[Use of specific antidotes in DOAC-associated severe gastrointestinal bleeding - an expert consensus - Antagonozation of direct oral anticoagulants in gastrointestinal hemorrhages]. / Einsatz von spezifischen Antidots bei DOAK-assoziierter schwerer gastrointestinaler Blutung ­ ein Expertenkonsensus.

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

[Perioperative anticoagulation with NOAC using the example of rivaroxaban]. / Perioperative Antikoagulation mit NOAK am Beispiel Rivaroxaban.

BACKGROUND: Recent findings require an update of earlier recommendations on the perioperative management of non Vitamin K antagonist oral anticoagulants (NOAC). METHOD: The present position paper summarises the outcomes of an expert panel discussion. RESULTS AND CONCLUSIONS: Based on the pharmacokinetic profile of rivaroxaban, a preoperative interruption of 24-72 hours is recommended depending on the patient's renal function, as well as individual and surgery-related bleeding risks. Similar NOAC-free intervals are recommended for patients with epidural catheters. Elective surgery should be delayed accordingly. A low molecular weight heparin (LMWH) "bridging" (in fact "switching") should be avoided because of an increased bleeding risk. Six to 8 hours after the intervention rivaroxaban can be re-initiated or, in case of more extensive interventions or an increased bleeding risk, after 24-72 hours; if necessary this interval could by bridged with LMWH, e. g. if the thromboembolic risk is considered high. In case of emergency surgery with a rivaroxaban pause of less than 9 hours, one should be prepared for a bleeding management including the use of prothrombin concentrate (PCC). Coagulation tests have no value for predicting perioperative bleeding, in contrast to a standardised bleeding history. As an overall estimate, the PT (Quick) can be determined with a suitable reagent. Currently, rivaroxaban-specific measurements of anti Xa levels are available at few specialised centres only. Moderate to severe haemorrhages can usually be managed by temporary interruption of rivaroxaban in conjunction with local and general haemostatic measures. Life-threatening bleeding events require a specific haemostasis management including the administration of PCC; these events are rare and usually have a favourable prognosis, except for intracranial haemorrhages.

Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients' preference.

Patients with indication for anticoagulation may prefer treatment with a vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC). A questionnaire may help to identify the preference of patients for one of the two types of oral anticoagulants and to develop a score for the recommendation to continue or to change the anticoagulant. A score was developed using a questionnaire containing biographic data and eight statements on attitudes on anticoagulation and was derived to trigger continuation or change the type of anticoagulant by defining ranges of terms and weighting of the significant statements identified by logistic regression analysis. Participating patients received either anticoagulation with VKA (group 1, n = 690), were transferred from VKA to NOAC (group 2, n = 158), received NOAC de novo (group 3, n = 137) or were transferred from NOAC to VKA (group 4, n = 19). Four statements were significantly (p values between 0.0347 and < 0.0001) associated with recommendations to maintain or to change the type of anticoagulant for patients in groups 1, 2, or 3 with predictive values of c = 0.83 between groups 1 and 2 and c = 0.71 between groups 1 and 3. From the total number of replies to the statements a score of three grades and two strengths (A = strong, B = moderate) was derived for the recommendations. This tool supports recommendations as to continue or to change the presently used type of oral anticoagulant based on the identification of patients' preferences.

S3 guidelines for the management of anticoagulation in cutaneous surgery.

BACKGROUND: An increasing number of patients are being treated with anticoagulants and platelet inhibitors. Whenever surgical procedures of the skin are required, questions arise regarding the perioperative management of anticoagulation. METHODS: Development of S3 guidelines following the requirements of the Association of Scientific Medical Societies, systematic literature search and analysis, use of GRADE methodology, structured consensus conference using a nominal group process. RESULTS: During cutaneous surgery, treatment with acetylsalicylic acid (ASA) should be continued if medically necessary. In procedures with a higher risk of bleeding and a positive bleeding history, INR should be determined preoperatively. Surgical procedures of the skin with a higher risk of bleeding should not be performed if the INR is above therapeutic range. Bridging from vitamin K antagonists (VKA) to heparin should not be performed just because of the surgery of the skin. As to direct-acting oral anticoagulants, the last dose should be taken 24 h preoperatively. CONCLUSIONS: The recommendations issued by the German guidelines group are mostly in line with recommendations provided by other guidelines. The American ìChest-Guidelineì recommends continuing VKAs and acetylsalicylic acid during minor dermatologic procedures. In their guidelines, the German College of General Practitioners and Family Physicians considers an INR of 2 to be adequate in surgical procedures on the skin.

[Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)]. / Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

Probleme der Digitalisierung sowie Protest gegen das Finanzstabilisierungsgesetz.

Wiederholt hatte der Vorstand des Berufsverbandes der Deutschen Hämostaseologen (BDDH) in Übereinstimmung mit anderen Berufs- und Ärzteverbänden auf die massiven Probleme der Digitalisierung im Gesundheitswesen hingewiesen. Ärzte waren sich weitgehend einig, dass die Digitalisierung in der aktuellen Form aufgrund fehlender Akzeptanz und massiven technischen Problemen nicht umsetzbar sein wird und zum Scheitern verurteilt ist.

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

Ablösung der In-Vitro-Diagnostika-Richtlinie auf die In-Vitro-Diagnostika-Verordnung (IVDR) 05/2022 und Programm für die BDDH-Veranstaltung im Rahmen des GTH-Kongresses 2022 in Leipzig.

ABLöSUNG DER IN-VITRO-DIAGNOSTIKA-RICHTLINIE AUF DIE IN-VITRO-DIAGNOSTIKA-VERORDNUNG (IVDR) 05/2022 (CHRISTOPH SUCKER, GüNTHER KAPPERT): Planmäßig soll am 26.05.2022 die bisher geltende In-Vitro-Diagnostika-Richtlinie durch die In-Vitro-Diagnostika-Verordnung (IVDR) ersetzt werden und würde dann an diesem Tag unmittelbar rechtlich wirksam.

[Anticoagulation and platelet aggregation inhibition : What needs to be considered in the ophthalmological practice]. / Antikoagulation und Thrombozytenfunktionshemmung : Was in der augenärztlichen Praxis zu beachten ist.

Several eye diseases requiring surgical intervention occur predominantly in elderly. Therefore, there is a significant co-incidence with systemic co-morbidities, which often do require anti-coagulation. There are several approaches to influence hemostasis pharmacologically. The number of options has increased substantially due to introduction of new drugs. This article provides an overview on the option range and gives insight, why this is of importance from the perspective of internal medicine. In addition, the basic principles of adjusting the therapy is being reviewed. Furthermore, the pharmacological inhibition of hemostasis in the context of eye surgery is being discussed. Available literature is analyzed to understand the necessity to interrupt or change the anti-coagulation for eye surgery.

Fondaparinux Pre-, Peri-, and/or Postpartum for the Prophylaxis/Treatment of Venous Thromboembolism (FondaPPP).

We analyzed data for women who received fondaparinux for ≥7 days during pregnancy. The study retrospectively included women who received fondaparinux pre-, peri- and/or postpartum for ≥7 days for prophylaxis/venous thromboembolism (VTE) treatment at German specialist centers (2004-2010). Data on pregnancy, VTE risk factors, anticoagulant treatment, pregnancy outcome and adverse events were extracted from medical records. 120 women (mean age 31.5 years) were included. Among 84 women with prior pregnancies, 41.0% had ≥1 abortion. Anticoagulation was indicated for prophylaxis in 92.5% cases, including 82.5% women with an elevated VTE risk (82.8% thrombophilia, 34.2% VTE history). All women received low-molecular-weight heparin (LMWH) as first-line therapy; 3 also unfractionated heparin. Treatment changed to fondaparinux, due to heparin allergy (41.7%) or heparin-induced thrombocytopenia (10.0%). Fondaparinux was generally well tolerated. Adverse events included bleeding events (n = 5), abortion (n = 2), premature births (n = 2), stillbirth (n = 1), arrested labors (n = 2), injection site erythema (n = 4) and unspecified drug hypersensitivity (n = 6). No VTE events or increased liver enzymes occurred during treatment. In this retrospective study, fondaparinux was effective and well tolerated. Trial registration: ClinicalTrials.gov NCT01004939.

How Do I Reverse Oral and Parenteral Anticoagulants?

An understanding of reversal strategies alone is important to safely and effectively care for patients in cases of bleeding or invasive procedures. The recent diversification in the number of licensed anticoagulants makes an understanding of drug-specific reversal strategies essential. Intravenous or oral vitamin K can reverse the effect of vitamin K antagonists (VKAs) within 12 to 48 hours and is indicated for any bleeding or an international normalized ratio >10 or 4.5 to 10 in patients with additional risk factors for bleeding. Furthermore, an additional administration of prothrombin complex concentrate (PCC) may be necessary in cases of major bleeding related to VKA. Protamine (chloride or sulfate) fully reverses the effect of unfractionated heparin and partially in low-molecular-weight heparin. Idarucizumab has been approved for dabigatran reversal, whereas andexanet alfa is approved for the reversal of some oral factor Xa inhibitors (apixaban, rivaroxaban). PCC seems to enhance the haemostatic potential for the reversal of the effect of FXa-inhibitors. So far, there are promising but only limited data on the efficacy of this approach available. Each reversal strategy needs an adequate management beyond the hemostatic treatment (volume replacement, stabilization of homeostasis, e.g., pH and temperature, resumption of anticoagulation after successful treatment of bleeding, etc.) that is crucial for the successful management of acute bleedings, urgent high-risk surgery, thrombolytic therapies or thrombectomies as well as overdosing of anticoagulants.

Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO).

INTRODUCTION: In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. METHODS: Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. RESULTS: We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. CONCLUSIONS: Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

Blood rheology at term in normal pregnancy and in patients with adverse outcome events.

Plasma volume expansion of more than 1.5 l and sustainable activation of the hemostatic system that results in a steady rise of the fibrinogen/fibrin turnover are contemporary physiological events during normal pregnancy. In contrast, adverse outcome of pregnancy i.e. pre-eclampsia commonly coincide with hemo concentration and over activation of blood coagulation both of which alter blood rheology. On the basis of 4,985 consecutively recorded singleton pregnancies values range of blood rheological parameters in women with normal and complicated outcome of pregnancy at the time of their delivery were compared. Plasma viscosity (pv) was determined using KSPV 1 Fresenius and RBC aggregation (stasis: E0 and low shear: E1) using MA1-Aggregometer; Myrenne. Seventy-nine point four percent (n=3,959) had normal pregnancy outcome and 1,026 with adverse outcome of pregnancy had pre-eclampsia (8.4%; n=423), had newborn with a birth-weight < 2,500 g (9.5%; n=473), had early-birth before week 37 (9.3%; n=464), and/or were diagnosed with intra uterine growth retardation (IUGR) (5.0%; n=250). In women with normal pregnancy outcome mean (+/-SD) of pv was 1.31+/-0.09 mPa s, of E0 was 21.6+/-5.3, and of E1 was 38.4+/-7.9 while in women with adverse outcome means for rheological parameters were statistically significantly different i.e. pv: 1.32+/-0.08 mPa s; p=0.006, E0: 22.1+/-5.5; p=0.002 and E1: 39.5+/-8.5; p=0.0006. Subgroup analysis revealed statistical significant lower pv in women who either had pre term delivery or a low birth-weight child (p<0.005) as compared to women who had normal pregnancy outcome while patients with pre-eclampsia had markedly higher low shear and stasis RBC aggregation (p<0.0001). None of the rheological results at term were correlated with either maternal age (r<0.04), BMI (r<0.09), maternal weight gain until delivery (r<0.04), or fetal outcome such as APGAR-score (r<0.09) art. pH in the umbilical cord (-0.05

Replacement Therapy in Patients with Von Willebrand Disease-Indications and Monitoring.

In patients with von Willebrand disease (VWD), replacement therapy may be indicated in the case of spontaneous bleeding, surgical interventions and injuries/trauma or as a prophylaxis of spontaneous bleeding episodes. The deficient von Willebrand factor (VWF) is replaced with or without factor VIII (FVIII). Dual VWF/FVIII concentrates can be beneficial in the case of low FVIII level, while repeated dosing may lead to very high FVIII levels, with a potential thrombogenic effect in individual VWD patients. An excessive FVIII:C increase can be limited by using a VWF product with a low level of FVIII, achieving a haemostatic adequate FVIII:C increase after 6 to 12 hours. Replacement therapy in patients with VWD shall be individualised considering VWD type, history and risk of bleeding and risk of thrombosis, as well as indication and the individually variable VWF and FVIII increase. Deviations from the dosages and minimum trough levels mentioned in guidelines or recommendations can be considered in justified cases. The objective of this review is to provide recommendations for specific constellations of replacement therapy based on the VWD-specific guidelines available in Europe, the available evidence, own experiences and the consensus of the interdisciplinary German author group.

Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data.

BACKGROUND: The purpose of this study was to determine the role of recombinant activated factor VII (rFVIIa) in abdominal, vascular, and urological surgery. METHODS: We conducted meta-analyses of case series and placebo-controlled studies reporting on the treatment or prophylaxis of bleeding with rFVIIa regarding 'reduction or cessation of bleeding', 'mortality', and 'thromboembolism'. RESULTS: All case reports (n = 15 case reports and 17 patients) documented an effect of rFVIIa in the treatment of bleeding. A meta-analysis of 10 case series revealed a reduction or cessation of bleeding in 39 out of 50 patients after administration of rFVIIa (estimated mean effect 73.2%, 95% confidence interval [CI] 51.0% to 95.4%) and a mean probability of survival of 53.0% (95% CI 26.4% to 79.7%). Among the rFVIIa responders, 19 out of 29 patients (66%) survived versus 1 out of 10 rFVIIa nonresponders (P = 0.003). Six out of 36 patients from the case series had a thromboembolic complication (estimated mean probability 16.5%, 95% CI 1.2% to 31.8%). Compared with a meta-analysis of eight placebo-controlled studies, no increased risk of thromboembolism was seen after administration of rFVIIa. CONCLUSION: The meta-analysis of case series showed that, in a mean of 73% patients, rFVIIa achieved at least a reduction of bleeding and that the probability of survival is increased in patients responding to rFVIIa. rFVIIa was not associated with an increased risk of thromboembolism compared with placebo.

Mean maternal second-trimester hemoglobin concentration and outcome of pregnancy: a population-based study.

Both anemia and the lack of physiological maternal plasma volume expansion during the second trimester are associated with higher maternal morbidity and poor fetal outcome. Mean hemoglobin levels between the 14th and 30th gestational weeks were calculated in 4985 consecutive pregnant women and were correlated with outcome data of pregnancy. It was found that 9.4% of participants (n=3959) had normal pregnancy outcome. Mean maternal hemoglobin levels were significantly lower in women with a normal pregnancy (11.96+/-0.94 g/dL) compared with women who had adverse outcome events (preeclampsia, n=423, 12.5 +/- 1.0 g/dL, P< .0001; early birth, n=464, 12.2+/-1.01 g/dL, P< .0001; low birth weight newborn, n=473, 12.2+/-1.10 g/dL, P< .0001; intrauterine growth retardation, n=250, 12.2+/-1.0 g/dL, P< .0001). The risk for any adverse outcome event was lowest with a mean hemoglobin between 11.0 and 12.0 g/dL (odds ratio, 0.625; 95% confidence interval, 0.43-0.89) and highest between 13.0 and 15.0 g/dL (odds ratio, 2.24; 95% confidence interval, 1.54-3.31). In this population-based study from a community in Western Germany, impaired plasma volume expansion was an independent risk factor for the development of an adverse outcome of pregnancy.