Linda L. Werner, DVM, Ph.D., ACVIM, ACVP
Uncontrolled bleeding involves abnormalities in one or more of the three functional phases of hemostasis, i.e., vascular, platelets or the clotting factor system. Successful clotting begins with the early formation of a hemostatic plug (primary hemostasis) of activated platelets at the vascular interface and is dependent upon many physical and biochemical interactions between platelets and the vessel walls. The final stages of clotting (secondary hemostasis) involve the formation of insoluble fibrin strands within and around the platelet plug as a result of the activation of the clotting factor (enzyme) cascade system. This process of fibrin enmeshment solidifies the previously unstable plug to prevent rebleeding.
Patients with defects in the clotting factor system can present with almost any type of bleeding pattern, but they do not typically show the spontaneous petechiae or ecchymoses associated with platelet or vascular phase defects.
INHERITED COAGULATION PROTEIN DISORDERS
Deficiencies of these proteins are associated with hemarthroses, epistaxis, hematuria, hematomas, reproductive failures, unthriftiness and osteopathies. Deficiencies of nearly all clotting factor proteins have been reported in animals however, not all are associated with clinical bleeding disorders (factor XII deficiency in cats).
Synthesis and Problems of Factor VIII (Hemophilia A):
The synthesis of this protein is complicated because of the two active portions, the von-Willebrand protein and the coagulant protein. The site of the synthesis of the coagulant protein is the liver and it is under sex-linked control (X chromosome). Therefore, males and homozygous females are clinically affected, while heterozygous females are asymptomatic, obligate carriers. Factor VIII is protected from inactivation by the von-Willebrand protein, and the von-Willebrand protein may also help regulate factor VIII synthesis.
Abnormal synthesis of the coagulant portion of the Factor VIII molecule results in the bleeding disorder known as classical hemophilia or hemophilia A. Mild deficiencies, 5-20% of normal, and moderate deficiencies, 1-5% of normal, may be associated with spontaneous or post-traumatic bleeding. Severe deficiency (less than 1%) is always associated with spontaneous hemorrhage.
Hemophilia B (Christmas Disease):
Hemophilia B is caused by a deficiency of factor IX and is also a sex-liked recessive trait. There is correlation between the degree of deficiency and the potential or tendency to bleed (see hemophilia A above). Occasionally a multiple inherited factor deficiency is encountered, such as factor VIII and IX deficiency in combined Hemophilia A and B.
Clinical signs of heritable clotting factor deficiencies can include the following: hemorrhagic tendencies since young age, familial history, breed/sex, reproductive failures, fading puppies. Bleeding can be delayed in onset, but progressive following trauma. Examples include deep spreading hematomas, delayed post-operative bleeds and lameness, swellings or “edema” following work or hard play.
Diagnosis of heritable coagulopathies:
Treatment of heritable coagulopathies:
ACQUIRED COAGULATION PROTEIN DISORDERS
Simple Clotting Factor Deficiencies (normal platelet counts and bleeding times) caused by decreased or impaired synthesis:
Unlike the inherited coagulation disorders, the acquired disorders are usually associated with multiple factor deficiencies. Disorders of hepatic function or lack of vitamin K give rise to absolute deficiency of multiple coagulation factors. In addition, there is evidence that both hepatic disease and vitamin K deficiency can result in the production of dysfunctional or incomplete clotting factor molecules, some of which are in fact anti-coagulants functionally.
Some acquired diseases can lead to increased destruction of or clearance of coagulation factors. Examples include: protein-losing states, especially protein-losing enteropathies. There can also be circulating inhibitors or antibodies to specific coagulation factors which arise spontaneously (autoimmune disease), or which result from prolonged treatment (of hemophiliacs) with blood products.
Vitamin K Deficiency:
Vitamin K1 is needed to produce biologically active (carboxylated) factors II, VII, IX, and X. Therefore, vitamin K antagonism results in the production of biologically inactive factors (“pre-factors”) II, VII, IX, and X. The “pre-factors”, however, are not totally inert. In fact, they function as inhibitors (antagonists) of clotting. Vitamin K is obtained from green vegetables and is fat soluble.
Causes of vitamin K deficiency include the following:
Clinical and diagnostic features of Vitamin K deficiency can include the following:
Treatment of severe bleeding from Vitamin K deficiency usually requires transfusion of fresh plasma or fresh whole blood and oral or parenteral administration of vitamin K1. Many “super” or second-generation rodenticides require prolonged vitamin K1 therapy of weeks or months.
Bleeding associated with hepatic disease is usually seen in late stages of compromised hepatic function. Patients with cirrhosis or portal caval shunting may have severe hemorrhages. There are many factors which may contribute to bleeding in hepatic disease, including the following:
Diagnosis of hepatic origin clotting factor deficiency can include the following findings: abnormalities in liver enzymes, function tests and hepatic imaging techniques. The tendency to bleed from hepatic insufficiency correlates somewhat with severity of hypoalbuminemia. Liver failure syndromes are seldom reversible in the long run.
COMBINED OR MIXED CLOTTING FACTOR AND PLATELET DISORDERS
Disseminated intravascular coagulation (consumption coagulopathy) is the most common example of a mixed bleeding disorder. DIC usually involves a triad of (consumption) thrombocytopenia, prolonged clotting times (PT, PTT, TT) and decreased fibrinogen. DIC is always secondary (and often endstage) to severe underlying disease or injury, such as the following:
DIC is caused by massive activation of clotting (associated with vascular damage and release of tissue thromboplastin). Ischemic organ dysfunctions (lungs, kidnsy) may occur due to thrombosis of microvasculature.
Rare patients who present in early hypercoagulable stage may actually have shortened clotting times (PT, PTT, TT) and normal or near normal platelet counts. However, most patients present for bleeding following entry into the hypocoagulable state which can occur following consumptive depletion of clotting factors and platelets.
Diagnosis of DIC should include at least 3-4 of the following:
Other types of combined or mixed clotting factor/platelet disorders can include combinations such as giving aspirin to a hemophiliac (A), a VWD dog who ingests rodenticide, or other combinations using “Murphy’s Laws”.