Decreased Plasma Antithrombin III
The physiologically most important inhibitor of coagulation is antithrombin or antithrombin III (ATIII). This low molecular weight glycoprotein primarily neutralizes activated factors IX, X, and II (thrombin) along with other coagulation proteins.
Heparin is a necessary cofactor to potentiate ATIII and enable its rapid inhibitor activity. ATIII is measured via chromogenic assays to evaluate functional activity; activity is expressed as the percent relative to a species-specific plasma pool from healthy animals. Plasma ATIII levels may be reduced by decreased liver production, excessive use, loss from the intravascular compartment, or increased catabolism. Inherited ATIII deficiency is not reported in animals. Newborn foals have lower ATIII levels than adult horses normally.43Chronic liver disease may result in failure to produce ATIII and a number of other important plasma proteins. However, horses with chronic liver disease were shown to have increased plasma ATIII levels.44 These findings suggest that ATIII may behave as an acute phase protein in horses, as some horses also had increased fibrinogen levels. A second group of horses in the study with acute diarrhea or colitis had decreased ATIII levels. ATIII is variably reported as a positive or negative acute phase protein in animals.1,44 Estrogens may contribute to ATIII deficiency due to negative effects on synthesis.1
In conditions such as DIC, ATIII is consumed and can be decreased as a result of binding to activated coagulation factors and subsequent hepatic clearance of the ATIII-factor complexes. Any pathologic activator of coagulation, including trauma, neoplasia, or sepsis, may cause reduction of plasma ATIII (Boxes 27.8 and 27.9). ATIII can be reduced as a component of coagulopathy secondary to endotoxemia in foals.45 Administration of unfractionated or low molecular weight heparin leads to decreased ATIII levels via increased activity and subsequent clearance of ATIII.46
Diseases that cause massive proteinuria or protein-losing enteropathy result in loss of ATIII in addition to other plasma proteins. Because of the small size of ATIII, it is lost in approximately the same proportion as albumin.
Nephrotic syndrome in humans and animals may lead to secondary hypercoagulability and thrombotic disease due to urinary ATIII loss and other■ BOX 27.8
Causes of Reduced Antithrombin III in Horses
Common Causes
Disseminated intravascular coagulation (DIC)
Protein-losing enteropathy (e.g., granulomatous enteritis, intestinal lymphosarcoma, nonsteroidal antiinflammatory drug toxicosis)
Chronic glomerulonephritis
Less Common Causes
Acute toxic enteritis
Acute hepatic necrosis Venous thrombosis
■ BOX 27.9
Causes of Reduced Antithrombin III in Ruminants
Common Causes
Disseminated intravascular coagulation (DIC) Renal amyloidosis
Johne's disease
Less Common Causes
Venous thrombosis
Hepatic failure complicating factors; hypoalbuminemia can be a useful predictor of thrombotic risk given concurrent loss of ATIII and albumin and may also play a contributory role.47,48
The major clinical sequela of ATIII deficiency is a tendency to develop venous thrombosis. Thrombosis in nephrotic syndrome was discussed earlier. Venous thrombosis is commonly recognized in horses with severe toxic colitis or endotoxemia, but the potential role of ATIII deficiency is unknown. Decreased ATIII has been documented in nonsurviving horses with colic and in horses with strangulating obstructions.49 The contribution of ATIII consumption in DIC to the clinical manifestations is complex and difficult to evaluate; however, use of ATIII concentrates in human patients with acute DIC has improved survival in some instances.44 As with all components of the hemostatic system, plasma ATIII must be evaluated in combination with other hemostasis values.