Hemophilia prothrombin complex concentrate

Factor IX Replacement Hemophilia B therapy may include recombinant (produced via transfection of mammalian cells with the human factor IX gene) or plasma-derived (concentrate from pooled plasma) factor IX (see Table 64-2). Guidelines for choosing the factor-concentrate formulation for hemophilia B are similar to the guidelines for hemophilia A. However, older-generation factor IX concentrates containing other vitamin K-dependent proteins (e.g., factors II, VII, and IX), called prothrombin complex concentrates (PCCs), have been associated with thrombogenic side effects. Consequently, these products are not first-line treatment for hemophilia B.11... 

Treatment algorithm for the management of patients with hemophilia A and factor VIII antibodies. BU, Bethesda unit PCC, prothrombin complex concentrate a PCC, activated prothrombin complex concentrate. 

Inhibitor formation has been observed in only a few patients with factor XI deficiency. Like patients with hemophilia A and B, these patients may be treated with prothrombin complex concentrates or recombinant factor Vila (2). 

This may explain the effectiveness of treating patients with hemophilia who have inhibitors with high doses of factor VIII. Another approach involves the use of prothrombin complex concentrate to treat bleeding episodes in patients with factor VIII inhibitors (38) however, thromboembolic complications related to higher doses of prothrombin complex concentrate have been described, although these are relatively rare (39,40). Thrombotic events are extremely rare when highly purified factor IX is used. Activated prothrombin complex concentrate is also effective in patients with factor VIII inhibitors (41). Serious complications are rare, but disseminated intravascular coagulation has been reported (42). 

The administration of prothrombin complex concentrate to reverse anticoagulant treatment has been associated with thrombotic complications, such as disseminated intravascular coagulation (8). However, such complications have typically occurred in patients with liver failure or after repeated treatment, such as in patients with hemophilia B treated with prothrombin complex concentrate (9). 

Before the high-purity products were approved for use, hemophilia B patients had been treated with factor IX concentrates that also contained other vitamin K-dependent proteins (factors II, VII, and X), known as prothrombin complex concentrates (PCCs). These products contain small amounts of activated factors generated during processing, and their use has been associated with thrombotic... 

Prothrombin complex concentrates are available in three main types the most effective are four-factor concentrates containing factors II, VII, IX, and X. Three-factor concentrates (mainly in use in the USA) lack factor VII and are less effective in reversing oral anticoagulation therapy. The third type consists of activated products, such as factor VIII inhibitor bypassing activity (FEIBA) these products are not indicated for reversal of oral anticoagulation, but they are indicated for treatment of inhibitors (anti-factor VIII antibodies) in patients with hemophilia A [31 ]. FEIBA is associated with thrombotic events [67 ]. 

Despite cases of transmission of hepatitis C associated with intravenous immunoglobulin in the 1990s, no cases of transmission of hepatitis, HIV, or Creutzfeldt-Jakob disease have since been reported with immunoglobulins [6 J. Before 1996, PCCs (prothrombin complex concentrates) were associated with minimal risk of transmission of infective agents [7 ]. There are no documented cases of viral transmission in patients with von Willebrand disease or hemophilia A treated with Haemate P/Humate P in over 25 years of clinical experience in Europe and more than 17 years in the USA [ ]. In the IMPACT-1 and IMPACT-2 trial in 124 patients there were no cases of HIV, hepatitis, or human B19 virus conversion. Furthermore, no cases of viral transmission have been reported during 30 years of post-marketing surveillance of Cl-esterase inhibitor concentrate [9, 10 ]. 

Hematologic Historically, there was concern that prothrombin complex concentrates were associated with thrombotic events such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and disseminated intravascular coagulation. These events resulted mainly from the use of prothrombin complex concentrates as source of factor IX in patients with hemophilia B, and in particular after surgery, but the reported incidence is low and there is considerable evidence that the risk of thrombosis has been minimized with current prothrombin complex concentrates by reduced use of activated factors and the... 

Treatment options for patients with inhibitors are high dosages of clotting factor or recombinant factor Vila for both hemophilia A and B or, in the case of hemophiha A, porcine factor VlllrC or activated prothrombin complex (37). Regular administration of intermediate or low-dose factor Vin concentrates leads to the rapid disappearance of factor VIII inhibitors in some high responders (27) this is thought to be due to the development of immune tolerance. 

If the inhibitor activity is under 10 Bethesda units/ml, patients can be treated with increased doses of factor VIII or IX concentrates (43). In addition, patients with hemophilia A with low or intermediate antibody titers can also be treated with porcine factor VIII (43). However, hemorrhagic episodes in patients with antibody activity over 10 Bethesda units/ml may result in life-threatening hemorrhage that cannot be treated by conventional therapy (26,43). Prevention or treatment of clinically significant bleeding episodes in these patients can be achieved by using so-called bypassing therapies, such as recombinant factor Vila and activated prothrombin complex (23/26,43). Recombinant factor Vila is both effective and safe in the treatment of inhibitors directed to either factor VIII or IX (44,45). 

---