Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. ...Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes.
Anticoagulation monitoring and specific reversal agent targets
DOAC: direct oral anticoagulant; dTT: diluted thrombin time; ECA: ecarin chromogenic assay; ECT: ecarin cloting time. Display omitted
•Antidotes for direct oral anticoagulant (DOAC) reversal have been developed.•The role of laboratory monitoring in DOAC reversal using antidotes is unclear.•Dabigatran level prior to idarucizumab could predict reversal outcome.•Oral FXa inhibitor levels cannot be easily measured following andexanet alfa.•DOAC measurement using commercialized assays is not possible after ciraparantag.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a complication of adenoviral-based vaccine against SARS-CoV-2 due to prothrombotic immunoglobulin (Ig) G antibodies to platelet factor 4 ...(PF4) and may be difficult to distinguish from heparin-induced thrombocytopenia (HIT) in patients treated with heparin.
We assessed the usefulness of competitive anti-PF4 enzyme immunoassays (EIAs) in this context.
The ability of F(ab′)2 fragments of 1E12, 1C12, and 2E1, 3 monoclonal anti-PF4 antibodies, to inhibit the binding of human VITT or HIT antibodies to PF4 was evaluated using EIAs. Alanine-scanning mutagenesis was performed to define the amino acids involved in the interactions between the monoclonal antibodies and PF4.
A strong inhibition of VITT IgG binding to PF4 was measured with 1E12 (median inhibition, 93%; n = 8), whereas it had no effect on the binding of HIT antibodies (median, 6%; n = 8). In contrast, 1C12 and 2E1 inhibited VITT (median, 74% and 76%, respectively) and HIT antibodies (median, 68% and 53%, respectively) binding to PF4. When a competitive anti-PF4 EIA was performed with 1E12 for 19 additional VITT samples, it strongly inhibited IgG binding to PF4, except for 1 patient, who had actually developed HIT according to the clinical history. Epitope mapping showed that 1E12 interacts with 5 key amino acids on PF4, of which 4 are also required for the binding of human VITT antibodies, thus explaining the competitive inhibition.
A simple competitive anti-PF4 EIA with 1E12 could help confirm VITT diagnosis and distinguish it from HIT in patients when both diagnoses are possible.
Women with hereditary fibrinogen disorders (HFDs) seem to be at an increased risk of adverse obstetrical outcomes, but epidemiologic data are limited.
We aimed to determine the prevalence of ...pregnancy complications; the modalities and management of delivery; and the postpartum events in women with hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
We conducted a retrospective and prospective multicentric international study.
A total of 425 pregnancies were investigated from 159 women (49, 95, and 15 cases of hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia, respectively). Overall, only 55 (12.9%) pregnancies resulted in an early miscarriage, 3 (0.7%) resulted in a late miscarriage, and 4 (0.9%) resulted in an intrauterine fetal death. The prevalence of live birth was similar among the types of HFDs (P = .31). Obstetrical complications were observed in 54 (17.3%) live birth pregnancies, including vaginal bleeding (14, 4.4%), retroplacental hematoma (13, 4.1%), and thrombosis (4, 1.3%). Most deliveries were spontaneous (218, 74.1%) with a vaginal noninstrumental delivery (195, 63.3%). A neuraxial anesthesia was performed in 116 (40.4%) pregnancies, whereas general or no anesthesia was performed in 71 (16.6%) and 129 (44.9%) pregnancies, respectively. A fibrinogen infusion was administered in 28 (8.9%) deliveries. Postpartum hemorrhages were observed in 62 (19.9%) pregnancies. Postpartum venous thrombotic events occurred in 5 (1.6%) pregnancies. Women with hypofibrinogenemia were at an increased risk of bleeding during the pregnancy (P = .04).
Compared with European epidemiologic data, we did not observe a greater frequency of miscarriage, while retroplacental hematoma, postpartum hemorrhage, and thrombosis were more frequent. Delivery was often performed without locoregional anesthesia. Our findings highlight the urgent need for guidance on the management of pregnancy in HFDs.
•There are no epidemiologic data on pregnancy in hereditary fibrinogen disorders (HFDs).•We report an international study of 425 pregnancies in women with hypofibrinogenemia and dysfibrinogenemia.•The prevalence of live birth was high, without differences among the types of HFD.•Retroplacental hematoma, postpartum hemorrhage, and thrombosis were frequent.
Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; ...activity <10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation.
Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686.
We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 91% cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 34% cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 34% patients).
Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder.
Assistance Publique-Hôpitaux de Paris.
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.
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.
Summary
The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation ...of the method is high (about 20–30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu) with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the “gold standard” VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.
Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on ...heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis.
Introduction
No evidence‐based guidelines for the management of patients suffering from afibrinogenaemia and hypofibrinogenaemia are available.
Aim and method
The aim of this study was to harmonize ...patient's care among invited haemophilia experts from Belgium, France and Switzerland. A Delphi‐like methodology was used to reach a consensus on: prophylaxis, bleeding, surgery, pregnancy and thrombosis management.
Results
The main final statements are as follows: (i) a secondary fibrinogen prophylaxis should be started after a first life‐threatening bleeding in patients with afibrinogenaemia; (ii) during prophylaxis the target trough fibrinogen level should be 0.5 g L−1; (iii) if an adaptation of dosage is required, the frequency of infusions rather than the fibrinogen amount should be modified; (iv) afibrinogenaemic patients undergoing a surgery at high bleeding risk should receive fibrinogen concentrates regardless of the personal or family history of bleeding; (v) moderate hypofibrinogenaemic patients (i.e. ≥0.5 g L−1) without previous bleeding (despite haemostatic challenges) undergoing a surgery at low bleeding risk may not receive fibrinogen concentrates as prophylaxis; (vi) monitoring the trough fibrinogen levels should be performed at least once a month throughout the pregnancy and a foetal growth and placenta development close monitoring by ultrasound is recommended; (vii) fibrinogen replacement should be started concomitantly to the introduction of anticoagulation in afibrinogenaemic patients suffering from a venous thromboembolic event; and (viii) low‐molecular‐weight heparin is the anticoagulant of choice in case of venous thromboembolism.
Conclusion
The results of this initiative should help clinicians in the difficult management of patients with congenital fibrinogen disorders.
Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic ...disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.
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