[Basics for the Use of Andexanet]. / Grundlagen zur Anwendung von Andexanet.

BACKGROUND: For life-threatening or uncontrollable bleeding in association with the thrombin inhibitor dabigatran, the monoclonal antibody fragment idarucizumab is available, and for bleeding in association with the direct factor Xa inhibitors rivaroxaban or apixaban, the modified recombinant FXa protein andexanet is available for reversal. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures. METHODS: An interdisciplinary group of experienced experts in the fields of angiology, hematology, internal medicine, clinical pharmacology, laboratory medicine, transfusion medicine, anesthesiology, intensive care, and hemostaseology developed recommendations relevant to daily clinical practice based on the current scientific evidence. RESULTS: Reversal of oral anticoagulants should be considered for severe bleeding in the following situations: (1) life-threatening bleeding or refractory hemorrhagic shock, (2) intracerebral bleeding, or (3) endoscopically unstoppable gastrointestinal bleeding. After successful hemostasis, anticoagulation (e.g., direct oral anticoagulant, vitamin K antagonist, and heparin) should be resumed promptly, taking into account individual bleeding and thromboembolic risk. DISCUSSION: This article aims to facilitate the management of patients with andexanet by all medical disciplines involved, thereby ensuring optimal care of patients during bleeding episodes.

Autologous blood donor screening indicated a lower prevalence of viral hepatitis in East vs West Germany: epidemiological benefit from established health resources.

Prevalence data concerning viral hepatitis and human immunodeficiency virus (HIV) in the general population are usually scarce. We aimed for a large cohort representative of the general population that required little funding. Autologous blood donors are relatively representative of the general population, and are tested for viral hepatitis and HIV in many countries. However, frequently these data are not captured for epidemiologic purposes. We analysed data from well over 35,000 autologous blood donors as recorded in 21 different transfusion centres for anti-hepatitis C virus (HCV), HBsAg and anti-HIV, as well as TPHA if available. We found a lower prevalence of hepatitis B virus and HCV in East vs West Germany, 0.2%vs 0.32% and 0.16%vs 0.32% respectively, which confirms earlier data in smaller cohorts, thus supporting the value of our approach. HIV was too rare to disclose significant differences, 0.01%vs 0.02%. TPHA was higher in East (0.34%) vs West Germany (0.29%) without significant differences. HCV was more frequent in women vs men. Transfusion institutes managing autologous blood donations should be used as a resource for epidemiological data relating to viral hepatitis and HIV, if such testing is performed routinely. This approach generates data relating to the general population with special emphasis on undiagnosed cases.

[Patients with oral anticoagulation--bridging anticoagulation in the perioperative phase]. / Patienten unter oraler Antikoagulation--Perioperatives Bridging.

Oral anticoagulation with a vitamin K-antagonist requires special consideration when surgery or interventional procedures are planned. This is mainly due to the half life of vitamin K-antagonists and to the need for safe and effective anticoagulation prior to and during surgery as well as in the postoperative period. So far, the continuous infusion of unfractionated heparin (UFH) has been the medication of choice to "bridge" patients to surgery. The use of low molecular weight heparins (LMWH) has been prospectively investigated in this setting and represents a safe alternative. The advantages of LMWH are the better dose-response relationship and reduced need for monitoring. This facilitates the bridging procedure to be started out of hospital, which may reduce hospital stay and associated costs. Furthermore, the so-called bridging of patients with oral anticoagulation prior to and during surgery reduces bleeding complications and maintains a safe anticoagulation for patients at risk.

[Oral anticoagulation : Current overview and perioperative management in ophthalmic surgery]. / Orale Antikoagulation : Aktuelle Übersicht und perioperatives Management in der Ophthalmochirurgie.

Antithrombotic treatment with oral anticoagulants and antiplatelet agents can increase the risk for perioperative bleeding. In contrast to other surgical fields, the optimal perioperative management in ophthalmic surgery has not yet been exactly defined and, thus, is not standardized. In this contribution, we provide an overview of currently available oral anticoagulants and discuss potential strategies for the management of these agents in different ophthalmic surgical procedures.

[Management of anticoagulants in ophthalmic surgery-a survey among ophthalmic surgeons in Germany]. / Umgang mit gerinnungshemmenden Substanzen in der Ophthalmochirurgie ­ eine Umfrage unter Ophthalmochirurgen in Deutschland.

INTRODUCTION: As our population ages and comorbidities rise, ophthalmic surgeons are increasingly faced with patients on anticoagulant therapy or with clotting disorders. The ophthalmic surgeon has to weigh the perioperative risk of haemorrhage when anticoagulation continues against the risk of thromboembolism caused by discontinuation or changing the patient's medication (bridging, switching, cessation). There are currently no guidelines or recommendations. METHODS: A survey was sent to the DOG (German Ophthalmologic Society) divisions and associated surgical organizations to determine the status quo. A questionnaire was sent out and filled out by the different groups of specialists. RESULTS: All four divisions of the DOG and four associated organizations returned completed questionnaires. Surgical interventions were listed that are carried out during anticoagulant therapy without exceptions, as well as interventions that were classified to require medical adjustment. Although the assessments varied, general consensus was achieved regarding interventions not requiring adjustments due to anticoagulants (i. e., intravitreal injection, cataract surgery, laser and corneal operations, simple muscle surgery), and those interventions requiring adjustments in medications (glaucoma operations, complex retina surgery, eye socket surgery, complex surgery of the lid). CONCLUSION: Main result of this survey was the specification of serious bleeding complications which are permanent vision loss and re-operation. They could serve as endpoint parameters for essential future investigations. Nevertheless, this survey makes clear that the decision about an adjustment of anticoagulant medication in ophthalmic surgery is currently made individually and not based on established standards.

Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis.

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.

[Preoperative identification of patients with impaired (primary) haemostasis. A practical concept]. / Präoperative Identifikation von Patienten mit (primären) Hämostasestörungen. Ein praktisches Konzept.

The findings of a large prospective study designed to identify primary and/or secondary haemostatic disorders before surgical interventions are presented. A total of 5649 unselected adult patients were enrolled to identify impaired haemostasis before surgical interventions. Each patient was asked to answer a standardized questionnaire concerning bleeding history. Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts (PC) including PFA-100 (platelet function analyzer): collagen-epinephrine (C/E), and collagen-ADP (C/ADP) were routinely done in all patients. Additional tests, bleeding time (BT), von Willebrand factor (VWF:Ag, VWF:Rcof) and a further haemostaseological diagnostic was performed only in patients with a positive bleeding history and/or evidence of impaired haemostasis; e.g., drug ingestion. The bleeding history was negative in 5021 patients (88.8%) but positive in the remaining 628 (11.2%). Impaired haemostasis could be verified only in 256 (40.8%) of these patients. The vast majority was identified with PFA-100: C/E (n = 250; 97.7%). The sensitivity of the PFA-100: collagen-epinephrine was the highest (90.8%) in comparison to the other screening tests (BT, aPTT, PT, VWF : Ag). The positive predictive value (to detection of impaired haemostasis) of the PFA-100: collagen-epinephrine with the standardized questionnaire was high (82%), but the negative predictive value was higher (93%). The use of a standardized questionnaire and, if indicated, the PFA-100: C/E and/or other specific tests not only ensure the detection of impaired haemostasis in almost every case but also a significant reduction of the costs. Based on these data, national regards are formulated or under construction.

[Platelet aggregation inhibitors and anticoagulants during ophthalmic interventions]. / Thrombozytenaggregationshemmer und Antikoagulantien bei augenchirurgischen Eingriffen.

In ophthalmology many patients undergo surgical treatment who need to take anticoagulant medication due to cardiovascular diseases. The proper handling of these drugs requires both correct assessment of the risk of thromboembolism as well as the rating of the risk of surgery-related hemorrhages. While there are established recommendations for estimation of the risk of thromboembolism based on a large body of prospective randomized trials, data regarding the evaluation of the related complications secondary to ophthalmic surgery are limited. In comparison to other surgical procedures, most interventions in ophthalmic surgery tend to have a relatively low risk of bleeding; therefore, in general there is no need to convert or discontinue anticoagulant drugs in patients undergoing opthalmic surgery. The sparse data available justifying the abrupt termination of anticoagulation are contrary to the approach currently widely distributed in clinical practice. This overview covers the relevant knowledge of the perioperative use of anticoagulant drugs. In addition, the data on the risk of hemorrhage in ophthalmological procedures are presented and discussed.

[Bleeding in patients receiving dual antiplatelet therapy after acute coronary syndrome - significance, prevention and interdisciplinary management]. / Interdisziplinäres Management von Blutungen unter dualer antithrombozytärer Therapie nach akutem Koronarsyndrom.

For secondary prevention of acute coronary syndrome, guidelines recommend dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 receptor antagonist such as clopidogrel, prasugrel or ticagrelor for a period of 12 months. Premature discontinuation of dual antiplatelet therapy is associated with an increased risk of ischaemic events. However, antiplatelet therapy is also associated with an increased risk of bleeding that should not be under- or overestimated. To ensure an optimal care of patients receiving dual antiplatelet therapy after an acute coronary syndrome, an interdisciplinary group of experienced experts in the fields of cardiology, cardiac surgery, gastroenterology, anaesthesiology, intensive care and haemostaseology gathered bleeding-related information and developed recommendations relevant to daily clinical practice. These include the significance of bleeding events in the course of treatment, measures for bleeding prevention and the adequate care of patients with bleedings.

[Bleedings under NOAC (non Vitamin-K dependent oral anticoagulants). Evidence and practical management]. / Blutungen unter NOAK1. Evidenz und praktisches Vorgehen.

UNLABELLED: The doses of these drugs are barely tested and the potential clinical thromboembolic risk must be taken into account. Despite the widespread use of NOAC (non vitamin-K dependent oral anticoagulants) and recommendations of regulatory agencies and first consensus meeting on handling the bleeding situation under NOAC, especially in hospitals without a large hemostatic focus, uncertainty still exists. In case of mild bleeding from a clinical perspective, the medical care of these patients and the delay of the next dose or discontinuation is advised. A special laboratory analysis is indicated i.e. in case of known higher grade liver and kidney failure, which can cause a prolonged elimination of NOAC. The administration of factor concentrates is not indicated in this situation. In case of moderate to severe bleeding, the primary measures focus on the stabilization of the heart and circulatory function and parallel on the treatment depending on the localization of the bleeding source. According to experience, mostly gastrointestinal bleeding occurs under the NOAC, which should be supplied endoscopically. In life-threatening bleeding in addition to the measures of hemodynamic stabilization usually a special haemostasis management is required, which should be mainly clinically oriented. After the assessment of bleeding predictor, the time of the last dose and the dose of NOAC should be learned, but other causes of bleeding, including Fibrinolysis, should be excluded or treated. Subsequently, routinely promptly rivaroxaban and/or apixaban sensitive thromboplastin time (Quick's value) and a thrombin time (thrombin-poor calibrator) for qualitative assessment can be carried out because only very few hospitals have specific tests (anti-Xa measurements, bovine thrombin), which could be promptly done. If there is a significant deviation from the normal range or to present preliminary value of particular patient, an effect of NOAC most likely exists. In life-threatening bleeding the use of factor concentrates (procoagulants) is indicated. The first-line therapy should be PPSB. Only in exceptional cases, especially when dabigatran is taken, the use of aPPSB (FEIBA®) for prompt haemostasis can be considered. The haemostasis should be always clinically estimated and not according to coagulation tests. The use of rFVIIa (Novo Seven®) shows different results in the bleeding therapy (reversal) under Dabigatran. The doses of these drugs are barely tested and the potential clinical thromboembolic risk must be taken into account. CONCLUSION: The current concepts of the newly developed antidotes are not clinically validated. First prospective, clinical registries have been started.

The antiatherosclerotic effect of Allium sativum.

In a randomized, double-blind, placebo-controlled clinical trial, the plaque volumes in both carotid and femoral arteries of 152 probationers were determined by B-mode ultrasound. Continuous intake of high-dose garlic powder dragees reduced significantly the increase in arteriosclerotic plaque volume by 5-18% or even effected a slight regression within the observational period of 48 months. Also the age-dependent representation of the plaque volume shows an increase between 50 and 80 years that is diminished under garlic treatment by 6-13% related to 4 years. It seems even more important that with garlic application the plaque volume in the whole collective remained practically constant within the age-span of 50-80 years. These results substantiated that not only a preventive but possibly also a curative role in arteriosclerosis therapy (plaque regression) may be ascribed to garlic remedies.

Capillary microscopic and rheological dimensions for the diagnosis of von Willebrand disease in comparison to other haemorrhagic diatheses.

It is known that angiodysplasia influence macrocirculation as well as microcirculation in patients with vWD. In the present study it was examined if intravital capillary microscopic dimensions (morphologic and dynamic) in skin (nailfold) in combination with rheologic parameters could give indications for the presence of vWD in patients with haemorrhagic diathesis. Patients with vWD (n = 100; 92 type 1: definite type 1:78 and possible type 1:14: 8 type 2A) have in comparison to patients with other haemorrhagic diathesis [thrombocytopathy (n = 122), thrombocytopenia (n = 101). severe haemophilia A (n = 50) and severe haemophilia B (n = 20). congenital dysfibrinogenaemia (n = 22), oral anticoagulation with phenprocoumone (n = 112)] and to apparently healthy subjects (n = 100) a significantly increased capillary torquation (median index: 3.5), a venolar and an arteriolar capillary dilatation (median: 16.5 microm; median: 15.1 microm) and the highest part of microscopic bleedings (extravasates) with 40% in the video capillary microscopy as morphological changes. Only the congenital dysfibrinogenaemia appears with a larger dilatation in venolar capillaries (median: 14.5 microm). Microscopic bleedings are much less common in other haemorrhagic diatheses with a frequency between 4% and 13%. In the vWD a significantly reduced duration of reactive hyperaemia (median: 150 sec). This is the only dynamic change that can be taken as a possible hint for a loss of flexibility within the precapillary vessels. A significantly reduced plasma viscosity (< 1.25 mPas) is typical for the vWD due to the increase of the shear stress in blood plasma because of the reduction of vWF-activities. Changes of the capillary morphology (dilatation, extravasates, capillary torquation) and the hypoplasmaviscosity are most sensitive for the vWD (75%, 65%, 40%, 80%) with a fairly high specifity (up to 93%) and a positive predictive value of 99%. As a conclusion it seems reasonable to discuss the introduction of video capillary microscopy as a screening test for haemostasiological and angiological centers.

Increased rate of factor V Leiden mutation in patients with cerebral venous thrombosis.

We investigated the association between cerebral venous thrombosis and hereditary resistance to activated protein C (APC) in 12 consecutive German patients with non-fatal cerebral venous thrombosis and in 187 controls without a history of thrombotic disorder. Three patients (25%) had a mutation in the factor V Leiden gene against only one subject in the control group. This difference was significant (P < 0.05), with an odds ratio of 11.7 (1.5-87; 95% confidence interval). Two patients carrying the mutation had additional common risk factors for thrombosis, and 2 had a positive family history of thromboembolism. We conclude that inherited APC resistance by a mutation in factor V Leiden is an important risk factor in non-fatal cerebral venous thrombosis. We recommend testing for APC resistance and, if abnormal for factor V Leiden mutation in patients with cerebral venous thrombosis.

Immune hemolysis-serological and clinical aspects.

The differential diagnosis of anemia must consider immune hemolytic anemias as a frequent cause. Whereas detection of anti-red blood cell (RBC) alloantibodies frequently induced by immunogenic stimuli (transfusion, pregnancy) is performed by routine serology, diagnosing autoimmune hemolytic anemias or drug-induced hemolytic anemias remains a challenge, usually requiring close collaboration of a number of disciplines. Positive direct antiglobulin test (Coombs' test) represents a central criterion in diagnosing immune hemolytic anemias, leading to further detailed analyses. The most-severe type of immune-mediated hemolysis is acute intravascular hemolysis after ABO incompatible RBC transfusion. This review highlights underlying biochemical aspects, immunohematological diagnostics, and the clinical relevance of RBC allo- and autoantibodies, including paroxysmal nocturnal hemoglobinemia and drug-induced hemolysis. Finally, current and partly experimental therapeutic strategies of immune hemolytic anemias are summarized.

Blood fluidity, fibrinogen, and cardiovascular risk factors of occlusive arterial disease: results of the Aachen study.

In the Aachen study the prevalence of arterial disease was established in 346 out of a cohort of 2821 subjects between 45 and 65 years of age. Rheological variables and risk factor profile for patients with peripheral occlusive arterial disease (POAD), coronary heart disease (CHD) and cerebrovascular insufficiency (CI) in comparison to a control group are given. Significantly elevated are hematocrit in males, plasma viscosity, erythrocyte aggregation and fibrinogen. It is evident that plasma viscosity is the rheological parameter most often elevated in patients with arterial disease (70.8%). In patients with CI (80.6%) plasma viscosity is elevated about four times more often than in healthy subjects. While 85.8% of healthy volunteers show no or only one elevated rheological parameter only 44.5% of the patients have this constellation. Risk factors are bundled in patients compared to healthy volunteers. 84.2% of the healthy volunteers have no or only one risk factor whereas patients with OAD show this constellation in only 30.9% (32.4% in POAD, 16.1% in CI and 32.4% in CHD).

Early rheological and microcirculatory changes in children with type I diabetes mellitus.

In order to determine early changes in microcirculation and hemorheological parameters in diabetics, a cross-sectional study was carried out with 273 children with diabetes mellitus type I during their vacation in a state country convalescent home for diabetic children and teenagers in Kaiserslautern. Compared to healthy children, typical changes of hemorheological variables as well as in the microcirculation of the skin and retina are observed in poorly controlled diabetic children. Morphological changes are obvious in capillary areas in form of marked capillary contortions and dilatations of venous branches, rigid erythrocytes, and hyperaggregable thrombocytes. An effort should be undertaken to normalize the pathologically changed parameters of blood fluidity and the microcirculation by an adequate control of blood glucose, and possibly by changes in dietary habits.

Hypervolumetric hemodilution with HES 100/0.5 10% in patients with peripheral arterial occlusive disease (Fontaine, stage II): an open clinical and pharmacological phase IV study.

The efficacy of three weekly interventions with hypervolumetric hemodilution of a new preparation of hydroxyethyl starch (HES 100/0.5, 10%, C2/C6 substitution ratio of 6.5) on pain-free walking distance of patients with peripheral arterial occlusive disease (PAOD) stage IIb on the Fontaine classification was investigated. In addition quantitative data on the pharmacokinetic properties of this HES preparation, and it's impact on hemorheology, hemostasis and homeostasis were shown. Ten patients were included according to a predefined protocol, and treated openly with 500 ml HES 100/0.5 10% on nine occasions over 18 days. Pain-free walking distance, the main outcome measure, showed a mean increase of 82 m (+60%). Hematocrit decreased 4 percentage points on average (5.5 percentage points one hour after interventions). Plasma viscosity dropped 5% on average with significant changes immediately after interventions only in patients whose baseline values had been equal to or above the 2 s reference area. Erythrocyte aggregation decreased by 16% in the course of treatment (8% immediately after interventions), systolic blood pressure by 13%, and total protein by 7%. Complement showed a trend towards lower values (-20%), and creatinine, pH and urine viscosity remained unchanged. Apart from complement changes, all reductions mirrored the dilution effects. As to pharmacokinetics, serum mean molecular weight distribution was very similar to that of the infusion. A minor adverse drug reaction (light, spontaneously disappearing pruritus) was observed in one case.

[Platelet reactivity index by Grotemeyer]. / Plättchenreaktivitätsindex nach Grotemeyer.

In 1974 Wu and Hoak described a method for determining circulating platelet aggregates. This method was modified by Grotemeyer in 1983. The platelet reactivity index (PR) is based on the ratio of platelet aggregates in blood samples obtained in different buffer solutions. Platelet aggregates are resolved, when blood is sampled in EDTA-buffer, but remain fixed when EDTA-formalin-buffer is used. Generally, the PR is preferred, because in vitro manipulations of platelets are not necessary, and the results are estimated automatically. PR values above 1.05 are suspicious for elevated platelet aggregation. PR values above 1.2 indicate pathological changes in platelet aggregation. The PR is inexpensive (4.0 D ) and rapid to perform. PR-values were used successfully to identify non-responders to secondary prophylaxis with acetylsalicylic acid (ASA), i. e. patients suffering from stroke (33%) and after cardiac ischaemia (18%). Furthermore, elevated PR-values correlated significantly with the incidence of arterial thromboembolic complications. The PR correlated well in a own prospective study (drug monitoring) with values received from the retention test Homburg (RT-H) and the platelet function analyser (PFA-100). These data indicate that the values of the PR seems to be highly predictive for the evaluation of the ASA therapy. However, the PR is not suitable for the determination of ASA overdosage.

Thrombophilia screening in young patients with cryptogenic stroke. Prevalence of gene polymorphisms compared to healthy blood donors and impact on secondary stroke prevention.

UNLABELLED: The clinical relevance of thrombophilia screening in stroke patients is still a matter of debate, and descriptions of larger patterns of genetic variability are rare. We assessed the frequency of hereditary hypercoagulability in young patients with cryptogenic stroke (n = 44) and in healthy blood donors (n = 282) without prior cardiovascular event. Furthermore, we focused on the impact of thrombophilia screening on secondary stroke prevention. RESULTS: Compared to the control group (19-67 years; median 38.5 years; 64% women), there was a lower prevalence of the FVII-R353Q mutation (p = 0.033) in stroke patients (17-52 years; median 36 years; 59.1% women). Of note, the FVII-R353Q mutation lowers FVII plasma levels, probably reducing the risk of cardiovascular events. The prevalence of the remaining 13 gene polymorphisms did not differ significantly. However, the prevalence of FV Leiden mutation tended to be higher among stroke patients. CONCLUSION: Overall, extended screening for inherited thrombophilia had an impact on medical stroke prevention in every sixth patient with cryptogenic stroke.

[Risk of bleeding and haemorrhagic complication with rivaroxaban--periprocedural management of haemostasis]. / Blutungsrisiko und Blutungsnotfälle unter Rivaroxaban. Periinterventionelles Hämostasemanagement.

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.