Questions remain about urgent reversal of coagulopathy

Warfarin-related hemorrhages are increasing, doubling mortality.

Despite available guidelines, many questions remain about the best agent and dose for the urgent reversal of coagulopathy, the time window for efficacy and how long to optimally maintained a normal international normalized ratio, J. Claude Hemphill III, MD, MAS, said at the International Stroke Conference 2007.

“The issue is [that] everyone should have an institutional protocol,” Hemphill said. “Randomized trials are probably going to be necessary to fundamentally change practice even though guidelines have been out there for a long time.”

Warfarin-related intracranial hemorrhages are increasing in incidence. Warfarin doubles intracerebral hemorrhage-related mortality, increases the risk for hematoma expansion, and bleeding continues for a longer duration, according to Hemphill, associate professor at the University of California, San Francisco. Furthermore, patients not on warfarin but who have an intracerebral hemorrhage are at risk for hematoma expansion. Hemphill highlighted and discussed treatment guidelines and options for the urgent reversal of coagulopathy.

Reversal agents

When reversing warfarin, the usual way is to transfuse two units of fresh frozen plasma, re-check the international normalized ratio and administer as necessary, and also administer vitamin K, according to Hemphill. Previous studies found that the earlier the clinician administered fresh frozen plasma, the more likely the INR would correct by 24 hours. However, “sometimes this does not work,” he said.

There are three other treatment strategies: directly compete with the vitamin K antagonist, replace the native coagulation factors, or bypass the central part of the coagulation cascade and give recombinant factor VIIa, according to Hemphill.

Some guidelines suggest administering vitamin K at 5 mg to 10 mg, but the full effect is only at 12 to 24 hours after administration. Vitamin K has a short duration and should be administered as part of all reversal protocols, Hemphill said.

Fresh frozen plasma is more of the standard approach because it has coagulation factors in the non-concentrated form; however, thawing and ABO compatibility testing must be performed.

Prothrombin complex concentrate takes about 20 minutes to reconstitute, Hemphill said, and does not require compatibility testing or thawing. There are 16 different preparations available worldwide, often with somewhat different amounts of factor VII or factor IX. In some institutions prothrombin complex concentrate it is not available at all. Clinicians could administer recombinant factor VIIa as off-label use; it has rapid reconstitution and low volume. The problem is that data are unclear as to what dose to use, Hemphill said. There is also risk for thrombosis.

U.S. guidelines for warfarin reversal are published in Chest every three years, and various thrombotic and antithrombotic agents for treatment are examined. The guidelines suggest, “in patients with life-threatening bleeding and elevated [international normalized ratios], give them prothrombin complex concentrate or factor VII supplemented by vitamin K.”

“All three of the international guidelines that are available recommend giving a reversal agent beyond fresh frozen plasma,” Hemphill said.

However, there are no randomized clinical trials evaluating the currently available guidelines to determine which recommendations are best to follow, and there is limited observational data studying small patient numbers, differing doses and agents.

“The fundamental principle of reversing coagulopathy is that any intracerebral hemorrhage on a patient on warfarin should be considered life-threatening, period,” he said. “That’s qualitative, but that fits in the guidelines. And the goal is to normalize the coagulation immediately.” – by Tara Grassia

For more information:

• Hemphill JC. Urgent reversal of coagulopathy: treatment options. Session V: Concurrent symposia A. Presented at: American Heart Association/American Stroke Association International Stroke Conference; Feb 7-9, 2007; San Francisco.