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

1975 ◽  
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.

scholarly journals Feiba Immuno: A Preparation with Factor Eight Inhibitor Bypassing Activity

1977 ◽  
Author(s):  
F. Elsinger
Keyword(s):  
Factor Viii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Active Principle ◽  
Factor Viii Inhibitor ◽  
Factor V ◽  
In Vitro Experiments ◽  
Factor X ◽  
Viii Inhibitor

FEIBA IMMUNO is a preparation in which a new activity is generated capable of bypassing factor VIII. The preparation which is used to treat patients with inhibitors (especially inhibitors to factor VIII) is standardized in FEIBA units, i.e. in terms of its in vitro capacity to shorten the activated PTT of a factor VIII inhibitor plasma.It could be concluded from different in vitro experiments that none of the classic’ activated coagulation factors is responsible for the factor VIII bypassing reaction; FEIB-activity seems to be correlated to a new complex of coagulation factors.To get an answer to the question which coagulation factors are essential for FEIB-activity, we tried to generate this activity from different deficient plasmas; from these experiments the following conclusions could be drawn:, the presence of at least factors VII, IX, and X is essential for the generation of the molecular species responsible for factor VIII as well as factor X bypassing activity, but factor V is not bypassed. This activity is not factor Xa itself. Factors VIII and V are not necessary for the generation of this active principle, but factor V is finally needed for its bypassing action.

scholarly journals Experimental Studies on Factor VIII Inhibitor Bypassing Activity

1977 ◽  
Author(s):  
H. Vinazzer
Keyword(s):  
Factor Viii ◽  
Calcium Chloride ◽  
Experimental Studies ◽  
Factor Xa ◽  
Factor Viii Inhibitor ◽  
Factor V ◽  
Factor X ◽  
Tissue Thromboplastin ◽  
Viii Inhibitor ◽  
Thrombin Formation

The exact action of factor VIII inhibitor bypassing activity (FEIBA) is still unclear. For this reason, a series of experimental studies was carried out. Procoagulant activities were examined by standard one-stage methods while factor Xa and thrombin were measured by chromogenic substrates. Activities of factors II, VII, IX, and X were similar to PPSB fractions. In addition, low factor V activity and a phospholipid were detected. No activated factor X was present in FEIBA but there was a trace amount of 2.1 NIH units of thrombin per 100 FEIBA units. On addition of calcium chloride slow thrombin formation could be observed which however, reached 1100 NIH units of thrombin per 100 FEIBA units within an incubation time of 10 min. The velocity of thrombin formation was greatly enhanced by addition of a PTT reagent and of thromboplastin respectively. Factor Xa on the other hand, was neither formed after addition of calcium chloride nor by a PTT reagent. Tissue thromboplastin however, activated Xa from FEIBA in the same manner as a PTT reagent plus barium sulfate plasma. From these results, the conclusion could be drawn that thrombin could readily be made available from FEIBA while activation of Xa either needed the complete endogenous pathway or the presence of tissue thromboplastin. The procoagulant activity of FEIBA therefore, could be attributed to direct thrombin formation. By this process, an activation of the clotting mechanism in plasmas deficient in endogenous coagulation factors, and a complete independence from the presence or absence of a specific antibody could be explained.

Acquired Haemophilia: Functional Study of Antibodies to Factor VIII

1981 ◽  
Vol 45 (03) ◽  
pp. 285-289 ◽  
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.

In Vitro Thrombogenicity Tests of Factor IX Concentrates

1979 ◽  
Vol 42 (05) ◽  
pp. 1355-1367 ◽  
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.

Factor-VIII Inhibitor in Less Severely Affected Haemophilic Patients

1975 ◽  
Author(s):  
E. G. D. Tuddenham ◽  
A. L. Bloom ◽  
J. C. Giddings ◽  
C. A. Barrett
Keyword(s):  
Factor Viii ◽  
Factor Viii Inhibitor ◽  
Factor Viii Level ◽  
Replacement Treatment ◽  
Viii Level ◽  
Viii Inhibitor ◽  
In Vivo Recovery ◽  
Better Than

The occurrence of factor VIII inhibitor in five mild or moderately affected liaemophilic patients is described. In four patients the inhibitor inactivated endogenous factor VIII an dtemporarily converted them to severely affected haemophiliacs with factor VIII level of 0%. In the fifth patient, a brother of one of the others, the inhibitor although more potent did not inactivate the patient’s own factor VIII and did not completely inactivate normal factor VIII in vitro. This patient responded to treatment with factor-VIII concentrate but the in-vivo recovery was reduced. The patient’s plasma was tested against a panel of normal donors but it inactivated factor VIII in each to a similar extent and no evidence for normal factor-VIII groups was obtained. In the other patients the response to replacement treatment was also better than that usually seen in severely affected haemophilic patients with inhibitor. In the two related patients the inhibitors have so far persisted but in the unrelated patients the inhibitors eventually disappeared and did not always recur with subsequent therapy. The incidence of factor- VIII inhibitor in less severe haemophiliacs (factor VIII > 3% ) in this centre is 6% suggesting that the complication is more frequent in this type of patient than hitherto recognised.

Human Factor VIII Inhibitor Alloantibodies with a C2 Epitope Inhibit Factor Xa-catalyzed Factor VIII Activation: A new Anti-factor VIII Inhibitory Mechanism

2002 ◽  
Vol 87 (03) ◽  
pp. 459-465 ◽  
Author(s):  
Keiji Nogami ◽  
Katsumi Nishiya ◽  
Yoshihiko Sakurai ◽  
Ichiro Tanaka ◽  
John Giddings ◽  
...  
Keyword(s):  
Factor Viii ◽  
Factor Xa ◽  
Factor Viii Inhibitor ◽  
Inhibitory Mechanism ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Human Factor Viii ◽  
Sds Page ◽  
Viii Inhibitor ◽  
C1 Domains

SummaryFactor VIII (FVIII) inhibitor alloantibodies react with the A2, C2, or A3-C1 domains of FVIII and inactivate FVIII activity. We recently demonstrated that an anti-C2 monoclonal antibody with a Val2248Gly2285 epitope, inhibited factor Xa (FXa)-catalyzed FVIII activation, and that a FXa binding site for FVIII was located within residues Thr2253-Gln2270. In this study, we investigated whether anti-C2 alloantibodies inhibit FXa-catalyzed FVIII activation. Anti-C2 alloantibodies from four patients inhibited FVIII activation by FXa in onestage clotting assay. Furthermore, analysis by SDS-PAGE showed that all alloantibodies inhibited FVIII proteolytic cleavage by FXa independently of phospholipid. To confirm direct inhibition of FVIII and FXa interaction, we examined the effect of alloantibodies on FVIII binding to anhydro-FXa, a catalytically inactive FXa, in ELISA. All alloantibodies and C2-affinity purified F(ab)’2 preparations inhibited FVIII binding to anhydro-FXa dose-dependently. Our results revealed a new inhibitory mechanism of FVIII, mediated by inhibition of FXa in the presence of anti-C2 alloantibodies.

Thrombogenicity Of Antihemophiliac Preparations With Factor VIII Inhibitor Bypassing Activity

1981 ◽  
Author(s):  
D J Melewski ◽  
J L Ambrus ◽  
C M Ambrus ◽  
K Tourbaf
Keyword(s):  
Factor Viii ◽  
Coagulation Factors ◽  
Male Rats ◽  
Factor Viii Inhibitor ◽  
Sprague Dawley ◽  
Prothrombin Complex Concentrates ◽  
Production Methods ◽  
Isolated Segment ◽  
Complex Preparation ◽  
Viii Inhibitor

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.

Factor VIII Inhibitor Bypassing Activity (FEIBA) Reversal for Apixaban and Rivaroxaban in Patients With Acute Intracranial and Nonintracranial Hemorrhage

2021 ◽  
pp. 106002802110045
Author(s):  
Aleah R. Hunt ◽  
Shawn N. Coffeen ◽  
Dane L. Shiltz ◽  
Calvin Ice ◽  
Jessi Parker
Keyword(s):  
Factor Viii ◽  
Controlled Trial ◽  
Safety Data ◽  
Case Series ◽  
Factor Xa ◽  
Factor Viii Inhibitor ◽  
Post Discharge ◽  
Viii Inhibitor ◽  
Fxa Inhibitor ◽  
Record Review

Background: The clinical use of factor VIII inhibitor bypassing activity (FEIBA) for factor Xa (FXa) inhibitor reversal is derived from small studies with notable variation in patient eligibility for use, dosage regimens, concurrent supportive care, and outcome measures. Consequently, additional effectiveness and safety data are warranted to expand the literature evaluating FEIBA for FXa inhibitor reversal. Objective: This study sought to determine the incidence of observed effective hemostasis within 24 hours of post-FEIBA® administration as well as in-hospital and 30-day post-discharge incidences of thromboembolic event (TEE) and mortality between apixaban and rivaroxaban in the intracranial hemorrhage (ICH) and non-ICH populations. Methods: This case series evaluated patients between January 1, 2014 through July 1, 2019 who received at least one FEIBA® dose for apixaban or rivaroxaban reversal secondary to acute ICH or non-ICH. Patient demographics, FEIBA® dosages, adjunct treatments, effectiveness, and safety outcomes were retrospectively collected from electronic medical record review. Modified hemostasis outcomes, adapted from criteria previously published by Sarode et al., TEE, and mortality between apixaban and rivaroxaban in the ICH and non-ICH populations were evaluated. Results: Among the 104 patients evaluated, 62 received apixaban and 42 rivaroxaban. Thirty apixaban and 25 rivaroxaban users experienced ICH, whereas 32 apixaban and 17 rivaroxaban users experienced non-ICH. Among the combined ICH and non-ICH populations, effective hemostasis occurred in 89%, TEE in 8%, and mortality in 13%. No statistically significant differences were observed within ICH and non-ICH populations receiving apixaban or rivaroxaban regarding effective hemostasis, TEE, or mortality. Conclusion and Relevance: The combined ICH and non-ICH overall rates of effective hemostasis, TEE, and mortality were comparable to preexisting studies of FEIBA for factor Xa inhibitor reversal. The limitations inherent to the study design warrant a randomized controlled trial with an active comparator to confirm these observations.

scholarly journals Factors Affecting the Factor X Activator Activity of Human Platelets

1977 ◽  
Author(s):  
J. Vermylen ◽  
N. Semeraro
Keyword(s):  
Factor Viii ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Activate Factor ◽  
Factor Viii Inhibitor ◽  
Factor X ◽  
Factors Affecting ◽  
Coagulant Activity ◽  
Viii Inhibitor

Several recent studies have indicated that patients with a thrombotic tendency have enhanced platelet coagulant activity. It therefore is of importance to attempt to identify factors which modify platelet coagulant activities. Recent work in our laboratory has provided evidence that human platelets possess the capacity to directly activate factor X.Adenosine-5'-diphosphate, collagen, acetylsalicylic acid and prostaglandin E1 do not modify this activity. All endotoxins studied however clearly enhanced this activity.Furthermore, infusion of ‘activated’ prothrombin concentrates in haemophiliacs with or without factor VIII inhibitor enhanced the activity of this platelet activator of factor X. The hypothesis has been put forward that this may be the mechanism through which ‘activated’ prothrombin concentrates ‘bypass’ factor VIII of IX inhibitors. Platelet isolated from platelet-rich plasma to which the ‘activated’ prothrombin concentrate had been added at a concentration approaching the maximal concentration achieved following in vivo infusion, also showed an increase in platelet coagulant activity. Work is in progress to identify the component in ‘activated’ prothrombin concentrates which enhances platelet coagulant activity.

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