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PubMed1978

Prothrombin complex concentrates. Use in treatment of hemophiliacs with factor VIII inhibitors.

The development of factor VIII inhibitors has been a major problem in the management of hemophiliacs. The use of prothrombin complex concentrates (PCC) has been advocated as a method of overcoming this problem. We utilized PCC in the treatment of nine hemophiliac patients who had significant levels of inhibitor. Acute bleeding episodes were successfully treated in all nine patients. Single infusions of PCC were usually adequate for control of joint and soft tissue bleeding episodes, while multiple infusions were usually required for more serious hemorrhages. In addition, programs of repeated infusions were used to heal chronically inflamed joints in three patients. The only side effect of treatment was one episode of asymptomatic elevation of liver function values that resolved spontaneously. There were no thrombotic events associated with the PCC infusions. Therapy with PCC is recommended for the management of hemophiliacs with factor VIII inhibitors.

Adolescent↗

PubMed1991

The factor VIII bypassing activity of prothrombin complex concentrates: the roles of factor VIIa and of endothelial cell tissue factor.

An experimental model incorporating cultured endothelial cells (EC) was used to study the "factor VIII bypassing" activity of prothrombin complex concentrates (PCC), a property exploited in the treatment of hemophiliacs with alloantibodies to factor VIII. Two PCC preparations were ineffective as stimuli of tissue factor expression by EC. However, incubation with a combination of PCC plus endotoxin (lipopolysaccharide, LPS) or tumor necrosis factor (TNF) induced much greater tissue factor expression than was seen in response to either substance alone. PCC expressed an additional direct procoagulant activity at the EC surface, which could not be attributed to either thrombin or factor Xa, and which was diminished by an anti-tissue factor antibody. Therefore factor VIIa, which was detectable in both PCC preparations, likely provided this additional direct procoagulant activity at the EC surface. We also excluded the possibility that coagulation proteases contained in or generated in the presence of PCC are protected from inactivation by AT III. Therefore, PCC can indirectly bypass factor VIII by enhancing induced endothelial tissue factor expression, and also possess direct procoagulant activity, probably mediated by factor VIIa.

Amino Acid Sequence↗

PubMed1984

Inhibitor treatment using unactivated prothrombin complex concentrates: the Pennsylvania experience--1978-1982.

Data were analyzed on 48 patients with Factor VIII:C inhibitors, 31 of whom were treated with more than 6.7 million units of unactivated prothrombin complex concentrates (PCC) during the years 1978 through 1982 for more than 1,000 bleeding episodes. Twelve of the patients who were on home therapy used 3.1 million units, or 47% of the total PCC usage. Only one patient had a severe life-threatening allergic reaction to PCC, and no thrombotic complications were observed, supporting the concept that these products are safe when used in doses of 50-75 u/Kg. Fifty percent of hemarthroses and 65% of muscle hemorrhages were treated with no more than two infusions per episode, suggesting that PCC was effective at least half of the time. Comparison of the number of days hospitalized per year for inhibitor and non-inhibitor patients also indicated that PCC was effective, although not as effective as AHF therapy in non-inhibitor patients. The life styles of PCC treated patients were comparable to what might be expected for non-inhibitor patients with severe disease, and no deaths were attributed to PCC treatment failure during the four year period. Of major concern, however, was the cost of therapy. In 1981-82, the average use of PCC for inhibitor patients was 106,000 units per treated patient per year, compared to 40,000 AHF units for all Factor VIII deficient treated patients per year. Much of this usage was for recurrent hemarthroses in a small number of patients requiring eight or more infusions per episode.

Antigens↗

PubMed1978

Use of prothrombin complex concentrates in hemophiliacs with inhibitors: clinical and laboratory studies.

Nine patients with severe classic hemophilia and inhibitors against factor VIII were treated for 156 bleeding episodes with 503 infusions of Proplex, Konyne, or Auto-Factor IX, three preparations of prothrombin complex concentrates (PCCs). Approximately two thirds of the bleeding episodes were managed successfully. Although the prothrombin time (PT) and partial thromboplastin time (PTT) were shortened after most PCC infusions, there was no evidence of disseminated intravascular coagulation. The degree of shortening of PT or PTT was not related to the particular PCC preparation used, dose, or cessation of hemorrhage. All PCC preparations contained activated clotting factors, as manifested by their ability to shorten the PTT of normal plasma, factor-VIII-deficient plasma, and factor-IX-deficient plasma. Shortening, which was greater with Auto-Factor IX than with the other products, was inhibited partially by a factor IX antibody and blocked completely by prolonged incubation with plasma. Although the nature of the procoagulant material in PCCs is uncertain, these products are of proven benefit to hemophilic patients with high-titer inhibitors. Side effects have been minimal and inhibitor titers have not risen.

Adolescent↗

PubMed1993

Acute myocardial infarction complicating prothrombin complex concentrate therapy in an 8-year-old boy with hemophilia A and factor VIII inhibitor.

PURPOSE: An 8-year-old boy with mild hemophilia A and inhibitors developed an acute myocardial infarction during treatment with prothrombin complex concentrates. CONCLUSIONS: This rare complication warrants restriction of dosage and length of treatment with these products to the recommended guidelines. It also appears that noninvasive cardiac monitoring of these patients is beneficial.

Blood Coagulation Factors↗

PubMed1991

Use of factor VII-deficient beagles bred by artificial insemination to evaluate mechanisms of thrombosis associated with prothrombin complex concentrates.

Artificial insemination with frozen semen was used to breed beagles homozygous for a deficiency in clotting factor VII, with plasma concentrations of 2-3% of normal adult beagle pooled plasma. The factor VII-deficient beagles were used to determine if factor VII activity has a role in the thrombogenic activity of prothrombin complex concentrates (PCCs) containing factors II, IX and X by evaluating changes in selected indicators of thrombogenicity. No differences were seen between the responsiveness of the factor VII-deficient and normal beagles, indicating that the thrombogenic activities of PCCs are mediated via effects on the intrinsic clotting system.

Animals↗

PubMed1976

Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal.

A randomised clinical trial was undertaken to compare the value of a factor II, IX, and X concentrate (Prothromplex) with intravenous vitamin K1 (2-5 mg) in reversing an overdose of oral anticoagulants. Rapid partial correction of the prothrombin time, partial thromboplastin time, and the clotting factor assays were observed with the concentrate, but these changes were not always sustained. In contrast vitamin K1 did not show any great effect at two hours but at 24 hours there was always over-correction despite the conservative dosage, prothrombin times being shorter than the therapeutic range. The prothrombin complex concentrate provides a quicker, more controlled but less sustained method of reversing the coumarin defect than vitamin K1. But there remains a significant risk of hepatitis even with a preparation for which strenuous efforts have been made to minimise this risk by screening for hepatitis B virus. The risk should be carefully considered before such concentrates are infused in non-urgent conditions.

Anticoagulants↗

PubMedDate not supplied

Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models.

The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animals studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given s bolus injections 5 min and 3.0 mg/kg neutralized the r-hirudin-induced prolongation and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

Animals↗

PubMed1996

The effect of non-activated prothrombin complex concentrate (Proplex ST) on intraperitoneal hematoma in a hemophilia A patient with a factor VIII inhibitor.

A 28-year-old severe hemophiliac with a factor VIII inhibitor was admitted to our hospital with a massive and serious intraperitoneal hematoma. He was a high-responder patient showing maximal serum inhibitor levels as high as 255 Bethesda Units/ml (BU/ml). He was successfully treated with "bypass therapy" using a prothrombin complex concentrate (PCC).

Adult↗

PubMed1997

Measurement of factor VII and of activated factor VII in healthy individuals and in prothrombin complex concentrates.

We established reference ranges for factor VII clotting activity (FVII:C), factor VII amidolytic activity (FVII:AM), and activated factor VII (FVIIa) in 102 healthy individuals. The reference ranges were 65-160 U/100 ml, 70-165 U/100 ml, and 30-170 mU/ml, respectively (2.5 and 97.5 percentiles). Freezing and thawing of the plasma samples had no influence on the assay results. Due to the small sample size, the results were not influenced by gender, age, smoking habits, and oral contraceptive use. The plasma levels of FVII:C, FVII:AM, and FVIIa were significantly correlated with each other. The significant correlation between FVIIa and FVII:AM indicates that FVIIa is not completely independent of circulating FVII mass. There was also a significant, though weak, correlation between FVIIa and FVII:C/FVII:AM ratios. Sixteen batches of prothrombin complex concentrates (PCC) from 3 manufacturers were also analysed. FVIIa could be detected in all preparations, with considerable variations from batch to batch. In contrast to the results obtained in plasma from normal individuals, there was a close correlation between FVIIa and FVII:C/FVII:AM ratios. The preparations could be characterized by their FVII and FVIIa potencies and by their FVII:C/FVII:AM ratios. In PCC, FVII:C was very strongly correlated with FVIIa, whereas no significant correlation was observed between FVII:AM and FVII:C and between FVII:AM and FVIIa, respectively. These results demonstrate that the FVII:C assay used is sensitive for detecting FVIIa. Thus, we cannot confirm that FVIIa sensitivity of one-stage clotting assays for FVII:C is low when a rabbit thromboplastin and a non-adsorbed FVII-deficient plasma is used.

Adolescent↗

PubMed1977

The activation of prothrombin complex concentrates by calcium in vitro.

The activation of prothrombin concentrate mixtures incubated "in vitro" was investigated. "Activation" was assessed by the correcting effect of suct mixtures on the APTT of a test plasma containing a factor VIII inhibitor and also by the generation of free thrombin. Thrombin itself was found to have insignificant activating effect. Prothrombin concentrates incubated with near-physiological levels of calcium appeared to correct the abnormal APTT to an increasing degree as the calcium concentration was increased. Free thrombin was generated with calcium cencentrations greater than those required for APTT correction. The activation process could be stopped at any stage by adding citrate which removed ionized calcium from the incubation mixture.

Blood Coagulation Tests↗

PubMed1979

Effect of treatment with activated prothrombin complex concentrate (FEIBA) on factor VIII-antibody level.

The influence of treatment with an activated prothrombin complex preparation (FEIBA) on the antibody level was studied in 10 haemophiliacs with an antibody to factor VIII. The antibody level was observed to rise at least once in five patients, while in the remaining five patients no rise occurred. In all, 6 out of 31 treatments were followed by an anamnestic rise of the antibody level, corresponding to 19.4%. A rise of the inhibitor level following FEIBA treatment is likely to occur in patients who show a marked antibody rise after factor VIII treatment (good responders), but have a low antibody level at the time of treatment. High doses of FEIBA and simultaneous of red cells may also enhance the likelihood of an anamnestic response. Stimulation of antibody production is probably due to the presence of small amounts of factor VIII in this preparation.

Antibodies↗

PubMed1977