Inherited Coagulation Disorders

Jeffrey W. Norris

Reductions in protein levels and/or activities associated with coagulation pathways have been documented in all species of domestic herd animals. These deficiencies arise either as the result of genetic transmission or are acquired secondary to intoxication or an underlying disease process.

Prekallikrein Deficiency

Deficiency of prekallikrein, which is involved in initiation of the intrinsic pathway of coagulation, has been described in families of both miniature horses in the United States and Belgian horses in Canada.^1,2 In the family of miniature horses, a 4-year-old intact male and his female sibling were identified as having approximately fivefold decreases in circulating prekal­likrein activity but no history of inappropriate bleeding.¹ The family of Belgian horses was first identified when a 7-year-old stallion had inappropriate hemorrhage for 7 days following an otherwise uncomplicated castration surgery.² Despite packing the incision sites with gauze sponges, the horse's hematocrit decreased by 19% over this period of time.

During initiation of the intrinsic pathway of coagulation, prekallikrein and factor XII are thought to undergo coordinated activation in a reciprocal manner. Recent studies have dem­onstrated that these two factors play critical roles in thrombosis but not hemostasis.^3,4 This subtle role of prekallikrein in the coagulation system is consistent with observations that many patients with prekallikrein deficiency are asymptomatic, but bleeding in response to trauma (e.g., surgery) is possible.

Blood from the affected horses in these studies had pro­longed activated partial thromboplastin times (aPTTs) but normal prothrombin times (PTs).^1,2 Prekallikrein activities in plasma from the two affected miniature horses were less than 20% that of normal horses, but insufficient data were available to determine if suspected carriers had significantly reduced circulating prekallikrein activity compared with clinically normal horses.¹ In addition to the Belgian stallion with a history of inappropriate bleeding, 13 members of his family had circulating prekallikrein levels below the refer­ence range, including two full siblings with activities stabilizing factor VIII in circulation, vWF promotes platelet-endothelial adhesion at sites of vascular injury. vWF deficiency was reported in a Quarter Horse filly that had multiple instances of inappropriate bleeding from mucous membranes, conjunctiva, and injection sites during the first 6 months of life.³¹

Clinical tests of the filly's coagulation function gave subtly altered results compared with normal horses. She had a normal platelet count, normal PT, and slightly prolonged aPTT. Plasma factor VIII clotting activity measured at the low end of the normal range. vWF antigen was reduced to 18% of normal and activity was less than 10% of normal in plasma from the filly.

Coagulation function, including factor VIII and vWF activities, was normal in the filly's dam, while the stallion was unavailable for study. Evidence that the vWF deficiency was heritable was obtained by protein electrophoresis that showed abnormal vWF structures in both the filly and the mare. Several types of vWF defects are recognized in human medicine with structural abnormalities being characteristic of type 2 vWF disease. The underlying mutation that led to vWF deficiency in the filly is unknown.

In Simmental cattle, vWF deficiency was first reported in a 10-month-old heifer with epistaxis and hematoma formation.³² Despite observations that platelet counts and clinical coagulation tests were all within normal limits, inappropriate bleeding in this cow was corrected with administration of fresh-frozen, platelet-poor plasma.

The 10-month-old heifer and one of its siblings also had platelets with markedly reduced aggregation in response to the physiologic agonist ADP.³² This has also been observed in human patients with platelet-type von Willebrand disease, as well as in a transgenic mouse model of this form of the disease.^35,36 However, the mutation leading to vWF deficiency in Simmental cattle is unknown, and additional testing is necessary to discriminate platelet-type von Willebrand disease from other types of vWF deficiency in these cattle.

Deficiency of Vitamin K-Dependent Factors

A combined deficiency of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) was reported in five lambs from a flock of Rambouillet sheep.³⁷ Signs became apparent in affected lambs at birth and included excessive subcutaneous bleeding, hemoarthroses, tissue pallor, and bleeding from the umbilicus in newborn lambs following parturition.

Extensive testing of the coagulation cascade provided evidence for a defect associated with vitamin K-dependent coagulation factors in these lambs.³⁷ Standard clinical coagula­tion tests (aPPT and PT) were prolonged in affected lambs. In plasma from these lambs, activities of factor X and protein C were undetectable, while the activities of factors II, VII, and IX were markedly decreased. However, no abnormali­ties in either clinical coagulation test or any of the activities from the aforementioned individual factors were detected in the sire or ewes from which the affected lambs were bred.

The affected lambs were produced following breeding of three ewes to a single sire across multiple years. This observation combined with the reduced γ-glutamyl carboxylase activities in liver samples from the lambs suggested the deficiency was inherited.^37,38 Breeding data from the original study also sup­ported an autosomal recessive mode of transmission.³⁷ Genetic analysis of the flock revealed a single nucleotide polymorphismin exon 4 of the gene encoding γ-glutamyl carboxylase, GGCX, with the expected allelic frequencies in the affected lambs and their parents.³⁸ This mutation creates a STOP codon leading to premature termination of the protein.

Fibrinogen Deficiency

Fibrinogen, factor I, deficiency can be associated with an absolute loss of total circulating fibrinogen, afibrinogenemia, or a loss of clotting capacity, dysfibrinogenemia. Afibrinogen­emia has been reported in a Saanen kid.³⁹ Although the underlying genomic mutation is unknown, heritability of the afibrinogenemia was demonstrated through a backcross to the doe, which led to the hypothesis that transmission was autosomal and had incomplete dominance. A likely case of dysfibrino­genemia was reported for a Border Leicester lamb; however, heritability was not determined.⁴⁰

Signs associated with fibrinogen deficiency are severe. The Saanen kid was reported to have experienced prolonged umbili­cal bleeding, hematomas, hemarthroses, anemia, and prolonged bleeding from venipuncture sites.³⁹ Inappropriate bleeding episodes occurred with increasing frequency in this patient, and she survived for approximately 14 months. Similar signs were reported in the Border Leicester lamb, which was eutha­nized after diagnosis.⁴⁰

Clinical coagulation tests will show prolongation of both aPTT and PT in cases of fibrinogen deficiency but are not capable of discriminating fibrinogen deficiency from inherited or acquired deficiencies in vitamin K-dependent coagulation factors. Antigen amount and functional tests for fibrinogen should be used together when assessing possible cases of fibrinogen deficiency as no one test can discriminate afibrino­genemia from dysfibringenemia.⁴¹