill animals.

References

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Laurenson MP, Hopper K, Herera MA, et al. Concurrent diseases and conditions in dogs with splenic vein thrombosis. J Vet Intern Med 2010 2010;24:1298-1304.

Johnson LR, Lapin MR, Baker DC. Pulmonary thromboembolism in 29 dogs: 1985-1995. J Vet Intern Med 1999;13:338-345.

Mellett AM, Nakamura RK, Bianco D. Prospective study of clopidogrel therapy in dogs with primary immune-mediated hemolytic anemia. J Vet Intern Med 2011;25:71-75.

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