Comparing cryoprecipitate-poor plasma to fresh frozen plasma as replacement therapy in thrombotic thrombocytopenic purpura: An updated meta-analysis.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis
BACKGROUND:Cryoprecipitate-poor plasma (CPP) has been suggested as a promising alternative to the standard fresh frozen plasma (FFP) in plasma exchange therapy (TPE) for thrombotic thrombocytopenic purpura (TTP) given its lower concentrations of von Willebrand Factor (VWF). However, its efficacy and safety remain a topic of debate. STUDY DESIGN AND METHODS:We conducted a systematic review and meta-analysis comparing CPP to FFP during TPE in patients with TTP. PubMed, Embase, and Cochrane Central were systematically searched for studies reporting outcomes of all-cause mortality, relapse rate, response to treatment, and the mean number of TPE sessions. Sensitivity analyses restricted to randomized controlled trials (RCTs) were performed. Review Manager v5.4 and RStudio v4.1.2 were used for statistical analysis. The protocol was prospectively registered in PROSPERO (ID CRD42023440665). RESULTS:Eight studies, including three RCTs and five non-randomized studies, met the eligibility criteria. A total of 290 patients with TTP were included, of whom 144 (49.7 %) received CPP and 146 (50.3 %) received FFP. Use of CPP was associated with lower mortality (RR 0.41; 95 % CI 0.23-0.72; p = 0.002; I²=0 %), while the subgroup analysis restricted to RCTs showed no statistical difference between groups (p = 0.36). No significant differences were found in relapse rate, response to treatment, or mean number of TPE sessions between groups. CONCLUSION:Our findings show that the use of CPP is not inferior to FFP in TPE. Given the limited population, future clinical trials are needed to elucidate its benefits compared to FFP in patients with TTP.
10.1016/j.transci.2024.104040
Thrombin generation after prothrombin complex concentrate or plasma transfusion during cardiac surgery.
Journal of thrombosis and thrombolysis
Thrombin generation (TG) is reduced after cardiac surgery using cardiopulmonary bypass (CPB), contributing to coagulopathy and bleeding. Plasma transfusion or four-factor prothrombin complex concentrate (PCC) are commonly used to treat coagulopathic bleeding after CPB without knowledge of how each may restore TG. To determine the effect of PCC infusion on restoration of thrombin generation compared with plasma transfusion, we performed a laboratory-based secondary analysis of a randomized, controlled trial of adult patients undergoing cardiac surgery to assess efficacy and safety of 4 F-PCC versus plasma for treatment of perioperative coagulopathic bleeding after CPB. Participants were randomized to receive either PCC (15 IU/kg) or plasma (10-15 ml/kg) after separation from CPB. Participant blood samples were obtained at pre-specified serial timepoints, with laboratory assays for TG and factor levels subsequently performed. The primary outcome was change in thrombin generation (TG) parameters after each randomized treatment through postoperative day 5. Secondary outcomes included serially derived clotting factor levels. Of 100 randomized participants, 99 were included in this laboratory analysis (PCC group, N = 51; plasma group, N = 48). After treatment, participants in the PCC group compared with those in the plasma group showed higher endogenous thrombin potential (ETP, Median, Interquartile range, IQR: 688 [371-1069] vs. 1088 [550-1691] nM minutes, P = 0.01), a greater increase din ETP (P = 0.002) and peak TG (P = 0.01) in the timepoints between heparin reversal and after treatment administration. Both groups demonstrated similar values in all TG assays by postoperative day 1 (P > 0.05). The PCC group also demonstrated higher levels of proteins C, S, and Factors II, VII, IX and X, early after treatment (P < 0.001 for all comparisons). Antithrombin levels were initially higher in the plasma group after treatment (Median, IQR: 66% [61-71%] vs. 56% [51-65%], P = 0.002) but differences did not persist beyond postoperative day 3. In this laboratory analysis from a recent randomized trial in adult cardiac surgery, PCC administration restored thrombin generation more rapidly than plasma in the early postoperative period without laboratory evidence of hypercoagulability. ClinicalTrials.gov identifier: NCT02557672 [1].
10.1007/s11239-024-03061-3
Reduced Plasma Selenoprotein P Is Associated With Type I Antithrombin Deficiency and a Prothrombotic State.
Archives of pathology & laboratory medicine
CONTEXT.—:A positive association between antithrombin activity and selenium level was reported. Selenoprotein P, the most important selenium carrier, was identified within human plasma fibrin clots. OBJECTIVE.—:To investigate the relationship between selenoprotein P and antithrombin and its role in modulation of fibrin clot properties in antithrombin-deficient patients. DESIGN.—:Proteomic analysis of plasma fibrin clots was performed with mass spectrometry. In 108 patients with genetically confirmed type I (57%) or type II (43%) antithrombin deficiency and in healthy controls (n = 50), we assessed plasma selenoprotein P levels and thiobarbituric acid-reactive substances by enzyme-linked immunosorbent assay, along with fibrin clot permeability, clot lysis time, and thrombin generation. RESULTS.—:Clot-bound antithrombin concentration was 0.46 ± 0.32 mg/g protein, while selenoprotein P level was 30-fold lower (0.015 ± 0.012 mg/g). Type I compared to type II antithrombin-deficient patients had higher clot-bound antithrombin and selenoprotein P levels (both P < .001), associated together (ρ = 0.93, P < .001). Individuals with type I compared to type II antithrombin deficiency or controls had about 40% lower plasma selenoprotein P levels (P < .001). In antithrombin-deficient patients, plasma selenoprotein P was associated with antithrombin antigen (ρ = 0.35, P < .001) and thiobarbituric acid-reactive substances (ρ = 0.42, P < .001). Plasma selenoprotein P correlated also with endogenous thrombin potential (r = -0.33, P < .001), fibrin clot permeability (r = 0.43, P < .001), and clot lysis time (r = -0.40, P < .001) in antithrombin-deficient patients but not in controls. CONCLUSIONS.—:Patients with type I antithrombin deficiency had higher clot-bound selenoprotein P and reduced plasma selenoprotein P levels. Plasma selenoprotein P was associated with prothrombotic fibrin clot phenotype and enhanced thrombin generation.
10.5858/arpa.2024-0162-OA
Cryo-EM structure of the human native plasma coagulation factor XIII complex.
Blood
The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma pro-transglutaminase that covalently crosslinks pre-formed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of two catalytic FXIII-A and two protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryo-electron microscopy structure of a native, human plasma-derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the two subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudo-symmetric heterotetramer of two FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a "crown-like" assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit and Sushi domain 2 with the symmetry related A' subunit and vice versa. We also report four novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.
10.1182/blood.2024025369
Clot formation and fibrinolysis assays reveal functional differences among hemostatic agents in hemophilia A plasma.
Research and practice in thrombosis and haemostasis
Background:Measuring the activity of hemostatic agents used to treat hemophilia A often requires drug-specific assays. assays show hemophilic clots have abnormal characteristics, including prolonged clotting time and decreased resistance to fibrinolysis. The ability of certain agents to correct these parameters is associated with hemostatic efficacy . Objectives:To compare effects of established and emerging hemostatic agents on clot formation and fibrinolysis in hemophilia A plasma. Methods:Pooled and individual hemophilia A platelet-poor plasmas were spiked with replacement (recombinant factor VIII [rFVIII], PEGylated rFVIII, polysialylated rFVIII, and porcine rFVIII) or bypassing (emicizumab, rFVIIa, and activated prothrombin complex concentrate) products. Effects on tissue factor-initiated clot formation and fibrinolysis were measured by turbidity. Results:Compared to normal pooled plasma, hemophilia-pooled plasma showed reduced clot formation and increased fibrinolysis, and all replacement agents improved these characteristics. rFVIII and PEGylated rFVIII produced similar effects at similar concentrations, whereas polysialylated rFVIII produced slightly higher and porcine rFVIII slightly lower effects at these concentrations. Bypassing agents enhanced clot formation and stability, but patterns differed from replacement agents. The clotting rate showed a concentration-response relationship for all agents. High concentrations of all products produced effects that exceeded the normal range in at least some parameters. Responses of individual donors varied, but all agents improved clot formation and stability in all donors tested. Conclusion:Clotting and fibrinolysis assays reveal hemostatic effects of replacement and bypassing therapies at clinically relevant concentrations. These assays may help characterize hemostatic agents and optimize dosing.
10.1016/j.rpth.2024.102337
Elevated plasma factor XI is associated with postthrombotic syndrome.
Thrombosis research
INTRODUCTION:Postthrombotic syndrome (PTS), a common complication of deep vein thrombosis (DVT), is largely inflammatory by nature with contribution of prothrombotic mechanisms. The role of factor (F)XI in PTS has not been explored yet. We investigated whether elevated FXI is associated with PTS occurrence. MATERIALS AND METHODS:We enrolled 180 consecutive patients (aged 43 ± 13 years) with first-ever DVT. After 3 months FXI levels were measured, along with inflammatory markers, thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. We assessed PTS using the Villalta score and recorded symptomatic venous thromboembolism (VTE) at a 1-year and venous ulcers at a median 53 months follow-up. RESULTS:Baseline median FXI was 102 % [IQR 92-113 %] and showed positive association with Villalta score (R = 0.474, P < 0.001). Patients with PTS (n = 48, 26.7 %) had 16.1 % higher FXI (P < 0.001) and FXI ≥120 % occurred more often in PTS patients (odds ratio [OR] 5.55, 95 % confidence interval [CI] 2.28-13.47). There were associations of baseline FXI with Ks and CLT along with thrombin activatable fibrinolysis inhibitor (TAFI) activity, C-reactive protein, and interleukin-6, but not with fibrinogen, or thrombin generation. After age adjustment higher FXI was independently associated with PTS occurrence (OR per 1 % 1.06, 95 % CI 1.02-1.09) and VTE recurrence (OR 1.03, 95 % CI 1.01-1.06). At long-term follow-up, patients with venous ulcers had 13.6 % higher baseline FXI (P = 0.002). CONCLUSIONS:Elevated FXI in association with inflammation and prothrombotic fibrin clot properties may contribute to the development of PTS following DVT.
10.1016/j.thromres.2024.109086
Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro.
British journal of anaesthesia
BACKGROUND:Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. METHODS:Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 μM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin-antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. RESULTS:In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml) and supplementing antithrombin (1.5-4.5 μM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml) and antithrombin (3 μM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin-antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. CONCLUSIONS:Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.
10.1016/j.bja.2024.02.027
Dried Plasma for Major Trauma: Past, Present, and Future.
Life (Basel, Switzerland)
Uncontrollable bleeding is recognized as the leading cause of preventable death among trauma patients. Early transfusion of blood products, especially plasma replacing crystalloid and colloid solutions, has been shown to increase survival of severely injured patients. However, the requirements for cold storage and thawing processes prior to transfusion present significant logistical challenges in prehospital and remote areas, resulting in a considerable delay in receiving thawed or liquid plasma, even in hospitals. In contrast, freeze- or spray-dried plasma, which can be massively produced, stockpiled, and stored at room temperature, is easily carried and can be reconstituted for transfusion in minutes, provides a promising alternative. Drawn from history, this paper provides a review of different forms of dried plasma with a focus on in vitro characterization of hemostatic properties, to assess the effects of the drying process, storage conditions in dry form and after reconstitution, their distinct safety and/or efficacy profiles currently in different phases of development, and to discuss the current expectations of these products in the context of recent preclinical and clinical trials. Future research directions are presented as well.
10.3390/life14050619
Whole blood storage duration alters fibrinogen levels and thrombin formation.
The journal of trauma and acute care surgery
INTRODUCTION:Whole blood resuscitation for hemorrhagic shock in trauma represents an opportunity to correct coagulopathy in trauma while also supplying red blood cells. The production of microvesicles in stored whole blood and their effect on its hemostatic parameters have not been described in previous literature. We hypothesized that microvesicles in aged stored whole blood are procoagulant and increase thrombin production via phosphatidylserine. METHODS:Whole blood was obtained from male C57BL/6 male mice and stored in anticoagulant solution for up to 10 days. At intervals, stored whole blood underwent examination with rotational thromboelastography, and platelet-poor plasma was prepared for analysis of thrombin generation. Microvesicles were prepared from 10-day-old whole blood aliquots and added to fresh whole blood or platelet-poor plasma to assess changes in coagulation and thrombin generation. Microvesicles were treated with recombinant mouse lactadherin prior to addition to plasma to inhibit phosphatidylserine's role in thrombin generation. RESULTS:Aged murine whole blood had decreased fibrin clot formation compared with fresh samples with decreased plasma fibrinogen levels. Thrombin generation in plasma from aged blood increased over time of storage. The addition of microvesicles to fresh plasma resulted in increased thrombin generation compared with controls. When phosphatidylserine on microvesicles was blocked with lactadherin, there was no difference in the endogenous thrombin potential, but the generation of thrombin was blunted with lower peak thrombin levels. CONCLUSION:Cold storage of murine whole blood results in decreased fibrinogen levels and fibrin clot formation. Aged whole blood demonstrates increased thrombin generation, and this is due in part to microvesicle production in stored whole blood. One mechanism by which microvesicles are procoagulant is by phosphatidylserine expression on their membranes.
10.1097/TA.0000000000004317
Acid Treatment of FVIII-Containing Plasma Samples Unmasks a Broad Spectrum of FVIII-Specific Antibodies in ELISA.
Hamostaseologie
During routine treatment, plasma samples of patients with hemophilia A or acquired hemophilia A are frequently analyzed for the presence of FVIII-specific antibodies. While only inhibitory antibodies can be detected by the Bethesda assay, inhibitory and non-inhibitory antibodies can be detected by ELISA. However, plasma samples of patients frequently contain endogenous or substituted FVIII, hence interfering with both types of analyses. One option for the inactivation of FVIII is heat denaturation, which unfortunately has been shown to lead to high background signals complicating the discrimination of negative and positive plasma samples. In the current study, we developed a method of acid denaturation for FVIII-containing plasma samples that can help identify samples containing FVIII-specific antibodies and compared the effects of heat and acid denaturation on the detection of FVIII-antibody interactions in a monoclonal setting. The aim of our study was to establish an analysis that allows safer treatment decisions in the context of tolerance to FVIII.
10.1055/a-2329-1781
Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.
The AAPS journal
Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.
10.1208/s12248-024-00952-4
The impact of von Willebrand factor on fibrin formation and structure unveiled with type 3 von Willebrand disease plasma.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
Normally, von Willebrand factor (VWF) remains inactive unless its A1A2 domains undergo a shear stress-triggered conformational change. We demonstrated the capacity of a recombinant A2 domain of VWF to bind and to affect fibrin formation, altering the fibrin clot structure. The data indicated that VWF contains an additional binding site for fibrin in the A2 domain that plays a role in the incorporation of VWF to the polymerizing fibrin. This study is to examine the hypothesis that active plasma VWF directly influence fibrin polymerization and the structure of fibrin clots. The study used healthy and type 3 von Willebrand disease (VWD) plasma, purified plasma VWF, fibrin polymerization assays, confocal microscopy and scanning electron microscopy. The exposed A2 domain in active VWF harbors additional binding sites for fibrinogen, and significantly potentiates fibrin formation (P < 0.02). Antibody against the A2 domain of VWF significantly decreased the initial rate of change of fibrin formation (P < 0.002). Clot analyses revealed a significant difference in porosity between normal and type 3 VWD plasma (P < 0.008), further supported by scanning electron microscopy, which demonstrated thicker fibrin fibers in the presence of plasma VWF (P < 0.0003). Confocal immunofluorescence microscopy showed punctate VWF staining along fibrin fibrils, providing visual evidence of the integration of plasma VWF into the fibrin matrix. The study with type 3 VWD plasma supports the hypothesis that plasma VWF directly influences fibrin polymerization and clot structure. In addition, a conformational change in the A1A2 domains exposes a hidden fibrin(ogen) binding site, indicating that plasma VWF determines the fibrin clot structure.
10.1097/MBC.0000000000001309
Plasma von Willebrand factor levels in patients with cancer: A meta‑analysis.
Oncology letters
von Willebrand Factor (VWF) is well recognized for being dysregulated in various malignancies and has emerged as a potential biomarker for cancer detection. The present meta-analysis aimed to elucidate the association between plasma VWF and the incidence and metastasis of cancer. For this purpose, a comprehensive search was conducted across multiple databases from their inception until March 3, 2023. This culminated in the selection of 15 original studies on various types of cancer, including a collective sample of 1,403 individuals. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were employed as statistical parameters to determine the association between plasma VWF and the incidence and metastasis of cancer. These were estimated using a random-effects model. The pooled data revealed that the plasma VWF levels of patients with cancer were significantly elevated compared with those of healthy controls (SMD, 0.98; 95% CI, 0.59-1.36), and a significant association was observed between plasma VWF levels and cancer metastasis (SMD, 0.69; 95% CI, 0.33-1.06). The symmetry of the Begg's funnel plots indicated that no significant bias was present in the analyses of VWF in cancer and its metastasis. In summary, the results of the present meta-analysis support the hypothesis that increased plasma VWF levels may serve as a biomarker for cancer and metastatic progression.
10.3892/ol.2024.14532
Plasma levels of complement components C5 and C9 are associated with thrombin generation.
Journal of thrombosis and haemostasis : JTH
BACKGROUND:The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. OBJECTIVES:This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. METHODS:Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Français du Sang Alpes-Méditerranée [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. RESULTS:Eighteen proteins were associated (P < 1.33 × 10⁻) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. CONCLUSION:This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.
10.1016/j.jtha.2024.04.026
Plasma kallikrein supports FXII-independent thrombin generation in mouse whole blood.
Blood advances
ABSTRACT:Plasma kallikrein (PKa) is an important activator of factor XII (FXII) of the contact pathway of coagulation. Several studies have shown that PKa also possesses procoagulant activity independent of FXII, likely through its ability to directly activate FIX. We evaluated the procoagulant activity of PKa using a mouse whole blood (WB) thrombin-generation (TG) assay. TG was measured in WB from PKa-deficient mice using contact pathway or extrinsic pathway triggers. PKa-deficient WB had significantly reduced contact pathway-initiated TG compared with that of wild-type controls and was comparable with that observed in FXII-deficient WB. PKa-deficient WB supported equivalent extrinsic pathway-initiated TG compared with wild-type controls. Consistent with the presence of FXII-independent functions of PKa, targeted blockade of PKa with either small molecule or antibody-based inhibitors significantly reduced contact pathway-initiated TG in FXII-deficient WB. Inhibition of activated FXII (FXIIa) using an antibody-based inhibitor significantly reduced TG in PKa-deficient WB, consistent with a PKa-independent function of FXIIa. Experiments using mice expressing low levels of tissue factor demonstrated that persistent TG present in PKa- and FXIIa-inhibited WB was driven primarily by endogenous tissue factor. Our work demonstrates that PKa contributes significantly to contact pathway-initiated TG in the complex milieu of mouse WB, and a component of this contribution occurs in an FXII-independent manner.
10.1182/bloodadvances.2024012613
Reduced plasma factor X is associated with a lack of response to recombinant activated factor VII in patients with hemophilia A and inhibitor, but does not impair emicizumab-driven hemostasis in vitro.
Thrombosis research
BACKGROUND:The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding. AIM AND METHODS:We identified 'unresponsiveness' to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions. RESULTS:Our data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 μg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL). CONCLUSIONS:Unresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy.
10.1016/j.thromres.2024.03.023