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PubMed1998

Levels of prothrombin activation peptide F1+2 in patients with a bleeding tendency.

Numerous recent publications point to significant improvements in haemostasis in the bleeding patient suffering from haemophilia with inhibitors when a recombinant activated factor VII (rFVIIa) molecule is administered in high doses. In theory, activated factor VII (FVIIa) is believed to initiate haemostasis through its physiological interaction with tissue factor at sites of cellular injury, whereby factor X (FX) activation and, in consequence, thrombin formation is amplified. There has been speculation, however, whether high circulating FVII procoagulant (FVII:C) levels may induce systemic coagulation activation. The present retrospective investigation was undertaken to study, ex vivo, the influence of treatment with rFVIIa as assessed by the sensitive marker of prothrombin conversion, prothrombin fragment F1+2, in plasma samples. Study subjects consisted of: seven people suffering from thrombocytopenia participating in a study of the influence of rFVIIa on the bleeding time, in whom serial plasma samples had been collected before and subsequently at 10, 60 and 180 min after infusion of rFVIIa; four haemophilia A patients with inhibitors to FVIII undergoing surgery; two haemophilia A patients with inhibitors treated with rFVIIa for minor bleedings on 16 occasions in whom plasma samples had been collected before and 10-15 min after rFVIIa infusion; and two FVII-deficient patients undergoing treatment with rFVIIa. A group of seven haemophilia A patients with no signs of inhibitors subjected to a pharmacokinetic study of a plasma-derived FVIII concentrate served as controls. In the group of thrombocytopenic patients our results showed a mean increase in F1+2 following doses of 50 microg/kg body weight and 100 microg/kg body weight of rFVIIa of 1.1 and 1.4 nmol/l, respectively, with a gradual increase over time, but there was no significant correlation between FVII:C and the corresponding values of F1+2. During and after haemophilic inhibitor surgery, a mean increase in F1+2 of 1.44 nmol/l (range 0.6-3.2 nmol/l) was found, whereas 16 matched samples collected during treatment for minor bleedings showed a mean increase in F1+2 of 0.10 nmol/l (range -0.12 to 0.20 nmol/l). In FVII-deficient individuals, the mean rise in F1+2 was <0.10 nmol/l. In the control group, the mean elevation of F1+2 was 0.13 nmol/l (range -0.5 to 0.7 nmol/l). Hence, our results show that only discrete changes in F1+2 follow administration of rFVIIa.

Adult↗

PubMed1997

[Effects of aprotinin on heparinized whole blood activated clotting time and whole blood prothrombin time].

When aprotinin is used during cardiopulmonary bypass, there is a prolongation of the activated clotting time (ACT), which is used to monitor heparinization. The aim of this study was to observe the effects of aprotinin and heparin on whole blood ACT and whole blood prothrombin time (BPT). The results showed that when kaolin was used as the contact activator, the intrinsic clotting system was also inhibited by aprotinin, the observed ACTs with various dose aprotinin and concomitant heparin were significantly prolonged (Q = 0.757, P < 0.01). There was a dose-dependent prolongation of BPT by heparin (r = 0.985, P < 0.01). However, the heparin-mediated prolongation of BPT was not enhanced by aprotinin. The authors conclude that aprotinin prolongs heparinized whole blood activated clotting time but was not whole blood prothrombin time.

Adult↗

PubMed1999

Double fluorescent-amplification refractory mutation detection (dF-ARMS) of the factor V Leiden and prothrombin mutations.

Simultaneous fluorescent [F] detection of the factor V Leiden (G1691A) and the prothrombin 3'-untranslated region (G20210A) mutations were performed in a single tube polymerase chain reaction (PCR). Amplification refractory mutation detection system (ARMS) formed the basis of this assay design. Fluorescent-labelled primers incorporated into amplicons during the reaction facilitated detection directly by GeneScan analysis without further manipulation. To test the efficacy of this double [F]-ARMS (dF-ARMS) method, 48 patients with unexplained thrombotic tendencies were investigated for their factor V Leiden and prothrombin genotypes. These results corresponded exactly with data achieved using the more conventional methods of restriction fragment length polymorphism (RFLP)-PCR and direct DNA sequencing. Three out of the 48 patients in this group were found to be compound heterozygotes.

Alleles↗

PubMed2007

Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor.

Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 10-14 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs.

Adolescent↗

PubMed2002

Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose.

We investigated the effect of prothrombin complex concentrate (PCC) on the international normalized ratio (INR) and blood coagulation system in two emergent patients treated with warfarin for secondary prevention of cardioembolic stroke due to nonvalvular atrial fibrillation. An 80-year-old woman developed massive subcutaneous hemorrhage and swelling on her right upper extremity with weak pulsation of the right radial artery and had an INR above 10. An 83-year-old man had pleural effusion with an INR value of 6.69 and pleural puncture was immediately required. We administered 500 IU of PCC to the two patients (17.2 IU/kg and 12.5 IU/kg) with 10 mg of vitamin K. The INR decreased to 1.12 and 1.85, respectively, with an increase of plasma levels of protein C and coagulant factors IIa, VIIa, IXa, and Xa 10 min after administration. The plasma levels of the thrombin-antithrombin III complex increased (from 4.0 to 12.0 micro g/l and from 0.5 to 28.9 micro g/l, respectively, normal value <3.0), but prothrombin fragment 1+2 increased minimally 10 min after administration (from 0.4 to 1.1 nmol/ml and from 0.4 to 0.7 nmol/ml, respectively, normal value 0.4-1.4 nmol/ml). Plasma levels of D-dimer remained unchanged. The massive subcutaneous hemorrhage in the former patient improved in 14 days. Anticoagulation was restarted in the latter patient after 14 days of PCC administration. There were no embolic episodes during the month after PCC administration. In conclusion, a small amount of PCC may be effective in immediately correcting increased INR levels with increased plasma levels of protein C and coagulant factors IIa, VIIa, IXa, and Xa and may partially activate the coagulation system without any effects on plasma levels of D-dimer.

Aged↗

PubMed2004

A case of systemic lupus erythematosus with postpartum hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and concomitant high phosphatidylserine-dependent anti-prothrombin antibody levels.

In August 1994, a 19-year-old woman presented to her dermatologist with a slight fever, arthralgia, and a butterfly rash. Discoid lupus erythematosus was suspected, and serological testing yielded positive results for antinuclear antibody. She was diagnosed with systemic lupus erythematosus without organ failure and was treated with only nonsteroidal antiinflammatory drugs. She became pregnant in June 2001, at age 26. In November her obstetrician noted that she had severe hypertension, edema of the low limbs, and proteinuria. On admission, she was diagnosed with severe preeclampsia, and cesarean section was performed. On hospital day 3 the patient developed sudden epigastric pain and vomiting. Laboratory tests revealed thrombocytopenia, liver dysfunction, and microangiopathic hemolytic anemia, leading to a diagnosis of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Plasma exchange was performed for 5 days. The thrombocytopenia, liver dysfunction, and proteinuria diminished quickly. Later testing revealed a high titer of plasma phosphatidylserine-dependent anti-prothrombin antibody. This case is useful for exploring the relations between SLE, HELLP syndrome, and anti-prothrombin antibody.

Journal Article↗

PubMed1985

Two separable steps in the development of platelet prothrombin-converting activity.

Platelets catalyze conversion of prothrombin to thrombin in the presence of coagulation Factors Va and Xa. Bovine Factor Va was found to bind to human and bovine platelets washed by centrifugal pelleting. Factor Va was bound to sites varying in affinities but only those sites saturated at approximately 1 mM are active. Platelets in citrate or benzamidine-anticoagulated plasma or those washed by gel filtration bound substantially less Factor Va with these affinities, indicating that the binding sites increased in number or affinity or both during the centrifugal pelleting and redispersal. Thrombin production catalyzed by platelets with developed binding sites started at a low initial rate but after a lag period rapidly reached a maximum rate. Addition of 0.25 mM dinitrophenol increased the lag period and decreased the maximum rate obtained concomitantly with the reduction in ATP levels. Neither dinitrophenol nor its induced depletion of the ATP levels reduced Factor Va binding. Therefore, the activation of platelet prothrombin-converting activity was separated into two steps; one being the development of the high-affinity binding sites and the other a step partially dependent on sufficient levels of ATP within the platelet.

Adenine Nucleotides↗

PubMed1991

Safety of vapour heated prothrombin complex concentrate (PCC) Prothromplex S-TIM 4.

The risk of infection after application of vapour heated prothrombin complex concentrate PROTHROMPLEX S-TIM 4 (PCC) was investigated in patients undergoing cardiovascular surgery. The study was conducted according to the recommendations of the International Committee on Thrombosis and Hemostasis (ICTH) with the exception that most patients required other blood products in addition to PCC. Twenty-One patients were eligible to test for the risk of acquiring hepatitis NANB (ALT-levels) and samples from 12 patients were available that could be screened for anti-HCV. Twenty patients qualified for evaluation of the risk of developing hepatitis B, and 67 patients qualified to test for HIV-1-Infection. None of these patients showed any signs of infection. Vapour heating of prothrombin complex concentrate seems to lower the risk of transmitting viral diseases considerably.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Isolation and partial characterization of a prothrombin-activating enzyme from the venom of the Australian rough-scaled snake (Tropidechis carinatus).

A prothrombin activator from the venom of Tropidechis carinatus has been isolated by means of gel filtration and benzamidine-based affinity chromatography, a novel use of the latter technique. Two bands possessing prothrombinase activity were obtained from the affinity chromatography procedure and designated A1 and A2. The bulk of the enzyme activity was recovered in peak A2 which represented 27-31% of the starting activity and a 14-16-fold purification. The venom contained, in total, around 5% by weight of the two isoforms of the prothrombin activator. The two fractions were electrophoretically similar on polyacrylamide electrophoresis, migrating with a mol. wt of 64,500 under native conditions and as a single band of 41,500 under reducing conditions. The prothrombinase was dependent on factor Va, phospholipid and calcium ions for its activity and is, thus, a member of the type II class of prothrombinases requiring such co-factors. The enzyme did not possess any phospholipase activity nor did it cleave the substrates N-alpha-benzoyl-L-arginine-p-nitroanilide (BAPNA), N-benzoyl-L-tyrosine ethyl ester (BTEE), azocollagen or azocasein, indicating a lack of amidolytic, esterolytic and broad-spectrum protease activity.

Animals↗

PubMed2001

Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor.

UNLABELLED: Melagatran is the active form of the oral, direct thrombin inhibitor H 376/95. In several animal models of thrombosis, the antithrombotic properties of melagatran have been demonstrated, without any increase in experimental bleeding. However, as with all anticoagulants, in emergency situations, reversal of the anticoagulation may be necessary. In this study, increasing doses of activated prothrombin complex concentrate (APCC, Feiba) or recombinant factor VIIa (r-F VIIa, NovoSeven) were superimposed on high doses of melagatran, or saline, in anaesthetised rats. The haemostatic effect was evaluated in two bleeding time models and a potential prothrombotic effect was evaluated in an arterial thrombosis model. Compared with melagatran alone (0.5 micromol/kg/h), Feiba in doses of > or =25 U/kg significantly shortened the prolonged bleeding time and reduced blood loss. In addition, Feiba > or =50 U/kg when added to melagatran (2 micromol/kg/h), significantly reduced bleeding time. No potentiation of thrombus formation was observed when Feiba was added to melagatran, compared with controls. NovoSeven at high doses (2-10 mg/kg) produced a nonsignificant trend in reduction of blood loss and with the highest dose (10 mg/kg) producing only a mild nonsignificant reduction in bleeding time. The prolonged prothrombin time (PT) and the ecarin clotting time (ECT) were more effectively shortened by Feiba than by NovoSeven. In contrast, whole blood clotting time (WBCT) was more effectively shortened by NovoSeven than by Feiba. Activated partial thromboplastin time (APTT) was shortened by NovoSeven but was prolonged by Feiba. Thrombin-antithrombin (TAT) complex formation was increased in a dose-dependent fashion more effectively by Feiba than by NovoSeven. CONCLUSION: Feiba (APCC) reversed prolonged bleeding time and blood loss in rats treated with high doses of melagatran and compared with the control group thrombus formation was not potentiated. NovoSeven (r-F VIIa) at high doses had less pronounced effects on blood loss and bleeding times compared with Feiba.

Animals↗

PubMed1967

Studies on the formation of the prothrombin-converting complex.

1. It has been shown that factor V accelerates the rate of conversion of prothrombin into thrombin by activated factor X, and that this activity does not depend on the presence of phospholipid. 2. Although the mechanism by which factor V increases the rate of reaction is not clear, it seems unlikely that it is converted into an enzyme. 3. The rate of conversion of prothrombin by purified activated factor X and factor V was increased threefold in the presence of phospholipid, and it is suggested that the lipid acts by adsorbing the proteins on its surface and hence increasing the local concentration of the reactants.

Journal Article↗

PubMed1999

Management of haemophilia in patients with high-titre inhibitors: focus on the evolution of activated prothrombin complex concentrate AUTOPLEX T.

Numerous therapeutic strategies have been applied to the management of patients with inhibitors to factors VIII or IX. Different treatment approaches are analysed including prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs), porcine factor VIII concentrate, inhibitor neutralization, immune tolerance therapy, immunosuppressive regimens and recombinant factor VIIa. Clinical data are reported in the analysis of several treatments. PCCs and aPCCs have gained widespread acceptance as the standard first-line approach for patients with inhibitors. The aPCC AUTOPLEX T has achieved a high response rate with a low level of thrombotic events. Four case studies are presented in which AUTOPLEX T has been used successfully. Administration of platelet concentrate or, in elective surgery, waiting for inhibitor levels to decline are useful adjuncts to some treatments. The optimal treatment depends on the patient's inhibitor status--low responder (minimal or no increase in inhibitor levels upon administration of replacement clotting factor) or high responder (replacement clotting factor generates inhibitor production). A suggested algorithm for treating high-responder inhibitor patients is presented.

Adult↗

PubMed1981

The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial.

We designed a double-blind trial to study the effect of an "activated" prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in hemophiliacs with antibodies to factor VIII. Fifteen patients received either FEIBA or the control preparation (a nonactivated prothrombin-complex concentrate) for a total of 150 bleeding episodes (four mucocutaneous bleeding, 117 joint bleeding, and 29 muscle bleeding). In 64 per cent of the episodes, FEIBA was judged by the physician to be effective; the control preparation was perceived as effective in 52 per cent of the episodes in which it was used. Pairwise comparison of FEIBA and the control preparation for bleeding in the same joint or muscle showed a significantly better result with FEIBA (P = 0.0085). Joint mobility after the use of FEIBA was significantly improved (P = 0.006). There was a high incidence of hepatitis (three of the 15 patients) and of transient disturbances of liver function (nine of 15) during the 15-month observation period.

Adolescent↗

PubMedDate not supplied

One-stage prothrombin times and subcutaneous haemorrhagic speckling in lambs.

The one-stage prothromhin times of 100 lambs from ten different farms varied from 13 to 24 seconds with a mean of 16.6 seconds. The extent and severity of subcutaneous haemorrhagic speckling of carcases was assessed in 775 animals from the same farms and the prevalence of this lesion was similar to that found at the same works during the 1977/78 season. The means of both one-stage prothrombin times and speckling varied significantly between groups of lambs from different farms but there was no statistical association between the prevalence of speckling and the one-stage prothrombin times.

Journal Article↗

PubMed1991

Potential thrombogenicity of heat-treated prothrombin complex concentrates in Haemophilia B.

We have studied the potential thrombogenicity of two different heat-treated prothrombin complex concentrates (PCC) in patients with Haemophilia B. Seven patients were studied on nine separate occasions. Four of the patients had chronic hepatitis C (HCV) associated liver disease and three were HIV-antibody positive. The PCCs were Profilnine (Alpha Therapeutics, Thetford, UK) and 9A (Bio-Products Laboratory, Elstree, UK) and the dose administered ranged from 35 to 60 U/kg. Blood samples were taken on ten separate occasions; twice before the infusion and at 15, 40, 60, 75 and 120 min and 4, 8 and 24 h after the infusion of PCC. Investigations included prothrombin time, kaolin cephalin clotting time, thrombin time, fibrin(ogen) degradation products, factor VIII, factor IX, antithrombin III and fibrinopeptide A (FPA). Fibrinopeptide A rises were seen following two of six infusions of 9A and one of three infusions of Profilnine. On all three occasions the rise in FPA was transient, returning to baseline levels within 120 min. Plasma beta-thromboglobulin (BTG) was assayed in three patients and in one patient, the rise in FPA was followed by an increase in BTG. No other changes were observed and there were no clinical features of disseminated intravascular coagulation. Our results indicate that even with normal clinical doses of PCC, intravascular thrombin generation can occur in patients with Haemophilia B. However, this effect is inconsistent both with respect to PCC batch and patient, but may occur in the absence of HIV infection and HCV liver disease.

Blood Coagulation↗

PubMed1991

Prevalence of HIV infection in a cohort of patients with congenital coagulation defects of the prothrombin complex factors.

Twenty-seven patients suffering from congenital coagulation defects of the prothrombin complex factors were investigated: six had haemophilia B; 14, factor VII defect; four, factor X defect; and three, factor II defect. Nineteen patients (70.3%) had previously received plasma and/or clotting factors concentrates. Among these, markers of hepatitis B infection (HBV) were present in five cases (26.3%) and hepatitis C (HCV) antibodies were found in seven cases (36.8%). The HIV1 prevalence was similarly high. In fact, five patients (26.3%), previously infused with factor IX or prothrombin complex factors concentrates, developed HIV1 infection. No patient with factor VII deficiency became HIV1 positive, despite the administration of unheated factor VII concentrates and the consequent HBV and HCV contamination. In the HIV1 positive group, three patients showed a false positivity for HIV2 antibodies. Five years after seroconversion, three patients developed AIDS (stage IV) and died, one had persistent generalized lymphadenopathy (stage III), and one with post-hepatitis liver cirrhosis was asymptomatic (stage II) for HIV infection. The significant decrease in total white cells, T4 lymphocytes and platelet counts and increase of beta 2-microglobulin and neopterin levels confirmed the prognostic value of these markers for the progression of HIV1 disease. Only one HIV1 negative transfused patient developed anti-HTLV-I p19 antibodies.

Adult↗

PubMed1994

A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate.

A prospective cross-over study was carried out on 19 patients with haemophilia B. comparing the pharmacokinetics of a purified factor IX concentrate prepared by metal chelate affinity chromatography (9MC) with a conventional three-factor prothrombin complex concentrate (9A). The highly purified factor IX concentrate was shown to have a half-life comparable to the PCC; the in vivo recovery of the purified concentrate was significantly greater than that of the complex (P < 0.01). The 20% change in the value of the International Standard for Factor IX Concentrate, introduced in 1988, might have been expected to lower the recovery values. However, the in vivo recovery for both concentrates was somewhat higher than reported previously, particularly in the older literature. In nine patients, serial assays for fibrinopeptide A, prothrombin fragment F1+2 and thrombin-antithrombin complexes (TAT) were performed to assess the potential thrombogenicity of the two concentrates. Evidence was obtained that there was significantly less activation of coagulation following administration of purified factor IX (9MC), as compared to the activation that occurred after the PCC.

Blood Coagulation↗

PubMed1977

A bleeding syndrome in infants due to acquired prothrombin complex deficiency: a survey of 93 affected infants.

A bleeding syndrome due to severe prothrombin complex deficiency is reported in 93 infants. Most were breast fed (98 per cent), aged 2 weeks to 1 year and there were no serious preceding or associated diseases. Hemorrhagic diathesis, pallor and mild hepatomegaly were the major manifestations. The incidence of intracr anial bleeding was strikingly high (63 per cent) particularly with subdural and subarachnoid hemorrhage. Acute onset, short course and rapid clinical and laboratory improvement after vitamin K therapy were observed. Mortality rate was 35 per cent but has been reduced to 17 per cent since 1969. The location of bleeding, prompt diagnosis and early treatment are the major factors affecting prognosis. Severe prothrombin complex deficiency due to vitamin K deficiency accounted for the pathogenesis of bleeding. Possible causes of vitamin K deficiency were discussed but definite conclusions could not be drawn.

Cerebral Hemorrhage↗