ABSTRACT
The association between endometriosis and autoimmune diseases is well known, however no acquired platelet function defect has been described so far. We describe the case of two patients with endometriosis associated with an antiplatelet glycoprotein VI (anti-GPVI) antibody. The two women with deep pelvic endometriosis associated with secondary infertility presented a mild bleeding tendency, a deficient platelet aggregation response to collagen, convulxin or CRP and a severe GPVI deficiency. Immunoblot revealed a combined FcRγ deficiency but no indication of GPVI cleavage. In the first case, platelet count was normal and an anti-GPVI IgG was detected in plasma. A first corticosteroids administration normalized in vitro platelet functions but further administrations were unsuccessful. Three IVF attempts failed. Conservative laparoscopic surgery was carried out after antifibrinolytic treatment without bleeding. The second case presented with a history of moderate thrombocytopenia and a weak anti-GPVI in the context of infertility and autoimmune disease, the Sjögren syndrome resolved after corticosteroids and hydroxychloroquine treatment. Acquired GPVI deficiencies are rare. It would be useful to determine whether the association with endometriosis is coincidental or not by more systematic investigations. It does not seem that in these patients, GPVI deficiency is associated with an increased risk of bleeding.
What is the context? ⢠Evidence for an immune system dysfunction is reported in endometriosis and the association between endometriosis and autoimmune diseases is well known.⢠No autoimmune platelet function defect has been described so far.What is new?⢠We report two unrelated patients with endometriosis-associated infertility presenting a platelet glycoprotein VI deficiency due to an autoantibody.⢠In both cases, a deficient platelet aggregation response to collagen, convulxin or CRP and a severe GPVI deficiency were observed.⢠Immunoblot revealed no indication of GPVI cleavage.What is the impact? ⢠Our observation raises the question whether GPVI could be a preferential target for the development of anti-GPVI autoantibodies associated with endometriosis.⢠It does not seem that in these patients, GPVI deficiency is associated with an increased risk of severe bleeding disorder.
Subject(s)
Endometriosis , Infertility , Humans , Female , Platelet Membrane Glycoproteins , Endometriosis/complications , Endometriosis/drug therapy , Antibodies , Platelet Count , Blood PlateletsABSTRACT
[Figure: see text].
Subject(s)
COVID-19/complications , COVID-19/pathology , Endothelium, Vascular/pathology , Multiple Organ Failure/virology , Thrombosis/virology , Biomarkers/blood , COVID-19/immunology , Complement Activation , Critical Care , Cytokines/blood , Female , Humans , Liver Failure, Acute/virology , Male , Microcirculation , Middle Aged , Nucleosomes/metabolism , Respiratory Insufficiency/virology , SARS-CoV-2ABSTRACT
PURPOSE: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in ten different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in nonsyndromic or syndromic forms of albinism. METHODS: Two hundred thirty albinism patients lacking a molecular diagnosis of albinism were screened for pathogenic variants in candidate genes with known links to pigmentation or HPS pathophysiology. RESULTS: We identified two unrelated patients with distinct homozygous variants of the BLOC1S5 gene. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. CONCLUSION: Mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of Hermansky-Pudlak syndrome, HPS-11.
Subject(s)
Hermanski-Pudlak Syndrome , Alleles , Animals , Blood Platelets , Hermanski-Pudlak Syndrome/genetics , Humans , Mice , MutationABSTRACT
The laboratory diagnosis of heparin-induced thrombocytopenia (HIT) is based on an enzyme immunoassay combined with a functional test, and serotonin release assay (SRA) is the gold standard for detecting activating HIT antibodies. However, a recent atypical history of HIT prompted us to evaluate whether addition of platelet factor 4 (PF4) during SRA could improve its ability to detect pathogenic HIT antibodies. Using 5B9, a monoclonal antibody to PF4/H with a human Fc fragment, we first defined the optimal PF4 concentration for detecting low amounts of platelet-activating IgG with SRA. Plasma samples from 50 patients with suspected HIT were then studied, and SRA was positive in 17 cases (Group SRApos ), with relatively high levels of PF4-specific IgG (median optical density = 2·66). SRA was also systematically performed after adding 10 µg/ml of PF4 in the reaction mixture, and significant serotonin release was measured with samples from 9 additional patients (Group PF4-SRApos ). Importantly, levels of PF4-specific IgG were similar in these samples and those from the 24 persistently SRA negative patients. Moreover, the pre-test probability of HIT was intermediate/high in all 'SRApos ' or 'SRA-PF4pos ' patients. In conclusion, addition of exogenous PF4 might improve the detection of pathogenic HIT antibodies by SRA.
Subject(s)
Anticoagulants/adverse effects , Autoantibodies/blood , Heparin/adverse effects , Platelet Factor 4/immunology , Thrombocytopenia/diagnosis , Aged , Antibodies, Monoclonal/immunology , Anticoagulants/immunology , Biomarkers/blood , Heparin/immunology , Humans , Immunoglobulin G/blood , Male , Platelet Activation/immunology , Platelet Count , Sensitivity and Specificity , Serotonin/blood , Thrombocytopenia/blood , Thrombocytopenia/chemically inducedABSTRACT
Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains ß-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of ß-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 µmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbß3 BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans GLc5 decreased ATP release and TGF-ß1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.
Subject(s)
Blood Platelets/drug effects , Glucosides/pharmacology , Platelet Activation/drug effects , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Toll-Like Receptor 4/metabolism , beta-Glucans/pharmacology , Adenosine Triphosphate/metabolism , Blood Platelets/metabolism , Candida albicans , Fibrinogen/drug effects , Fibrinogen/metabolism , Fungi/chemistry , Humans , Neutrophils , P-Selectin/drug effects , P-Selectin/metabolism , Phosphorylation , Platelet Glycoprotein GPIIb-IIIa Complex/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein Kinase C/drug effects , Protein Kinase C/metabolism , Real-Time Polymerase Chain Reaction , Thrombin/drug effects , Thrombin/metabolism , Toll-Like Receptor 4/antagonists & inhibitors , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/metabolism , Up-RegulationABSTRACT
A rapid lateral flow immunoassay (LFIA) (STic Expert(®) HIT), recently developed for the diagnosis of heparin-induced thrombocytopenia (HIT), was evaluated in a prospective multicentre cohort of 334 consecutive patients. The risk of HIT was estimated by the 4Ts score as low, intermediate and high in 28·7%, 61·7% and 9·6% of patients, respectively. Definite HIT was diagnosed in 40 patients (12·0%) with positive results on both enzyme-linked immunosorbent assay (Asserachrom(®) HPIA IgG) and serotonin release assay. The inter-reader reproducibility of results obtained was excellent (kappa ratio > 0·9). The negative predictive value of LFIA with plasma samples was 99·6% with a negative likelihood ratio (LR) of 0·03, and was comparable to those of the particle gel immunoassay (H/PF4-PaGIA(®) ) performed in 124 cases. Positive predictive value and positive LR were 44·4% and 5·87, respectively, and the results were similar for serum samples. The probability of HIT in intermediate risk patients decreased from 11·2% to 0·4% when the LFIA result was negative and increased to 42·5% when it was positive. In conclusion, the STic Expert(®) HIT combined with the 4Ts score is a reliable tool to rule out the diagnosis of HIT.
Subject(s)
Heparin/adverse effects , Immunoassay/methods , Nanoparticles/chemistry , Thrombocytopenia/diagnosis , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Thrombocytopenia/chemically inducedABSTRACT
Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.
Subject(s)
Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Hematologic/epidemiology , Thrombocytopenia/diagnosis , Thrombocytopenia/epidemiology , Adult , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Complications, Hematologic/genetics , Retrospective Studies , Thrombocytopenia/genetics , Young AdultABSTRACT
Clopidogrel low response as assessed by several different biological tests correlates with poor prognosis after percutaneous coronary intervention (PCI). However, recent randomized clinical trials (RCT) testing the strategy of individual antiplatelet therapy tailoring based on one sole test have all shown negative results. Poor correlation between the different tests may explain the difficulties of patient selection and identification of "true poor responders" to clopidogrel. In this prospective study, clopidogrel response was assessed in 100 consecutive patients between 18 and 24 hours after a 600 mg clopidogrel loading dose using three different tests: light transmission aggregometry with 10 µmol ADP (LTA, results expressed as platelet aggregation percentage: PAP), Verify Now P2Y12 (VN, results expressed as P2Y12 reaction unit: PRU) and vasodilatator-stimulated phosphoprotein (VASP, results expressed as platelet reactivity index: PRI). Patients under chronic clopidogrel therapy were excluded. The mean PAP, PRU and PRI values were 38.6%, 176.1 PRU and 52.4%, respectively. When clopidogrel response was analyzed as continuous variable, there was a good correlation between the different tests: LTA/VN (R(2 )= 0.642, p < 0.001), LTA/VASP (R(2 )= 0.409, p < 0.001) and VN/VASP (R(2 )= 0.616, p < 0.001). However, when clopidogrel response was analyzed as pre-specified cut-off points to define patients as "poor or good responders" (according to the literature: 50% PAP for LTA, 235 PRU for VN and 50% PRI for VASP), only 47% of the patients were defined as "good" or "poor responders" by the three tests. Altogether, 33% of the patients were defined as "poor responders" by only one test, 20% by two tests and only 16% by the three tests. The correlation between the different tests is good when clopidogrel response is analyzed as continuous variable. Each individual is however rarely (less than 50%) defined as "poor or good responder" by all the three tests when pre-specified cut-off values are used. A sole test might not be sufficient to manage antiplatelet therapy in an individual patient and these results may explain the results of recent RCT showing the lack of benefit of systematic antiplatelet therapy monitoring strategy.
Subject(s)
Cell Adhesion Molecules/metabolism , Microfilament Proteins/metabolism , Phosphoproteins/metabolism , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , Receptors, Purinergic P2Y12/metabolism , Ticlopidine/analogs & derivatives , Clopidogrel , Drug Monitoring/methods , Female , Humans , Male , Middle Aged , Platelet Aggregation/drug effects , Platelet Function Tests , Prospective Studies , Ticlopidine/therapeutic useABSTRACT
BACKGROUND: Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. METHODS: This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. RESULTS: A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived. There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. CONCLUSION: These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.
Subject(s)
Purpura, Thrombotic Thrombocytopenic , Pregnancy , Humans , Female , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombotic Thrombocytopenic/therapy , Follow-Up Studies , Platelet Count , Retrospective Studies , Recurrence , Observational Studies as TopicABSTRACT
BACKGROUND: The presence of dextran sulfate (DS) in reagents and the type of blood collection tube (citrate/citrated-theophylline-adenosine-dipyridamole [CTAD]) can lead to discrepancies between unfractionated heparin (UFH) anti-Xa levels. OBJECTIVES: To evaluate the extent of the effect (1) of different reagents containing or not containing DS and (2) of the blood collection tubes, on UFH anti-Xa levels, in various clinical situations (NCT04700670). METHODS: We prospectively included patients from eight centers: group (G)1, cardiopulmonary bypass (CPB) after heparin neutralization (n = 39); G2, cardiothoracic intensive care unit (ICU) after CPB (n = 35); G3, medical ICU (n = 53); G4, other medical inpatients (n = 38). Blood was collected into citrated and CTAD tubes. Chromogenic anti-Xa assays were centrally performed, using seven reagent/analyzer combinations including two without DS. The association between anti-Xa levels and covariates was tested using a linear mixed-effects model. RESULTS: We analyzed 4,546 anti-Xa values from 165 patients. Median anti-Xa levels were systematically higher with reagents containing DS, whatever the patient group, with the greatest effect observed in G1 (0.32 vs. 0.05 IU/mL). Anti-Xa levels were slightly higher in CTAD than in citrate samples, irrespective of the assay. The model showed: (1) a significant dextran-patient group interaction (p < 0.0001), the effect of DS on anti-Xa levels varying from 30.9% in G4 to 296% in G1, and (2) a significant effect of CTAD, varying between patient groups (p = 0.0302). CONCLUSION: The variability of anti-Xa levels with a great overestimation of the values, using a reagent containing DS, can lead to different treatment decisions, especially after heparin neutralization by protamine. Clinical consequences of these differences remain to be demonstrated.
Subject(s)
Anticoagulants , Heparin , Humans , Heparin/adverse effects , Anticoagulants/therapeutic use , Prospective Studies , Critical Illness , Heparin, Low-Molecular-Weight , Citric Acid , Citrates/therapeutic use , Factor Xa Inhibitors , Partial Thromboplastin TimeABSTRACT
BACKGROUND: Light transmission aggregation (LTA) is used widely by the clinical and research communities. Although it is a gold standard, there is a lack of interlaboratory harmonization. OBJECTIVES: The primary objective was to assess whether sources of activators (mainly adenosine diphosphate [ADP], collagen, arachidonic acid, epinephrine, and thrombin receptor activating peptide6) and ristocetin contribute to poor LTA reproducibility. The secondary objective was to evaluate interindividual variability of results to appreciate the distribution of normal values and consequently better interpret pathologic results. METHODS: An international multicenter study involving 28 laboratories in which we compared LTA results obtained with center-specific activators and a comparator that we supplied. RESULTS: We report variability in the potency (P) of activators in comparison with the comparator. Thrombin receptor activating peptide 6 (P, 1.32-2.68), arachidonic acid (P, 0.87-1.43), and epinephrine (P, 0.97-1.34) showed the greatest variability. ADP (P, 1.04-1.20) and ristocetin (P, 0.98-1.07) were the most consistent. The data highlighted clear interindividual variability, notably for ADP and epinephrine. Four profiles of responses were observed with ADP from high-responders, intermediate-responders, and low-responders. A fifth profile corresponding to nonresponders (5% of the individuals) was observed with epinephrine. CONCLUSION: Based on these data, the establishment and adoption of simple standardization principles should mitigate variability due to activator sources. The observation of huge interindividual variability for certain concentrations of activators should lead to a cautious interpretation before reporting a result as abnormal. Confidence can be taken from the fact that difference between sources is not exacerbated in patients treated with antiplatelet agents.
Subject(s)
Platelet Aggregation , Ristocetin , Humans , Arachidonic Acid/pharmacology , Reproducibility of Results , Adenosine Diphosphate/pharmacology , Platelet Function Tests/methods , Platelet Aggregation Inhibitors/pharmacology , Epinephrine/pharmacology , Communication , Blood PlateletsABSTRACT
Ibrutinib, a first-class Bruton tyrosine kinase inhibitor, is known to be associated with adverse bleeding events and has been recently approved for the treatment of relapse Waldenström macroglobulinemia (WM). Here, we report the exhaustive clinical and biological follow-up of 2 patients treated by ibrutinib alone in the context of relapsed WM with an acquired von Willebrand syndrome (AVWS) complication. In two cases, ibrutinib has been shown to be quickly efficient and safe for treating both AVWS and its underlying condition the WM, without bleeding complications. Interestingly, ibrutinib treatment brings a rapid and extended over time normalization of von Willebrand factor clearance. These observations show that ibrutinib is a valuable therapeutic option in relapsed WM patients associated with AVWS and highlighting the need for further cohort studies with long-term follow-up of patients to confirm the efficacy and safety of a treatment by ibrutinib for WM patients with AVWS complication.
Subject(s)
Waldenstrom Macroglobulinemia , von Willebrand Diseases , Humans , Neoplasm Recurrence, Local , von Willebrand Diseases/diagnosis , von Willebrand Diseases/drug therapy , von Willebrand Diseases/etiology , Piperidines/therapeutic use , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/drug therapySubject(s)
Calreticulin/genetics , Cell-Derived Microparticles/pathology , Janus Kinase 2/genetics , Mutation , Thrombocythemia, Essential/pathology , Aged , Cell-Derived Microparticles/genetics , Female , Humans , Male , Middle Aged , Phenotype , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombosis/etiologyABSTRACT
BACKGROUND: In intensive-care unit (ICU) patients, pathophysiological changes may affect the pharmacokinetics of enoxaparin and result in underdosing. OBJECTIVES: To develop a pharmacokinetic model of enoxaparin to predict the time-exposure profiles of various thromboprophylactic regimens in COVID-19 ICU-patients. METHODS: This was a retrospective study in ICUs of two French hospitals. Anti-Xa activities from consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated with enoxaparin for the prevention or the treatment of venous thrombosis were used to develop a population pharmacokinetic model using non-linear mixed effects techniques. Monte Carlo simulations were then performed to predict enoxaparin exposure at steady-state after three days of administration. RESULTS: A total of 391 anti-Xa samples were measured in 95 patients. A one-compartment model with first-order kinetics best fitted the data. The covariate analysis showed that enoxaparin clearance (typical value 1.1 L.h-1) was related to renal function estimated by the CKD-EPI formula and volume of distribution (typical value 17.9 L) to actual body weight. Simulation of anti-Xa activities with enoxaparin 40 mg qd indicated that 64% of the patients had peak levels within the range 0.2 to 0.5 IU.mL-1 and 75% had 12-hour levels above 0.1 IU.mL-1. Administration of a total daily dose of at least 60 mg per day improved the probability of target attainment. CONCLUSION: In ICU COVID-19 patients, exposure to enoxaparin is reduced due to an increase in the volume of distribution and clearance. Consequently, enoxaparin 40 mg qd is suboptimal to attain thromboprophylactic anti-Xa levels.
Subject(s)
COVID-19 , Enoxaparin , Anticoagulants , Critical Illness , Enoxaparin/therapeutic use , Humans , Retrospective Studies , SARS-CoV-2ABSTRACT
BACKGROUND: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays. OBJECTIVE: To develop a pretest score for HIT. DESIGN: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839). SETTING: Thirty-one tertiary hospitals in France, Switzerland, and Belgium. PATIENTS: Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts. MEASUREMENTS: Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results. RESULTS: Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥40% decrease in platelet count over ≤6 days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 (95% CI, 0.76-0.82). In the validation cohort, the area under the receiver operating characteristic curve was 0.77 (95% CI, 0.74-0.80). Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group. LIMITATION: The performance of the score may depend on settings and practices. CONCLUSION: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pretest score, which may guide clinical decisions regarding diagnostic testing and anticoagulation.
Subject(s)
Heparin , Thrombocytopenia , Anticoagulants/adverse effects , Heparin/adverse effects , Humans , Platelet Count , Prospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombocytopenia/epidemiologyABSTRACT
BACKGROUND: Inhibitors of tyrosine kinases downstream of the B-cell receptor, such as Bruton's tyrosine kinase (Btk) or Spleen tyrosine kinase (Syk), used alone or in combination are new therapeutic options in the treatment of B-cell malignancies. A challenge in the development of second-generation Btk inhibitors is to limit their side effects such as the increased bleeding risk. Considering the pivotal role of Syk in immunoreceptor tyrosine-based activation motif mediated platelet signaling, the impact of inhibiting this kinase on platelet functions is also worth analyzing. OBJECTIVES: We investigated the effect of a novel Btk inhibitor, tirabrutinib, and a Syk inhibitor, entospletinib, alone and in combination on platelet signaling and functions in vitro and ex vivo. METHODS: Platelet aggregation, secretion, and signaling responses as well as thrombus growth under flow were analyzed in the presence of the inhibitors alone or in combination in vitro, at clinically relevant doses, and ex vivo in patients treated with these inhibitors in the context of a phase I trial. RESULTS: Although tirabrutinib alone had modest effects on platelet activation in vitro and ex vivo, entospletinib alone efficiently inhibited washed platelet aggregation in response to collagen. However, entospletinib weakly affected platelet activation in platelet-rich plasma, in whole blood and ex vivo. Importantly, the combination of tirabrutinib and entospletinib induced a significant decrease in platelet response to collagen in vitro and ex vivo correlating with mild bleedings reported in some of the treated patients. CONCLUSION: These new results should contribute to improve the safety of these targeted therapies.
Subject(s)
Platelet Aggregation , Protein-Tyrosine Kinases , Agammaglobulinaemia Tyrosine Kinase , Hemostasis , Humans , Platelet Activation , Syk KinaseABSTRACT
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature. METHODS: The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis. RESULTS: Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p = 0.03). CONCLUSION: This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.
Subject(s)
Anticoagulants/adverse effects , Heparin/adverse effects , Thrombocytopenia/chemically induced , Adult , Aged , Aged, 80 and over , Antigens, Human Platelet/genetics , Female , France , Humans , Integrin beta3/genetics , Male , Middle Aged , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Polymorphism, Genetic , Prognosis , Prospective Studies , Receptors, IgG/genetics , Risk Assessment , Risk Factors , Thrombocytopenia/diagnosis , Thrombocytopenia/mortality , Thrombocytopenia/therapy , Time Factors , Young AdultABSTRACT
BACKGROUND: Defining hemostatic profile for preterm infants is a challenge when severe bleedings are frequent. METHODS: The aim was to define the hemostatic profile at birth of infants with spontaneous prematurity and to evaluate whether characteristic profiles can predict the development of intraventricular hemorrhage (IVH) in prematures. RESULTS: We included 122 newborns with a median age of 315/7 gestational age (GA) [292/7;340/7] and median weight of 1145 g [785;1490]. Levels of fibrinogen, factor II (FII) and factor V (FV) rose with GA (p = 0.017,p = 0.009, p = 0.001). In the group of 230/7 - 286/7 GA, the 5th percentile was defined as 0.6 g/L for fibrinogen, 15 IU/dL for FII and 16 IU/dL for factor V (n = 30). In the group of 290/7-326/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 41 IU/dL for factor V (n = 46). In the group of 330/7-366/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 30 IU/dL for factor V (n = 46). Level of fibrinogen was higher in case of vaginal delivery and lower in case of IUGR. Only lower level of FV at birth was significantly associated with IVH (63.5 [46.0; 76.5] vs 74.0 [58.0; 89.0], p = 0.026) with an unadjusted OR per SD increase in FV of 0.57 (95%CI, 0.34 to 0.96). After adjustment for age, the association between FV level and IVH was slightly attenuated (adjusted OR, 0.70; 95%CI, 0.40 to 1.23) but remained not significant (p = 0.22).There was no correlation with FII and fibrinogen. CONCLUSIONS: We can define hemostastic profile of prematures and corroborate references ranges for studied parameters. Further large studies are still called for, to correlate the grade of hemorrhage and the factor V level at birth.
Subject(s)
Blood Coagulation Factors/metabolism , Cerebral Hemorrhage/blood , Cerebral Hemorrhage/etiology , Infant, Premature, Diseases/blood , Infant, Premature, Diseases/etiology , Female , Gestational Age , Humans , Infant, Newborn , Infant, Premature , Male , Platelet Count , Predictive Value of Tests , Retrospective StudiesABSTRACT
BACKGROUND/AIM: Colorectal cancer (CRC) is associated with high incidence and mortality rates. Carcinoembryonic antigen (CEA), a prognostic biomarker for recurrent CRC following curative resection, suffers from low sensitivity, especially in early-stage screening. Intraplatelet angiogenesis regulators (IPAR), such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), have been identified as important regulators of tumor growth in CRC. The aim of this study was to confirm the higher preoperative level of IPAR (VEGF and PDGF) in CRC patients compared to controls and to measure IPAR in CEA-negative CRC patients. METHODS: The data and blood of 30 CRC patients and 30 presumably healthy controls were prospectively analyzed and compared. RESULTS: We confirmed elevated preoperative intraplatelet VEGF and PDGF levels in CRC patients compared to controls. Importantly, IPAR were significantly elevated even in CEA-negative CRC patients. CONCLUSION: Elevated preoperative intraplatelet VEGF and PDGF levels in CRC patients suggest new possibilities for postoperative monitoring in CRC patients, especially when CEA is negative.
ABSTRACT
Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe français d'étude sur l'hémostase et la thrombose, subcommittee "CEC et biologie délocalisée") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists.