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In the recently updated German S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," a new chapter was incorporated about recurrent venous thromboembolism (VTE) in patients on anticoagulation treatment. Despite the high efficacy of anticoagulation in most patients, approximately 2% experience a recurrent VTE event while receiving anticoagulant drugs. The proper diagnosis of the recurrent VTE is important and possible only with the knowledge of localization and thrombus burden of the primary VTE event. Possible reasons for recurrent VTE events in patients on anticoagulation are non-adherence to medication, sub-therapeutic drug levels due to resorption disorders or drug interactions, or concomitant disease with high thrombogenicity. Cancer is the most common underlying disease, but it is important to investigate and understand possible other causes whenever a breakthrough VTE event occurs. This results in the recommendation that in patients with VTE recurrence on therapeutic anticoagulation, in particular, the presence of malignant disease, antiphospholipid syndrome, and rare diseases like paroxysmal nocturnal hemoglobinuria or Behçet's disease should be considered. For VTE recurrence during heparin therapy, heparin-induced thrombocytopenia type II needs to be ruled out, even if platelet counts are within the normal range. Although the mechanisms of recurrence on anticoagulation can be evaluated in a certain degree, clinical evidence for the management of recurrent VTE in anticoagulated patients is minimal and mainly based on expert opinion. Switching anticoagulant medication and intensifying anticoagulant treatment are possible options., Competing Interests: R.K. received research grants from Bayer, CSL Behring, Leo Pharma, Octapharma and honoraria from Bayer, CSL Behring, Daiichi Sankyo, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, Viatris.H.R. received honoraria from Bayer, Bristol-Myers Squibb/Pfizer, Viatris.J.B.W. received research grants from Bayer, Daiichi Sankyo, LEO, Pfizer, Alexion, AstraZeneca and honoraria from Bayer, Daiichi Sankyo, LEO, Pfizer, Alexion, AstraZeneca, Norgine, Sanofi.B.L. received honoraria from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Lumira DX, Pfizer, Sanofi, Viatris., (Thieme. All rights reserved.)

It is an honor and a great pleasure for us to be guest editors for this special issue of Hämostaseologie - Progress in Haemostasis , which addresses important issues surrounding the complex of venous thromboembolism (VTE). In February 2023, the revised guideline on "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism" has been published on the website of the Association of the Scientific Medical Societies in Germany (AWMF)1. This guideline was drawn up under the leadership of the German Society of Angiology (DGA), and representatives of 17 scientific societies contributed to its content. As an S2k guideline, its recommendations are consensus based and are the result of a systematic review and evaluation of current evidence and consideration of the benefits and harms of diagnostic and therapeutic options. In this special issue, guideline authors provide a comprehensive overview of selected guideline topics which might be of clinical relevance to our readers and our community of haemostaseologists., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT., Competing Interests: HR took participation on a Data Safety Monitoring Board or Advisory Board and he got payment or honoraria for lectures, presentations, speakers bureaus or educational events from Bayer, Bristol-Myers Squibb, Pfizer and Viatris., (Thieme. All rights reserved.)

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of venous thromboembolism (VTE). Most DVTs affect the lower-extremity veins. Since the symptoms of DVT are non-specific, a prompt and standardised diagnostic work-up is essential to minimise the risk of PE in the acute phase and to prevent thrombosis progression, post-thrombotic syndrome and VTE recurrence in the long-term. Only recently, the AWMF S2k guidelines on Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism have been revised. In the present article, we summarize current evidence and guideline recommendations focusing on lower-extremity DVT (LEDVT). Depending on whether the diagnostic work-up is performed by a specialist in vascular medicine or by a primary care physician, different diagnostic algorithms are presented that combine clinical probability, D-dimer testing and diagnostic imaging. The diagnosis of ipsilateral recurrent DVT poses a particular challenge and is presented in a separate algorithm. Anticoagulant therapy is an essential part of therapy, with current guidelines clearly favouring regimens based on direct oral anticoagulants over the traditional sequential therapy of parenteral anticoagulants and vitamin K antagonists. For most DVTs, a duration of therapeutic-dose anticoagulation of at least 3 to 6 months is considered sufficient, and this raises the question of the risk of VTE recurrence after discontinuation of anticoagulation and the need for secondary prophylaxis in the long-term. Depending on the circumstances and trigger factors that have contributed to the occurrence of DVT, management strategies are presented that allow decision-making taking into account the individual bleeding risk and patient's preferences., Competing Interests: BL took participation on a Data Safety Monitoring Board or Advisory Board from Bayer Vital, Bristol-Myers Squibb, Lumira DX, Pfizer and Viatris. She got Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Pfizer, Sanofi and Viatris. She got consulting fees from Bayer Vital, Bristol-Myers Squibb, Lumira DX, Pfizer and Viatris., (Thieme. All rights reserved.)

The lifetime risk of venous thromboembolism (VTE) is slightly higher in women than in men. There are several issues related to VTE that are unique to women. Combined hormonal contraceptives and pregnancy increase the risk of VTE in women of childbearing age, whereas hormone replacement therapy increases the VTE risk of postmenopausal women. Hereditary thrombophilia and risk factors such as older age, obesity, or smoking contribute to the risk increase. In women diagnosed with acute hormone-related VTE who are treated with oral anticoagulants, adequate contraception is mandatory to avoid unwanted pregnancies. According to current knowledge, hormonal contraception may be continued during anticoagulant therapy but must be switched to an estrogen-free contraception method at least 6 weeks before the termination of anticoagulation. VTE is also a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Currently, assisted reproduction technologies such as in vitro fertilization are widely used to treat couples affected by infertility. Complications of fertility treatment comprise VTE cases, especially in women with ovarian hyperstimulation syndrome. With this review, we intended to focus on VTE issues in women and summarize current evidence and guideline recommendations., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

In the last couple of years sex specific health issues have continually been gaining attraction by physicians of different medical specialities. Sex differences have been described e.g. in the pathogenesis and mortality in patients affected by COVID-19, in metabolic regulation and cancer mechanisms.1 2 3 In the field of haemostasis, many aspects concerning risk factors, clinical presentation and management of thromboembolic disease and bleeding disorders also display sex differences., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. The risk of venous thromboembolism (VTE) is increased in AT-deficient women during pregnancy and the postpartum period and is especially high in women with a prior history of VTE. A thorough assessment of VTE risk is recommended in pregnant AT-deficient women, comprising the degree and type of AT deficiency, genetic mutations, personal and family history, and additional preexisting or pregnancy-specific risk factors. Due to a lack of adequate study data, there is limited guidance on the management of AT deficiency in pregnancy, including the need for prophylactic anticoagulation, the appropriate dose of low-molecular-weight heparin (LMWH), and the role of AT substitution. LMWH is the medication of choice for the pharmacological prophylaxis and treatment of VTE in pregnancy. Patients with a history of VTE should receive full-dose LMWH during pregnancy and the postpartum period. AT concentrates are a treatment option when anticoagulation is withheld in potentially high-risk events such as childbirth, bleeding, or surgery and in cases of acute VTE despite the use of therapeutic dose anticoagulation. Women with AT deficiency should be counseled at specialized centers for coagulation disorders or vascular medicine, and close cooperation between obstetricians and anesthesiologists is warranted before delivery and during the peripartum period., Competing Interests: Susanne Heimerl has recieved Payment or honoraria for presentations from Takeda Pharmaceutical and Roch. Also Support for attending meetings from Takeda Pharmaceutical and Swedish Orphan Biovitrum.Birgit Linnemann has recieved consulting fees and Payment for lectures and presentations from Bayer, BMS/Pfizer, Daichi Sankyo, Leo, Sanofi., (Thieme. All rights reserved.)

Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. Because there is a lack of adequate study data, management strategies for the prevention of VTE during pregnancy have mainly been deduced from case-control and observational studies and extrapolated from recommendations for non-pregnant patients. The decision for or against pharmacologic thromboprophylaxis must be made on an individual basis weighing the risk of VTE against the risk of adverse side effects such as severe bleeding complications. A comprehensive, multidisciplinary approach is often essential as the clinical scenario is made more complex by the specific obstetric context, especially in the peripartum period. As members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH), we summarize the evidence from the available literature and aim to establish a more uniform strategy for VTE risk assessment and thromboprophylaxis in pregnancy and the puerperium. In this document, we focus on women with hereditary thrombophilia, prior VTE and the use of anticoagulants that can safely be applied during pregnancy and the lactation period., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Due to a lack of adequate study data, therapeutic strategies for pregnancy-related VTE are deduced from observational studies and extrapolated from recommendations for nonpregnant patients. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low-molecular-weight heparins (LMWHs) are the anticoagulant treatment of choice in cases of VTE during pregnancy. Once- and twice-daily dosing regimens are suitable. There is no evidence that measurement of factor Xa activities and consecutive LMWH dose adjustments improve clinical outcomes. There is no support for the routine use of vitamin K antagonists, direct oral thrombin or factor Xa inhibitors, fondaparinux, or danaparoid in uncomplicated pregnancy-related VTE. Management of delivery deserves special attention, and treatment strategies depend on the time interval between the diagnosis of acute VTE and the expected delivery date. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months., Competing Interests: B.L. received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Siemens Healthcare. S.H. received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Roche, Stago, CSL Behring, Daiichi Sankyo, and Swedish Orphan Biovitrum. C.H. received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Leo Pharma., (Georg Thieme Verlag KG Stuttgart · New York.)

A thrombophilic disorder is a hereditary or acquired condition that increases the risk of thrombosis. The most common hereditary thrombophilias that predispose to venous thrombosis in the Caucasian population are the heterozygous forms of the factor V Leiden and prothrombin G20210A mutation that are generally detected by direct DNA genotyping. Immunologic antigen assays and chromogenic or clot-based activity assays are used to identify deficiencies in the natural coagulation inhibitors antithrombin, protein C and protein S. Because pre-analytical errors and acquired causes of low antithrombin, protein C or protein S levels are considerably more common than hereditary deficiencies, all potential conditions that may lower activity levels of the natural coagulation inhibitors (e.g. concomitant liver disease, pregnancy, anticoagulant therapy) must be considered and excluded before the diagnosis of an inhibitor deficiency can be made. To avoid misclassification, the diagnosis should not be made based on a single abnormal test result. Thus, repetitive testing when the patient is not on anticoagulant therapy is mandatory to confirm the diagnosis. Screening for antiphospholipid syndrome (APS) comprises testing for lupus anticoagulants (LAs) and the presence of IgG or IgM antibodies directed against phospholipids and phospholipid-binding proteins such as β-2-glycoprotein-I. A combination of clot-based assays has been recommended to demonstrate LA activity, whereas solid-phase immunoassays allow the detection of anti-cardiolipin and anti-β-2-glycoprotein-I antibodies. The diagnosis of APS requires the persistence of antiphospholipid antibodies for at least 12 weeks together with thrombotic and/or obstetric features of APS., Competing Interests: Prof. Dr. B. Linnemann received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Siemens Healthcare.Priv.-Doz. Dr. C. Hart received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Leo Pharma., (Georg Thieme Verlag KG Stuttgart · New York.)

Central venous catheters (CVCs) are important for the treatment of patients with cancer, especially in the perioperative and palliative care settings. These devices not only allow for the administration of chemotherapy, parenteral nutrition, and other intravenous therapies, but they may also improve the patients' quality of life by reducing the need for repeated peripheral venipunctures. Thrombotic and infectious complications are common, especially in the long-term use of CVCs. There are different types of thrombotic complications associated with CVCs, that is, a thrombotic occlusion of the catheter, a mural thrombus at the catheter tip and classical deep vein thrombosis, which occurs most frequently in the upper extremity where the majority of long-term catheters are inserted. Infections are common complications associated with CVCs. Patients with cancer who receive intensive chemotherapy and those patients who undergo hematopoietic stem cell transplantation have a markedly increased risk for insertion site and bloodstream infections. In this review, the epidemiology and risk factors that predispose patients to CVC-related thrombosis and infection are discussed. The diagnostic and therapeutic options according to the published data and the current guidelines are summarized and data for establishing primary and secondary preventative strategies are provided., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Central venous catheters (CVCs) are important tools in the care of patients with acute or chronic diseases, but catheter-related thrombosis and thrombotic occlusions are frequent complications, especially if CVCs are implanted for long-term use. In this review we focus on the management of these complications. Risk factors for catheter-related thrombosis include dislocation of the catheter tip, the presence of malignant disease and hypercoagulability. Catheter-related thrombosis is associated with catheter infection, pulmonary embolism and post-thrombotic syndrome. Catheter-related thromboses which most frequently involve the subclavian vein are usually diagnosed by duplex ultrasound examination and treated with anticoagulation therapy for a minimum of three months or longer if the catheter is left in place. Prevention of catheter-related thrombotic complications includes proper positioning of the CVC with the catheter tip lying in the proximal superior vena cava and regular flushing of the catheter with saline solution or unfractionated heparin. The use of anticoagulants for primary prevention is currently not recommended., (Georg Thieme Verlag KG Stuttgart · New York.)

The prevalence of coagulation disorders in patients with upper extremity deep-vein thrombosis (UE-DVT) is unknown due to only a few observational studies of limited size reporting varying results. Therefore, we aimed to evaluate the prevalence of thrombophilia in patients with UE-DVT compared to patients with lower extremity deep vein thrombosis (LE-DVT). One hundred fifty consecutive patients (15 to 91 years of age) with UE-DVT were recruited from the MAISTHRO (MAin-ISar-THROmbosis) registry. Three hundred LE-DVT patients matched for gender and age served as controls. Thrombophilia screening included tests for the factor V Leiden mutation, the prothrombin G20210A mutation, antiphospholipid antibodies and factor VIII (FVIII), protein C, protein S and antithrombin activities. At least one thrombophilia was present in 34.2% of UE-DVT and 39.2% in UE-DVT that was unrelated to venous catheters relative to 55.3% in LE-DVT patients (p<0.001). In particular, a persistently elevated FVIII is less likely to be found in UE-DVT patients than in those with LE-DVT and is the only thrombophilia that is differentially expressed after controlling for established VTE risk factors [OR 0.46, (95% CI 0.25-0.83)]. Although less prevalent than in LE-DVT patients, thrombophilia is a common finding in patients with UE-DVT, especially in those with thrombosis that is unrelated to venous catheters.