Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants?

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.

Acute coronary syndrome in patients treated by vitamin K antagonists or non-vitamin K antagonist oral anticoagulants: Proposed management algorithm for the first 48hours.

Around 10% of patients with acute coronary syndrome are treated by vitamin K antagonists or non-vitamin K antagonist oral anticoagulants for various indications. The initial management of these patients is highly complex, and new guidelines specify that, only during percutaneous coronary intervention, a bolus of unfractionated heparin is recommended in one of the following circumstances: (1) if the patient is receiving a non-vitamin K antagonist oral anticoagulant; or (2) if the international normalized ratio is<2.5 in a patient being treated with a vitamin K antagonist. In this review, we report on five key messages essential for the management of these patients. There are no randomized studies to date, and we propose two diagnostic and/or therapeutic decision algorithms. However, randomized studies are needed to validate these strategies.

COVID-19 and the Concept of Thrombo-Inflammation: Review of the Relationship between Immune Response, Endothelium and Coagulation.

COVID-19, caused by the SARS-CoV-2 virus, has revealed a complex interplay between inflammation and coagulation, leading to the emergence of the concept of thrombo-inflammation. This concept recognizes that COVID-19 is not solely a respiratory illness, but a systemic disease with significant vascular and hematological components. COVID-19 is associated with an unusual prothrombotic state, with intense endothelial activation leading to vasculopathy, cytokine storm, complement system activation and a hypercoagulability state (the activation of platelets and the coagulation cascade, impaired fibrinolysis). The aim of this review is to discuss the different pathological pathways described in COVID-19 that lead to thromboembolic events. Widespread vaccination and post-COVID-19 immunization allows control over the severity of this pandemic. A better understanding of the pathophysiology of COVID-19 can improve the management of frail patients who are hospitalized in intensive care units.

How to assess hypercoagulability in heparin-induced thrombocytopenia? Biomarkers of potential value to support therapeutic intensity of non-heparin anticoagulation.

BACKGROUND: In case of heparin-induced thrombocytopenia (HIT), the switch to a non-heparin anticoagulant is mandatory, at a therapeutic dose. Such a treatment has limitations though, especially for patients with renal and/or hepatic failure. Candidate laboratory tests could detect the more coagulable HIT patients, for whom therapeutic anticoagulation would be the more justified. PATIENTS AND METHODS: This was a monocentre observational prospective study in which 111 patients with suspected HIT were included. Nineteen were diagnosed with HIT (ELISA and platelet activation assay), among whom 10 were classified as HITT + when a thrombotic event was present at diagnosis or during the first following week. Two plasma prethrombotic biomarkers of in vivo activation of the haemostasis system, procoagulant phospholipids (ProcoagPPL) associated with extracellular vesicles and fibrin monomers (FM test), as well as in vitro thrombin potential (ST Genesia; low picomolar tissue factor) after heparin neutralization (heparinase), were studied. The results were primarily compared between HITT + and HITT- patients. RESULTS: Those HIT + patients with thrombotic events in acute phase or shortly after (referred as HITT+) had a more coagulable phenotype than HIT + patients without thrombotic events since: (i) clotting times related to plasma procoagulant phospholipids tended to be shorter; (ii) fibrin monomers levels were statistically significantly higher (p = 0.0483); (iii) thrombin potential values were statistically significantly higher (p = 0.0404). Of note, among all patients suspected of suffering from HIT, we did not evidence a hypercoagulable phenotype in patients diagnosed with HIT compared to patients for whom the diagnosis of HIT was ruled out. CONCLUSION: The three tests could help identify those HIT patients the most prone to thrombosis.

Factors Influencing Anti-Xa Assays: A Multicenter Prospective Study in Critically Ill and Noncritically Ill Patients Receiving Unfractionated Heparin.

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.

Decompressive surgery in cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored. METHODS: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included. RESULTS: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent. CONCLUSIONS: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence.

Direct Oral Anticoagulants versus Vitamin K Antagonists in Individuals Aged 80 Years and Older: An Overview in 2021.

Two main types of oral anticoagulants are available in France: vitamin K antagonists (VKA) and, more recently, direct oral anticoagulants (DOAC). The benefit−risk profile appears to be favorable for DOAC, which is as effective as VKA but safer (fewer cases of severe and cerebral bleeding). In a study in 2017, we observed that older adults did not seem to receive the same modalities of oral anticoagulants as younger individuals for various reasons. To assess anticoagulation prescribing practices over time, we repeated this cross-sectional study by comparing very old individuals taking DOAC to those taking VKA. Ambulatory individuals aged 80 years and older were included. They were affiliated with the Mutualité Sociale Agricole of Burgundy and were refunded for a medical prescription of oral anticoagulation in March 2021. The demographic characteristics, registered chronic diseases (RCD), number and types of prescribed drugs, and mortality of the DOAC group and the VKA group were compared. A total of 4275 subjects were included in the study: 67.44% (2883) received DOAC and 32.56% (1392) received VKA. The two groups were similar in age. In the DOAC group, there were more women (54.98% vs. 46.98%) (p < 0.001), fewer RCD (91.47% vs. 93.68%) (p = 0.014), and lower rates of venous thromboembolism (2.53% vs. 6.75%) (p < 0.001), severe heart failure (56.50% vs. 68.03%) (p < 0.001), and severe kidney diseases (1.38% vs. 3.59%) (p < 0.001), but there were more subjects with Alzheimer's disease (7.49% vs. 4.31%) (p = 0.001). Individuals in the DOAC group had fewer prescriptions of furosemide (48.53% vs. 55.75%) (p < 0.001) and fibrates (2.32% vs. 3.88%) (p = 0.044). They also had more prescriptions of proton pump inhibitors (43.95% vs. 39.44%) (p = 0.006) and antirheumatics (1.60% vs. 0.65%) (p = 0.009) than those in the VKA group. There was no difference in mortality. This study revealed that prescribing practices for DOAC have changed over time.

Titanate nanoribbon-based nanobiohybrid for potential applications in regenerative medicine.

Nanoparticles capable of mimicking natural tissues represent a major technological advancement in regenerative medicine. In this pilot study, the development of a new nanohybrid composed of titanate nanoribbons to mimic the extracellular matrix is reported. During the first phase, nanoribbons were synthesized by hydrothermal treatment. Subsequently, titanate nanoribbons were functionalized by heterobifunctional polyethylene-glycol (PEG) to graft type I collagen on their surface. Biological properties of this new nanobiohybrid such as cytotoxicity to cardiac cells and platelet aggregation ability were evaluated. The so-formed nanobiohybrid permits cellular adhesion and proliferation favoring fine cardiac tissue healing and regeneration.

Management of urgent invasive procedures in patients treated with direct oral anticoagulants: An observational registry analysis.

BACKGROUND: Patients treated with direct oral anticoagulants (DOACs) may require urgent procedures. Managing these patients is challenging due to different bleeding risks and may include laboratory testing, procedural delays, or haemostatic/reversal agent administration. OBJECTIVE: We evaluated management strategies and outcomes of urgent, non-haemostatic invasive procedures in patients treated with DOACs. METHODS AND RESULTS: In a descriptive cohort study, we prospectively evaluated 478 patients in the GIHP-NACO registry, from June 2013 to November 2015. Hospitalised patients receiving dabigatran (n = 160), rivaroxaban (n = 274), or apixaban (n = 44) requiring urgent, procedural interventions were evaluated, of which 384/478 (80 %) were surgical procedures. Orthopaedic surgery included 216/384 patients (56 %), while gastrointestinal surgery included 75/384 (20 %) patients. On admission, the median age was 79 (70-85), and creatinine clearance was <60 mL·min-1 in 316/478 (66 %) patients. DOAC concentration was determined in 277 (58 %) patients and was 85 ng·mL-1 (median; range 0-764), 61 ng·mL-1 (3-541), and 81 ng·mL-1 (26-354) for dabigatran, rivaroxaban, and apixaban, respectively. Procedures were delayed in 194/455 (43 %) of the cases. Excessive bleeding was observed in 62/478 (13 %) procedures, and haemostatic agents were administered in 76/478 (16 %) procedures. By day 30, major cerebral and cardiovascular events were observed in 38/478 (7.9 %) patients, and mortality was 28/478 (5.9 %). CONCLUSIONS: In the GIHP-NACO registry, before specific antidotes were available, DOAC treated patients undergoing urgent invasive procedures were delayed in nearly half of the cases, and showed a low rate of excessive bleeding, suggesting that most urgent procedures can be performed safely without DOAC reversal. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov. Identifier: NCT02185027.

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.

OBJECTIVE: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. METHODS: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. RESULTS: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). CONCLUSIONS: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.

Study of in vitro thrombin generation after neutralization of heparin.

INTRODUCTION: Thrombin generation (TG) documents hypercoagulability. TG in platelet-poor plasma is exquisitely sensitive to heparins, which thus must be neutralized before testing. Heparinase and hexadimethrine bromide (polybrene) have been used for that purpose, but their effects per se on TG have been poorly studied so far. METHODS: (i) TG was studied in commercial normal pooled plasma (NPP; CryoCheck® , Cryopep) in absence or presence of neutralizing agents. (ii) NPP was spiked with increasing concentrations of unfractionated heparin (UFH; up to 1.0 IU/mL) or low-molecular-weight heparin (LMWH; enoxaparin up to 1.2 IU/mL) and TG studied after incubation of heparinase (Hepzyme® ; 15 minutes) or polybrene (0.025 mg/mL; 10 minutes). RESULTS: (i) With ThromboScreen reagent to initiate TG, addition of heparinase was associated with increased peak, whereas polybrene caused lengthening of lag time and time to peak, compared with nonsupplemented NPP. (ii) With polybrene, TG was completely restored over the whole range of UFH and LMWH studied. By contrast, heparinase failed to fully restore TG in presence of UFH concentrations ≥0.8 IU/mL or LMWH concentrations ≥1.0 IU/mL. Those effects were matched with detectable tiny residual amounts of non-neutralized heparin (as assessed with an anti-Xa assay) and were less pronounced with a higher picomolar concentration of tissue factor (DrugScreen reagent). CONCLUSION: Polybrene fully restored TG of heparinized plasma at the expense of an alteration of TG, pointing to the need to use adapted reference ranges. Heparinase failed to do so in presence of high concentrations of both heparins.

Case report: Umbilical vessel aneurysm thrombosis and factor V Leiden mutation leading to fetal demise.

Complicated pregnancies are nowadays a major public health concern, with possible lethality or sequelae both for the mother and the fetus. Blood coagulation disorders (including antiphospholipid syndrome, factor V Leiden mutation and antithrombin deficiency) and hypertensive gestational disorders are very well-known contributors of complicated pregnancies with poor fetal outcome, such as intrauterine growth retardation (IUGR) and fetal demise. Less commonly, vascular malformations of the placenta can also potentially lead to serious complications such as IUGR and fetal death. These malformations include hypercoiled umbilical cord, umbilical cord knot, umbilical cord varix, umbilical cord arterial or venous aneurysm, and velamentous insertion of the umbilical cord potentially leading to Benckiser's hemorrhage. Here, we report the case of a 29-year-old Gravida 2 Para 0 mother with previous history of stillbirth and smoking, admitted to the obstetrics department for the absence of fetal movement at 38 weeks of amenorrhea (WA). First-trimester and second-trimester routine ultrasounds were otherwise normal. Ultrasound performed at 38 WA revealed a 83 × 66 × 54 mm cystic heterogenous mass at the umbilical cord insertion. After delivery, fetal and placental pathology as well as maternal blood testing were performed. Fetal pathology was otherwise normal, except for diffuse congestion and meconial overload suggesting acute fetal distress. Fetal karyotype was normal (46 XX). Placental pathology revealed an umbilical artery aneurysm (UAA) at the base of the insertion of the umbilical cord, lined with a CD34+ CD31+ endothelium. After dissection, the aneurysm was filled with hemorrhagic debris, indicating aneurysm thrombosis. Histopathology revealed associated maternal vascular malperfusion (MVM) and increased peri-villous fibrin (IPF). Maternal blood tests revealed heterozygous factor V Leiden mutation, without other associated auto-immune conditions (such as antiphospholipid syndrome). Umbilical artery aneurysms remain extremely rare findings in the placenta, with <20 reported cases. Umbilical artery aneurysms have tendency to be located at the base of the insertion of the placenta, and lead to fetal demise in more than 60% of cases, mainly due to aneurysmal thrombosis, hematoma, possible vascular compression and/or rupture. Umbilical vessel aneurysms can be associated with trisomy 18 or 13. In our case, the association of factor V Leiden mutation, a hypercoagulable state, with UAA could explain massive thrombosis of the aneurysmal lumen and sudden fetal demise. Further consideration of current guidelines for surveillance and management of UAA would allow appropriate planned delivery in maternal care settings.

GFHT proposals on the practical use of argatroban - With specifics regarding vaccine-induced immune thrombotic thrombocytopaenia (VITT).

Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg × kg-1 × min-1, with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly advised to involve a health practitioner experienced in the management of difficult cases in haemostasis. The first laboratory assessment should be performed 4 h after the initiation of argatroban infusion, with further controls at 2-4-h intervals until steady state, and at least once daily thereafter. Importantly, full anticoagulation should be rapidly achieved in case of widespread thrombosis. Cerebral vein thrombosis (which is typical of VITT) should not call for an overly cautious anticoagulation scheme. Argatroban administration requires baseline laboratory assessment and should rely on an anti-IIa assay to derive argatroban plasma levels using a dedicated calibration, with a target range between 0.5 and 1.5 µg/mL. Target argatroban plasma levels can be refined based on meticulous appraisal of risk factors for bleeding and thrombosis, on frequent reassessments of clinical status with appropriate vascular imaging, and on the changes in daily platelet counts. Regarding the use of aPTT, baseline value and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient's/mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged: one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg × kg-1 × min-1 up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.

Specific Features of the Coagulopathy Signature in Severe COVID-19 Pneumonia.

Rationale: COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia. Methods: Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared. Results: At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients (p = 0.0049) and more frequently developed venous thrombotic complications (p = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; p = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10). Conclusion: We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation. Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT03505281.

Heparin-induced thrombocytopenia: Construction of a pretest diagnostic score derived from the analysis of a prospective multinational database, with internal validation.

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.

Impact of Platelet Reactivity in ACS Patients on Clinical Outcomes with Triple Antithrombotic Therapy.

Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients on oral anticoagulants (OAC) remains a clinical conundrum. In fact, combining an OAC with dual antiplatelet therapy (triple antithrombotic therapy, TAT) increases the risk of bleeding. Clopidogrel is the only thienopyridine recommended in TAT patients. Whether its response plays a relevant role in this setting remains uncertain. We aimed to evaluate the level of platelet reactivity inhibition (PRI) achieved by oral TAT in Acute Coronary Syndrome (ACS) patients undergoing PCI and its relationship with outcomes. We performed a multicenter prospective observational study and assessed PRI by vasodilator-stimulated phosphoprotein (VASP) index following a loading dose of clopidogrel. The primary endpoint was the incidence of major adverse cerebral or cardiovascular events (MACCE) at six months based on High on Treatment Platelet Reactivity (HTPR, VASP > 50%). The secondary endpoint was the incidence of bleeding at six months based on Low on Treatment Platelet Reactivity (LTPR, VASP < 16%). 491 patients were followed up for six months: 7.7% experienced MACCE and 17.3% experienced bleeding. There was no significant relationship between HTPR and MACCE, neither between LTPR and bleeding. Vitamin-K antagonist (VKA) treatment was associated with more MACCE and bleeding events, and the majority of events occurred within the first months. VASP index failed to predict outcomes in post-ACS patients with TAT. We confirm that direct acting OAC should be prioritized over VKA in TAT regimen.

Assessment of Shear-Dependent Kinetics of Primary Haemostasis With a Microfluidic Acoustic Biosensor.

Primary haemostasis is a complex dynamic process, which involves in-flow interactions between platelets and sub-endothelial matrix at the area of the damaged vessel wall. It results in a first haemostatic plug, which stops bleeding, before coagulation ensues and consolidates it. The diagnosis of primary haemostasis defect would benefit from evaluation of the whole sequence of mechanisms involved in platelet plug formation in flow. This work proposes a new approach that is based on characterization of the shear-dependent kinetics that enables the evaluation of the early stages of primary haemostasis. We used a label-free method with a quartz crystal microbalance (QCM) biosensor to measure the platelet deposits over time onto covalently immobilized type I fibrillar collagen. We defined three metrics: total frequency shift, lag time, and growth rate. The measurement was completed at four predefined shear rates prevailing in small vessels (500, 770, 1000 and 1500 s-1) during five minutes of perfusion with anticoagulated normal whole blood. The rate of the frequency shift over the first five minutes was strongly influenced by shear rate conditions, presenting a maximum around 770 s-1, and varying by a factor larger than three in the studied shear rate range. To validate the biosensor signal, the total frequency shift was compared to results obtained by atomic force microscopy (AFM) on final platelet deposits. The results show that shear-dependent kinetic assays are promising as an advanced method for screening of primary haemostasis.

Anti-Domain I ß2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study.

BACKGROUND: Antibodies binding to domain I of ß2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome. METHODS: This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months. RESULTS: We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation-based test. The APCsr was higher in patients with anti-domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15-9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69-21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93-16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33-11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36-18.28]; P = 0.02) remained significant predictors of thrombosis over time. CONCLUSIONS: Our study shows that novel tests for antibodies recognizing domain I of ß2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.