Managing bleeding disorders (Proceedings)

In a previous lecture the clinically practical tools for evaluating bleeding disorders were presented. This lecture will cover the management of primary and secondary hemostatic disorders including newer drugs and blood products, and the topic is illustrated with case discussions.

In any clinic hemorrhage is a very common clinical problem in dogs and less so in cats.  Depending on the (internal or external) bleeding site, acuteness, and degree of bleeding, dogs 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; dogs with a bleeding tendency often exhibit recurrent and/or multiple sites of hemorrhage. Similarly, differentiating between primary (thrombocytopenia, -pathias, von Willebrand's disease, vasculopathies) and secondary (hereditary and acquired coagulopathies) hemostatic defects is important to choose the correct therapy.  Clinical features and practical laboratory tests to assess bleeding patients is the topic of another presentation by the same author. It should be noted that many of those tests can be used in an emergency setting and are also used to carefully monitor the response to treatment and course of the underlying disease.

Therapeutic considerations for the bleeding dog include:

• Resuscitate and emergency care.

• Local hemostasis to prevent further blood loss.

• Transfusion with packed Red Blood Cells in case of severe anemia and tissue hypoxia.

• Specific blood component therapy to correct hemostatic deficiencies.

• Specific drug therapy where available.

• Withdrawal of 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 bared a considerable risk for acute adverse reactions.  Lyophylized canine albumin has recently been generated and its efficacy and safety seems good.  With peracute blood loss PCV changes are not observed for hours until fluid shifts from the extravascular space 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 are 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 oozing blood, such as gelatin, thrombin, bone wax, and fibrin glue. Some dogs including greyhounds may have a vasculopathy or dogs in heat undergoing surgery may show excessive bleeding which may be prevented or treated with an inhibitor of fibrinolysis – epsilon aminocaproic acid (Amikar).

Animals with massive blood loss may benefit from pRBCs or whole blood transfusions.  Ideally, dogs are initially DEA 1.1 typed, to provide type specific blood products, and crossmatched, if they had received blood previously (>4 days).  There is no specific PCV at which to transfuse, but it is rather the overall clinical assessment of tissue oxygenation that is determining the transfusion trigger in each patient.  The simple formula of Volume 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 (transfusion reaction) may account for the deficit.  

Animals with chronic blood loss generally have 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 cardiac decompensation and death.  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 will also ameliorate the bleeding tendency, likely due to the fact that red cells are a major part of any clot. Additional information on blood transfusion is provided in another lecture.

In case of 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 questions.  Most recently a clinical field study has been completed to evaluate lyophylized platelets compared to regular platelet concentrates.  While the normal survival of platelets is 7-10 days in circulation, typically transfused platelets are short-lived, particularly in dogs with immune-mediated thrombocytopenia.  Large quantities of platelet transfusions are needed to make a difference in the platelet count (~ 20,000/10 ml/kg plt count rise) and allo-sensitization may occur.  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.  Platelet support may also be needed in dogs with hereditary thrombopathias, such as Glanzmann thrombasthenia, and acquired thrombopathies (drugs). 

Dogs which seriously bleeding due to von Willebrand disease are best treated with cryprecipitate at 2-5ml/kg every 6-8 hours until hemorrhage is controlled.  Most recently lyophilized canine von Willebrand factor concentrate has been made commercially available, but no data has yet been published on its efficacy. 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 sc/iv once (or repeated once on the second day) has been shown to shorten the buccal mucosal bleeding time and hemorrhagic tendency despite only marginally changing the plasma von Willebrand factor concentration.

While 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.  Depending on the cause of vitamin K deficiency higher or lower doses of vitamin K are administered (1-5mg/kg BID/SID). Vitamin K1 rather than K3 should be used. Oral absorption is very fast and effective and subcutaneous or intravenous 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 has been established, the administration of a coagulation factor gene product could be simple and affordable, and 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 assure adequate blood flow and tissue oxygenation. The use of unfractionated or Low Molecular Heparin or aspirin continue to be controversial.  There are no controlled studies showing clinical efficacy of these agents in DIC.  High dose tightly controlled used of heparin has been shown in one study to prevent thrombotic complications in dogs with immune-mediated hemolytic anemia.  Similarly, the use of fresh frozen plasma or other plasma products in an attempt to replenish antithrombin 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.