In veterinary clinical practice hemorrhage is a very common clinical problem. Depending on the (internal or external) site, acuteness, and degree of bleeding, animals may have overt signs of hemorrhage, show specific organ failure (e.g., thoracic hemorrhage, hemoabdomen), and/or signs related to the systemic effects of hypovolemia, anemia and/or hypoproteinemia. Differentiating between normal and abnormal hemostasis by clinical and laboratory assessment is crucial; animals with a bleeding tendency often exhibit recurrent and/or multiple sites of hemorrhage. Similarly, differentiating between primary (thrombocytopenia, thrombocytopathias, von Willebrand's disease, vasculopathies) and secondary (hereditary and acquired coagulopathies) hemostatic defects is important to choose the correct therapy. It should be noted that many of those tests can be used in clinic setting and are also used to monitor the response to treatment and course of the underlying disease.
Therapeutic considerations for the bleeding animal include:
Resuscitation and emergency care
Local hemostasis to prevent further blood loss
Transfusion with packed Red Blood Cells (pRBCs) in case of severe anemia and tissue hypoxia
Specific blood component therapy to correct hemostatic deficiencies
Specific drug therapy where available
Withdraw any offending agents and/or treat underlying disease
The general principles of resuscitation and emergency care apply to dogs with hemorrhage, such as restore hydration, open airway, oxygenation, and body temperature. For rehydration, crystalloid fluids are typically used, as colloids have anticoagulant effects and may worsen the bleeding. In case of dangerously low oncotic pressures, fresh frozen plasma (FFP) and albumin may be used. In the past, only human albumin was available which bore a considerable risk for acute adverse reactions. Lyophilized canine albumin has recently been generated and its efficacy and safety have been assessed. With peracute blood loss it should be noted that PCV changes are not observed for hours until fluid shifts occur or after the animal is rehydrated. Dogs with acute hemorrhagic gastroenteritis may lose more fluid than red blood cells and become hemoconcentrated until they are rehydrated. Thereafter, they become anemic and often severely hypoproteinemic.
While ligatures, hemostats and compression can stop visual bleeding from trauma or surgery, surgical intervention should be cautiously considered to not cause more harm to the patient. Thus, adequate hemostatic function should be first assured or restored with appropriate blood products or medical treatment, whenever possible. There are also a variety of local hemostatic agents that might be applied at a wound, such as gelatin, thrombin, bone wax, and fibrin glue.
Animals with massive blood loss may benefit from pRBCs or whole blood transfusions to counter the anemia. Ideally, dogs are initially DEA 1.1 typed to given type-specific blood products and are crossmatched, if they had received blood previously (>4 days). There is no specific PCV at which to transfuse, but rather the overall clinical assessment of tissue oxygenation is determining the transfusion trigger in each patient. The simple formula of volume (whole blood) to transfuse = desired PCV rise x kg Body Weight x 2 is adequate to estimate the target PCV. In case the expected PCV rise is not achieved, continued blood loss, fluid shifts, and an acute hemolytic crisis may account for the deficit. Animals with chronic blood loss have generally well adapted to their low hematocrits and may cope well with a PCV of 10%. Their heart, however, functions at maximal capacity (large cardiac output) to compensate for the anemia. They are generally not dehydrated and additional fluids may result in severe volume overload and sudden cardiac decompensation. Thus, the fluid and blood volume should be appropriately chosen, and the dog's cardiovascular system should be carefully monitored. Interestingly, it has been shown that a rise in PCV to above 20% will also ameliorate bleeding, likely due to the fact that red blood cells are a major part of any clot.
Therapy of thrombocytopenia is mostly dependent on the underlying cause and severity of clinical signs of bleeding rather than the actual platelet count. It is well appreciated that despite severe thrombocytopenia due to immune-mediated thrombocytopenia (ITP), these animals may be at lesser bleeding risk than the ones with myelosuppressive disorders. Hence, therapy of thrombocytopenia involves treatment of the underlying disease, withdrawal of any potential triggering agents, supportive care, and emergency control of bleeding and correction of severe anemia.
Platelet transfusions are very rarely indicated and restricted to serious uncontrolled bleeding into the brain or other critical sites. In case of severe thrombocytopenia, platelet products are rarely used for a variety of reasons. Fresh platelet concentrates and platelet-rich plasma (unchilled, <24 hours gently agitated) need to be freshly prepared and are rarely available. For a while frozen platelets were offered, but their efficacy has been questioned in a recent study. Most recently a clinical field study has been started to evaluate lyophilized platelets compared to regular platelet concentrates. While the normal survival of platelets is 7-10 days in circulation, transfused platelets are typically short-lived, particularly in dogs with immune-mediated thrombocytopenia. In clinical practice, thrombocytopenic, seriously bleeding patients may be the ones that could benefit more from a fresh whole blood transfusion to provide platelet and red blood cell support. At 1 hour post transfusion, the anticipated platelet rise per transfusion is only modest (20,000/µl per 10ml fresh whole blood/kg transfusion). Nevertheless, platelet concentrates or platelet-rich plasma are used to stop life-threatening bleeding due to severe thrombocytopenia. And in case there is a combined hemostatic deficiency and anemia, fresh whole blood that has not been chilled could be given. Large quantities of platelet transfusions are needed to make a difference in the platelet count (~ 20,000/10 ml/kg platelet count rise) and allo-sensitization may occur. Platelet support may also be needed in dogs with hereditary thrombopathias, such as Glanzmann thrombasthenia, and acquired thrombopathias (drugs).
As any drug may potentially trigger thrombocytopenia, all drugs should be withdrawn except those absolutely required for treating a life-threatening condition (e.g., phenobarbital for active seizures); a change in class of drugs may also be helpful to address the frequent occurrence of drug-induced thrombocytopenia. Since infections are common causes of thrombocytopenia, and PCR and serology screens for infectious diseases may not be back for days (except SNAP tests), thrombocytopenic dogs are often empirically treated with antimicrobials. Most commonly, doxycycline at 10mg/kg BID for 2 weeks is used, however in certain geographic areas other antimicrobials may also be indicated; for instance babesiosis may cause severe thrombocytopenia before the hemolytic disease is recognized, and sepsis-associated thrombocytopenia requires intense parenteral antibiotic administration. Furthermore, cancer-associated thrombocytopenia is best corrected by treating the cancer.
In cases of ITP immunosuppressive therapy is used to inhibit platelet phagocytosis by macrophages and platelet-antibody production. Glucocorticosteroids are still the first and main immunosuppressive agents; they impair platelet destruction by blocking macrophages, interfere with platelet-antibody interactions, hamper any inflammatory response, and finally inhibit anti-platelet antibody production. Whilst most clinicians start off with prednisone at a dose of 2mg/kg PO BID, dexamethasone at 0.6mg/kg can be administered IV daily in cases with gastrointestinal signs. There is no evidence that dexamethasone is superior to prednisone if used at the equivalent dose (dexamethasone is 6 times more potent than prednisone); however, some clinicians are hesitant to use the high prednisone dose. In fact, a high initial steroid pulse dose has been suggested to be effected but may also be associated with more serious side effects. Any immunosuppressive dose of glucocorticosteroids may induce serious side effects including gastrointestinal ulcers, thromboembolism, iatrogenic hyperadrenocorticism, and bacterial infections. Interestingly there is one additional immunosuppressive agent that is considered highly effective and relatively safe in the initial management of severe acute ITP. Vincristine at a dose of 0.02mg/kg (0.5mg m2 body surface) strictly IV once (may be repeated after a week) has been shown to accelerate the platelet count rise, when used in combination with prednisone. Potential mechanisms of action of vincristine include binding of tubulin and inhibition of macrophages. Other immunosuppressive agents may be considered if prednisone ± vincristine fail or intolerable side effects occur. These may include cyclosporine, danazol, azathioprine, and intravenous human immunoglobulin; none of these drugs have been approved or shown to be efficacious and safe in any clinical studies in dogs. A recent limited study on the use of intravenous human immunoglobulin showed similar effects to vincristine, but at considerably higher expense. In addition, new immunosuppressive agents are being introduced, such as mycophenolate and leflunomide. Finally, splenectomy may be considered in refractory or relapsing cases of ITP, but no data are available in dogs.
Dogs seriously bleeding due to von Willebrand disease are best treated with cryoprecipitate at 2-5ml/kg every 6-8 hours until hemorrhage is controlled. In milder cases or to prevent hemorrhage during minor surgery in dogs with von Willebrand disease, desmopressin (DDAVP) at a dose of 1 μg/kg subcutaneously once (or repeated once on the second day) has been shown to shorten the buccal mucosal bleeding time and hemorrhage, despite only marginally changing the plasma von Willebrand factor concentration.
Whilst for any coagulopathy fresh or fresh frozen plasma could be administered (10ml/kg or to effect), for some coagulopathies other therapeutic options should be considered. Coagulopathies due to rodenticide poisoning, and several hereditary coagulation factor deficiencies can be treated with cryo-poor plasma, while Hemophilia A and fibrinogen deficiency require cryoprecipitate. The frequency of treatment depends on the clinical signs of bleeding and factor deficiencies. Depending on the cause of vitamin K deficiency, higher or lower doses of vitamin K are administered (1-5mg/kg BID). Vitamin K1 rather than K3 should be used. Oral absorption is very rapid and effective and subcutaneous injections may be considered if nothing per os can be administered or gastrointestinal absorption is impaired (cholestasis, inflammatory bowel disease, antibiotics). Porcine and human coagulation factors have been experimentally studied in bleeding dogs and have also been used anecdotally in clinics. Human recombinant FVIIa may be used if FFP is not available in some coagulopathies, although its efficacy and safety have not been extensively studied in dogs. The cuticle bleeding time was normalized in Beagle dogs with FVII deficiency. Finally, the dog has served as an excellent large animal model to develop and assess the efficacy and safety of hemophilia A and B and the initial experiments are promising with plasma factor levels of >5% already being beneficial. Once a vector and protocol have been established and the administration of a coagulation factor gene product could be simple and affordable, it is foreseeable that this could be applied to the canine patients.
The management of DIC remains unrewarding unless the trigger can be removed or the underlying disease can be controlled. Rehydration is of utmost importance to ensure adequate blood flow and tissue oxygenation. The use of unfractionated or Low Molecular Heparin or aspirin continues to be controversial. There are no controlled studies showing clinical efficacy of these agents in DIC. Similarly, the use of fresh frozen plasma or other plasma products in an attempt to replenish anti-thrombin III and consumed clotting factors is controversial unless the animal exhibits overt signs of hemorrhage. However, a thorough discussion of the management of DIC is beyond the scope of this presentation.