Recombinant Factor VIIA in the Treatment of Bleeding

Madhu V. Midathada, MD; Paulette Mehta, MD; Milton Waner, MD; Louis M. Fink, MD

Disclosures

Am J Clin Pathol. 2004;121(1) 

In This Article

Liver Disease

Liver disease might result in substantial reduction in the synthesis of factors involved in coagulation and in factors controlling fibrinolysis.[18] Also, there might be moderate thrombocytopenia. When there is bleeding, it often is in the upper gastrointestinal tract. There often is a decrease in the synthesis of the vitamin K—dependent coagulation factors, and fresh frozen plasma (FFP) and vitamin K are used to control bleeding in these cases. The use of large amounts of FFP might be limited by the patient's ability to cope with the required fluid load. Prothrombin complex concentrates (PCCs) have been used to treat acquired factor VIII or IX inhibitors, but they are associated with adverse effects such as allergic reactions, heparin-induced thrombocytopenia, and thromboembolic complications, including disseminated intravascular coagulation (DIC).[19] Activated PCCs such as FEIBA, Proplex T, and Autoplex T (Baxter Healthcare, Deerfield, IL) have a higher margin of safety with much less risk of viral transmission and a low level of thrombotic events.[20,21,22,23]

rFVIIa has been used to treat patients with acute hepatic trauma, bleeding after liver biopsy, chronic liver disease with cirrhosis, and after liver transplantation.[24] rFVIIa seems to be safe and effective for patients in these situations and permits several invasive procedures without the complications of bleeding. This has been studied in experimental studies and in patients with liver failure. A study of the effects of rFVIIa on bleeding after a grade V liver injury on coagulopathic pigs revealed that the blood loss was reduced when rFVIIa was used as an adjunct to abdominal packing.[25] Testing in anesthetized swine revealed that administration of rFVIIa early after injury decreased bleeding and prolonged the time from injury to death after experimental trauma.[26,27] There was no evidence of thrombosis in the vital organs. A study done to evaluate the efficacy of rFVIIa in cirrhosis showed improvement in clot formation with rFVIIa, but there was no evidence of antifibrinolytic effect in patients with cirrhosis or in patients undergoing orthotopic liver transplantation as evidenced by clot lysis time.[28]

Correction of the PT in nonbleeding patients with cirrhosis was shown in a study with escalating doses of rFVIIa.[29] There was a transient improvement in PT with the 3 doses tested, and no adverse effects were noted. The effect of rFVIIa on the PT in 10 patients with cirrhosis with ongoing variceal bleeding was studied in a single-center, open-label trial.[30] rFVIIa normalized the PT in all patients within 30 minutes with immediate bleeding control, and the effect lasted 2 to 4 hours. There were no signs of DIC and no deaths. Chuansumrit et al[31] studied the effect of rFVIIa in normalizing the PT in 5 children with liver diseases, 3 of whom had massive bleeding. The study showed that rFVIIa was effective in normalizing the coagulation parameters, stopping bleeding episodes, and permitting invasive procedures.

There are a number of other case studies reported on the use of rFVIIa in liver diseases. For example, Berthier et al[32] reported the use of rFVIIa in 2 patients with cirrhosis to treat persistent bleeding following dental extractions; the bleeding was not controlled despite repeated administration of FFP in one of them. Bleeding stopped promptly in both patients but recurred in one who did not receive concomitant local treatment. Similarly, Jeffers et al[33] evaluated the effect of 4 doses of rFVIIa (5, 20, 80, and 120 µg/kg) on the correction of PT and the time to achieve hemostasis in patients with cirrhosis with coagulopathy who were undergoing laparoscopic liver biopsy. The study included 71 patients with advanced liver disease with a platelet count of 60 x 103/µL (60 x 109/L) or less and a PT 3 to 15 seconds higher than the reference range. Normalization of PT and time to hemostasis were measured. The duration of normalization of PT was longer in patients treated with higher doses of rFVIIa. Hemostasis was achieved in 74% of the patients in 10 minutes. None required transfusions or operative intervention to control bleeding. Complications reported were 1 thrombotic event (portal vein thrombosis) and 1 event of DIC, which were considered not related to treatment. Kositchaiwat and Chuansumrit[34] report their experience with use of rFVIIa in 7 patients with prolonged PTs due to liver disease. The patients' PTs were 3 seconds longer than those of control subjects and did not respond to the administration of FFP and vitamin K. With the use of rFVIIa, percutaneous liver biopsies and endoscopy were performed with no reported adverse reactions.

Data on the use of rFVIIa before procedures to treat coagulopathy-associated hepatic dysfunction or the effects of warfarin were studied, and the use of rFVIIa was reported to reverse the coagulopathy with no significant complications. The PT international normalized ratio (INR) reduced from a mean of 2.8 to 1.4 after rFVIIa in a study of 37 patients, and in another study of 17 patients, the average pretreatment PT was 28.6 seconds and the average posttreatment PT was 15.1 seconds following a single dose of rFVIIa.[35,36]

rFVIIa has been used during and after liver transplantation with effective hemostasis achieved. There have been reports of successful preoperative and postoperative administration of rFVIIa to prevent bleeding during liver transplantation.[37,38] Shami et al[39] reviewed their experience with rFVIIa before liver transplantation in patients with fulminant liver failure. rFVIIa was more effective than FFP in transiently correcting laboratory parameters of coagulopathy, was associated with less frequent anasarca, permitted the performance of invasive procedures, and was associated with slightly better overall survival. Another pilot study on transfusion requirements in liver transplantation was used to assess the effects of rFVIIa on coagulation variables, and thromboelastography was used to monitor hemostasis during liver transplantation. Compared with the control group, there was significant shortening of the PT and activated partial thromboplastin time (aPTT). The mean PT improved from 21.8 to 11.7 seconds, and the mean aPTT improved from 38.5 to 33.7 seconds in the study group following administration of rFVIIa.[40]

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