ADDENDA Jan. 8, 2006

7. Dr. Ravindra Sarode, Director of Transfusion Medicine and Hemostasis Reference Laboratory at the University of Texas, Southwestern Medical Center (attribution used with permission) reports that with the approval of their Blood Utilization Review Committee, his institution has been using a Prothrombin Complex Concentrate (PCC) product for reversal of warfarin effect (mainly overdose) for almost a year.  A key consideration in their product selection process was if the product's package insert listed the levels of all the Vitamin K dependent factors.  Not all of the various product's package inserts do.  He reports that when they examined the package inserts of PCC products that they did not select, one package insert only listed levels of FII and FX, while another product package insert only listed levels of FII and FVII.

He reports that they have not seen any thrombotic side effects since beginning to use a PCC product for reversal of warfarin effect, although the product's package insert lists all possible reactions including thrombosis.  He adds that it is important to differentiate PCC products from activated PCC products used for treating hemophilacs with inhibitors, which have activated factors FX and FVII in higher amounts, and which may have a greater prothrombotic potential.  He comments that in his opinion the main benefit of using a PCC product for warfarin overdose reversal is that one does not need to know the patient's ABO blood type, the risks of volume overload and TRALI are extremely remote, and if the product is infused at the recommended dosage and rate (see prescribing information), the INR shows improvement rather quickly.  He comments that in their experience the use of PCC has worked out well for several CHF patients who have had coumadin overdose. For patients with very high INRs (>10) and very long PTTs, they sometime also transfuse a few FFPs. They also recommend a low dose of vitamin K (1-2 mg IV or even oral) per recent Chest guidelines. They dispense PCC from their Blood Bank, so that it is easy for them to monitor and evaluate patient outcomes.  In fact, Dr. Sarode states that all requests for FFP for patients with an INR of 5.0 or greater are evaluated by one of his blood bank residents, and if the INR prolongation is due to warfarin overdose, PCC is recommended along with low dose vitamin K and/or FFP. He mentions that his institution is currently doing a study to look at vitamin K dependent factors before and after PCC infusion, to assess the effect of the PCC infusion on those levels.  He also reports that they have published data that might suggest that the clinical efficacy of recombinant FVIIa would be reduced in a warfarin overdose patient with an INR >6, because FII and FX levels are often <10% in such cases, and adequate thrombin generation requires that a patient have these substrates.

ADDENDA Jan. 9, 2006

8. A Quality Manager at a Blood and Tissues Bank in Santander, Spain reports that the Guidelines of the British Committee for Standards in Haemtaology (British Journal of Haematology, Volume 126 Page 11-28, July 2004), state that "Over-anticoagulation from excessive effects of warfarin can be reversed by a range of measures. From the most mild to the most severe circumstances these are: withdrawing warfarin, giving vitamin K orally or parenterally (e.g. 5 mg by slow intravenous injection; grade B recommendation, level III evidence); transfusing FFP, or transfusing PCC (FII, FVII, FIX and FX, or separate infusions of FII, FIX and FX concentrate and FVII concentrate). PCC (50 units/kg) is preferred to FFP. Details have been previously published (BCSH, 1998; Makris & Watson, 2001). Makris et al (1997) showed that FFP contains insufficient concentration of the vitamin K factors (especially FIX) to reverse warfarin, supporting the finding that FFP is not the optimal treatment. The BCSH guidelines on oral anticoagulation (BCSH, 1998) only recommend FFP (15 ml/kg) if there is major bleeding in a patient on warfarin if PCC is not available. Simultaneous administration of intravenous vitamin K (5 mg) is also recommended, although they comment that levels of individual factors will typically remain less than 20%". Thus, at least from this guidelines, the Spanish colleague believes that the best option for warfarin associated bleeding may be PCC.

ADDENDA Jan. 10, 2006

9. Dr. Frank Boulton, Chair British Committee on Standards in Haematology (BCSH) Transfusion Task Force (attribution used with permission) reports that the BCSH has pronounced on this issue in both 1998 and 2004; the first pronouncement came from their Haemostasis Task Force and the second from their Blood Transfusion Task Force. The most recent guideline can be found HERE and additional background can be found HERE.

Dr. Boulton states that based on the BCSH position, it can be seen that either FFP or PCC are recommended but that PCC are rather preferred. He acknowledges that even the most recently developed PCC may have a residual pro-thrombotic risk, so caution is urged when using them. PCCs are still available in the UK. Using rVIIa was not considered in either of these Guidelines, and would probably not be recommended by UK practitioners outside a well-designed protocol, and he reports not being aware of any such protocol for massive bleeding associated with warfarin. (Where vitamin K antagonists are not associated with the cause of bleeding, see Boffard et al, Journal of Trauma Injury, Infection and Critical Care 2005;59:8-18; but also the critical comments by S Dzik in Transfusion Medicine Reviews, 2005;19:323-4).

10. Richard S. Newman, M.D. Director, Coagulation and HLA Labs and Associate Director, Blood Bank at the U.C. Irvine Medical Center reports that in September 2004, the American College of Chest Physicians consensus conference on antithrombotic therapy recommended the use of recombinant FVIIa (rFVIIa) in addition to vitamin K as an alternative treatment option for patients taking warfarin who developed serious bleeding, irrespective of the patient’s INR. (Ansell J, et al. The pharmacology and management of the vitamin K antagonists. In: 7th ACCP consensus conference on antithrombotic therapy. Chest 2004; 126 (supplement): 204S-233S.) Also of note, in January 2005, rFVIIa was reported to be of significant clinical benefit for the treatment of spontaneous, intracerebral hemorrhage when administered within 4 hours of the event. (Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352: 8: 777-785.) In this study, there was a significant decrease in hematoma expansion, mortality (29% decreased to 18%), morbidity and enhanced functional outcome at 3 months post-event, when single doses of the drug (ranging from 40 to 160 mcg/kg) were administered. The risk of rFVIIa noted in this study was a 3.5 fold increased risk (7% vs. 2% in controls) of serious thromboembolic phenomena (myocardial ischemia and cerebral infarcts). A just-published review of consensus recommendations for the treatment of intracerebral hemorrhage associated with anticoagulant therapy notes: "..Mortality …as high as 67% (is seen) in patients receiving oral anticoagulant therapy (OAT)…Several features make rFVIIA a promising candidate for OAT-intracerebral hemorrhage (ICH) treatment… Nevertheless, patients on OAT have an increased risk for thromboembolism, and it is possible that the safety profile in patients with OAT-ICH could be different from that in spontaneous ICH." (Steiner T, et al. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 2006;37:256-262.) Bearing the aforementioned recent publications in mind, including a mortality rate as high as 67%, Dr. Newman wonders how many basic scientists out there would prefer to get a 40 ug/kg dose of rFVIIa vs. a consensus recommended dose of prothrombin complex concentrate (PCC) if they had an ICH while on OAT. In Dr. Newman's center where they do not stock PCC, but do stock rFVIIa for trauma patients with major blood loss, he reports that he would not hesitate recommending rFVIIa.

ADDENDA Jan. 13, 2006

11. Dr. Frank Boulton, who previously responded in ADDENDUM #9 above reports that in "In today's mail I received the latest British Journal of Haemotology which has just published an update from the haemostasis task force of the BCSH 'Guidelines on oral anticoagulation (warfarin): third edition - 2005 update' (BJH 2006;132:277-285). Section 6 ('managing bleeding and excessive anticoagulation') places a bit more emphasis on intravenous vit K for rapid reversal, but otherwise has much the same message".

ADDENDA Jan. 15, 2006

12. Dr. Ravindra Sarode, whose comments appear in ADDENDUM #7 of January 8, 2006 offers a response to the query by Dr Newman (ADDENDUM #10 of January 10, 2006): "How many basic scientists out there would prefer to get a 40 ug/kg dose of rFVIIa versus a consensus recommended dose of prothrombin complex concentrate (PCC) if they had an intracerebral hemorrhage (ICH) while on oral anticoagulation therapy (OAT)?" According to Dr. Sarode (who is a physician scientist), under those circumstances, he would prefer the PCC! Dr. Sarode believes that the NEJM article mentioned (Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352: 8: 777-785) by Dr. Newman should not be used to argue in favor of using rFVIIa when patients suffer an ICH while taking OAT. The NEJM article reported a placebo controlled study in which 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset were assigned to receive placebo (96 patients) or 40 µg of rFVIIa per kilogram of body weight (108 patients), 80 µg per kilogram (92 patients), or 160 µg per kilogram (103 patients) within one hour after the baseline scan. Dr. Sarode comments that upon reading the aforementioned article, he did not see Protimes or INRs reported with the study data, and that most of the patients evaluated probably had NORMAL CLOTTING factors levels, including levels of Factors X and II (which are important substrates for rFVIIa), because the study specifically excluded patients with a history of thromboembolic disease (including myocardial infarction, angina, DVT, ischemic stroke, and claudication) and those on anticoagulants. According to Dr. Sarode, the NEJM study did not evaluate the effect of rFVIIa on patients who suffer an ICH while taking OAT, and he is unaware of data regarding the efficacy of rFVIIa in patients with very low (<10%) FII and X. In a different study, which included patients with OAT, Freeman and colleagues (Freeman WD, Brott TG, Barrett KM, Castillo PR, Deen HGJ, Czervionke LF, Meschia JF. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79:1495-1500) treated 7 ICH patients who were on OAT with rFVIIa at initial doses ranging from 15 µg/kg to 90 µg/kg. Most also received vitamin K and FFP. Reversal of INR was prompt, but in 5 patients a delayed rise in INR required further treatment with FFP or rFVIIa. There were no early thrombotic complications. Is it possible that in those cases, the administration of FFP provided enough FX and FII to allow the rFVIIa to be effective? The authors acknowledged that conclusions about the efficacy or cost-effectiveness of rFVIIa in patients with ICH on OAT cannot be drawn from this small group. Thus, without compelling data, Dr. Sarode does not believe we can conclude that rFVIIa will be effective for that selected group of patients. He also cautions that unless there is a randomized controlled trial comparing PCC versus rFVIIa, rFVIIa should be used with caution in patients with a known hypercoagulable state. He points out that many patients on OAT have hypercoagulable states (which is why they are being treated with oral anticoagulation). He concludes saying that he would prefer receiving PCC over rFVIIa, in the event that he suffered an intracerebral hemorrhage while receiving oral anticoagulation therapy.

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