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

Platelet Disorders

There is evidence supporting the role of the factor VII tissue-dependent coagulation system in the initial platelet activation for coagulation.[51] Infusion of rFVIIa has been shown to shorten the bleeding time in rabbits. Kristensen et al[52] reported a reduction in bleeding time in 55 (52.4%) of 105 patients with thrombocytopenia who received an infusion of rFVIIa. No major adverse effects related to the drug study were observed with the exception of an anaphylactoid reaction in 1 patient. Nine infusions of rFVIIa were given to 8 patients with thrombocytopenia with overt bleeding. Bleeding decreased in all patients and stopped in 6.[52]

The mechanism of action of rFVIIa, ie, increased thrombin generation on the membrane of activated platelets, might suggest potential use of rFVIIa in thrombocytopenia and thrombocytopathy.[53] Kjalke et al[54] studied the effect of rFVIIa in promoting thrombin generation using 2 in vitro models, a reconstituted model and a plasma-based model. In both systems, a platelet density—dependent lowering of the thrombin generation peak was observed. The magnitude of rFVIIa was most pronounced in the plasma-based model. These data suggested that rFVIIa might help adhesive hemostasis at low platelet densities by increasing the initial thrombin generation, thereby compensating for the low platelet number.[54]

rFVIIa seems effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia.[34,55,56,57,58,59] In a report about 7 patients with congenital bleeding disorders (Glanzmann thrombasthenia, 5; Bernard-Soulier syndrome, 1; platelet-type pseudo—von Willebrand disease [vWD], 1; acquired thrombocytopathy associated with myelodysplasia and uremia, 2), rFVIIa was well tolerated.[60] There was 1 published case of thromboembolism as a postoperative complication in one of the patients.[60] A 68-year-old man with Glanzmann thrombasthenia and recurrent nonulcer duodenal bleeding had to undergo duodenectomy because of persistent bleeding. rFVIIa was given, and surgery was done successfully while he was receiving rFVIIa. Neither major blood loss nor other complications occurred postoperatively.[61] There has been a case report of the use of rFVIIa to treat postoperative hemorrhage following lumbar diskectomy in a 33-year-old woman with Glanzmann thrombasthenia and anti-HLA alloantibodies.[59] Successful control of recurrent nosebleeds in 2 teenage boys with Bernard-Soulier syndrome has been reported.[62]

Tengborn and Petruson[63] describe a 2-year-old boy with Glanzmann thrombasthenia who was treated successfully with rFVIIa for severe refractory epistaxis. Poon et al,[58,64] who administered rFVIIa to 4 pediatric patients with Glanzmann thrombasthenia for 24 uncontrollable bleeding episodes and 1 surgical prophylaxis, reported bleeding control in all but 1 bleeding episode. van Buuren and Wielenga[61] reported the use of rFVIIa in a patient with Glanzmann thrombasthenia and mild thrombocytopenia during a Billroth II gastrectomy for recurrent duodenal bleeding.

d'Oiron et al[65] used rFVIIa as first-line therapy in 3 patients with Glanzmann thrombasthenia and anti—platelet glycoprotein IIb/IIIa isoantibodies who were scheduled for invasive procedures. The clinical efficacy and tolerance was excellent in 2 patients, but the third patient had prolonged traumatic nasal bleeding and a thromboembolic complication 5 days after the rFVIIa therapy was discontinued.[65] International registry data on the use of rFVIIa in congenital platelet disorders show that it is relatively safe and effective when used in Glanzmann thrombasthenia. The registry received reports about 28 patients with Glanzmann thrombasthenia, and there were 2 adverse effects reported, which were thrombotic events.[58,65,66] One of the shortcomings of the registry data is the heterogeneity of the treatment protocol, including dosage, number of doses used, duration of treatment, and mode of treatment. The data are not yet sufficient to define the optimal regimens for various indications such as the type of bleeding or the type of procedure.[58]

Gerotziafas et al[67] describe 2 patients with severe thrombocytopathy and life-threatening bleeding who were treated successfully with rFVIIa. One was a 75-year-old man with WaldenstrF6m macroglobulinemia treated with fludarabine and who had severe nasal bleeding secondary to autoimmune thrombocytopenia that was not controlled by conventional means. The second patient was a 52-year-old woman with precursor B-cell lymphoblastic leukemia and severe thrombocytopenia secondary to chemotherapy, complicated by massive gastrointestinal bleeding. Bleeding was controlled promptly in both patients, and no adverse effects due to rFVIIa were observed.[67] Severe bleeding due to acquired thrombocytopathy related to myelodysplastic syndrome was reported to have been controlled effectively with rFVIIa.[68]

Meijer et al[68] describe a 76-year-old man with colon carcinoma and myelodysplastic syndrome who had surgery for liver metastasis and developed profuse postoperative gastrointestinal bleeding on the eighth day that did not respond to platelet concentrates, desmopressin, and tranexamic acid. Bleeding promptly stopped with administration of rFVIIa.[68]

rFVIIa was reported to have been used in a Jehovah's Witness with autoimmune thrombocytopenia who needed a splenectomy. Postsplenectomy hemorrhage developed, which was controlled successfully with rFVIIa.[59] Because rFVIIa is not derived from blood, the product is acceptable to Jehovah's Witnesses.[69,70]

High-dose rFVIIa is postulated to act on platelets and enhance thrombin generation, which might help provide hemostasis in patients with thrombocytopathies by several mechanisms.[71] Enhanced thrombin generation provides a strong signal for recruitment of other platelets and might provide mechanisms for bypassing the specific defect in thrombocytopathy. Thus, high-dose rFVIIa has been used to correct bleeding in patients with various thrombocytopathies, including Glanzmann thrombasthenia, Bernard-Soulier syndrome, and uremia.

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