fibrinopeptide-a and Hemophilia-B

We have looked for evidence of coagulation activation in six subjects with haemophilia B by performing a single-blind active control cross-over study comparing a recently developed factor IX concentrate with a conventional prothrombin complex concentrate (PCC). Samples were obtained before infusion and at 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h for assay of factor IX, prothrombin time, fibrinopeptide A (FPA), prothrombin fragment F1 + 2, D-dimer, thrombin-antithrombin complexes (TAT) and antithrombin III (ATIII). Following administration of the PCC there was evidence of coagulation activation in five of the six recipients for up to 6 h after the infusion. The factor IX concentrate induced a moderate degree of coagulation activation in one subject. There was no significant difference between the two products in respect of either recovery or half-life. This study provides further evidence that the new high purity preparations of factor IX concentrates produce significantly less coagulation activation than currently available PCCs. It remains to be established whether this will result in a corresponding reduction in thromboembolic complications in clinical use.

Topics: Adolescent; Adult; Antithrombin III; Blood Coagulation; Blood Coagulation Factors; Drug Contamination; Factor IX; Fibrinopeptide A; Hemophilia B; Humans; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Prothrombin; Single-Blind Method; Time Factors

Purer factor IX concentrates, containing very little or no factor II or X, have been developed in an attempt to avoid the thromboembolic complications that occur with prothrombin complex concentrates (PCC), which also contain factors II and X and variable amounts of factor VII. To evaluate ex vivo the thrombogenic potential of one of these purer concentrates, we studied whether large single doses produced signs of activation of the coagulation cascade in patients with haemophilia B, and compared the results with those obtained after infusion of a PCC. Seven patients were infused with 50 IU/kg of factor IX concentrate and seven additional patients were subsequently infused with 100 IU/kg of the same concentrate. After the infusions, factor IX levels rose in proportion to the administered dose while the concentrations of factor II and factor X did not rise at all. At both doses of concentrate, we did not observe significant post-infusion increments in the levels of the factor X activation peptide (a measure of the activity of the factor VIIa-tissue factor complex and/or the factor IXa-VIIIa-activated surface complex), prothrombin fragment 1 + 2 (a measure of factor Xa activity), and fibrinopeptide A (a measure of thrombin activity). We also infused 10 patients with a PCC (50 IU/kg). After the infusions, significant rises in the concentrations of the factor X activation peptide and prothrombin fragment were observed. Therefore, it appears that the infusion of a PCC to patients with haemophilia B can augment factor X activation and subsequently thrombin generation in vivo and that this process can be abrogated by the administration of more pure factor IX concentrate.

Topics: Adolescent; Adult; Blood Coagulation; Blood Coagulation Factors; Factor IX; Factor VII; Factor X; Factor Xa; Fibrinopeptide A; Hemophilia B; Humans; Middle Aged; Peptide Fragments; Prothrombin; Time Factors

Fibrin deposition and platelet thrombus dimensions on subendothelium were studied in four groups of patients with coagulation factor deficiencies. Five patients with factor VIII deficiency (APTT 120 +/- 8 sec) and three patients with factor IX deficiency (APTT 125 +/- 11 sec) were severe bleeders, whereas four patients with factor XII deficiency and seven with factor XI deficiency were either asymptomatic or only mild bleeders despite APTT values of 439 +/- 49 and 153 +/- 13 sec, respectively. Everted segments of deendothelialized rabbit aorta were exposed at a shear rate of 650 sec(-1) for 5 and 10 min to directly sampled venous blood in an annular chamber. Blood coagulation was evaluated by measuring fibrin deposition (percent surface coverage) on the subendothelium and post-chamber fibrinopeptide A levels; platelet thrombus dimensions on the subendothelium were evaluated by determining the total thrombus volume per surface area (using an optical scanning technique) and the average height of the three tallest thrombi. Consistent differences were observed among the patient groups for both the 5-min and 10-min exposure times. The larger of the 5- and 10-min exposure-time values was used to calculate group averages. Fibrin deposition in normal subjects was 81% +/- 5% surface coverage, and post-chamber fibrinopeptide A values were 712 +/- 64 ng/ml. Markedly decreased fibrin deposition and fibrinopeptide A levels were observed in factor VIII deficiency (2% +/- 1% and 102 +/- 19 ng/ml) and factor IX deficiency (11% +/- 7% and 69 +/- 11 ng/ml). In contrast, significantly higher values were obtained in patients deficient in factor XI (33% +/- 5% and 201 +/- 57 ng/ml) and factor XII (66% +/- 12% and 306 +/- 72 ng/ml). Differences in thrombus dimensions were also observed. In normal subjects, the value for thrombus volume and average height of the tallest thrombi were 8.3 +/- 1.3 cu micron/sq micron and 145 +/- 11 micron, respectively, and in patients were as follows: FVIII, 2.7 +/- 0.6 and 71 +/- 7; FIX, 4.5 +/- 1.8 and 88 +/- 14; FXI, 11.8 +/- 1.9 and 125 +/- 10; and FXII, 7.9 +/- 3.1 and 130 +/- 25. Platelet thrombus dimensions were normal in a patient with fibrinogen deficiency, indicating that the smaller thrombi in factor VIII and factor IX deficiencies were probably due to impaired evolution of thrombin rather than diminished fibrin formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Blood Platelets; Endothelium; Factor XI Deficiency; Factor XII Deficiency; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Hemophilia A; Hemophilia B; Humans; In Vitro Techniques; Male; Middle Aged; Partial Thromboplastin Time; Platelet Adhesiveness; Prothrombin Time; Thromboplastin

An episode of defibrination with bleeding following high dose Edinburgh Factor IX (D.E.F.IX) replacement in a patient with haemophilia B undergoing knee joint replacement is reported. We have also monitored plasma fibrinopeptide A levels in patients with haemophilia B following ten standard doses of D.E.F.IX (15-20 u/kg) and have been unable to document any change. Activation of the coagulation system, as previously noted, appears to be related to the use of Factor IX concentrates in high doses.

Topics: Adult; Blood Coagulation; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Factor IX; Fibrinopeptide A; Hemophilia B; Humans; Male

Topics: Animals; Blood Coagulation; Constriction; Factor V Deficiency; Factor VII Deficiency; Factor X Deficiency; Factor XI Deficiency; Factor XII Deficiency; Female; Fibrinopeptide A; Glass; Hemophilia A; Hemophilia B; Heparin; Humans; Jugular Veins; Male; Plasma; Rabbits