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

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

scholarly journals Prophylaxis therapy with bypassing agents in patients with haemophilia A and inhibitors undergoing surgery: A cost analysis in Spain

2020 ◽  
Vol 105 (1) ◽  
pp. 94-100
Author(s):  
María Mareque ◽  
María Eva Mingot‐Castellano ◽  
María Fernanda López‐Fernández ◽  
María Teresa Álvarez‐Román ◽  
Itziar Oyagüez
Keyword(s):  
Cost Analysis ◽  
Haemophilia A ◽  
Prophylaxis Therapy ◽  
Bypassing Agents

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.

Sequential Infusion of rFVIIa and Plasma-Derived Activated Prothrombin Complex Concentrate In Haemophilia A Paediatric Patient with Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4660-4660
Author(s):  
Giuseppe Lassandro ◽  
Francesco Antonio Scaraggi ◽  
Rosanna Scaraggi ◽  
Teresa Capriati ◽  
Domenico De Mattia ◽  
...  
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Conflicts Of Interest ◽  
Coagulation Factors ◽  
High Titre ◽  
Left Knee ◽  
Haemophilia A ◽  
Activated Prothrombin Complex Concentrate ◽  
End Of Treatment ◽  
Inhibitor Titre ◽  
Bypassing Agents

Abstract Abstract 4660 One of the serious complication in hemophilia therapy is the development of high titre inhibitors to FVIII and less often to others coagulation factors. It makes treatment of bleeds very challenging. We report a case of hemarthrosis in hemophilia A pediatric patient with inhibitors, treated with sequential infuson of rFVIIa (rFVIIa, NOVOSEVEN; Novo Nordisk A/S, Bagsvaerd, Denmark) and plasma activated prothrombin complex concentrate (pd- aPCC, FEIBA; Baxter AG Vienna Austria). rFVIIa and plasma activated prothrombin complex concentrate are, indeed, used as haemostatic bypassing agents to prevent eaemorrages, with the goal of limiting sequelae as arthropathy, or to control quickly heamostasis as intensive on–demand treatment. A 3 years old male patient affected by haemophilia A with inhibitors came to our observation for a traumatic hemarthrosis of the left knee. Clinic examination showed swelling and pain. His inhibitor titre was 29 Bethesda Units. First we infused rFVIIa for seven consecutive days at the dose of 90 ug/kg every 3 hours. This therapy didn't determinate any clinical improvement. Then we infused plasma activated prothrombin complex concentrate for the next consecutive seven days at the dose of 60 UI/kg every 12 hours. At the end of treatment we noticed pain disappearance and reducing swelling. Medical literature recently describes similar paediatric cases treated with sequential infusion of rFVIIa and plasma activated prothrombin complex concentrate. Our positive experience could stimulate to use haemostatic bypassing agents because apparently safe. We encourage to use this therapeutic scheme because it seem to reduce healing times of acute events. Disclosures: No relevant conflicts of interest to declare.

Thromboelastography (TEG) As a Global Assay to Elucidate Complex Nuances of Hemostasis in Pediatric Inhibitor Patients with High Titer Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2845-2845
Author(s):  
Natalie L Smith ◽  
Abimbola Onasoga ◽  
Linda Jacobson ◽  
Elizabeth Villalobos-Menuey ◽  
Katherine A. Ruegg ◽  
...  
Keyword(s):  
Young Children ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
High Titer ◽  
Healthy Adults ◽  
Healthy Children ◽  
Severe Hemophilia ◽  
Bypassing Agents ◽  
Inhibitor Titer ◽  
Over Time

Abstract Background: Pediatric severe hemophilia A patients with high titer inhibitors are often reported to have inadequate control of acute bleeding episodes because they do not respond to bypassing agents as predictably as with FVIII therapy for non-inhibitor patients. Thromboelastography (TEG) is a global assay of hemostasis that has promising benefits for use in clinical care for hemophilia patients. Aims: This study was performed to determine in pediatric inhibitor patients: 1) if baseline TEG, specifically R or reaction time that corresponds to time to thrombin generation and clot formation, is stable over time in individual inhibitor patients; 2) if there are any predictors of baseline TEG R time; 3) to determine response to recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisk, Copenhagen, Denmark); and 4) to determine predictors of TEG R time following rFVIIa. Methods: This analysis was conducted within a consented single institution prospective inceptional cohort study. Clinical data regarding healthy volunteers with no personal or family history of a bleeding or clotting disorder and pediatric hemophilia patients with and without inhibitors (assayed by Nijmegen modification of the Bethesda assay (BU)) were extracted from research records and electronic medical records. For this study, TEGs were performed in kaolin citrated samples with added TPA (final concentration 450 ng/mL). Descriptive data were presented as mean and SD. This report analyzed TEG R times, indicating time to clot formation and initial thrombin generation. Baseline TEGs were obtained at least five half-lives after the last infusion of each clotting factor or bypassing agent received. Post treatment TEGs were performed on patients 1 hour following a therapeutic treatment with rFVIIa. Results: R times on TEGs were obtained on 24 healthy adults, 23 healthy children, 15 children with severe hemophilia A without an inhibitor, and 12 children with severe hemophilia A and an inhibitor. 32 samples were obtained in the 12 children with inhibitors, with 1 to 11 samples from each child. Paired samples were obtained at baseline prior to and 1 hour following a dose (90-270 mg/kg) of rFVIIa. Mean TEG R times were 8.3 minutes (SD 1.4) for healthy adults, 7.7 minutes (SD 1.5) for healthy children, 20.2 minutes (SD 9.4) for children with severe hemophilia A and 102.1 minutes (SD 44.4) for children with severe hemophilia A and inhibitors. Healthy children did not differ from healthy adults (p=0.43), but children with hemophilia with inhibitors differed from healthy controls (p=0.046) and trended toward differences from children with hemophilia without inhibitors (p=0.08, however limited in sample number). Baseline R values in children with inhibitors did not correlate with age (r=-0.19) or inhibitor titer (r=0.23). Children studied on multiple occasions showed variability over time. TEG 1 hour following rFVIIa in a baseline state showed a mean R time of 25.1 minutes (SD 7.1). Post rFVIIa R time did not correlate with age (r=0.21) or inhibitor titer (r=-0.14), but showed considerable correlation with baseline TEG R time (Figure 1, r =0.65, p=0.013). Following infusion of rFVIIa, TEG R times of children with inhibitors never achieved the normal range. However, when rFVIIa was studied following multiple infusions without a washout, the mean TEG R was moderately, but non-significantly shorter at 20.6 minutes (SD 5.6). Conclusions: TEG R times in young children with severe hemophilia A with inhibitors are greatly prolonged compared to healthy children or adults, and moderately longer than that in children with severe hemophilia A without inhibitors. Baseline TEG R varies over time and cannot be predicted by age or inhibitor titer. Baseline TEG R time may be an important predictor of response to bypassing therapy and serial monitoring over time may be clinically useful to guide therapy. During the course of multiple infusions, moderately improved TEG R responses were determined compared with first infusions. This may, in part, explain our previously reported observation of longer duration of rFVIIa dosing in young children with inhibitors. Future studies employing TEG to help optimize response to bypassing agents are needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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

Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors

Haemophilia ◽  
2013 ◽  
Vol 20 (3) ◽  
pp. 369-375 ◽  
Author(s):  
H. T. T. Tran ◽  
B. Sørensen ◽  
C. J. Rea ◽  
S. Bjørnsen ◽  
T. Ueland ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Haemophilia A ◽  
Adjunct Therapy ◽  
Bypassing Agents

scholarly journals Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives

Blood ◽  
2013 ◽  
Vol 121 (11) ◽  
pp. 1944-1950 ◽  
Author(s):  
Guy Young ◽  
Benny Sørensen ◽  
Yesim Dargaud ◽  
Claude Negrier ◽  
Kathleen Brummel-Ziedins ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Objective Measure ◽  
Response To Treatment ◽  
Controversial Issues ◽  
Joint Mobility ◽  
Future Perspectives ◽  
Clotting Factors ◽  
Coagulation Assays ◽  
Current State ◽  
Bypassing Agents

Abstract Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient’s clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described.

scholarly journals Thrombin Generation Assay in Plasma from Hemophilia a Patients with or without Inhibitors on Concizumab Prophylaxis: Spiking with rFVIIa or aPCC

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3639-3639
Author(s):  
Marianne Kjalke ◽  
Mads Kjelgaard-Hansen ◽  
Søren Andersen ◽  
Ida Hilden
Keyword(s):  
Thrombin Generation ◽  
Significant Contribution ◽  
Hemophilia A ◽  
Employment Equity ◽  
Breakthrough Bleeding ◽  
Thrombin Generation Assay ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
Bypassing Agents

Introduction: Concizumab is a humanized monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI). Concizumab is currently in clinical development as a subcutaneous prophylactic therapy for hemophilia A and B patients with and without inhibitors. Breakthrough bleeding episodes experienced by inhibitor patients while on concizumab prophylaxis may be treated with the bypassing agents recombinant activated factor VII (rFVIIa; NovoSeven®) or activated prothrombin complex concentrate (aPCC; FEIBA®). Aim: To investigate the in vitro effect of rFVIIa and aPCC on hemophilia A plasma containing concizumab using a thrombin generation assay and pooled plasma spiked with concizumab or samples from patients treated prophylactically with concizumab. Methods: Pooled hemophilia A plasma was spiked with concizumab at 1, 3 and 10 nM and patient plasma samples from explorer4 (n=16; hemophilia with inhibitors; NCT03196284) and explorer5 (n=30; hemophilia A; NCT03196297) before and during concizumab prophylaxis at steady state exposure levels were assessed. Samples were spiked with rFVIIa (25 or 75 nM) or aPCC (0.25, 0.5 or 1 U/mL), and analyzed using a thrombin generation assay initiated with tissue factor (PPP-Low, Thrombinoscope). The effects of rFVIIa or aPCC in the absence or presence of concizumab were compared using ANOVA methodology. Results: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation both in the absence and presence of concizumab. A significant additional effect of rFVIIa and aPCC was observed for all concizumab concentrations spiked to the plasma pool. Overall, the effects of the combination of concizumab and rFVIIa or aPCC were mainly additive; however, a small but statistically significant drug-drug interaction was observed for rFVIIa (25 nM or 75 nM) and aPCC (0.5 U/ml or 1 U/mL) in the presence of 10 nM concizumab. At this concizumab concentration, the additive effect of aPCC corresponded to 68% of the total observed effect and the additive effect of rFVIIa to 85% of the total observed effect. At lower concizumab concentrations (1 and 3 nM), statistically significant drug-drug effects were only observed in combination with aPCC. No excessive thrombin generation above the level obtained with 1 IU/mL recombinant factor VIII (rFVIII) was observed at 1 nM concizumab combined with either rFVIIa (25 and 75 nM) or aPCC 0.5 U/mL. However, addition of 1 U/mL aPCC to 1 nM concizumab resulted in a thrombin peak modestly above the upper 95% confidence interval of the rFVIII range. In the experiments using plasma from patients treated with concizumab, the increase in thrombin peak upon addition of rFVIIa was within or below the range observed by spiking with 1 IU/mL rFVIII. The increase in thrombin peak upon addition of aPCC was within or above the rFVIII range. The effects of concizumab and rFVIIa or aPCC were mainly additive; however, a small, statistically significant contribution caused by drug-drug interaction was observed for concizumab and rFVIIa (75 nM) in both plasma from patients with and without inhibitors, and for 1 U/mL aPCC in plasma from patients with inhibitors. The additive effects of concizumab and rFVIIa corresponded to between 60% (25 nM rFVIIa, plasma without inhibitors) and 75% (75 nM rFVIIa, inhibitor plasma), and the additive effects of concizumab and 1 U/mL aPCC corresponded to 77% of the total observed effects. Conclusions: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation as expected both in the absence and presence of concizumab. Thus, the bypassing agents function as expected in plasma containing concizumab. The effects of concizumab and rFVIIa or aPCC were mainly additive. A small but statistically significant contribution was synergistic in accordance with the concizumab mechanism of action (Hilden I et al, Blood, 2012). These in vitro results support the concomitant use of bypassing agents to treat breakthrough bleeding episodes in hemophilia with inhibitor patients on concizumab prophylactic treatment. Disclosures Kjalke: Novo Nordisk A/S: Employment, Honoraria. Kjelgaard-Hansen:Novo Nordisk A/S: Employment, Equity Ownership. Andersen:Novo Nordisk A/S: Employment, Equity Ownership, Honoraria. Hilden:Novo Nordisk A/S: Employment, Equity Ownership, Patents & Royalties.

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