A Blood Center physician (who directs a Hemostasis Reference Laboratory) has a question regarding emergency reversal of warfarin effect. He hopes that the discussion surrounding the following question will help clarify if his center should maintain a single dose of prothrombin complex concentrate (PCC) in their inventory for this indication. According to the inquiring physician, emergency reversal of oral anticoagulant effect is occasionally required in response to life-threatening bleeding in the CNS or gastrointestinal tract. The inquiring physician lists several possible treatment options. One option is vitamin K therapy, but in the opinion of the inquiring physician, vitamin K therapy is too slow in its effect in these emergent situations. A second option is transfusion of plasma- based products (such as fresh frozen plasma or thawed plasma, in which the factor concentrations are equal to that of normal plasma). A third option (although possibly controversial) is infusion of prothrombin-complex concentrates (either non-activated such as Proplex T or activated complex concentrates such as Autoplex or FEIBA), or use of activated recombinant factor VIIa. The inquiring physician comments that decision-making in this area is complicated by the following facts:

1. The concentration of factors in plasma is low (as compared to a concentrate), and at least two reports in the literature indicate that time to hemostatic correction is long, and volume overload is a common complication of plasma therapy.
2. Current American College of Chest Physician recommendations include recommending prothrombin-complex concentrates, and publications indicate that reversal of oral anticoagulant effect is accomplished rapidly with these agents. These concentrates which used to be the mainstay of therapy in Hemophilia B or hemophilia A/inhibitor patients have largely been replaced by purified factor IX or recombinant factor products, and thus there are many places in USA (including the inquiring physician's own city) where there is no ready inventory.
3. While case reports indicate use of r-FVIIa for oral anticoagulant reversal, this is expensive, off-label use, and not sufficiently supported in the literature to recommend it as routine.

QUESTION: Are blood bankers remaining with plasma for emergency oral anticoagulant reversal, or are they maintaining a local inventory of PCC (such as 5000 factor IX units of prothrombin complex concentrate) to be available for the unfortunate anticoagulated patient who presents with a life-threatening CNS bleed?

In response to the above, the following replies were submitted.

1. A physician from a Department of Hemotherapy and Hemostasis in Barcelona wrote that at his institution the present policy in reversing oral anticoagulation is to administer FFP. Nevertheless it should be emphasized that in the face of life-threatening bleeding in a patient receiving oral anticoagulants the aim is, particularly in the presence of highly thrombotic risk situation such a cardiac prosthetic valve, to normalize the coagulation tests in order to restore hemostasis. In the responding physician's opinion, a consensus exists that an INR about 1.4 to 1.5 would be suffcient. Only in the case of severe risk of volume overload should the option of prothrombin complex concentrates be considered. However, one should bear in mind the significant risk of DIC development and thrombotic complications associated with the use of this concentrate. The responding physician reports that only once in 10 years has he had to consider administration of prothrombin complex concentrates. Most of the time an aggressive diuretic treatment allows the administration of the needed volume of FFP.

2. A physician blood banker with experience in the coumadin reversal issue reports that she usually advises giving 1 mg of vitamin K (as opposed to 10mg, which will make the patient refractory to recoumadinization for weeks) and 2-4 units of FFP depending on the clinical situation. She is of the opinion that by combining the vitamin K therapy and FFP transfusion therapy, a reversal can be achieved in most cases while avoiding fluid overload. She concludes with the caution that the key here is the clinical situation and the patient's response must be closely monitored.

ADDENDA May 31, 2002

3. A Professor of Medicine (Hematology), at a University in the state of Washington, is concerned about the risk of thrombosis from low-purity or especially activated "factor IX concentrates". He adds that PCC is a misnomer as there is no complex. Furthermore, currently availably low-purity factor IX concentrates have been purified over DEAE resins and do not contain factor VII. Factor VII is obviously the biggest concern in this setting as it has the shortest half-life. In his opinion, for life-threatening bleeding episodes, vitamin K can be administered in low dose with an effect in approx. 30 hrs if the patient lives that long; "immediate" reversal is achieved with FFP. The biggest concern he has about treating these patients with FFP is using too little and/or infusing it too slowly for fear of volume overload, at the expense of failing to achieve hemostasis. Aggressive diuresis and even limited plasma exchange may be necessary to bring and maintain plasma levels to hemostatic levels (>30-50%) for all 4 vitamin K-dependent factors. The Washingtonian adds that an alternative approach may be on the horizon, as preclinical studies with recombinant factor VIIa are encouraging. Furthermore, he is aware of a small series of patients with bleeding or in need of emergency surgery (Annals Int Med., in press) where a single, relatively low dose of VIIa was successful. This approach remains off-label at the present time. Also, the potential risk of exacerbating thrombosis in patients on warfarin for a recent thrombotic event remains to be assessed.

4. A blood banker from Boston believes that vitamin K carries an unwarranted reputation for slow correction of the INR among patients with vitamin K deficiency. He believes this is based on the experience of people who have chosen NOT to administer vitamin K intravenously. However, when given intravenously, vitamin K begins working instantly and results in a substantial fall in the INR within hours. Most "prothrombin concentrates" on the market have variable and low levels of factor VII. At the Bostonian's hospital they recommend using intravenous vitamin K and FFP for emergency cases. An excerpt from their policy manual follows: "As part of the emergency management of coumadin reversal the decision to actively intervene (using Vitamin K or clotting factors) or to simply reduce or discontinue warfarin sodium therapy is based in part on the INR but in large measure on the clinical circumstances. Reversal of the anticoagulant effect of warfarin sodium is not a benign procedure, with the risk of thrombosis dependent on patient factors such as the presence of an artificial heart valve, neoplasm, the need for rapid reversal and others. Although clinical judgment should prevail, in the opinion of the Boston blood banker, some general guidelines (see below) can be considered.

Management of patients on coumadin who are bleeding:

• If the INR is elevated and the patient is bleeding, administration of fresh frozen plasma is indicated along with Vitamin K 2.5 mg - 5 mg intravenously.
  
  
• Notes on coumadin reversal:

Intravenous vitamin K is associated with a small risk of severe allergic reaction. When administered intravenously, the rate should not exceed 1mg/minute. Reversal of anticoagulation by any means (vitamin K or FFP) is associated with a risk of thrombosis depending upon the patient's underlying need for anticoagulation.

Fresh frozen plasma dosage should be based on patient weight (usual adult dose is 10 mL/kg). If FFP is administered without concomitant vitamin K, the effect of FFP will dissipate in 8-12 hours. Therefore the INR must be monitored closely."

ADDENDA Jan. 5, 2006

5. A transfusion medicine physician in Tennessee reports that when some patients at her hospital undergo hip arthroplasty for degenerative joint disease, they are routinely transfused with two units of FFP just before surgery, if the patient has been on coumadin for a medical reason, in order to temporarily reverse the coumadin effect during the surgical procedure. A Protime is done just prior to and shortly after the FFP is given, and the surgery is only performed if the INR is less than 1.5. A second dose of FFP is generally not given unless further active bleeding occurs. Blood loss during surgery is carefully monitored. In the event that a patient needs emergency coumadin reversal due to active bleeding while anticoagulated, they usually administer two units of FFP plus a dose of Vitamin K. A second dose of two units of FFP are generally given 2-3 hours later. The INR is monitored, as is the clinical response to the plasma and Vitamin K therapy. She wonders if other institutions use similar approaches for both routine and emergency reversal of coumadin.

ADDENDA Jan. 6, 2006

6. A transfusion medicine specialist in Queensland, Australia, invites colleagues to consider the position statement of the Australasian Society for Thrombosis and Haemostasis (ASTH) concerning warfarin reversal. This can be viewed at: http://www.mja.com.au/public/issues/181_09_011104/bak10441_fm.html, and downloaded in pdf format. The print citation is: Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; the Warfarin Reversal Consensus Group. Warfarin Reversal: Consensus Guidelines, on Behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia (MJA) 2004; 181 (9): 492-497. Letters to the editor, and authors' response appeared in MJA 2005; 182 (7): 365-368, online at: http://www.mja.com.au/public/issues/182_07_040405/letters_040405_fm-3.html. Blood product therapy, when warranted, is a combination of PCC and FFP when both are available. That said, in most clinical situations neither is recommended; simply stopping warfarin therapy or, in addition, administering vitamin K, is deemed sufficient. A health professionals' data sheet about the particular PCC referred to in the position statement can be viewed at http://www.medsafe.govt.nz/profs/Datasheet/p/Prothrombinex-HTinj.htm.

Please submit comments to the e-Network Forum.

Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator