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Introduction: The dRVVT test for detecting lupus anticoagulants (LA) is difficult to interpret when patients are treated with vitamin K antagonists (VKA). Methods: We performed LA testing in 33 VKA-treated patients with definite antiphospholipid syndrome (APS) and compared the results with 100 controls subjects not receiving VKA and 110 APL-negative patients anticoagulated for reasons other than APS. Results: Compared with the dRVVT ratio before the initiation of VKA therapy, a higher cutoff value, defined as the 99th percentile, was established for VKA-treated patients with INR values between 2.0 and 3.5. A dRVVT ratio of >1.7 yielded a sensitivity of 81.3%, specificity of 99.1%, and positive and negative predictive values of 98.7% and 85.8%, respectively, for detecting LA. Cohen's kappa coefficient indicated good agreement for the dRVVT ratio obtained from testing with and without VKA treatment (κ = 0.813; 95% CI: 0.773-0.853), which was higher (κ = 0.941; 95% CI: 0.917-0.965) when the LA diagnosis was based on the results of both the dRVVT and a second test system (i.e., Mixcon-LA assay). Conclusions: Lupus anticoagulants testing in VKA-treated patients with APS according to current guidelines appears to be possible for the majority of patients without discontinuing anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Background: It is still not clear whether native or platelet count adjusted platelet rich plasma (PRP) should be used for platelet aggregation measurements. Aim: To evaluate the necessity of using adjusted PRP in platelet Function testing. Methods: Platelet aggregation with native PRP and adjusted PRP (platelet count: 250/nl, obtained by diluting native PRP with platelet poor plasma) was performed on the Behring Coagulation Timer (Ba®) using ADP, collagen, and arachidonic acid as agonists. Healthy subjects, patients on antiplatelet treatment, and patients with thrombocytosis (platelet counts in PRP> 1 250/nI) were investigated. Results: No significant differences in the maximum aggregation response were seen when using either native or adjusted PRP from healthy subjects and patients on antiplatelet treatment. Nevertheless, some patients taking aspirin or clopidogrel showed reduced inhibition of ADP and arachidonic acid induced aggregation in adjusted PRP but not in native PRP. The maximum velocity of healthy subjects and patients on antiplatelet treatment varied significantly as a result of the degree of dilution of the adjusted PRP. Surprisingly, the BCT provided good results when measuring platelet aggregation of native PRP from patients with thrombocytosis, whereas commonly used aggregometers could not analyse platelet aggregation of native PRP in these patients. Conclusion: The time consuming process of PRP adjustment may not be necessary for platelet aggregation measurements. Moreover, using adjusted PRP for monitoring aspirin or clopidogrel treatment may falsify results. Therefore, it may be better to use native PRP for platelet aggregation measurements, even in patients with thrombocytosis. [ABSTRACT FROM AUTHOR]

Abstract: Fibrinogen assays are an important screening tool for blood coagulation disorders. Although different methods are available, no consensus has been reached as to which method is preferable. In 27 patients with dysfibrinogenemia, plasma fibrinogen concentration was measured by Clauss and PT-derived methods on two fully automated coagulation analyzers utilizing different reagents. In addition, immunological and heat fibrinogen concentrations as well as global coagulation tests were measured. Results: The median fibrinogen determined by the Clauss assay was 0.40g/l, with a range of 0.30–2.07g/l (normal range: 2.67–4.37g/l) and 0.60g/l, with a range of 0.60–2.20g/l (normal range: 1.5–4.5g/l) using two different reagents. The median fibrinogen determined by the PT-derived method was 2.41g/l, with a range of 0.97–4.87g/l (normal range: 1.84–4.8g/l) and 2.64g/l, ranging from 1.38 to 4.39g/l (normal range: 2.0–4.0g/l) by the use of two different reagents. No correlation was found when comparing both methods using two reagents from different manufacturers. The PT-derived method “overestimated“ the fibrinogen by approximately five times the value measured by the Clauss assay. While fibrinogen measured by the PT-derived method correlated with fibrinogen antigen concentrations measured by the immunological fibrinogen (p<0.002) or heat fibrinogen method (p<0.002), fibrinogen measured by the Clauss method correlated with functional coagulation parameters, such as Reptilase Time (p<0.002), Thrombin Time (p<0.002) or Prothrombin Time (p<0.02). Conclusion: Although many patients with dysfibinogenemia are asymptomatic, in case of bleeding, immediately diagnosis and treatment is warranted. The Clauss assay is the diagnostic tool of choice when diagnosing or treating patients with low fibrinogen levels. The use of the PT-derived method may potentially pose a greater risk to patients, as the plasma concentration may be erroneously reported as normal. [Copyright &y& Elsevier]

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development., Competing Interests: Declaration of competing interests J.H.L.: Participation on Advisory or Steering Committees for Grifols, Octapharma, Takeda, and Werfen. J.R.S.: In-kind laboratory support from Diagnostica Stago. L.A.C.: L.A.C.’s research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier. L.A.C. holds a Tier 2 Research Chair from the University of Ottawa. J.M.C.: Participation on Scientific Advisory Boards and consulting for Abbott, Anthos, BMS, Pfizer, Roche, Sanofi, and Werfen; research funding from CSL Behring to the institution. J.D.: Serves on advisory committees for Pfizer, Sanofi, Leo Pharma, Bristol-Myers Squibb, and Janssen. E.L-L.: Lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Portola, CSL Behring, Norgine, Roche, Leo, AstraZeneca, and Aspen; institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Werfen, and CSL Behring. B.R.: Consultant for AbocaSRL on medical devices; Advisory Committee for Bayer AG. C.M.S.: Advisory for Norgine Pharma. D.S.: Honoraria for educational presentations and advisory fees paid indirectly to research institute from AstraZeneca, BMS-Pfizer, Roche, Servier. D.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. J.I.W.: Consultant or member of Advisory Boards or Steering Committees for Anthos, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson and Johnson, Merck, and Regeneron., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction:  Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data., Methods:  A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022., Results:  A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC., Conclusion:  Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC., Competing Interests: T.J.M. is a consultant for CSL Behring, Octapharma, Alexion-Astra Zeneca, and Cellphire. E.L.-L. has received lecture honoraria and advisory fees from Astra Zeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, Norgine, Roche, CSL Behring, Viatris, and Aspen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and CSL Behring. A.V. and D.S.S. are employees of CSL Behring., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

May-Thurner syndrome (MTS) is a pelvic venous disorder involving compression of the left common iliac vein by the right common iliac artery, which results in predisposition for deep vein thrombosis. Although MTS is increasingly recognized in young patients, specific guidelines on diagnosis and management for children, adolescents, and young adults do not exist so far. The aim of this study was to assess current diagnostic and therapeutic practice in Germany, Austria, and Switzerland in children and young adults with thrombosis and MTS.We designed an online survey with 11 questions, which we sent via a mailing list to all members of the German, Austrian, and Swiss Society of Thrombosis and Haemostasis Research. Between July and October 2022, 33 specialists answered the questionnaire. Most participating specialists worked at pediatric hospitals (61%). Numbers of annually treated thromboses ranged from <5 (26%) to >30 (13%). Most specialists used venous ultrasound to diagnose deep vein thrombosis, 53% magnetic resonance imaging. Only 25% of specialists systematically screened for MTS in deep vein thrombosis. MTS was managed with anticoagulation (65%), iliac vein stent placement (32%), or balloon angioplasty (13%). In total, 31% of specialists reported to use more than one therapeutic method. Diagnostic and therapeutic approaches for MTS differed between specialists. Lack of standardization resulted in individualized and highly diverse management. Prospective observational clinical studies investigating the outcome of different management strategies including long-term follow-up on outcome and incidence of postthrombotic syndrome will help in defining patient groups who benefit most from revascularizing interventional strategies and developing standardized guidelines., Competing Interests: FC: Support for attending meetings and/or travel: GTH meeting Frankfurt 2023, train ticket and hotel payed by NovoNordiskBG: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Parexel/CALYX, SIRTex Medical, BAYER, COOK, Siemens/VARIAN, Pharmacept, Ewimed, Guerbet, Terumo, Beacon Bioscience/ICON, Elsai, INARI, IPSEN; Support for attending meetings and/or travel: Parexel/CALYX, SIRTex Medical, BAYER, COOK, Siemens/VARIAN, Pharmacept, Ewimed, Guerbet, Terumo, Beacon Bioscience/ICON, Elsai, INARI, IPSENBZ: Grants or contracts from any entity: Grant funding from CSL Behring, Grant funding from Takeda; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Leader of the Pediatric commission of the German GTHEL-L: Consulting fees: Boehringer Ingelheim, BMS/Pfizer, Bayer, Leo Pharma; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Daiichi Sankyo, Boehringer Ingelheim, BMS/Pfizer, Bayer, Leo Pharma, CSL Behring, Astra Zeneca, Norgine, Alexion; Participation on a Data Safety Monitoring Board or Advisory Board: BMS/Pfizer, Boehringer Ingelheim, BayerSH: Consulting fees: Bayer, Boehringer Ingelheim; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Biomarin, Chugai; Support for attending meetings and/or travel: Biomarin; Participation on a Data Safety Monitoring Board or Advisory Board: Bayer, Boehringer Ingelheim, Sobi, Pfizer; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: ISTHMR: Grants or contracts from any entity: Pfizer, Octapharma, LFB, CSL, SOBI, Takeda, Chugai; Consulting fees: Pfizer, LFB, CSL, SOBI, Takeda, Chugai; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer, LFB, CSL, SOBI, Takeda, Chugai; Support for attending meetings and/or travel: Pfizer, Octapharma, LFB, CSL, SOBI, Takeda, Chugai; Participation on a Data Safety Monitoring Board or Advisory Board: Octapharma, CSL, SOBI, Takeda, ChugaiAG, WE, NH have no conflict of interest, (Thieme. All rights reserved.)

(1) Background: The clinical management of anticoagulated patients treated with direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA) needing emergency surgery is challenging. (2) Methods: The prospective German RADOA registry investigated treatment strategies in DOAC- or VKA-treated patients needing emergency surgery within 24 h after admission. Effectiveness was analysed by clinical endpoints including major bleeding. Primary observation endpoint was in hospital mortality until 30 days after admission. (3) Results: A total of 78 patients were included (DOAC: 44; VKA: 34). Median age was 76 years. Overall, 43% of the DOAC patients and 79% of the VKA patients were treated with prothrombin complex concentrates (PCC) ( p = 0.002). Out of the DOAC patients, 30% received no hemostatic treatment compared to 3% (1/34) of the VKA patients ( p = 0.002), and 7% of the DOAC patients and 21% of the VKA patients developed major or clinically relevant non-major bleeding at the surgical site ( p = 0.093). In-hospital mortality was 13% with no significant difference between the two treatment groups (DOAC: 11%, VKA: 15%; p > 0.20). (4) Conclusions: The 30-day in-hospital mortality rate was comparable between both patient groups. VKA patients required significantly more hemostatic agents than DOAC patients in the peri- and postoperative surgery period.

Abstract: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered., Objectives: To analyze, in patients with VITT, the long-term course of anti-platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations., Methods: 71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay., Results: Platelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT., Conclusion: Once the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia., Competing Interests: Declaration Of Competing Interests A.G. reports grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck-Sharp and Dome, Bristol-Myers Squibb (BMS), Paringenix, Bayer Healthcare, Gore Inc, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck-Sharp and Dome, Macopharma, BMS, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH e.V., outside the submitted work. T.T. reports personal fees and other from BMS, personal fees and other from Pfizer, personal fees from Bayer, personal fees and other from Chugai Pharma, other from Novo Nordisk, personal fees from Novartis, other from Daichii Sankyo, and other from Laboratoire français du Fractionnement et des Biotechnologies, outside the submitted work. E.L.-L. has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, CSL Behring, Viatris, Werfen, Norgine, and Aspen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and CSL Behring for a different research project. L.S. receives a young investigator grant of the medical faculty of the Universitätsmedizin Greifswald. There are no other competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus discovered in December 2019 that causes coronavirus disease 19 (COVID-19) and various vaccinations have been developed. The extent to which COVID-19 infections and/or COVID-19 vaccinations alter antiphospholipid antibodies (aPL) in patients with thromboembolic antiphospholipid syndrome (APS) remains unclear. Eighty-two patients with confirmed thromboembolic APS were included in this prospective non-interventional trial. Blood parameters including lupus anticoagulants, anticardiolipin IgG- and IgM-antibodies, and anti-ß2-glycoprotein I IgG- and IgM-antibodies were assessed prior to and after COVID-19 vaccination and/or COVID-19 infection. No increases in aPL in the total study population were detected. In fact, low but significant decreases were observed for anticardiolipin IgG- and anti-β2-glycoprotein I IgG-antibodies, while anticardiolipin IgM- and anti-b2-glycoprotein I IgM-antibodies slightly increased only in patients with COVID-19 infection and vaccination. Although the investigated patient group is known to have a high risk of recurrent thrombosis, only one arterial thrombotic event was diagnosed (1.2%, 1/82). This low recurrence rate was probably due to the high vaccination rates prior to infections and a high rate of effective anticoagulation. Our data show that COVID-19 infections and/or vaccinations do not deteriorate the clinical course of anticoagulated thromboembolic APS patients.

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days.