Direct Oral Anticoagulants as Successful Treatment of Heparin-Induced Thrombocytopenia: A Parisian Retrospective Case Series.

Background: Heparin-induced thrombocytopenia (HIT) is a prothrombotic life-threatening disorder caused by an adverse reaction to heparin exposure. In this context, it is imperative to stop heparin immediately and to replace it by a non-heparin anticoagulant therapy. Despite their advantages, the use of direct oral anticoagulants (DOACs) is only emerging for HIT treatment, and their use remains rare. Objective: To improve our knowledge on the emerging role of DOACs as treatment of HIT and give an overview of our local practices in this context. Patients/Methods: This is a multi-centric retrospective case series of HIT patients referred to our Parisian pharmacovigilance network and treated with DOACs. Results: We report the cases of seven patients from four healthcare centers, diagnosed with HIT (4T score ≥ 4, positive anti-PF4/heparin immunoassay and positive serotonin-release assay) and treated with DOACs. After a few days on substitutive parenteral treatment (n = 6) or directly at HIT diagnosis (n = 1), these patients were treated with either rivaroxaban (n = 6) or apixaban (n = 1) during acute HIT phase. Mean time to platelet count recovery after heparin discontinuation was 3.3 days (range 3-5). No patient experienced major or clinically relevant non-major bleeding or thrombosis that could be related to DOAC treatment during follow-up. Conclusions: Our cases studies are consistent with recent guidelines credit to the potential and safe use of DOAC during acute HIT in clinically stable patients.

[Acquired hemophilia A associated with bullous pemphigoid and multiple myeloma: a case report]. / Hémophilie A acquise associée à une pemphigoïde bulleuse et à un myélome multiple : à propos d'un cas.

Acquired hemophilia A (AHA) is a rare and potentially severe bleeding disorder caused by circulating autoantibodies directed against factor (F) VIII. Apart from idiopathic cases, AHA is associated with autoimmune diseases, cancers, use of medications, pregnancy and the post-partum period. We report the case of a 78-year-old a male patient presenting with symptoms of a hematoma after a fall three days previously. He is medically followed for multiple myeloma and bullous pemphigoid. Laboratory investigations revealed isolated and recent increased of activated partial thromboplastin time (80,6/32,1s) and a markedly low FVIII activity (< 1%). The high-titer of FVIII inhibitor (19 Bethesda units/mL) confirmed the diagnosis of AHA diagnosis. The symptoms were noticeably alleviated following bortezomib, cyclophosphamide and dexamethasone therapy. This report describes a rare case of AHA associated with bullous pemphigoid and multiple myeloma. These pathologies induce an immunity modification that can predispose or be associated with the development of anti-FVIII inhibitors. This case illustrates two possible physiopathological hypotheses for the development of AHA, which will be discussed in this case report.

Ticagrelor reversal: in vitro assessment of four haemostatic agents.

AIM: Management of ticagrelor-induced bleeding is challenging as platelet transfusion is ineffective. An effective strategy is needed. This study aimed to investigate in vitro the efficacy of four haemostatic drugs (HDs), namely recombinant activated factor VII (rFVIIa), fibrinogen concentrate (Fib), tranexamic acid (TXA) and factor XIII concentrate (FXIII) to improve the haemostatic capacity in the presence of ticagrelor. METHODS: Blood was spiked with ticagrelor then supplemented by either HD or control. Several assays were performed: ADP-induced platelet aggregation measured by impedance aggregometry, light transmission and two global assays, thrombolastography with the platelet mapping device (TEG-PM) and a platelet-dependent thrombin generation assay (TGA). RESULTS: Ticagrelor inhibited ADP-induced platelet aggregation and decreased the clot strength maximum amplitude (MA) in TEG-PMADP. None of the HDs corrected these parameters. However, rFVIIa shortened the coagulation time R using TEG-PMthrombin and the time to peak prolonged by ticagrelor in TGA. Fib increased MAthrombin and FXIII decreased LY30. TXA had no effects. CONCLUSIONS: Whereas none of the HDs corrected ticagrelor-induced platelet inhibition, rFVIIa shortened coagulation times, Fib increased clot firmness and FXIII decreased fibrinolysis. Consequently, they may bypass ticagrelor effects by acting on fibrin formation or fibrinolysis. Further studies are needed to confirm these data in vivo.

Impact of a pneumatic tube system transport on hemostasis parameters measurement: the experiment of Cochin universitary hospital (AP-HP, Paris, France).

Samples transported by pneumatic tube system are submitted to forces of acceleration and deceleration which can affect laboratory parameters. At Cochin hospital, majority of samples of hemostasis, except for platelets tests, are transported by pneumatic tube system. The objective of this study was to evaluate the impact of a pneumatic tube system (PTS) transport compared to hand-delivered transport on samples and to qualify Cochin hospital PTS according to requirements of standard ISO 15189. A bibliographical study was made and showed that pneumatic tube system particularly influences platelets tests. Four citrate tubes were collected in 5 healthy volunteers in the maternity: 2 tubes were transported by PTS and 2 others were hand-delivered to the laboratory. Five coagulation tests were analyzed: prothrombine time (PT), activated partial thromboplastin time (aPTT), factor (F) V, FVIII and platelet closure time with PFA-100TM collagen/epinephrine. For each volunteer, the results obtained by PTS and by hand-delivered transport were compared with formula usually used for biological analysis retake: 2.8 x standard deviation of reproductibility variation coefficient (SH GTA 01, COFRAC). This study did not show an impact of PTS on PT, aPTT, FV and FVIII. For PFA-100TM collagen/epinephrine, we noted an impact on 2/5 volunteers. These results, in agreement with the literature, led to the conclusion that Cochin hospital PTS is in compliance to transport samples for usual coagulation tests except platelet tests. This study allowed to issue French recommendations for PTS transport of hemostasis tubes qualification available on "Groupe français d'hémostase et thrombose" Web site.

Analytical performances of Hemoclot Protein C Reagent on ACL TOP analyzer.

Our study aimed to evaluate and validate according to standard NF EN ISO 15189 the original protocol ajustement of Hemoclot Protein C (PC) (Hyphen BioMed), clotting-based assay of PC on ACL TOP analyzer (Werfen/Instrumentation Laboratory). We evaluated the performance in terms of imprecision and we validate additional parameters in range B required by the SH GTA 04 (COFRAC): repeatability, reproducibility, detection and quantification limits, limits of linearity, stability, inter-samples and inter-reagents contamination, inaccuracy, evaluation of interferences (hemolysis, bilirubinemia and chyles). A comparison with Hemoclot PC on STA Compact analyzer (Stago) was performed. Coefficients of variation were lower than 5 %. Detection and quantification limits were respectively 8.3 % and 9.3 %. Superior limit of linearity was 140 %. The test didn't diplay any inter-samples and inter-reagents contamination. Reagent after reconstitution was stable 6 hours on ACL TOP. No interferences were observed for hemoglobin lower than 500 mg/dL, for bilirubin lower than and for chyles lower than 300 mg/dL. Comparison with Hemoclot PC on STA analyzer (Stago) was satisfactory. Hemoclot PC adjusted on ACL TOP analyzer showed satisfactory analytical performances with criteria chosen in our study. These data allow a better knowledge of the performances of this test and were useful to make a validation file in range B as recommended by SH GTA 04.

PT, aPTT, TT and the hemostatic safety threshold of dabigatran and rivaroxaban.

The proposals of the Working group on perioperative hemostasis (Groupe d'intérêt en hémostase péri-opératoire (GIHP)) concerning the perioperative management of patients receiving the direct oral anticoagulants (DOACs) are based on the measure of their anticoagulant activities (anti-Xa for rivaroxaban and anti-IIa for dabigatran) with a safety threshold ≤ 30 ng/mL. If the dosage of the drug is not available, proposals are based on the combination of a PT ≥80% and an aPTT ≤1.20. The aim of our study was to evaluate the performance of PT, aPTT and thrombin time to predict values above or below the safety threshold. The measurement of DOACs concentration was carried out in 64 samples from patients treated with rivaroxaban and 48 samples from patients treated with dabigatran. The PT and aPTT were measured for all samples, while the TT was measured only for patients receiving dabigatran. The absence of agreement between the global hemostasis tests and the DOACs concentrations was observed for 10% of patients receiving dabigatran and 27% of patients with rivaroxaban treatment. Apart from dabigatran for which the predictive negative value of PT and aPTT or TT allows to exclude a concentration >30 ng/mL in 100% of cases, our results highlight the risk of misinterpretation when using global coagulation tests (PT and aPPT) for determination of the safety threshold for patients receiving the DOACs.

The effectiveness of platelet supplementation for the reversal of ticagrelor-induced inhibition of platelet aggregation: An in-vitro study.

BACKGROUND: Management of ticagrelor-induced bleeding is challenging, as no antidote is currently available. Platelet transfusion, usually proposed to reverse antiplatelet drugs, has been suggested to be ineffective but few data are available. OBJECTIVE: To assess the efficacy of platelet supplementation to restore platelet aggregation inhibited by ticagrelor. DESIGN: In vitro study. SETTING: Blood samples were obtained from the French Blood Bank Institute. PARTICIPANTS: Healthy blood donors. INTERVENTIONS: Whole blood from healthy donors was spiked with ticagrelor or aspirin (used as a positive control). MAIN OUTCOME MEASURES: Platelet aggregation was investigated with impedance aggregometry on whole blood [expressed in ohms (V)] and light transmission aggregometry (expressed in %) on platelet-rich plasma using ADP or arachidonic acid as agonists for ticagrelor or aspirin, respectively. Platelet supplementation was defined as the addition of washed platelet suspension increasing at least 60% of whole blood platelet count. RESULTS: Ticagrelor (3.25 mM) inhibited ADP-induced platelet aggregation compared with control either in whole blood (2 vs. 13 V, P < 0.05) or in platelet-rich plasma (15 vs. 75% P < 0.05). Aspirin (25 mM) inhibited arachidonic acid-induced aggregation (1 vs. 7.5 V, P < 0.05 in whole blood and 5 vs. 77.5%, P = 0.01 in platelet-rich plasma). Platelet supplementation completely restored arachidonic acid-induced platelet aggregation in whole blood (10 vs. 1 V, P = 0.008) and platelet-rich plasma (73 vs. 5%, P < 0.01) in aspirin-treated samples, whereas it failed to correct ADP-induced aggregation (2 vs. 2 V in whole blood and 13.5 vs. 15% in platelet-rich plasma, P > 0.05) in ticagrelor-treated samples. We also report a case of a ticagrelor-treated patient in whom platelet transfusion failed to restore ADP-induced platelet aggregation. CONCLUSION: Platelet supplementation restored platelet aggregation in aspirin-spiked but not in ticagrelor-spiked samples. These results do not support the use of platelet transfusion to reverse the effects of ticagrelor.