Coagulopathies

Linda L. Werner, DVM, Ph.D., ACVIM, ACVP
IDEXX Veterinary Services, Inc.

2825 KOVR Drive
West Sacramento, CA 95691

 

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:

  1. Prolonged APTT (normal PT, BT and platelet count) typical for simple intrinsic factor deficiency (i.e. Hemophilia A and/or B).
  2. Prolonged PT (normal APTT, BT and platelet count) indicates VII deficiency (factor III deficiencies not described).
  3. Both PT and PTT are prolonged if common pathway factor deficiency (X, V, II, I).
  4. Specific factor quantitation by immunoassay or functional assays which involve performance of APTT and PT using mixture of patient plasma with known factor (single) deficient plasma. Identifies homozygotes and most carriers.
  5. Patients should be checked for platelet function defects as well by assessing mucosal bleeding time.
  6. Purebreds especially should be tested for VWD, regardless of the results of BT, APTT, and PT.
  7. Genetic screening.

Treatment of heritable coagulopathies:

  1. Hemostasis measures
  2. Supportive
  3. Fresh whole blood (<12 hours, unrefrigerated best if need optimal platelet function)
  4. Fresh plasma (not frozen) (<24 hours, refrigerated)
  5. Fresh frozen plasma
  6. Cryoprecipitate of plasma
  7. Treat underlying diseases – specific /supportive therapy.

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: 

  1. Coumadin rodenticides, warfarin-type. Newer generation compounds many times more potent. Single exposure can cause lethal hemorrhage.
  2. Pancreatic disease
  3. Steatorrhea, malabsorption syndromes
  4. Biliary obstruction
  5. Overzealous use of oral antibacterial drugs

Clinical and diagnostic features of Vitamin K deficiency can include the following:

  1. History of rodenticide exposure.
  2. Often present as acute collapse, bleeding into chest and/or abdominal cavity (also epistaxis, hematuria, GI bleeds, especially if the patient has VWD or carries VWD trait).
  3. Prolongation of PIVKA, PT and APTT. Platelet numbers vary from mild to moderate reductions (due to severe blood loss) to normal or even compensatory increase in platelet count.
  4. Bleeding times (BT) are normal unless the warfarin patient also has an underlying platelet function defect.
  5. Clinical response to replacement therapy with vitamin K1.

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.

Liver Disease:

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:

  1. Defective synthesis of clotting factors (may function as inhibitors or anticoagulants).
  2. Thrombocytopenia induced by splenic sequestration of platelets (shunting of increased blood volumes to the spleen when the liver is diseased).
  3. Increased fibrinolysis due to lack of hepatic clearance of activators of fibrinolysis
  4. Consumption coagulopathy (DIC) due to impaired clearance of activated factors.
  5. The lack of synthesis of inhibitors of clotting.

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:

  • Any cause of vascular compromise, ex. crush, trauma, burn
  • Shock – sepsis (often gram-negative), or hypovolemic
  • Malignancy – especially disseminated or metastatic
  • Heat stroke
  • Poisoning, including snake bite
  • Hepatic disease

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:

  • Underlying disease detection, history
  • Prolonged PT, PTT, TT, ACT
  • O-low fibrinogen levels
  • Thrombocytopenia
  • Prolonged bleeding time. Due to thrombocytopenia (<20,000 ul) and/or platelet function defects caused by products of fibrinolysis (FDPs)
  • Increased fibrin degradation products (FDPs)
  • Decreased levels of antithrombin III (Since excessive fibrinolysis is a natural sequelae to DIC, it follows that consumptive depletion of inhibitors of clotting can occur as well.)
  • RBC fragmentation (schistocytes) due to accumulation of excessive fibrin strands in microvasculature.

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”.