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PHARMACOLOGY: Pharmacodynamics: The coagulation factors II, VII, IX and X, are synthesized in the liver with the help of vitamin K, are commonly called the Prothrombin Complex.
Factor VII is the zymogen of the active serine protease factor VIIa by which the extrinsic pathway of blood coagulation is initiated. The tissue factor/factor VIIa complex activates coagulation factors X and IX, whereby factors IXa and Xa are formed. With further activation of the coagulation cascade, prothrombin (factor II) is activated and transformed to thrombin. By the action of thrombin, fibrinogen is converted to fibrin, which results in clot formation. The normal generation of thrombin is also of vital importance for platelet function as a part of primary haemostasis.
Isolated severe deficiency of factor VII leads to reduced thrombin formation and a bleeding tendency due to impaired fibrin formation and impaired primary haemostasis. Isolated deficiency of factor IX is one of the classical haemophilias (haemophilia B). Isolated deficiency of factors II or X is very rare, but in severe forms they cause a bleeding tendency similar to that seen in classical haemophilia.
Acquired deficiencies of the vitamin K dependent coagulation factors occur during treatment with vitamin K antagonists. If the deficiency becomes severe, a severe bleeding tendency results, characterized by retroperitoneal or cerebral bleeds rather than muscle and joint haemorrhage. Severe hepatic insufficiency also results in markedly reduced levels of the vitamin K dependent coagulation factors and a clinical bleeding tendency which, however, is often complex due to the simultaneous occurring low-grade intravascular coagulation, low platelet levels, deficiency of coagulation inhibitors and disturbed fibrinolysis.
The administration of human prothrombin complex concentrates provides an increase in plasma levels of the vitamin K-dependent coagulation factors and can temporarily correct the coagulation defect of patients with deficiency of one or several of these factors.
Paediatric population: There are insufficient data to recommend the administration of Prothromplex TOTAL 600 IU in children.
Pharmacokinetics: See Table 2.
Click on icon to see table/diagram/imageToxicology: Preclinical safety data: The factors of the human prothrombin complex (in a concentrate) are normal components of human plasma and behave like endogenous coagulation factors. Since higher doses lead to volume overload, toxicity testing after single administration has no significance. Toxicity studies after repeated administration in animal tests are unfeasible since interference through the development of antibodies to heterologous proteins occurs.
Since human coagulation factors are not seen as cancerogenic or mutagenic, experimental studies, especially in heterologous species, were not deemed necessary.
