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Bovine thrombin inhibitors: Eliminate their use and solve a preventable medical problem
Based upon increased concerns about the infectious and noninfectious risks of blood transfusions, physicians are now encouraged to use drugs in favor of blood components. Patients with von Willebrand’s disease are given DDAVP rather than cryoprecipitate to improve hemostasis, fibrinolytic inhibitors have been used in high blood loss surgeries, hematopoietic growth factors are administered to prevent or treat perioperative anemia, and new agents such as recombinant Factor VIIa have been used off-label for a growing list of hemorrhagic conditions. Older agents such as vitamin K and fibrin sealants are increasingly being used as adjunctive therapy for bleeding and hemorrhagic prophylaxis.
Our surgical colleagues have made good use of a number of topical hemostatic agents as means of reducing localized bleeding and limiting the likelihood of transfusion support for complicated surgical procedures. One of the mainstays of this approach has been topical thrombin (Factor II), which has been used for many years to achieve surgical hemostasis. This agent is easy to apply and store, inexpensive compared to other medical interventions, and is typically available from hospital pharmacies.
Bovine thrombin
Although the product has been shown to be efficacious as a topical agent, the only historically available product was prepared from bovine plasma; as a consequence, topical thrombin can provoke immune responses in the patient that can have serious medical consequences. Bovine thrombin preparations contain contaminants such as Factor V despite efforts by pharmaceutical companies to remove impurities.
The literature is replete with case reports and series that document that many patients exposed to bovine thrombin make antibodies against thrombin and in some cases Factor V. These bovine-induced antibodies, particularly antibodies to Factor V, can cross-react with human Factor V and induce a coagulopathy in the patient. They can also cause laboratory abnormalities in hemostatic evaluations and, less commonly, serious bleeding complications in patients who have been immunized to bovine Factor II and V by previous exposure to these preparations. These antibodies are most common in patients exposed through previous surgery with cardiac, vascular and spine operations being the most likely immunizing event. Antibodies can be detected in at least 20% of patients with a primary exposure, typically arising within 10 to 14 days of first exposure, and increasing in titer with repeated exposures.
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The clinical scenario where a patient with a history of previous surgery develops bleeding and the laboratory evaluation demonstrates an inhibitor to Factor V is known to many hematologists and coagulation laboratories. Unfortunately, our surgical colleagues are often unaware of this problem unless confronted with a case in the past; although bleeding can occur during the hospitalization where bovine thrombin was first used, most cases develop distant from the initial exposure. In many cases, it is difficult to document exposure to bovine thrombin in the medical record, so a history of surgery where its use was likely can be informative.
In patients with severe bleeding, the treatment is supportive with plasma components and platelets; platelets as a source of Factor V on the platelet surface may be most useful. Plasmapheresis or immunosuppressive therapy may be required. Unfortunately, some affected patients are not recognized quickly and the severe bleeding that may occur can require extended hospitalizations and blood support.
Treatment alternatives
Recently, a topical thrombin made from human plasma and a topical thrombin made by recombinant technology have been licensed for clinical use. These products offer the opportunity to prevent patients from developing inhibitors and bleeding associated with bovine thrombin treatment. Since bovine thrombin inhibitors are an iatrogenic problem, it is possible to avoid the exposure of naive patients or the re-exposure of previously immunized patients by their adoption. Hospital pharmacies are now able to eliminate bovine thrombin from their formularies, and medical staff committees are being asked to assist the pharmacy in these deliberations. The therapeutic efficacy of the new thrombins appears to be at least equivalent to bovine thrombin preparations.
Although moving away from bovine thrombin will enhance patient safety, deliberations at individual hospitals are complicated by the slight increase in cost of nonbovine materials and the fact that this problem is not often seen by surgeons who are the most common users of these hemostatic agents. Since hematologists are often aware of the diagnostic and therapeutic problems associated with bovine thrombin, we have an opportunity to enhance patient safety by advocating for elimination of the product from the pharmacy at hospitals where we manage laboratories, offer coagulation consultations and care for patients. Many of us serve on the Pharmacy and Therapeutics Committee or the Transfusion Practices Committee where these issues are addressed and our input in these deliberations can be an important step in eliminating this preventable medical problem.
Paul M. Ness, MD, is Director, Transfusion Medicine, Johns Hopkins Medical Institutions, Baltimore, and a member of the HemOnc Today Editorial Board. Dr. Ness has been an advisor to Zymogenetics, the producer of recombinant human thrombin.
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