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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.)

In premenopausal women treatment with direct oral anticoagulants (DOACs) can be associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists. These findings come from retrospective or prospective single-center studies and post hoc analysis of regulatory studies in which HMB was not a predefined safety outcome. In most of these publications, there is a lack of information about the use of different contraceptive methods which can influence HMB. Another limitation is the various definitions of HMB, which makes comparison between studies regarding the incidences of HMB difficult.Therefore, prospective studies are urgently needed to investigate the severity and duration of unaffected menstrual bleeding under oral anticoagulation independently of oral contraceptives or intrauterine devices. An ongoing multicenter German registry is aiming to compare the incidence of unaffected HMB in consecutive women of reproductive age (18-50 years) treated with different DOACs because of venous thromboembolism.When HMB occurs during oral anticoagulation, management includes interruption or dose reduction of anticoagulation with the danger of recurrent venous thrombosis, switch to another oral anticoagulant, or additional use of the antifibrinolytic agent tranexamic acid with the potential risk of thrombosis. Concomitant use of either oral hormonal contraceptive therapy or hormone-releasing intrauterine systems can also reduce HMB., Competing Interests: Lida Kalmanti declares no conflicts of interest.Edelgard Lindhoff-Last has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, CSL Behring, and Aspen, and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and CSL-Behring., (Thieme. All rights reserved.)

The antiphospholipid syndrome (APS) is an acquired autoimmune disorder associated with arterial, venous, or microvascular thrombosis and/or pregnancy complications mainly in young age. The diagnosis is made by the persistent detection of anticardiolipin antibodies, β2-glycoprotein I antibodies (β2GPIA), and/or lupus anticoagulants (LAs) for at least 12 weeks. Patients should present with at least one clinical and one laboratory criterion. Patients presenting with all three types of antibodies and vascular events are high-risk patients and should receive vitamin K antagonists (VKAs) as long as the antibodies persist. In patients with prior arterial thrombosis, VKA with or without low-dose aspirin is the current treatment of choice. The international normalized ratio (INR) should be between 2 and 3 although in some cases keeping the target INR above 3 may be necessary. Patients with venous thrombosis and negative LA may alternatively be treated with direct oral anticoagulants although more data are needed. Minimizing vascular risk factors is always necessary in APS patients. Aspirin can be given as primary prevention in asymptomatic patients with positive antiphospholipid antibodies without thrombosis or pregnancy complications especially when additional vascular risk factors are present. Catastrophic APS occurs in less than 1% of APS patients and presents as a thrombotic storm. Early use of a combined triple therapy such as anticoagulation, plasma exchange, and steroids with either or not addition of immunoglobulins is important to reduce mortality., Competing Interests: Edelgard Lindhoff-Last has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo and Werfen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo and Werfen., (Georg Thieme Verlag KG Stuttgart · New York.)

The worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in "real-life" conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists., Competing Interests: The author declares that she receives financial support for research projects from Bayer Vital, DAIICHI Sankyo, BMS/Pifzer, CSL Behring, Werfen; honoraria from Bayer Vital, DAIICHI Sankyo, BMS/Pfizer, CSL Behring, Aspen; participates in national and/or international advisory boards of Bayer Vital, BMS/Pfizer, Werfen, Boehringer Ingelheim, (Schattauer GmbH.)

Unlabelled: Rivaroxaban, the first direct factor-Xa inhibitor anticoagulant, has been approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for stroke prophylaxis in patients with non-valvular atrial fibrillation and for the treatment of deep vein thrombosis. There is no requirement for coagulation monitoring with rivaroxaban in routine clinical practice. However, in certain clinical circumstances such as life-threatening bleeding or an emergency operation the measurement of the thromboplastin time with a sensitive reagent will deliver first information. A quantitative determination of rivaroxaban plasma concentration is possible using an anti-factor Xa assay. In the case of a patient under long-term anticoagulation with rivaroxaban requiring an elective surgery, a discontinuation of rivaroxaban 20 to 30 hours before the operation is sufficient to normalize the associated bleeding risk, as long as the renal and liver function is normal. A longer interval should be taken into consideration, when the patient presents a renal and liver impairment or is of a higher age. In the event of an emergency operation effective rivaroxaban concentrations might be present. Nevertheless, we advise against using a prophylactic dose of factor concentrates., Recommendations: From a clinical perspective, in the event of a minor bleeding we recommend a temporary discontinuation of rivaroxaban, whereas for clinically relevant major or severe bleeding events a mechanical compression or a limited surgical i.e. interventional treatment is required. Supportive measures such as the administration of blood products or tranexamic acid might be beneficial. In addition to haemodynamic supportive measures life threatening bleeding events demand a comprehensive haemostasis management, as well as the application of PCC.

Unlabelled: Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis., Recommendation: In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient's individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

Recurrent venous thromboembolism is associated with increased mortality in 5-9% of the patients. On the other hand prolonged anticoagulation can increase the bleeding risk which can also be responsible for an increased mortality. Therefore, it is necessary to validate the recurrence risk of venous thromboembolism on an individual basis. In this review the most relevant risk factors for recurrent venous thromboembolism are analyzed. Spontaneous thrombosis is associated with significantly increased recurrence rates in comparison to risk associated venous thrombosis. In addition, a positive D-dimer result after stop of anticoagulation, an increased amount of residual thrombus in proximal veins analyzed by compression sonography, a proximal localization of thrombosis, symptomatic pulmonary embolism and male sex are clinically relevant risk factors for increased recurrence rates. While mild thrombophilic defects like heterozygous factor V Leiden mutation are not associated with a clinically relevant recurrence risk, inherited inhibitor deficiencies and the antiphospholipid-syndrome are known to be responsible for an increased recurrence rate of venous thromboembolism. A new recurrence risk-score (RR-Score) for individual judgement of patients with a first spontaneous venous thrombosis is introduced.

Both for diagnosis of congenital and acquired platelet dysfunction as well as for therapy monitoring after application of platelet function inhibitors various methods have been established for evaluation of platelet function. In contrast to the gold standard of platelet function testing, the light transmission aggregometry in platelet rich plasma the Point-of-care (POC) analyzers allow fast analysis of platelet function without extensive laboratory work up. The conditions of the pre-analytical phase, however, are still of enormous importance in the prevention of medical errors. There is increasing clinical data in monitoring the effect of platelet aggregation inhibitors, showing that quantitative determination of the platelet function degree correlates with risk of increased bleeding or stent thrombosis. However, it is still unclear, which is the optimal test system, to predict the clinical outcome of these patients.

Unlabelled: During the use of fractionated or unfractionated heparin adverse events frequently occur that can endanger the continuation of therapy. Especially in pregnant patients with thromboembolic complications it may be difficult to find a suitable alternative anticoagulant when heparin-induced thrombocytopenia type II (HIT II) or allergic skin reactions occur. There are still limited data on the use of danaparoid in pregnancy. The main reason for heparin intolerance in the 59 reviewed pregnancies were either HIT II, described in 37/59 (62.7%) pregnancies, or cutaneous adverse effects in 19/22 (86.4%) of non-HIT-associated pregnancies (22/59, 37.3%)., Results: 40/59 pregnancies were carried to term under use of danaparoid and resulted in the delivery of a healthy infant. In 16/19 pregnancies, danaparoid was stopped due to a major adverse event. Five patients showed bleeding complications, seven fetal losses were documented, but there was no association with the use of danaparoid. In 31/59 (52.5%) pregnancies adverse events were documented, 14/31 (45.2%) could be attributed to danaparoid. Anti-Xa-activity was not detected in five fetal cord blood samples and in four maternal breast-milk samples., Conclusion: Danaparoid can be used as an alternative anticoagulant in pregnant women with high risk for thrombosis and heparin intolerance.

The detection of the DNA-sequence of human coagulation factors and inhibitors has introduced the possibility of differentiated mutation analysis in patients with venous thrombosis. Since venous thromboembolism is a multifactorial disease, women are at an increased risk to develop venous thrombosis due to hormonal contraception, during pregnancy and the puerperium. In addition, pregnancy complications like early or late fetal loss, pregnancy-induced hypertensive disorders and very recently recurrent embryo implantation failure have been suspected to be associated with thrombophilia. Therefore, it is of major importance to define inherited thrombophilic disorders, in which genetic diagnosis is of clinical relevance. While most of the genetic defects described so far represent a risk factor for venous thrombosis, only a minority of these defects actually needs DNA analysis to be detected: mutation analysis is clinically relevant, when factor V Leiden mutation is suspected, because relative risks concerning venous thrombosis as well as pregnancy complications clearly differ between homozygote and heterozygote forms of this frequently observed mutation. Similarly detection of the prothrombin mutation G20210A is of clinical relevance, although data for the very rarely observed homozygote variant are not sufficiently available. In contrast, detection of the homozygote variant of the MTHFR-mutation C677T is not useful, since clinical relevance could not be proven in a majority of studies concerning women specific risk situations. Inherited deficiencies of antithrombin, protein C and protein S are rare with high rates of different mutations. Genetic analysis seems only useful in patients with wide intraindividual variations of coagulation inhibitor activities. Genetic analysis concerning the PAI-1 4G/5G polymorphism or the factor XIII Val34Leu polymorphism can not be recommended in women specific risk situations because of insufficient data.

Resistance to acetylsalicylic acid (ASA) or clopidogrel is understood from the clinical point of view as failure of the drugs to prevent recurrent vascular occlusions. Non-response to ASA and clopidogrel is defined from the laboratory aspect as an inability to cause in vitro detectable platelet function inhibition. It would be beneficial to monitor non-response to ASA or clopidogrel with platelet function methods, which detect the specific effect of these drugs, and thus prevent clinical events caused by failure of therapy. Non-response to ASA and clopidogrel are detected with different platelet function methods, which are not always clinically standardized and are assessing only the global platelet function and not the specific drug effect. Although various studies reporting 5 to 59% non-response for both drugs, support a clinical relevance of ASA and clopidogrel non-response, well-designed clinical prospective trials are required to identify patients with antiplatelet drug resistance. Furthermore, mechanisms explaining this phenomenon of drug resistance are still unknown.

In contrast to low molecular weight heparin and unfractionated heparin fondaparinux is a selective synthetic factor Xa inhibitor. It was approved for thromboprophylaxis after major orthopaedic surgery three years ago. Because of its excellent bioavailability after subcutaneous application once daily independent of body weight (within the range of 50-100 kg) monitoring of the substance is usually not necessary. Since its recent approval for therapeutic use in acute venous thrombosis monitoring might be useful in special clinical situations (e. g. suspected over- or underdosing, renal insufficiency or severe bleeding complications). Based on standard laboratory methods for the chromogenic determination of the anti-factor Xa activity of low molecular weight heparin several chromogenic substrate assays were published for monitoring. Only fondaparinux should be used for calibration and measured fondaparinux levels should be expressed in mug/ml of the fondaparinux calibrator. Because of its single synthetic chemical entity, a linear dose/response relationship over a wide concentration range is observed and measurements are of high precision.