Activated Prothrombin Complex Concentrates. Managing Hemophilia with Factor VIII Inhibitor. G. Mariana, M.A. Russo, and F. Mandelli, editors

In hemophilia A patients with inhibitor to Factor VIII, prothrombin complex, concentrates were found effective in treating hemorrhagic episodes. However, in several patients DIC or thromboembolic complications developed. Some of the manufacturers have altered production methods eliminating certain activated coagulation factors from the preparations. After these modifications some of these preparations were found to be less effective clinically. In the first study, we compared potential thrombogenicity of two preparations: Autoplex and FEIBA and as control prothrombin complex preparation with no appreciable activated factor content (Prothromplex) for the ability to induce thrombosis in an isolated segment of the renal vein of C57BL6(J), ICR/HA male mice, and Sprague-Dawley male rats. The minimum thrombosis inducing dose was 200 prothrombin complex units per kilogram of Prothromplex, 25 FEIBA units of FEIBA and 0.45 FEIBA units of Autoplex. The fact that Autoplex is approximately 51 times more active them FEIBA can probably be explained by the fact that the latter contains more factor IXa and Xa activity than the former.

Download Full-text

Prothrombin-Complex Concentrates, Thromboses, and Factor VIII Inhibitors: Evidence for a Coagulant Formed by the Interaction of Factors X and II

10.1055/s-0039-1689419 ◽

1975 ◽

Cited By ~ 1

Author(s):

G. H. Tishkoff

Keyword(s):

Factor Viii ◽

Human Factor ◽

Factor Xa ◽

Activated Partial Thromboplastin Time ◽

Factor Viii Inhibitor ◽

Factor V ◽

Prothrombin Complex Concentrates ◽

Corrective Effect ◽

Viii Inhibitor

Kurcyznski and Penner have reported on the use of prothrombin concentrates in the management of bleeding in hemophilia patients with Factor VIII inhibitor. Several commercial concentrates showed marked ability to shorten the activated partial thromboplastin time (APTT) of Factor VIII inhibitor plasma after 40 min preincubation. Significantly, purified human Factor Xa and thrombin did not evidence corrective effect. Highly purified human Factors X and II, isolated by affinity chromatography from partially activated prothrombin complex, effectively corrected the APTT when combined, but were inactive when tested separately. Preliminary studies suggest that Factor V is essential. This study indicates that the thrombogenic properties of prothrombin concentrates in vivo may be due in part to a coagulant complex formed by the interaction of X, V, and a prothrombin intermediate.

Download Full-text

Effect of prothrombin complex concentrates on factor VIII inhibitor levels

Blood ◽

10.1182/blood.v54.6.1358.bloodjournal5461358 ◽

1979 ◽

Vol 54 (6) ◽

pp. 1358-1368

Author(s):

CK Kasper

Keyword(s):

Immune Response ◽

Factor Viii ◽

Prothrombin Complex Concentrate ◽

Hemophilia A ◽

Factor Viii Inhibitor ◽

Prothrombin Complex Concentrates ◽

Before And After ◽

Inhibitor Level ◽

Viii Inhibitor

Factor VIII inhibitor levels were measured on 261 occasions in 76 hemophilia-A inhibitor patients before and after prothrombin complex concentrate infusion at 13 treatment centers. A rise in inhibitor level to at least twice the pretreatment value occurred in 35 treatment episodes (13.5%), in 27 patients (36%). In 16 patients (21%), such an anamnestic immune response occurred with the first treatment. Factors predisposing to anamnestic responses may include patient idiosyncrasy, low pretreatment inhibitor levels, and exposure to concentrate over several days.

Download Full-text

In Vitro Comparison Of Activated & Nonactivated Prothrombin Complex Concentrates (PCC)

10.1055/s-0038-1653032 ◽

1981 ◽

Author(s):

J Lazerson ◽

C F Abildgaard ◽

J Harrison

Keyword(s):

Factor Viii ◽

Clinical Efficacy ◽

Factor Viii Inhibitor ◽

In Vitro Test ◽

Prothrombin Complex Concentrates ◽

Vitro Test ◽

Viii Inhibitor ◽

Relationship Of ◽

The Relationship

In order to determine whether any in vitro test is related to clinical efficacy of PCC we compared nonact ivated PCC (Konyne-Cutter, Proplex-Hyland; Prothromplex- Immuno) with activated PCC (Autoplex-Hyland, FEIBA-Immuno, Antiinhibitor Correctional Concentrate (AlCC)-Cutter). The non-activated partial thromboplastin time (NAPTT), factor VIII correctional activity (FVIIICA) by the Hyland method, and factor VIII inhibitor bypassing activity (FEIBA) by the Immuno method were performed on all PCC according to the manufacturer’s specifications, utilizing their reagents. The results are reported as averages as interlot differences were minimal.No differences in results were obtained in FVIIICA assay of Autoplex whether inhibitor plasma or noninhibitor (factor VIII deficient) plasma was used as substrate, in contrast to the FEIBA assay where substitution of noninhibitor plasma resulted in a threefold decrease in final units of FEIBA (i.e. 5 units vs 16 units).It is concluded that the non-activated PCC contain 1/3 to 1/2 the factor VIII correctional activity of the activated PCC and that the NAPTT depending on the dilution selected is only a poor correlate of either. The relationship of the assays to clinical efficacy remains unknown.

Download Full-text

Effect of prothrombin complex concentrates on factor VIII inhibitor levels

Blood ◽

10.1182/blood.v54.6.1358.1358 ◽

1979 ◽

Vol 54 (6) ◽

pp. 1358-1368 ◽

Cited By ~ 20

Author(s):

CK Kasper

Keyword(s):

Immune Response ◽

Factor Viii ◽

Prothrombin Complex Concentrate ◽

Hemophilia A ◽

Factor Viii Inhibitor ◽

Prothrombin Complex Concentrates ◽

Before And After ◽

Inhibitor Level ◽

Viii Inhibitor

Abstract Factor VIII inhibitor levels were measured on 261 occasions in 76 hemophilia-A inhibitor patients before and after prothrombin complex concentrate infusion at 13 treatment centers. A rise in inhibitor level to at least twice the pretreatment value occurred in 35 treatment episodes (13.5%), in 27 patients (36%). In 16 patients (21%), such an anamnestic immune response occurred with the first treatment. Factors predisposing to anamnestic responses may include patient idiosyncrasy, low pretreatment inhibitor levels, and exposure to concentrate over several days.

Download Full-text

Acquired Haemophilia: Functional Study of Antibodies to Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650189 ◽

1981 ◽

Vol 45 (03) ◽

pp. 285-289 ◽

Cited By ~ 14

Author(s):

J P Allain ◽

A Gaillandre ◽

D Frommel

Keyword(s):

Factor Viii ◽

Functional Study ◽

Factor Viii Inhibitor ◽

Acquired Haemophilia ◽

Viii Inhibitor ◽

Kinetics Of ◽

Antibody Function ◽

Native Plasma

SummaryFactor VIII complex and its interaction with antibodies to factor VIII have been studied in 17 non-haemophilic patients with factor VIII inhibitor. Low VIII:C and high VIIIR.Ag levels were found in all patients. VIII:WF levels were 50% of those of VTIIRrAg, possibly related to an increase of poorly aggregated and electrophoretically fast moving VIIIR:Ag oligomers.Antibody function has been characterized by kinetics of VIII :C inactivation, saturability by normal plasma and the slope of the affinity curve. Two major patterns were observed:1) Antibodies from 6 patients behaved similarly to those from haemophiliacs by showing second order inhibition kinetics, easy saturability and steep affinity slope (> 1).2) Antibodies from other patients, usually with lower titres, inactivated VIII :C according to complex order kinetics, were not saturable, and had a less steep affinity slope (< 0.7). In native plasma, or after mixing with factor VIII concentrate, antibodies of the second group did not form immune complexes with the whole factor VIII molecular complex. However, dissociation procedures did release some antibodies from apparently low molecular weight complexes formed in vivo or in vitro. For appropriate management of non-haemophilic patients with factor VIII inhibitor, it is important to determine the functional properties of their antibodies to factor VIII.

Download Full-text

A Higher than Expected Incidence of Factor VIII Inhibitors in Multitransfused Haemophilia A Patients Treated with an Intermediate Purity Pasteurized Factor VIII Concentrate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651565 ◽

1993 ◽

Vol 69 (02) ◽

pp. 115-118 ◽

Cited By ~ 131

Author(s):

Kathelijne Peerlinck ◽

Jef Arnout ◽

Jean Guy Gilles ◽

Jean-Marie Saint-Remy ◽

Jos Vermylen

Keyword(s):

Factor Viii ◽

Randomized Trials ◽

Specific Factor ◽

Factor Viii Inhibitor ◽

Haemophilia A ◽

Viral Inactivation ◽

Gradual Decline ◽

Inhibitor Level ◽

Factor Viii Concentrates ◽

Viii Inhibitor

SummaryIn May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation.Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII.This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

Download Full-text

In Vitro Thrombogenicity Tests of Factor IX Concentrates

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657035 ◽

1979 ◽

Vol 42 (05) ◽

pp. 1355-1367 ◽

Cited By ~ 8

Author(s):

C V Prowse ◽

A Chirnside ◽

R A Elton

Keyword(s):

Factor Viii ◽

Partial Thromboplastin Time ◽

Generation Time ◽

Activated Partial Thromboplastin Time ◽

Factor Ix ◽

In Vitro Tests ◽

Factor Viii Inhibitor ◽

Factor Ixa ◽

Viii Inhibitor

SummaryVarious factor IX concentrates have been examined in a number of in vitro tests of thrombogenicity. The results suggest that some tests are superfluous as in concentrates with activity in any of these tests activation is revealed by a combination of the non-activated partial thromboplastin time, the thrombin (or Xa) generation time and factor VIII inhibitor bypassing activity tests. Assay of individual coagulant enzymes revealed that most concentrates contained more factor IXa than Xa. However only a small number of concentrates, chiefly those that had been purposefully activated, contained appreciable amounts of either enzyme.

Download Full-text