A prothrombin activity level of ~10% has been identified as the minimum level required for hemostasis per multiple national registries.27 However, to achieve and maintain hemostasis, FII troughs of 20% to 30% are recommended. The ideal method for replacement would be with a prothrombin concentrate. Unfortunately, prothrombin deficiency is one of the few RBDs without a dedicated factor concentrate for replacement.36 The mainstay of treatment for acute bleeding events or long-term prophylaxis remains prothrombin complex concentrates (PCC) or fresh frozen plasma (FFP).
FFP infusions at 15-20 ml/kg per dose can be used for acute bleeding and are expected to raise FII activity level by 25%.28 To maintain hemostasis in the post-surgical setting or in cases of severe bleeding, FFP at 3-10 ml/kg every 12-24 hours is advised to maintain safe and adequate correction.28,36,37 However the potential for volume overload with repeated FFP infusions could limit use in some patients with volume restrictions. The use of PCCs should be considered in these cases.
In many countries, FFP is a plasma-derived product that is tested for viral contamination but is not usually virally-inactivated. In some countries, pathogen-reduced FFP via methylene blue or solvent/detergent treatment is available. For example, Octaplas (Octapharma; Hoboken, NJ) is a solvent/detergent-treated pooled plasma product available for the replacement of multiple coagulation factors.38 In the United States, this product is currently FDA-approved for patients with liver disease or patients undergoing cardiac or liver transplant only. Some blood banks provide donor-retested FFP produced from a single unit of plasma. In this case, the donor must return and test negative on a second donation for the first donation to be released.
PCCs can be dosed at 20-40 units/kg for acute bleeding, or 20-40 units/kg once weekly for prophylaxis, to maintain a FII trough of >10%.28,36,39,40 For major surgery, dosing of PCC at 20-40 units/kg before surgery followed by 10-20 units/kg every 48 hours post-operatively has been recommended.28,36 FII activity levels do not increase significantly during pregnancy, and infusion of PCCs at 20-40 units/kg is recommended prior to delivery for women with severe prothrombin deficiency.41 Dosing of PCCs is based on FIX units. Doses of PCC at 20-40 (FIX) units/kg is expected to raise plasma FII activity level by 40-80%.39 The mean in vivo recovery of FII using Kcentra® (CSL Behring; King of Prussia, PA) is reported as ~2% per 1 unit/kg of Kcentra infused for acute bleeding and surgery.
PCCs contain FII, VII, IX, and X to varying amounts. For instance, 3-factor PCCs such as Bebulin® VH (Shire, Lexington, MA) contain negligible amounts of FVII, while 4-PCC product Kcentra® is labeled as such due to >10% FVII content. Differences in factor content not only varies between products but also from lot to lot. The major component of Bebulin® VH is FX (FX > FII >FIX) whereas, the major component of Profilnine® SD (Grifols; Los Angeles, CA) is FII (FII > FIX > FX). Alloantibodies to FII in prothrombin deficiency have not been reported.
PCCs are plasma-derived products that are virally inactivated via pasteurization, nanofiltration, and solvent/detergent methods. Treatment with PCCs may lead to accumulation of multiple coagulation factors that could potentially increase the risk of thrombosis, particularly in cases where frequent high doses are given.19,42
Cryoprecipitate is not an option for bleeding in prothrombin deficiency due to the lack of any prothrombin in the product.
Anti-fibrinolytic agents are often used for mild bleeding symptoms or minor surgical procedures.
Hormonal therapies containing estrogens with or without progesterone in females with menometrorrhagia and severe prothrombin deficiency (prothrombin activity level <5%) has been beneficial in reducing menstrual blood loss.5
Comprehensive management of prothrombin deficiency and other rare bleeding disorders is available at hemophilia treatment centers (HTCs) throughout the United States and Europe.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
