In short
Prothrombin is a human clotting factor that is part of prothrombin complex concentrate (PCC), a medicine used to reverse the effects of blood thinners. It is being studied in a Phase 3 trial of 436 participants to see whether a PCC product can reverse the anticoagulant effect of direct oral Factor Xa inhibitors before urgent surgery. Prothrombin is already authorised as a medicine and appears in this trial as the comparison treatment.
Prothrombin, also known as coagulation factor II, is a protein made by the liver that plays a central role in blood clotting. In medicine, prothrombin is given as part of a prothrombin complex concentrate (PCC), which also contains clotting factors II, VII, IX and X, together with the anticoagulant proteins C and S. The product used in the registered trial is PROTHROMPLEX TOTAL®, given as an intravenous infusion.
Key points
- Phase 3 trial (2022-503012-16-00) is testing prothrombin complex concentrate against standard of care for reversing Factor Xa inhibitor anticoagulation.
- The trial plans to enrol 436 participants who need urgent surgery or an invasive procedure.
- Prothrombin is given as a 50 IU/kg intravenous infusion in the trial.
- The main measure is effective haemostasis during surgery, assessed by the surgical team.
- The trial is currently authorised, meaning it has regulatory approval to proceed.
- Prothrombin complex concentrate is already used to reverse warfarin and is available under brand names such as Kcentra and Balfaxar.
What is prothrombin?
Prothrombin is a human clotting factor, also called coagulation factor II. It is the precursor of thrombin, the enzyme that converts fibrinogen into fibrin to form a blood clot. In the clinical trial registry, the substance is recorded as part of a fixed combination product containing human coagulation factor IX, protein C, prothrombin, human coagulation factor VII, protein S and human coagulation factor X. The product name in the registry is coagulation factor IX, II, VII and X in combination, and the medicine is authorised for use. Common brand names for prothrombin complex concentrate include Kcentra and Balfaxar. In the United Kingdom, PROTHROMPLEX TOTAL® is listed on the Mid Yorkshire Hospitals formulary as a blood-related product available from pathology.
How does prothrombin work?
Prothrombin complex concentrate works by replacing clotting factors that have become deficient because of anticoagulant treatment. The concentrate supplies factors II, VII, IX and X, as well as the antithrombotic proteins C and S, which restore the blood's ability to clot. This reverses the effect of warfarin, a vitamin K antagonist, and is used to stop bleeding or reduce the risk of bleeding when an urgent procedure is needed. The trial listed in the registry is testing whether the same approach works for patients taking direct oral Factor Xa inhibitors such as apixaban, rivaroxaban or edoxaban.
Which conditions is prothrombin used or studied for?
- Urgent reversal of warfarin anticoagulation — prothrombin complex concentrate is used to reverse the effects of warfarin in people who have acute major bleeding or need urgent surgery.
- Bleeding or risk of bleeding during urgent procedures — it is given to help stop bleeding or to decrease the risk of bleeding when an urgent procedure is needed.
- Reversal of direct oral Factor Xa inhibitors — the registered Phase 3 trial is studying prothrombin complex concentrate in patients taking apixaban, rivaroxaban or edoxaban who need urgent surgery or an invasive procedure.
How is prothrombin given?
Prothrombin complex concentrate is given by injection into a vein, as an intravenous infusion. It is administered by a healthcare professional in a hospital or clinic setting. In the registered trial, the dose is 50 international units per kilogram of body weight (50 IU/kg), given intravenously. The dose of prothrombin complex concentrate is based on units of Factor IX, and vitamin K is given at the same time when reversing warfarin.
What do the clinical trials show?
One Phase 3 trial is registered for prothrombin in the reversal of direct oral Factor Xa inhibitor-induced anticoagulation. The trial, with the EU CT number 2022-503012-16-00, is authorised and plans to enrol 436 participants. It compares TAK-330, a prothrombin complex concentrate product, with standard of care 4F-PCC in patients who need urgent surgery or an invasive procedure within 15 hours of their last dose of a Factor Xa inhibitor, or at any time if their anti-FXa levels are above a defined threshold.
The main measure in the trial is the occurrence of intraoperative effective haemostasis, assessed at the end of surgery using a four-point haemostatic efficacy scale. The assessment is made by the principal investigator, the surgeon or a qualified member of the surgical team. Prothrombin appears in this trial as the comparator, meaning the product is being used as the standard of care against which the new product TAK-330 is measured.
What side effects are known?
The most serious side effects of prothrombin complex concentrate are arterial or venous thromboembolism, which means blood clots forming in arteries or veins, and disseminated intravascular coagulation, a condition where blood clots form throughout the body's small blood vessels. Other side effects include high or low blood pressure, fast heart rate, nausea and vomiting, joint pain, headache, and changes in mental status. Hypersensitivity reactions, including anaphylaxis, can occur, and there is a risk of transmission of infectious agents.
Drug interactions
Prothrombin complex concentrate reverses the effects of warfarin. According to the Cleveland Clinic patient information, interactions are not expected with this medication, although the list may not describe all possible interactions.