scholarly journals Bleeding phenotype of patients with moderate haemophilia A and B assessed by thromboelastometry and thrombin generation

Haemophilia ◽  
2021 ◽  
Author(s):  
Ragnhild J. Måseide ◽  
Erik Berntorp ◽  
Vuokko Nummi ◽  
Riitta Lassila ◽  
Geir E. Tjønnfjord ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Haemophilia A

Thrombin generation and phenotypic correlation in haemophilia A

Haemophilia ◽  
2005 ◽  
Vol 11 (4) ◽  
pp. 326-334 ◽  
Author(s):  
C. P. Beltran-Miranda ◽  
A. Khan ◽  
A. R. Jaloma-Cruz ◽  
M. A. Laffan
Keyword(s):  
Thrombin Generation ◽  
Phenotypic Correlation ◽  
Haemophilia A

Pharmacokinetics of Global Assays of Haemostasis in Severe Haemophilia A.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1620-1620
Author(s):  
Peter Collins ◽  
Elizabeth Stephens ◽  
Georgia Florou ◽  
Nicola Macartney ◽  
Lee Hathaway ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Initial Rate ◽  
Maximum Velocity ◽  
Close Correlation ◽  
Poor Correlation ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Post Infusion ◽  
Time Point

Abstract Global haemostatic assays (GHA) may be useful in the management of patients with severe haemophilia A. We studied 12 patients with baseline FVIII <1 IU/dL. After a 72 hour washout patients were infused with 50IU/kg recombinant FVIII and samples taken into citrated plasma, with or without corn trypsin inhibitor (CTI), pre- and 0.25, 1, 3, 6, 24, 34, 48, 54 and 72 hours post-infusion. At each time point FVIII was measured using a one stage and an antigenic assay. Blood taken into CTI was used to perform thrombin generation assays (TGA) in platelet rich (PRP) and poor plasma (PPP) and whole blood low-dose tissue factor thromboelastography (Rotem) (LD-TF TG). Tissue factor (TF) concentrations in PRP were 0.1 and 0.25pM and in PPP 1 and 2.5pM. At the pre-infusion time point FI, FII, FV, FVII, FIX, FX, FXI, FXII, VWF:Ag, TFPI and TAFI were measured. In PRP TGA were unrecordable pre-infusion in most patients with both a 0.1 and 0.25pM TF trigger, hence this assay was unsuitable for assessing low concentrations of FVIII. Post infusion in PRP the endogenous thrombin potential (ETP) and peak thrombin (PT) increased towards the normal range (mean ± 1SD of 30 controls) and then decreased with time. The ETP could not be measured in the majority of patients after 30 hours. The only TGA parameter in PRP that could be measured at all time points in the majority of patients was the initial rate of thrombin formation calculated by linear regression. In PPP a similar pattern was observed except that ETP and PT could be measured in most patients to a FVIII level of 1 IU/dL, whilst initial rate could be measured at levels <1IU/dL . Variability of TGA was such that no parameters correlated with FVIII level between patients, however, within an individual there was a very strong correlation between FVIII level and lag time, ETP, PT and initial rate. This suggests that underlying global haemostatic potential varies widely between patients and that a certain level of FVIII will correct haemostasis to a different level in each patient but that within patients FVIII correlates closely with TGA. This was further demonstrated by mathematically modelled TGA parameters to predefined FVIII levels of 1, 10, 20, 50, 75 and 100IU/dL and, although there was again a wide variability between patients, there was a reproducible relationship between ETP, PT and initial rate with FVIII level. LD-TF TG could be measured in almost all patients even at baseline FVIII. The parameters that were most useful for following FVIII levels were maximum velocity of clot formation (Vmax) and time to Vmax. Similar to TGA there was a wide inter-patient variation and FVIII corrected assay parameters to variable levels. There was poor correlation between parameters of thrombin generation and the LD-TF TG assays suggesting that the two assays were measuring different aspects of haemostasis. In conclusion we have demonstrated that a defined FVIII level in individual patients corrected GHA to a variable extent but that within an individual there is a close correlation between FVIII and GHA parameters suggesting that these assays may be useful for monitoring patients during FVIII replacement therapy and give additional information to FVIII levels. At FVIII levels around 1IU/dL only the initial rate of thrombin generation could be measured in all patients and this may be a useful parameter to assess trough levels during prophylaxis. The clinical utility of these assays needs to be confirmed in studies that link bleeding endpoints to assay parameters.

scholarly journals Thrombin generation assay using factor IXa as a trigger to quantify accurately factor VIII levels in haemophilia A

2011 ◽  
Vol 9 (8) ◽  
pp. 1549-1555 ◽  
Author(s):  
M. NINIVAGGI ◽  
Y. DARGAUD ◽  
R. Van OERLE ◽  
B. De LAAT ◽  
H. C. HEMKER ◽  
...  
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Haemophilia A ◽  
Thrombin Generation Assay ◽  
Factor Ixa

scholarly journals The Relationship between Thrombin Generation Assay and FVIII Levels in Patients with Mild to Moderate Haemophilia (A)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2454-2454
Author(s):  
Pu-Lin Luo ◽  
Steven K. Austin ◽  
Kiran Parmar ◽  
Dan P Hart ◽  
Michael Laffan
Keyword(s):  
Research Funding ◽  
Thrombin Generation ◽  
Haemophilia A ◽  
Contact Activation ◽  
Extrinsic Pathway ◽  
Two Stage ◽  
One Stage ◽  
Thrombin Generation Assay ◽  
The Relationship

Abstract Introduction Haemophilia A (HA) phenotypes (mild, moderate and severe) are based on the baseline FVIII levels, however considerable variation in the bleeding phenotype exists between patients with similar FVIII level. Moreover, approximately 40% of patients with mild HA have large discrepancies between FVIII measured by one stage (FVIII:C1) and two stage methods (FVIII:Chr2) and it is unclear which method correlates best with in vivo FVIII function and bleeding phenotype. The Thrombin Generation assay (TGA), a global measure of haemostasis may be a better predictor of bleeding phenotype but pre-analytical factors such as contact activation can confound the results. Choice of initiating conditions may also be critical in determining sensitivity: recent studies have suggested that initiation with FIXa rather than tissue factor (TF) in detecting low levels of FVIII:C in severe HA, however its utility in mild to moderate HA patients has yet to be determined. The aim of this study is to establish the relationship between FVIII:C and TGA and the influence of contact factor activation in TF and FIXa triggered TGA in patients with mild to moderate HA. Methods This is a prospective cohort study. Patients aged >18 with known congenital HA and FVIII:C 0.01- 0.2 iu/ml were recruited from 3 Haemophilia Comprehensive Care Centres in London. Peripheral blood was drawn into citrate Vacutainer tubes containing 0.106M trisodium citrate (1:9 volume) and Vacutainer tubes preloaded with CTI (50µg/ml). Samples underwent double centrifugation (2500g) to obtain platelet free plasma. Thrombin generation assay, using a standard calibrated automated thrombogram was triggered with either TF (1pmol) or FIXa (5nM). Factor FVIII levels were assessed by one stage APTT based (FVIII:C1) and two stage chromogenic (FVIII:Chr2) methods. Mutation analysis was carried out in all patients. Results 40 patients were recruited in the study. Five patients (13%) had standard FVIII discrepancy (FVIII:C1/FVIII:Chr2>1.5) with 4 different FVIII mutations located on the inter-domain surface of the A2 domain (p.Tyr683Ser, p.Arg550Cys, p.Gly498Arg, p.MET681.Le). One patient had reverse FVIII discrepancy. In TF triggered TGA, the presence of CTI resulted in significant reduction in mean ETP (nmol .min)(455. vs 278, p<0.01, 95% CI 104-243), mean Peak thrombin (nM) (37.81 vs 16.54, t(6.6) p<0.01 95%CI 14.7-27.3), and mean Velindex (nM/min) (4.86 vs 1.29 t(7.0), p<0.01, 95% CI2.3-4.19) and a longer mean ttPeak (min) (14.26 vs 16.22, t(-3.2) p=0.02 95% CI-3.1- -0.76). In contrast, the presence of CTI did not affect ETP (1143 vs 1042, p=0.19 95% CI -54-256), mean Peak thrombin (252 vs 251, p=0.6 95%CI 27-46) or Velindex (118.54 vs 119.15 p= 0.95, 95%CI -23-12.9) in FIXa triggered TGA. There was a good correlation between FVIII:Chr2 and ETP (r=0.56, p=<0.001) Peak (r=0.6, p=<0.001) and Velindex (r=0.7, p=<0.001) in TF(CTI-) triggered TGA, however no relationship was seen between FVIII:C and TG parameters (ETP r=-0.01 p=0.9, Peak r=-0.003, p=0.97 and Velindex r=0.018, p=0.9) in TF(CTI+) triggered TGA. In both FIXa(CTI-) and FIXa (CTI+) triggered TGA, there was a good correlation seen between Lagtime (r=-0.6 p=<0.01), Peak (r=0.4-0.6, p=<0.01) ttpeak (r= -0.6, p=<0.01) and Velindex (r=0.69 <0.01) with FVIII:Chr2 but not with ETP. In patients with standard FVIII discrepancy (n=5), their ETP and Peak levels in TF and FIXa triggered TGA were in keeping with the ETP and Peak levels of non-discrepant patients with similar FVIII:C2 and significantly lower than that of non-discrepant patients with similar FVIII:C1. Conclusions Our study confirms that at low TF triggered TG, contact factor activation in vitro is an important preanalytical variable. Curiously any TG correlation with FVIII level is lost once the contact pathway is inhibited suggesting that TG remains largely determined by the extrinsic pathway in this system. In contrast, factor FIXa triggered TG is unaffected by inhibition of contact activation and demonstrates a good correlation to FVIII:C with or without CTI. This can be explained by suggesting that the supply of FIXa negates any effect of XIa from contact activation and that TG by this route is more completely dependent on FVIII. Therefore a FIXa triggered TGA may offer a better alternative in the assessment of haemophilia and further studies are underway to determine whether this is a better predictor of bleeding phenotypes. Disclosures Luo: Pfizer: Research Funding. Austin:Pfizer: Research Funding. Laffan:Pfizer: Honoraria; Roche: Consultancy, Speakers Bureau.

scholarly journals Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B

2005 ◽  
Vol 93 (03) ◽  
pp. 475-480 ◽  
Author(s):  
Suzette Béguin ◽  
Anne Lienhart ◽  
Raed Al Dieri ◽  
Christine Trzeciak ◽  
Jean Bordet ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Factor Ix ◽  
Haemophilia A ◽  
Clotting Factors ◽  
Time To Peak ◽  
Promising Tool ◽  
Generating Capacity ◽  
Generation Capacity ◽  
Generation Test

SummaryIn haemophilia patients, a relationship is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX (FVIII/FIX) activity. However, it is known from clinical experience, that some haemophilia patients, despite similar FVIII/FIX plasma levels, could exhibit different bleeding phenotype. After determining preanalytical test conditions, we evaluated the thrombin generation capacity from haemophilia plasma samples in various conditions and the potential usefulness of thrombin generation test (TGT) in haemophilia patients. In a series of 46 haemophilia patients (34 haemophilia A and 12 haemophilia B patients), we found a significant correlation between plasmatic FVIII/FIX levels and endogenous thrombin potential (ETP), peak and time to peak obtained by thrombin generation measurement. In addition, a correlation was found between severe clinical bleeding phenotype and ETP. Our results suggest that TGT could be a promising tool to evaluate haemostasis capacity in patients with haemophilia. Our ex vivo results, obtained 24 hours after FVIII concentrate administration, showed that in patients presenting similar plasmatic FVIIII levels, thrombin generation capacity may be significantly different. These results suggest that in patients with haemophilia, TGT could be useful for individually tailoring prophylactic regimens as well as for adapting clotting factors infusions in surgical situations, in addition to FVIII/FIX plasma clotting activities.

scholarly journals Thrombin generation in plasma of patients with haemophilia A and B with inhibitors: Effects of bypassing agents and antithrombin reduction

2020 ◽  
Vol 82 ◽  
pp. 102416 ◽  
Author(s):  
Tami Livnat ◽  
Alfica Sehgal ◽  
Kun Qian ◽  
Huy Van Nguyen ◽  
Kate Madigan ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Haemophilia A ◽  
Bypassing Agents

The Defective Down Regulation of Fibrinolysis in Haemophilia A Can Be Restored by Increasing the TAFI Plasma Concentration

2001 ◽  
Vol 86 (10) ◽  
pp. 1035-1039 ◽  
Author(s):  
Laurent Mosnier ◽  
Ton Lisman ◽  
Marijke van den Berg ◽  
Karel Nieuwenhuis ◽  
Joost Meijers ◽  
...  
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Coagulation Factor ◽  
Clot Lysis ◽  
Haemophilia A ◽  
Intrinsic Pathway ◽  
Extrinsic Pathway ◽  
Down Regulation ◽  
Plasma Clot

SummaryTAFI (thrombin activatable fibrinolysis inhibitor) down regulates fibrinolysis after activation by relatively high concentrations of thrombin generated during coagulation via thrombin mediated factor XI activation and subsequent activation of the intrinsic pathway. It is this secondary burst of thrombin that is severely diminished in haemophilia A, a deficiency of coagulation factor VIII. We therefore investigated the role of TAFI in haemophilia A by measuring the clot lysis times of tissue factor induced fibrin formation and tPA mediated fibrinolysis. In haemophilia A plasma clot lysis times were normal at relatively high tissue factor concentrations but severely decreased at moderate to low tissue factor concentrations, indicating that the thrombin generation via the extrinsic pathway was insufficient to activate TAFI. Addition of factor VIII, TAFI or thrombomodulin restored the clot lysis times at low tissue factor concentrations. This confirms the hypothesis that the bleeding disorder in haemophilia A is not merely a defect in the initial clot formation but is in fact a triple defect: reduced thrombin formation via the extrinsic pathway at low tissue factor concentrations, a reduced secondary burst of thrombin generation via the intrinsic pathway and a defective down regulation of the fibrinolytic system by the intrinsic pathway.

scholarly journals The Effect of DDAVP Infusion on Thrombin Generation in Platelet-rich Plasma of von Willebrand Type 1 and in Mild Haemophilia A Patients

2000 ◽  
Vol 84 (10) ◽  
pp. 638-642 ◽  
Author(s):  
Irene Keularts ◽  
K. Hamulyak ◽  
H.C. Hemker ◽  
Suzette Béguin
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Platelet Rich Plasma ◽  
Von Willebrand Disease ◽  
Clotting Factor ◽  
Haemophilia A ◽  
The Individual ◽  
Von Willebrand ◽  
Mild Haemophilia

SummaryIn von Willebrand disease (vWD) type 1 and mild haemophilia A patients we studied the effect of an infusion of DDAVP (0.3 µg/kg body weight) on thrombin generation in platelet-rich plasma (PRP) and platelet-poor plasma (PPP). Baseline thrombin generation in PRP was diminished both in the haemophilia A and vWD patients. It was normal in vWD plasma when sufficient procoagulant phospholipids were present, either via adding phospholipid vesicles to PPP or via scrambling of the platelet membrane with ionomycin in PRP. In haemophilia A plasma, thrombin generation did not normalize by providing procoagulant phospholipids. Treatment with DDAVP temporarily restored thrombin generation in PRP to normal in both diseases.To investigate the individual roles of von Willebrand factor (vWF) and factor VIII, we also studied the effect of factor VIII infusion on thrombin generation in a severe haemophilia patient. It appears that at a fixed normal vWF concentration, <25% factor VIII is sufficient for normal thrombin generation in PRP. At a sufficient factor VIII concentration, however, thrombin generation is still lower than normal in vWD patients; ∼40% of vWF is required for half-normal thrombin generation in PRP.It thus appears that vWF is also a clotting factor, in the sense that it is required for normal thrombin generation. This underlines the importance of the interaction between coagulation and the platelets in normal haemostasis. Thrombin generation in PRP appears to be a suitable test to reflect the combined function.

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