Coagulation Diseases

Chapter 23 Coagulation Diseases



Marjory B. Brooks


Coagulation disorders comprise a group of bleeding diatheses caused by dysfunction of the clotting cascade and subsequent failure of fibrin clot formation. Included in this discussion of coagulation disorders are von Willebrand disease and the complex syndrome of disseminated intravascular coagulation. Common bleeding diatheses that are not coagulation disorders include thrombocytopenia and acquired platelet dysfunction (platelet disorders are discussed in Chapter 22). Initial examination should aim to differentiate bleeding caused by localized blood vessel injury or vessel disease from bleeding due to a systemic platelet or coagulation defect.



ETIOLOGY


Categories of bleeding disorders are listed in Table 23-1 and include coagulation factor deficiencies, von Willebrand disease, and disseminated intravascular coagulation.


Table 23-1 CLASSIFICATION AND CAUSES OF COAGULATION DISORDERS




















Category Cause
Coagulation factor deficiency
Acquired (multiple) factor deficiencies
Decreased factor production
Liver failure (acute necrosis, chronic cirrhosis, portosystemic shunts)

Decreased factor activation
Vitamin K deficiency (anticoagulant rodenticide toxicity, biliary obstruction, malabsorption, neonatal)

Heparin excess (iatrogenic, mast cell tumor)

Pathologic inhibitors (fibrin degradation products, anti-factor antibodies)
Inherited (single) factor deficiencies
X-linked traits—Males affected
Hemophilia A—Factor VIII deficiency (most common defect in dogs and cats; German

shepherd breed has high prevalence)

Hemophilia B—Factor IX deficiency (especially Airedale and Bichon, but any purebred and mixed-breed dogs and cats)

Autosomal traits—Males and females affected
Dysfibrinogenemia and hypofibrinogenemia (borzoi, French bulldog, DSH cats)

Prothrombin deficiency (boxer, English cocker)

Factor VII deficiency—Mild bleeding (beagle), moderate to severe bleeding (malamute)

Factor X deficiency—Severe bleeding (American cocker spaniel, Jack Russell terrier, DSH cat)

Factor XI deficiency—Severe bleeding (English springer spaniel, Kerry blue terrier, DSH cat)

Factor XII deficiency—No abnormal bleeding (common in cats, DSH and purebred)
von Willebrand disease
Inherited—Autosomal trait; 3 subtypes
Type 1—Variable severity in affected dogs, high prevalence (Doberman pinscher, golden retriever, standard poodle, Pembroke corgi, Bernese mountain dog, miniature pinscher, dachshund, others)

Types 2 and 3—Severe bleeding in affected dogs (German wirehaired and shorthaired pointer, Scottish terrier, Shetland sheepdog, Chesapeake retriever, others)
Disseminated intravascular coagulation
Factor depletion and systemic fibrinolysis
Neoplasia (hemangiosarcoma, prostatic and mammary carcinoma, lymphoid tumors)

Sepsis

Liver disease

Pancreatitis

Intravascular hemolysis

Severe tissue injury (burns, crush wounds)

DSH, domestic shorthair.




Coagulation Factor Deficiencies



Acquired Deficiencies


Acquired deficiencies of functional coagulation factors are common disorders and are caused by decreased production of coagulation factors, release of inactive factors, or inhibition of factor activity.



Production Defect

Coagulation factors are proteins synthesized primarily or exclusively in the liver. Clinically significant reduction in these factors most often accompanies acute fulminant necrosis, chronic cirrhosis, and portosystemic shunting diseases; each of these causes severe liver failure and marked reduction in functional hepatic mass.



Inactive Factors




Vitamin K Deficiency



• The prothrombin group of coagulation factors (factors II, VII, IX, and X) require vitamin K for post-translational carboxylation. This modification allows the factors to assume an active conformation and participate in the coagulation cascade.

• The most common vitamin K deficiency state in small animal medicine occurs after ingestion of anticoagulant rodenticides. These poisons prevent intrahepatic vitamin K recycling, which depletes vitamin K from body stores. Potency and duration of effect vary for different poisons. Overdose of the anticoagulant drug warfarin causes bleeding via the same mechanism.
• Posthepatic biliary obstruction and infiltrative bowel disease also cause vitamin K deficiency by reducing its intestinal absorption.

• Occasionally, bleeding due to vitamin K deficiency is seen in neonatal puppies. Typically, these puppies are born prematurely or are delivered by cesarean section.


Factor Inhibition




Heparin



• Heparin inhibits fibrin clot formation by enhancing the activity of the plasma anticoagulant protein, antithrombin III, several thousand-fold.

• Bleeding due to iatrogenic factor inactivation results from overdose of heparin for treatment of thrombotic disorders or excessive heparinization of transfused blood products.

• Release of heparin from mast cell tumor granules often causes local tissue hemorrhage and edema. In rare cases, massive degranulation of disseminated tumor causes systemic anticoagulation.


Pathologic Inhibitors



• High plasma concentration of fibrin(ogen) degradation products can interfere with mature fibrin clot formation.

• Autoantibodies and alloantibodies directed against specific coagulation factors have been reported in human patients and should be included in the differential of acquired coagulopathy in animals.

• Antibodies directed against phospholipid-binding proteins, referred to as “lupus anticoagulants,” cause prolongation of in vitro clotting times but are associated with clinical thrombotic syndromes.


Inherited Deficiencies


Inherited factor deficiencies are caused by mutations in genes coding for specific coagulation proteins or vitamin K recycling enzymes. These defects are typically found in certain lines of purebred dogs and cats and are often propagated when asymptomatic carriers are bred. Hereditary bleeding disorders may also arise from new, spontaneous mutations in previously unaffected families of purebred or mixed-breed animals. Inheritance patterns vary for different factor deficiencies.



X-linked Traits

Hemophilia is by far the most common severe coagulation factor deficiency and is inherited as an X-linked recessive trait. Spontaneous mutations causing hemophilia arise frequently in dogs and cats.


• Males inheriting one abnormal gene from their mother express the trait, whereas females inheriting one abnormal gene from either parent are asymptomatic carriers.

• Mutations in the factor VIII gene cause hemophilia A and arise about 5 times as often as those in the factor IX gene. Hemophilia B is a specific deficiency of factor IX.

• German shepherds, especially those with European dogs in their pedigree, have the highest breed prevalence of canine hemophilia A.


Autosomal Traits

Males and females express these traits with equal frequency.


• Clinically significant bleeding disorders due to inherited deficiencies of factors XI, X, VII, and II and fibrinogen have been described.

• Factor XII deficiency is common in cats but does not cause a clinical bleeding diathesis.

• A combined deficiency of vitamin K-dependent factors (II, VII, IX, and X) has been reported in Devon Rex cats and Labrador retriever dogs.


Von Willebrand Disease


Von Willebrand (vWD) disease is the most common hereditary bleeding disorder in dogs. Bleeding in affected individuals is caused by deficiency or dysfunction of von Willebrand factor (vWF), a plasma protein critical for normal platelet function in the primary phase of hemostasis.


• The trait is autosomal; both males and females can transmit and/or express vWD.

• Exacerbation of the bleeding tendency of vWD may be seen in association with concurrent thrombocytopenia, infection, hormonal fluctuation, or endocrinopathy (especially thyroid insufficiency). Avoid giving drugs with antiplatelet effects, such as aspirin and other nonsteroidal anti-inflammatory drugs, plasma expanders, and heparin, to vWF-deficient patients.

• Breeds with high prevalence or severe forms of vWD include Doberman pinscher, Scottish terrier, Shetland sheepdog, German wirehair and shorthair pointer, Pembroke Welsh corgi, Chesapeake retriever, and Australian shepherd. The vWD trait can occur in any breed and is occasionally diagnosed in mixed-breed dogs.


Disseminated Intravascular Coagulation


Disseminated intravascular coagulation (DIC) is a dynamic disease process caused by systemic activation of the coagulation cascade. The loss of localized clot formation results in thrombotic occlusion of small and midsize vessels, with compromise to tissue blood supplies and secondary activation of fibrinolytic pathways.


• Disorders that trigger the DIC process cause widespread damage to vascular tissue, platelet aggregation and consumption, or intravascular release of tissue factor.

• DIC most often accompanies severe inflammatory disease syndromes and diseases causing severe tissue injury such as sepsis, neoplasia (especially hemangiosarcoma, hepatic neoplasia, lymphoma, and prostatic and mammary carcinoma), burn or crush wounds, pancreatitis, and intravascular hemolysis.

• Bleeding may develop in patients with DIC as coagulation factors, platelets, and regulatory hemostaticproteins are depleted in the systemic thrombotic process.


CLINICAL SIGNS


Coagulation disorders are characterized by spontaneous hemorrhage and/or excessive bleeding after surgery or trauma. Hemorrhage into the central nervous system (CNS) may cause acute onset of neurologic dysfunction or sudden death. Thrombocytopenia (see Chapter 22), rather than coagulation factor deficiency, is by far the most common cause of petechiae in small animals. Hemorrhagic macules, papules, and ecchymoses are lesions most characteristic of primary or secondary vasculitic diseases and rarely are caused by coagulopathy.


• Coagulation factor deficiencies tend to cause spontaneous bleeding into the chest, abdomen, or muscles, and subcutaneous hematoma formation.

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Aug 27, 2016 | Posted by in SMALL ANIMAL | Comments Off on Coagulation Diseases

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