Thromboembolism In Small Animal Practice

Dr. Anthony Carr, DACVIM (internal medicine) Associate Professor
University of Saskatchewan, Saskatoon, Canada




Hemostasis results through a complex interaction between platelets, blood vessel wall and coagulation factors. This system is also intimately tied to inflammatory responses so that diseases that are associated with significant inflammation will also activate the hemostatic system, for instance sepsis, infectious canine hepatitis, FIP, and IMHA. The ultimate goal of the hemostatic system is to form a clot to prevent further hemorrhage. Counterbalancing the clotting reaction is fibrinolysis and a variety of proteins meant to inactivate active clotting factors. This helps limit clotting to the area where it is needed. Hemostasis can be divided into primary hemostasis, coagulation and fibrinolysis. Thrombosis is fortunately a rare event in small animal practice, however when it does occur it is virtually always a devastating event with high morbidity and mortality.


The etiology of thrombosis in nephrotic syndrome is multifactorial. The association of increased risk has been found in both human and veterinary patients. Factors contributing include decreased anticoagulant activity, increased platelet aggregability, reduced fibrinolysis and increased amounts of clotting factors. Incidence varies in studies from 10-40% of nephrotics, although severity of disease may not be predictive of risk. Other factors to consider include hyperviscosity, hypovolemia and dyslipidemia.

Platelet activity: Evidence includes thrombocytosis, in vitro aggregation studies showing enhanced reactivity to a variety of agonists (ADP, epinephrine, collagen, arachnidonic acid), spontaneous aggregation and elevated β-thromboglobulin levels. Hypoalbuminemia is commonly thought to be the main reason for the hyperaggregability because in patients with a low albumin, platelets will respond more rapidly after stimulation with agonists including AA. AA is released by aggregating platelets and albumin would bind this free AA. Addition of albumin normalizes this change. This may however be an in vitro phenomenon and is only relevant at very low albumins (<1.0 g/dl). Hypercholesterolemia and hyperfibrinogenemia also may be factors (fibrinogen also affects ADP response). These studies are relevant since only the AA related problems can be blocked with aspirin.

Studies using in vitro models of blood flow have also cast doubt on the significance of the aggregation studies. Although the platelets are more likely to aggregate in suspension, they do not aggregate under flow conditions. Instead fibrin was formed that blocked endothelial cell/platelet interaction. Addition of excess fibrinogen to normal platelets mimicked the findings in nephrotic patients.

Anticoagulant proteins: Reduced levels of ATIll have been found and are related somewhat to degree of proteinuria. This often has been linked to increased risk of thrombosis. Other studies have shown increased levels of Protein C, a2-macroglobulin, and heparin cofactor, which may partially counterbalance the low ATIII. Tissue factor pathway inhibitor levels are normal.

Fibrinolysis: Generally it has been shown that fibrinolysis is decreased. Clot lysis times are increased. Elevated levels of PAI, lipoprotein (a) and α 2-macroglobulin would interfere with fibrinolysis. In addition, high levels of fibrinogen and low albumin interfere with plasminogen binding to fibrin.

Elevated clotting factors: Levels of fibrinogen, vWf, factor V, factor VIII and factor XIII are increased in nephrotic syndrome. This is felt to be a result of increased hepatic synthesis or vascular injury.

Renal coagulation: Some authors attribute more value to abnormalities of glomerular coagulation than the systemic changes. Studies have shown increased fibrinolysis and coagulation in nephrotic patients (elevated D-dimer, fibrinopeptide A) that is believed to be a local phenomenon secondary to thrombin generation. Evidence for this scenario include immunohistochemical proven deposition of coagulation-fibrinolysis proteins in biopsy specimens, immunoelectron microscopy showing endothelial deposits of vWf and fibrin- related antigen, and that renal glomeruli monocytes and macrophages will produce tissue factor when stimulated by T -lymphocytes or cytokines (TNF, IL-l). Thrombin also induces mesangial proliferation, which would lead to glomerulosclerosis. The fibrin generated also facilitates cellular proliferation and migration.

Platelet activation in the kidney would generate thromboxane and reduce GFR, induce vasoconstriction, increase glomerular permeability because of release of α-granule particles that neutralize the charge afforded by heparan sulfates and induce mesangial proliferation through release of growth factors.

Pharmacologic manipulations: Aspirin has been shown to be beneficial in slowing the progress of membranous glomerulonephritis in people (950mg/day). Heparin may be very beneficial as it has been able to normalize fibrinopeptide A levels in nephrotics. Fibrinopeptide A is a sensitive indicator of thrombin activity on fibrinogen. Additionally heparin is known to inhibit mesangial cell growth in vitro. The effects of EFA on glomerulonephritis have been investigated in humans and have proven to be beneficial. In those instances where emboli have occurred warfarin may be indicated.


Aortic thromboembolism is a serious complication of feline cardiomyopathy and often predates evidence of heart disease. A retrospective study identified 58% of cats having hypertrophic cardiomyopathy, 27% having intermediate-form, 6.3% having restrictive and 3.2 % having dilated cardiomyopathy. Left atrial enlargement was common with 56.9% having a LA:Ao of 2.0 or greater. Only 5.2% had a normal ratio. Radiographically 88.8% had cardiomegaly and 66.3% had evidence of congestive heart failure. Survival rate was determined as follows: died during hospitalization 28%, euthanized 35%, survived 37%. Warfarin was started in 18 of 22 survivors that were followed. Average survival time of those that died was 9.7 months. Four cases are still alive with an average survival time of 24.3 months. Reembolization occurred in 50% of cases.

Etiology of Thrombi: Perturbations of blood flow in the dilated left atrium are felt to be an important factor in pathogenesis of emboli in cardiomyopathy. In addition, endomyocardial lesions may be sites for thrombus formation. Platelet aggregation studies have shown a potential hyperaggregable state. Taurine has been examined in regard to its effect on hemostasis without conclusive results. A single study of cats with cardiomyopathy examined the coagulation parameters of the patients. Unfortunately, 9 of 11 cats had heart disease secondary to increased thyroid hormone. Increased ATIII, increased platelet aggregation to collagen and decreased platelet response to ADP were found. Definite conclusions cannot be reached from this study.

Therapy of Established Thrombi: Predominantly rest and recreation will cure the cat with an aortic embolus. Improving cardiovascular function is beneficial. The direct effects of cardiac drugs on hemostasis have been investigated but it is still uncertain that this is a significant factor in improving survival. Heparin can be given and may slow down further clot enlargement. Streptokinase efficacy is questionable though TPA does (although it kills 50% of cats treated). The use of phenothiazines (chlorpromazine, acepromazine) may improve collateral circulation or more likely have modulating affects on serotonin to inhibit platelet activity. Nitroglycerin would also inhibit platelet reactivity by being metabolized to NO, which decreases calcium influx into the platelet that leads to platelet aggregation, by binding to fibrinogen.

Prophylaxis of Thrombi: Presently aspirin is commonly used in cats with CM. The benefits of this have not been documented. Recently warfarin has been recommended. Usual dose is 0.5mg/cat/day. Therapy is monitored using PT and INR (international normalization ratio). Goal is an INR 2.0 to 3.0 of baseline. INR = (patient PT/control PT)ISI. The ISI number is supplied with the batch of thromboplastin used. Bleeding complications can occur. The authors initiated heparin therapy concurrently and then tapered this as the warfarin took effect (3-5 days). Survival is purported to be improved.


The pathogenesis of emboli in IMHA remains unexplained. Although the distribution of clots in some cases is consistent with DlC in other cases, the large PTE would not be consistent. The effect of RBC membranes and Hb may be procoagulatory. Hemoglobin is a natural NO absorber and would counteract vasodilatory and platelet inhibitory effects of NO. In addition, the concomitant culture of endothelial cells with LPS and Hb increased tissue factor release significantly in comparison to LPS alone. Hemoglobin alone did not have this stimulatory affect. Of course, in many IMHA dogs, the integrity of the GI mucosa is questionable at best and LPS may be present.

The hepatic damage occurring in IMHA may potentiate thromboembolic risk. The liver is vital for the clearance of activated coagulation complexes. Hepatic dysfunction is common in IMHA and may result from hypoxia or blood clots. Elevations of bilirubin have been associated both with thromboembolic risk and survival. Whether this is cause and effect or merely a reflection of the severity of the disease remains unknown. Severe thrombocytopenia (<50.000) was significantly associated with risk of thromboembolism my retrospective on IMHA. Again, this may be a sign of more severe disease.


The frequency of thromboembolism associated with endogenous hyperadrenocorticism or exogenous administration of corticosteroids has not been published although the clinical impression does exist that there is an association. In humans the changes, occurring in hemostasis after renal transplantation and administration of immunosuppressive therapy with corticosteroids and cyclosporine closely parallels the changes seen in Cushing's disease. It is known that corticosteroids induce increased synthesis of a wide variety of proteins.

Abnormalities of Hemostasis: shortened APTT, increased factor VIII, increased vWf, tissue plasminogen activator and tissue plasminogen activator inhibitor. The increased PAI level would override the increase in TPA and cause a hypofibrinolytic state. The increase in VIII and vWf together with a shortened APTT would indicate a hypercoagulable state. This may also be indicative of vascular disease as it closely parallels blood pressure and it is known that vWf, PA and PAI are endothelial disease markers. In dogs increases in factor V and X were found. ATIII and plasminogen levels were elevated. It is difficult to interpret the relevance of these findings.


HEPARIN: Heparin is the most commonly used anticoagulant in veterinary medicine. It can be used in vivo and in vitro. Heparin has both antithrombotic and anticoagulatory effects. Pharmaceutical grade heparin is a heterogeneous mixture of anionic sulfated mucopolysaccharides with molecular weights ranging from 1200 to 40,000 Daltons. Relative antithrombotic and anticoagulatory activity is related to molecular size.

The reversible binding of heparin to antithrombin III (AT 111), a protease inhibitor is responsible for the majority of the anticoagulatory effect of heparin. Affinity for AT III is dependent upon molecular size. Binding to AT III causes a conformational change in the AT ill molecule that significantly enhances its inhibitory effect on various activated coagulation factors, especially thrombin and activated factor X (Xa). After inactivation has occurred, the heparin molecule dissociates from the complex and is available for further interactions. Heparin acts as a template to which thrombin and AT III can bind and thereby interact to form an inactive compound. Simultaneous binding of factor Xa to AT III and heparin is not required for inactivation. Low molecular weight (LMW) fractions of heparin only inactivate factor Xa because they are not large enough to bind thrombin and AT III concurrently. The additional inactivation of thrombin by high molecular weight (HMW) fractions of heparin increases their anticoagulatory ability. Heparin also binds to endothelial cell walls imparting a negative charge, affects platelet aggregation and adhesion as well as increasing levels of plasminogen activator. Heparin administration leads to an increase in the levels of tissue factor inhibitor.

The majority of an administered dose of heparin is bound extensively to endothelial cells, macrophages and plasma proteins, which act as storage pools. Once these pools have been saturated, free heparin appears in the plasma, which is excreted slowly by the kidney. Heparin is metabolized by the liver and also by the RES. The kinetics of heparin are highly variable between individuals and within the individual. A fixed dose cannot be expected to produce a uniform level of anticoagulation or antithrombotic effect.

TISSUE PLASMINOGEN ACTIVATOR: Tissue type plasminogen activator predominantly exerts its effect in association with fibrin clots. Its specificity for clots makes it therapeutically attractive. Unlike other plasminogen activators, t-P A was felt to not induce a systemic proteolytic state. This may be inaccurate.

ASPIRIN: Aspirin acetylates cyclooxgenase, which leads to decreased production of various eicosanoids by the platelet. The most pivotal eicosanoids for hemostasis are prostacyclin (pGI2) and thromboxane A2 (TXA2). Prostacyclin is a potent vasodilator and inhibitor of aggregation while TXA2 is a vasoconstrictor and a strong aggregatory stimulus.

Endothelial cell cyclooxygenase activity is inhibited, but recovers more rapidly. This inhibition is considered deleterious since endothelial cells produce PGI2, which is antithrombotic. Proposed explanations for the more rapid recovery of endothelial cell cyclooxygenase activity include reduced sensitivity to ASA of the endothelial cell cyclooxygenase, ability to synthesize new cyclooxygenase and the pharmacologic distribution of ASA. This latter theory postulates that platelets are exposed to ASA in the enterohepatic circulation prior to ASA being hydrolyzed. At low doses, endothelium will primarily be exposed to circulating salicylate rather than ASA. Higher doses will result in circulating ASA leading to endothelial cell cyclooxygenase inhibition. The differential inhibition of platelet and endothelial cell cyclooxygenase has resulted in research efforts to find an ideal dose of ASA that will maximally limit proaggregatory platelet TXA2 and minimally decrease levels of antithrombotic PGI2.

TICLOPIDINE: Ticlopidine is an antiplatelet drug that is undergoing extensive testing for use in the prevention of thrombotic diseases. In humans, it has been proven to be as effective as ASA in the prevention of stroke. The drug limits platelet aggregation response to a variety of stimuli. Cyclooxygenase is not inhibited so that endothelial PGI2 levels are not affected. Inhibition of aggregation persists for the lifespan of the platelet. Onset of antiplatelet effect is approximately 2 to 5 days after treatment is initiated, possibly indicating that an intermediate breakdown product is the actual agent responsible for the clinical response. Experience with ticlopidine in veterinary medicine is limited. In healthy dogs 62 mg/kg daily inhibited platelet aggregation responses. In heartworm infected and heartworm embolized dogs higher dosages were necessary.