Hemostasis may be defined as the body system responsible for repairing injured blood vessels and maintaining healthy blood flow. This system incorporates elements of coagulation, fibrinolysis and anticoagulation. Disorders of hemostasis can result in mild to marked bleeding tendencies or in a hypercoagulable state.
Primary hemostasis occurs following vascular injury, the initial event in hemostasis is constriction of the blood vessel, vasoconstriction. The decreased surface area reduces the degree of blood loss and makes it easier for platelets to cover the wound. The damaged vessel lining (endothelium) then attracts platelets which bind together to close the gap. The binding of platelets at the site of injury is mediated by Von Willebrand's Factor (vWF). This aggregation of platelets, although fragile and easily washed away by the blood stream, forms the "platelet plug" which is responsible for initial cessation of bleeding.
As the events of primary hemostasis are unfolding, vessel injury and release of platelet factors initiate the coagulation cascade and formation of the fibrin clot, secondary hemostasis. The factors involved in the coagulation cascade have specific names, but are usually designated by roman numerals. The intrinsic pathway involves interactions between factors VIII, IX, XI, XII. The extrinsic pathway" is Interactions with factor VII. Both the intrinsic and extrinsic pathways converge on a common pathway where factors II, V, and X (thrombin) interact. Thrombin mediates the conversion of fibrin from fibrinogen and the production of polymerized fibrin strands. These fibrin strands are interwoven into the platelet plug, creating a stable and firm clot.
Disorders of Primary Hemostasis
Disorders of primary hemostasis are generally thought to include thrombocytopenia (low platelet numbers) and thrombocytopathia (poor platelet function). Clinical signs of a primary bleeding disorder include petechiae, ecchymoses and mucosal surface bleeding at one or more sites. Examples of common sites for mucosal bleeding include nasal passages, gastrointestinal surfaces, oral membranes, and urogenital surfaces.
In order for bleeding to occur due to thrombocytopenia alone the platelet count must fall below at least below 50,000 /µl. Causes of thrombocytopenia can be grouped according to their mechanism of action. These mechanisms include platelet destruction, sequestration, consumption, or decreased production.
The most common cause of platelet destruction is immune-mediated thrombocytopenia (ITP) which can occur as a primary (idiopathic) immune mediated disorder or as a secondary disease process (due to infection or allergic drug reaction). In primary or idiopathic ITP autoantibodies are produced by an overzealous immune system which attacks otherwise normal platelets. In secondary ITP, the binding of drugs, infectious organisms or neoplastic antigens to normal platelets results in an immune response against the platelets which are attacked and eliminated by a normally functioning immune system. In addition, certain infectious diseases (i.e., Ehrlichia platys) can infect the platelets directly resulting in platelet loss. Immune mediated thrombocytopenia typically results in rapid and severe decreases in platelet numbers (often less than 10,000 /µl). Clinical signs frequently include petechial and ecchymotic hemorrhages, epistaxis, oral bleeding, and gastrointestinal blood loss.
Diagnostics to determine the cause of thrombocytopenia include evaluation of blood smears, manual platelet count, complete blood count (CBC), infectious disease serology and evaluation of bone marrow aspirate cytology. Cytology samples can be submitted for pathology review, special staining for infectious disease testing and for anti-megakaryocyte antibody testing.
A diagnosis of idiopathic ITP must be based on the exclusion of other causes. Drug reactions can generally be detected by thorough historical questioning and medical records review. Any drug is technically capable of inducing thrombocytopenia as an idiopathic drug allergy. Medications associated with the induction of thrombocytopenia include sulfa and beta-lactam antibiotics, chlorambucil (a chemotherapy drug) and vaccinations (if the animal has been vaccinated recently). Infectious causes of thrombocytopenia can be ruled out by negative serologic tests. Many veterinarians prescribe a short course of appropriate antibiotics, such as doxycycline, while waiting for test results. Neoplastic causes of thrombocytopenia are generally detected by screening diagnostic tests including chest x-rays, abdominal ultrasound, and bone marrow aspirate cytology. Tumors commonly associated with thrombocytopenia include splenic and liver masses (hematoma, hemangioma, hemangiosarcoma) and lymphoma (which may result in impaired platelet destruction or paraneoplastic ITP). In addition to detecting or staging occult lymphoma, bone marrow aspirate cytology may provide prognostic information by allowing the clinical pathologist to determine relative numbers of platelet precursors (megakaryocytes) in the bone marrow. In addition, some laboratories offer anti-platelet or anti-megakaryocyte antibody tests for the confirmation of ITP.
Successful treatment of immune mediated thrombocytopenia requires primary management of any underlying cause. Most tick borne infections can be successfully treated with doxycycline antibiotics. If an underlying cause can not be found, immunosuppressive medications (prednisone, azathioprine, cyclosporine etc.) are used to stop immune destruction of the platelets, which should allow renewed platelet production in the bone marrow. Some cases of infectious, neoplastic or drug induced thrombocytopenia also require transient immunosuppression. Vincristine, a commonly administered chemotherapy agent, also causes early release of platelets from the bone marrow. Although not all clinicians agree on the functionality of these platelets, vincristine is an accepted therapy for refractory ITP. When immunosuppression fails, more aggressive therapy can include splenectomy. The spleen is a blood filter with significant immune system function. As such, it is commonly the anatomic site of platelet destruction. In select cases, splenectomy may result in remarkable improvements in platelet numbers and less reliance on expensive and side effect prone medications.
Sequestration (or pooling) of platelets occurs mostly in the spleen and liver. These organs have large vascular channels which allow pooling of blood. Sequestration or storage of platelets usually results in rather mild thrombocytopenia and rarely results in clinical bleeding tendency. Thus, sequestration may be clinically suspected as a cause of mild thrombocytopenia, especially when hepatosplenomegaly is present.
Consumption of platelets can occur in association with numerous disorders. Disseminated intravascular coagulation (DIC) causes severe consumptive thrombocytopenia and marked coagulopathy through a variety of mechanisms. Most causes of platelet consumption cause only mild to moderate thrombocytopenia. For instance clinical bleeding due to trauma generally does not result in severe thrombocytopenia unless marked polytrauma or sepsis trigger DIC. Other disorders associated with moderate platelet consumption include neoplasia and vasculitis. When clinical bleeding due to thrombocytopenia is observed, diagnosis of platelet consumption generally takes the form of screening tests for DIC.
Diseases of the bone marrow often result in decreased platelet production. Generally speaking, bone marrow disease results in neutropenia first, followed by thrombocytopenia, and lastly, by non-regenerative anemia. However, clinical signs of thrombocytopenia (bleeding) are usually more visible to pet owners than signs of anemia and leukopenia (fever, lethargy, weakness, tachypnea) and are more likely to trigger an in depth medical evaluation.
Common bone marrow disorders include infectious agents, infiltrative neoplasias, immune-mediated disorders (which target bone marrow precursors) and toxic drug effects. Certain tick-borne infections such as Ehrlichia species can cause thrombocytopenia through a variety of mechanisms, including myelosuppression. Other infectious organisms that can affect platelet production include: fungal, protozoal, and viral diseases such as histoplasmosis, leishmaniasis, and feline retroviruses (FeLV, FIV). These feline retroviruses may also predispose to infiltrative bone marrow neoplasms such as high stage lymphoma and leukemias. Multiple myeloma is another malignant cancer with a predisposition for the marrow. The prognosis for bone marrow disorders causing decreased platelet production is generally poor, unless the underlying disease can be eliminated.
Thrombocytopathy refers to diseases causing platelet dysfunction. Animals with platelet dysfunction will have the same clinical signs as patients with low platelet numbers. Although the platelet count will be normal, signs of petechiae, ecchymoses and mucosal surface bleeding may be present.
Impaired platelet function can be due to congenital diseases, drug effects, and acquired illness. Drug induced platelet dysfunction can occur with anti inflammatory agents (for example NSAIDS) and some synthetic colloids (for example dextran). Synthetic colloids are thought to stick to the platelet surface and interfere with platelet aggregation. Acquired diseases can interfere with platelet function through similar mechanisms. This effect lasts for the life of the platelet, and clinical effects will be noted until new platelets are released from the bone marrow.
The most common inherited platelet function disorder is von Willebrand's disease. Von Willebrand's factor (vWF) is a key mediator in allowing coagulation to proceed. Impaired platelet binding results in excessive bleeding from venipuncture, surgery sites and trauma, but rarely results in spontaneous hemorrhage.
Von Willebrand's factor is produced and stored in endothelial cells and released in response to injury. Von Willebrand's disease results from complete absence of vWF or from selective deficiencies of the most active multimers. Classification of von Willebrand's disease can be made based on clinical severity and the degree of vWF deficiency. Dogs with type-1 disease have reduced vWF activity (<50%), but all multimers are present (albeit in reduced concentrations). In type-2 disease, the most effective high molecular weight multimers are deficient. In type 3 disease, virtually all multimers are absent and vWF activity is extremely low (<0.1%). The clinical bleeding associated with type-1 disease is variable. Type-1 von Willebrand's disease has been reported in Dobermans, Standard poodles, German shepherds, Greyhounds, Irish Wolfhounds, Shelties and many other dog breeds. Both type-2 and type-3 disease are associated with severe clinical bleeding. Type- 2 disease is uncommon in dogs, but has been reported in German shorthaired pointers and German wirehaired pointers. Type-3 disease has been reported in Scottish terriers, Chesapeake Retrievers and Shelties.
Standard coagulation times (PT, PTT) and platelet counts will not detect animals with von Willebrands disease. However, commercial laboratories offer von Willebrand's assays. Clinical bleeding is associated with vWF concentrations less than 20%. vWF assay is useful not only to diagnose the disease, but also to determine disease severity. Recently, some laboratories have developed DNA based testing for screening breeding animals for genetic evidence of von Willebrand's disease. One screening test for thrombocytopathy (including von Willebrand's disease) is the buccal mucosal bleeding time (BMBT).
Treatment of von Willebrand's disease is generally centered around management of a bleeding crisis following trauma or surgery. Successful treatment requires supplementing von Willebrand's factor using whole blood or fresh frozen plasma and/or arginine vasopressin (DDAVP) is a synthetic hormone used to treat central diabetes insipidus. A side effect of this medication is the release of stored von Willebrand's factor from endothelium. This side effect can be helpful in dogs with type-1 or type-2 von Willebrand's disease, since some functional vWF may be present in these animals. DDAVP is commercially available as a prescription nasal spray, which can be administered in a sterile fashion to dogs via subcutaneous injection or as eye drops. DDAVP can be administered to the patient approximately 30 minutes prior to surgery or it can be administered to a donor so that blood products harvested from the donor are "loaded" with as much vWF as possible.
Successful treatment of bleeding associated with disorders of primary hemostasis can be directed at specific etiologies once a thorough evaluation has been performed. In the absence of a complete diagnosis (i.e., while test results are pending), therapy may be directed at supportive care. Increased platelet numbers can be achieved by administration of platelet rich blood products. In the case of hereditary disorders affecting platelet function no cure is available. Transfusion of fresh whole blood only raises the platelet count to a minor degree. Thus, fresh whole blood transfusion may be indicated when a thrombocytopenic animal presents with active hemorrhage. However, the increase in platelet numbers is so small and transient that such transfusions are not indicated for the specific purpose of raising the platelet count in otherwise stable animals.
Disorders of Secondary Hemostasis
Disorders of secondary hemostasis include diseases of the coagulation cascade and fibrin clot formation. Animals with such hemostatic defects have clinical signs of hemorrhage into body cavities, hemarthroses, large subcutaneous or intramuscular hematomas, and mucocutaneous bleeding. There is some overlap between the clinical signs associated with disorders of primary and secondary hemostasis. Fortunately, diagnostic tests of the coagulation cascade can largely be evaluated independent of platelet function. The most common tests are the prothrombin time (PT) and activated partial thromboplastin time (PTT). These test results are not affected by platelet numbers or function. The PT is prolonged with factor deficiencies along the common (factors II, V, and X) and extrinsic (VII) pathways. The PTT is prolonged with factor deficiencies along the common and intrinsic (VIII, IX, XI, and XII) pathways. The activated clotting time (ACT) provides a rough assessment of the PTT. ACT is prolonged by severe thrombocytopenia.
Congenital deficiencies of specific coagulation factors results in clinical syndromes known as hemophilias. Hemophilia A is associated with congenital deficiency of factor VIII. Hemophilia B is associated with congenital deficiency of factor IX. Both of these disorders result in marked prolongation of the PTT and ACT, with a normal PT. Thus, distinguishing between these disorders requires sending plasma samples for advanced testing. Both hemophilia A and B have been reported in many breeds as a recessive X-chromosome linked inherited disorder which is more common in males. Dogs with hemophilia can have spontaneous hemorrhage. Most cases are diagnosed as young dogs during excessive bleeding during dental eruption or following spay/neuter surgeries. Treatment of bleeding crises associated with hemophilia requires transfusion with plasma or whole blood. Occasionally, bleeding crises can be severe enough to trigger DIC. Long term or maintenance therapies are not available or practical. Therefore, management would consist of avoiding trauma and surgery.
Acquired deficiencies of coagulation factors are common in veterinary practice. The most common source of factor deficiency is associated with ingestion of warfarin-based anticoagulants (such as coumadin, bromadiolone, brodifacoum, maki, etc). Accidental or malicious poisoning with these compounds results in long term antagonism of vitamin K1. Many of the clotting factors involved in the coagulation cascade are dependent upon vitamin K1 as a cofactor for synthesis of their active forms. The vitamin K dependent factors are II, VII, IX, and X. Anticoagulant rodenticide ingestion results in prolongation of both the PT, PTT, and ACT tests and severe clinical bleeding episodes. Treatment of rodenticide ingestion includes detoxification strategies for acute ingestion (induction of vomiting, administration of activated charcoal), followed by vitamin K1 supplementation. Transfusion with fresh whole blood and plasma products is important in anemic animals and in animals with hemothorax and intrapulmonary hemorrhage. Duration of treatment depends upon the specific rodenticide ingested. However, most warfarin-based rodenticides in use today require treatment for at least one month.
Acquired vitamin K deficiency may also result from systemic disease in some animals. Vitamin K is a fat-soluble vitamin whose absorption is enhanced by bile salt emulsification of fats in the intestinal tract. Animals with significant hepatic disease (especially cats) are predisposed to vitamin K malabsorption and clotting factor deficiency. In addition, significant liver disease can result in failure of clotting factor synthesis and is a common trigger of DIC (with resulting consumption of factors). Cats appear particularly susceptible to vitamin K malabsorption and protein synthesis failure. In dogs, such problems are most likely to occur with diseases causing complete biliary obstruction. Treatment requires parenteral vitamin K supplementation and management of underlying liver disease. Coagulation parameters in both species respond rapidly (i.e., within 12-24 hours) to vitamin K supplementation when fat soluble vitamin malabsorption is the only problem. However, animals with DIC or failure of protein synthesis require factor replacement via plasma or whole blood transfusion.
The basic approach to the bleeding patient is directed at providing hemostasis, collecting necessary diagnostic samples and providing therapy and supportive care. In the emergent setting, cage side testing may be the most useful for rapid assessment. These tests include BMBT, PT, PTT, ACT, platelet count and hematocrit.
A clinical approach to bleeding cats and dogs is facilitated by a working knowledge of basic principles of hemostasis. Although there is some overlap in clinical signs, disorders of primary hemostasis are more likely to present with cutaneous and mucous membrane bleeding. Disorders of secondary hemostasis are more likely to present with intracavitary bleeding and large hematoma formation. Assessment of primary hemostatic defects (platelet numbers and function) can be accomplished rapidly and in concert with assessment of secondary hemostatic defects (coagulation cascade). Treatment and prognosis associated with these disorders depends on the specific cause and clinical setting.
1. Hammer AS, Couto CG, Swardson C, Getzy D. (1991), J Vet Intern Med, Vol.5, No. 1, pp. 11-14.
2. Millis DL, Hauptman JG, Fulton RB. (1993), Vet Surg, Vol. 22, No. 2, pp. 93-97.
3. Hargis AM, Feldman BF. (1991), JAVMA, Vol. 198, No. 5, March, pp. 891-894.
4. Scott-Moncreiff JC, Treadwell NG, McCullough SM, Brooks MB. (2001), JAAHA, Vol. 37, pp. 220-227.