scholarly journals Factor VIII Inhibitor-Bypassing Agents Act by Inducing Thrombin Generation and Can Be Monitored by a Thrombin Generation Assay

2003 ◽  
Vol 33 (1) ◽  
pp. 16-22 ◽  
Author(s):  
P.L. Turecek ◽  
K. Váradi ◽  
B. Keil ◽  
C. Negrier ◽  
E. Berntorp ◽  
...  
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Factor Viii Inhibitor ◽  
Thrombin Generation Assay ◽  
Viii Inhibitor ◽  
Bypassing Agents

Spontaneous disappearance of high titre factor VIII inhibitor 15 years after unsuccessful ITI

2009 ◽  
Vol 29 (02) ◽  
pp. 149-150
Author(s):  
K. Thom ◽  
J. Falger ◽  
I. Pabinger ◽  
C. Male
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
High Titre ◽  
Bleeding Complications ◽  
Factor Viii Inhibitor ◽  
Fviii Inhibitor ◽  
Spontaneous Disappearance ◽  
Viii Inhibitor ◽  
Bypassing Agents ◽  
High Doses

SummaryThe most serious complication of haemophilia A is development of a high-titre factor VIII (FVIII) inhibitor which renders the patient unresponsive to FVIII replacement. Bleeding complications can only be controlled using FVIII-inhibitor bypassing agents but their effect is less certain. The ultimate goal is to eliminate the inhibitor by immune tolerance induction therapy (ITI) using daily high doses of FVIII. The success rate of ITI using various protocols is between 56 and 79% (1, 2). If ITI is unsuccessful, the inhibitor usually persists throughout life.We report on a patient with a high titre FVIII inhibitor that persisted after ITI but spontaneously disappeared 15 years later.

Thrombin Generation Assay: Use in Monitoring Treatment of Patients with Coagulation Factor Inhibitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3087-3087
Author(s):  
Aine N. McCormick ◽  
Peter L. Turecek ◽  
Katalin Varadi ◽  
Geoffrey F. Savidge
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Coagulation Factor ◽  
Rational Approach ◽  
Factor Viii Inhibitor ◽  
Specific Time ◽  
Time Intervals ◽  
Monitoring Method ◽  
Standard Curve ◽  
Thrombin Generation Assay

Abstract Treatment of severe Haemophilia A relies upon the infusion of plasma derived or recombinant Factor VIII concentrates. The development of antibodies to these products is approximately 25–30% in severe cases and remains a major clinical challenge to management. Treatment in inhibitor cases with high antibody levels is based on the effect of products that bypass Factor VIII in the cascade and activate the common pathway either directly or through the extrinsic pathway. These include recombinant Factor VIIa and Factor VIII inhibitor bypassing activity (FEIBA®). At present, the use and dosage of bypassing products is severely constrained by the current inability to measure directly their beneficial effect using a standardised assay, and clinical management rests exclusively upon clinical assessment. The thrombin generation assay (TGA) provides a convenient and reproducible method for quantifying thrombin produced following activation of the cascade, and is measured by means of monitoring a fluorescent residue that arises following cleavage of an artificial thrombin substrate. Through sequential measurements quantifiable kinetic data may be collated and assessed. We have used the TGA to assess thrombin generation in inhibitor patients using samples taken at specific time intervals from patients after administration of FEIBA (n=4) or rFVIIa (n=3) following informed consent. In a number of experiments, platelets from the patient’s pre-infusion platelet rich plasma (PRP) were added. Peakthrombin (nM), peaktime (min) and maximum initial rates of thrombin generation (nM/min) from each sample were quantified, and the maximum initial rates of thrombin generation were further processed using PKAnalyst® Pharamacokinetic Data Analysis software program to define one and two PK compartment elimination models following bolus injection. Thrombin generation parameters were found to persist at levels greater than those measured for the pre infusion samples for periods beyond 6 hours post FEIBA and for 2 hours post rFVIIa, prior to reinfusion of rFVIIa. In PK evaluation studies FEIBA was found to have a relative thrombin generation T1/2 of 1–3.7 hr using the one compartment model, while rFVIIa was found to have a relative thrombin generation T1/2 of 0–2.8 hr following a single infusion. A second infusion of rFVIIa gave a relative thrombin generation T1/2 of 1.2–1.8 hr suggesting a cumulative effect. The addition of platelets from pre-infusion PRP to the assay enhanced thrombin generation by approximately 30% in all samples studied. The TGA was also used to quantify the thrombin generation produced by FEIBA and rFVIIa in samples obtained at specific time intervals post treatment, using a pre infusion sample spiked with a range of FEIBA/rFVIIa concentrations to generate a standard curve. This standard curve was then used to estimate the relative FEIBA/rFVIIa concentrations in the post infusion samples with and without the addition of platelets. We consider that the use of the TGA in this clinical setting demonstrates its value as a monitoring method highly effective for providing a rational approach to dosage adjustments of FEIBA/rFVIIa in the treatment of patients with FVIII inhibitors. This valuable analytical means for monitoring FVIII bypassing treatment is of considerable relevance in relation to surgery and the management of acute bleeds in this patient category.

scholarly journals Parallel Evaluation of Three Global Hemostatic Assays in Response to Factor VIII Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1172-1172
Author(s):  
Ping Chen ◽  
Jayesh Jani ◽  
Gang Zheng ◽  
Thomas S. Kickler
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Conflicts Of Interest ◽  
Factor Viii Inhibitor ◽  
Healthy Individuals ◽  
Factor Inhibitor ◽  
Viii Inhibitor ◽  
Parallel Evaluation ◽  
Dose Dependent ◽  
Different Levels

Abstract Background Current laboratory tests measuring factor and factor inhibitor levels are limited in their ability to fully evaluate the hemostasis status of hemophilia patients. There are global assays including thromboelastogragh (TEG), Innovance ETP, and thrombinoscope measuring thrombin generation potential, which have potentials to provide more objective and clinically relevant markers to guide clinical management. However, performance characteristics of these global assays are not well-studied, and no parallel comparisons of three global assays have been made. Material and Methods With plasmas of 20 healthy individuals the normal variation of thrombin generation potential was determined for all three global assays. With five commercially available and three clinical plasma samples with different levels of factor VIII inhibitors, serial dilutions were made, and thrombin generation potentials were measured with the global assays. Results The means and standard deviations for thrombin generation potential of healthy individuals are 761.27±70.30 mm/min, 2126.43±441.62 nM/min, and 411.04±48.87 mA, by TEG, throminoscope and Innovance ETP respectively. Thrombinoscope shows a dose-dependent response to different levels of factor VIII inhibitors from the same patients, while Innovance ETP shows virtually no response to factor 8 inhibitors regardless of inhibitor levels. TEG appears more sensitive to factor VIII inhibitors than thrombinoscope, as a moderate level of factor VIII often abolishes thrombin generation by TEG (see Figure 1 for an example). Importantly, it was shown that the same levels of factor VIII inhibitor from different patients result in different level of inhibition for thrombin generation potential by thrombinoscope (Figure 2), which potentially explains the phenotypic heterogeneity of patients with same levels of factor VIII inhibition. Conclusion Global assays like thrombinoscope, but not Innovance ETP, offer an objective measurement of hemostasis in hemophilia patients with factor VIII inhibitors, which may lead to individualized hemophilia patient management. Future studies are warranted to validate the global assays clinically. Disclosures No relevant conflicts of interest to declare.

A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 546-551 ◽  
Author(s):  
Jan Astermark ◽  
Sharyne M. Donfield ◽  
Donna M. DiMichele ◽  
Alessandro Gringeri ◽  
Steven A. Gilbert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Factor Viia ◽  
Factor Viii Inhibitor ◽  
Open Label ◽  
Activated Prothrombin Complex Concentrate ◽  
Treatment Data ◽  
Bleeding Episodes ◽  
Viii Inhibitor ◽  
The Difference ◽  
Bypassing Agents

Abstract The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (−11.4%-15.7%), P = .059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.

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.

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

1993 ◽  
Vol 69 (02) ◽  
pp. 115-118 ◽  
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.

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