Thrombozytenhemmung und -aktivierung: Mechanismen und klinische Implikationen

Zusammenfassung : Die Empfindlichkeit der Aktivierung von Thrombozyten ist Teil des delikaten Gleichgewichts, welches Hämostase von Thrombose unterscheidet. Unter physiologischen Bedingungen wird es durch die Hemmung der Thrombozytenaktivität und Entfernung von Agonisten erhalten. Unter pathologischen prothrombotischen Bedingungen versucht der Mediziner, das Gleichgewicht mit Hilfe von Arzneimitteln wiederherzustellen. Die Resultate dieser Behandlungen verbessern sich stetig, aber dennoch sind ein besseres Verständnis der Mechanismen und die Suche nach alternativen Inhibitoren nach wie vor wichti

Protein C Replacement in Severe Meningococcemia: Rationale and Clinical Experience

Severe meningococcemia, which is associated with hemodynamic instability, purpura fulminans and disseminated intravascular coagulation, still has a high mortality rate, and patients who survive are often left invalids because of amputations and organ failure. Clinical studies have shown that levels of protein C are markedly decreased in patients with severe meningococcemia and that the extent of the decrease correlates with a negative clinical outcome. There is a growing body of data demonstrating that activated protein C, in addition to being an anticoagulant, is also a physiologically relevant modulator of the inflammatory response. The dual function of protein C may be relevant to the treatment of individuals with severe meningococcal sepsis. In the present review we give a basic overview of the protein C pathway and its anticoagulant activity, and we summarize experimental data showing that activated protein C replacement therapy clearly reduces the mortality rate for fulminant meningococcemi

Recombinant human factor VIIa prevents hysterectomy in severe postpartum hemorrhage: single center study

Objective: To evaluate the effectiveness of human recombinant activated factor VII (rhFVIIa, NovoSeven) in avoiding hysterectomy postpartum in the management of severe postpartum hemorrhage (PPH). Methods: We performed a prospective cohort study at our university tertiary care center. Patients with severe post partum hemorrhage (blood loss >2000 mL) and failed medical and uterus-preserving surgical management, were treated with intravenous bolus administration of rhVIIa. Main outcome measures were cessation of bleeding, postpartum hysterectomy and thromboembolic events. Results: In 20/22 patients included, PPH was caused primarily by uterine atony, including 7 (32%) with additional lower genital tract lesion; in two women, it was due to pathologic placentation (placenta increta, 9%). One case of amniotic fluid embolism and one woman with uterine inversion were included. Recombinant hFVIIa was successful in stopping the PPH and in preventing a hysterectomy in 20/22 women (91%). The remaining two patients with persistent bleeding despite rhFVIIa treatment, who underwent postpartum hysterectomy, had placenta increta. No thromboembolic event was noticed. Conclusions: This study describes the largest single center series of rhFVIIa treatment for fertility preservation in severe postpartum hemorrhage published to date. Our data suggest that administration of rhFVIIa is effective in avoiding postpartum hysterectomy after conservative medical and surgical measures have failed. Although randomized studies are lacking, rhFVIIa should be considered as a second-line therapeutic option of life-threatening postpartal bleeding, in particular if preservation of fertility is warranted and hysterectomy is to be avoide

Does point of care prothrombin time measurement reduce the transfusion of fresh frozen plasma in patients undergoing major surgery? The POC-OP randomized-controlled trial

<p>Abstract</p> <p>Background</p> <p>Bleeding is a frequent complication during surgery. The intraoperative administration of blood products, including packed red blood cells, platelets and fresh frozen plasma (FFP), is often live saving. Complications of blood transfusions contribute considerably to perioperative costs and blood product resources are limited. Consequently, strategies to optimize the decision to transfuse are needed.</p> <p>Bleeding during surgery is a dynamic process and may result in major blood loss and coagulopathy due to dilution and consumption. The indication for transfusion should be based on reliable coagulation studies. While hemoglobin levels and platelet counts are available within 15 minutes, standard coagulation studies require one hour. Therefore, the decision to administer FFP has to be made in the absence of any data. Point of care testing of prothrombin time ensures that one major parameter of coagulation is available in the operation theatre within minutes. It is fast, easy to perform, inexpensive and may enable physicians to rationally determine the need for FFP.</p> <p>Methods/Design</p> <p>The objective of the POC-OP trial is to determine the effectiveness of point of care prothrombin time testing to reduce the administration of FFP. It is a patient and assessor blind, single center randomized controlled parallel group trial in 220 patients aged between 18 and 90 years undergoing major surgery (any type, except cardiac surgery and liver transplantation) with an estimated blood loss during surgery exceeding 20% of the calculated total blood volume or a requirement of FFP according to the judgment of the physicians in charge. Patients are randomized to usual care plus point of care prothrombin time testing or usual care alone without point of care testing. The primary outcome is the relative risk to receive any FFP perioperatively. The inclusion of 110 patients per group will yield more than 80% power to detect a clinically relevant relative risk of 0.60 to receive FFP of the experimental as compared with the control group.</p> <p>Discussion</p> <p>Point of care prothrombin time testing in the operation theatre may reduce the administration of FFP considerably, which in turn may decrease costs and complications usually associated with the administration of blood products.</p> <p>Trial registration</p> <p>NCT00656396</p

Thrombophilia and outcomes of venous thromboembolism in older patients.

BACKGROUND Limited data exist on thrombophilic risk factors and clinical outcomes in the elderly with venous thromboembolism (VTE). OBJECTIVES To describe the prevalence of laboratory thrombophilic risk factors and their association with VTE recurrence or death in a cohort of elderly people with VTE. METHODS In 240 patients aged ≥65 years with acute VTE without active cancer or an indication for extended anticoagulation, we performed laboratory thrombophilia testing 1 year after the index VTE. Recurrence or death was assessed during the 2-year follow-up. RESULTS A total of 78% of patients had ≥1 laboratory thrombophilic risk factor(s). Elevated levels of von Willebrand factor, homocysteine, coagulant activity of factor VIII (FVIII:C), fibrinogen, FIX:C, and low antithrombin activity were the most prevalent risk factors (43%, 30%, 15%, 14%, 13%, and 11%, respectively). Additionally, 16.2% of patients experienced VTE recurrence and 5.8% of patients died. Patients with a von Willebrand factor of >182%, FVIII:C level >200%, homocysteine level >15μmol/L, or lupus anticoagulant had a significantly higher rate of recurrence than those without these risk factors (15.0 vs. 6.1 [P = .006], 23.5 vs. 8.2 [P = .01], 17.0 vs. 6.8 [P = .006], and 89.5 vs. 9.2 [P = .02] events per 100 patient-years, respectively). Furthermore, patients with a high fibrinogen level or hyperhomocysteinemia with a homocysteine level ≥30 μmol/L had significantly higher mortality than patients with normal levels (18.5 vs. 2.8 [P = .049] and 13.6 vs. 2 [P = .002] deaths per 100 patient-years, respectively). After adjustments for relevant confounders, these associations remained unchanged. CONCLUSION Laboratory thrombophilic risk factors are common in elderly people with VTE and allow for the identification of a population at the risk of worse clinical outcomes

Efficacy and Safety of Rivaroxaban for Postoperative Thromboprophylaxis in Patients After Bariatric Surgery: A Randomized Clinical Trial.

IMPORTANCE Venous thromboembolism (VTE) is a leading cause of morbidity and mortality after bariatric surgery. Clinical end point studies on thromboprophylaxis with direct oral anticoagulants in patients undergoing bariatric surgery are lacking. OBJECTIVE To assess the efficacy and safety of a prophylactic dose of 10 mg/d of rivaroxaban for both 7 and 28 days after bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS This assessor-blinded, phase 2, multicenter randomized clinical trial was conducted from July 1, 2018, through June 30, 2021, with participants from 3 academic and nonacademic hospitals in Switzerland. INTERVENTION Patients were randomized 1 day after bariatric surgery to 10 mg of oral rivaroxaban for either 7 days (short prophylaxis) or 28 days (long prophylaxis). MAIN OUTCOMES AND MEASURES The primary efficacy outcome was the composite of deep vein thrombosis (symptomatic or asymptomatic) and pulmonary embolism within 28 days after bariatric surgery. Main safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and mortality. RESULTS Of 300 patients, 272 (mean [SD] age, 40.0 [12.1] years; 216 women [80.3%]; mean body mass index, 42.2) were randomized; 134 received a 7-day and 135 a 28-day VTE prophylaxis course with rivaroxaban. Only 1 thromboembolic event (0.4%) occurred (asymptomatic thrombosis in a patient undergoing sleeve gastrectomy with extended prophylaxis). Major or clinically relevant nonmajor bleeding events were observed in 5 patients (1.9%): 2 in the short prophylaxis group and 3 in the long prophylaxis group. Clinically nonsignificant bleeding events were observed in 10 patients (3.7%): 3 in the short prophylaxis arm and 7 in the long prophylaxis arm. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, once-daily VTE prophylaxis with 10 mg of rivaroxaban was effective and safe in the early postoperative phase after bariatric surgery in both the short and long prophylaxis groups. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03522259

Prothrombinase-Induced Clotting Time to Measure Drug Concentrations of Rivaroxaban, Apixaban, and Edoxaban in Clinical Practice: A Cross-Sectional Study.

Prothrombinase-induced clotting time (PiCT) is proposed as a rapid and inexpensive laboratory test to measure direct oral anticoagulant (DOAC) drug levels. In a prospective, multicenter cross-sectional study, including 851 patients, we aimed to study the accuracy of PiCT in determining rivaroxaban, apixaban, and edoxaban drug concentrations and assessed whether clinically relevant drug levels could be predicted correctly. Citrated plasma samples were collected, and the Pefakit® PiCT was utilized. Ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to measure drug concentrations. Cut-off levels were established using receiver-operating characteristics curves. We calculated sensitivities and specificities with respect to clinically relevant drug concentrations. Spearman's correlation coefficient between PiCT and drug concentrations was 0.85 in the case of rivaroxaban (95% CI 0.82, 0.88), 0.66 for apixaban (95% CI 0.60, 0.71), and 0.78 for edoxaban (95% CI 0.65, 0.86). The sensitivity to detect clinically relevant drug concentrations was 85.1% in the case of 30 µg L-1 (95% CI 82.0, 87.7; specificity 77.9; 72.1, 82.7), 85.7% in the case of 50 µg L-1 (82.4, 88.4; specificity 77.3; 72.5, 81.5), and 85.1% in the case of 100 µg L-1 (80.9, 88.4; specificity 73.2%; 69.1, 76.9). In conclusion, the association of PiCT with DOAC concentrations was fair, and the majority of clinically relevant drug concentrations were correctly predicted

Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with haemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of haemophilia A and B gene therapy with vectors derived from adeno-associated virus (AAV), 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 centres 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 primary source of data for pharmacovigilance, post-marketing 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

Determination of Anti-Xa Inhibitor Plasma Concentrations Using a Universal Edoxaban Calibrator

A universal calibrator for the determination of all anti-Xa inhibitors would support laboratory processes. We aimed to test the clinical performance of an anti-Xa assay utilizing a universal edoxaban calibrator to determine clinically relevant concentrations of all anti-Xa inhibitors. Following a pilot study, we enrolled 553 consecutive patients taking rivaroxaban, edoxaban, or apixaban from nine study centers in a prospective cross-sectional study. The Technochrom$^{®}$ anti-Xa assay was conducted using the Technoview$^{®}$ edoxaban calibrator. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), anti-Xa inhibitor drug concentrations were determined. Sensitivities and specificities to detect three clinically relevant drug concentrations (30 µgL$^{-1}$, 50 µgL$^{-1}$, 100 µgL$^{-1}$) were determined. Overall, 300 patients treated with rivaroxaban, 221 with apixaban, and 32 with edoxaban were included. The overall correlation coefficient (r$_{s}$) was 0.95 (95% CI 0.94, 0.96). An area under the receiver operating characteristic curve of 0.96 for 30 µgL$^{-1}$, 0.98 for 50 µgL$^{-1}$, and 0.99 for 100 µgL$^{-1}$ was found. The sensitivities were 92.3% (95% CI 89.2, 94.6), 92.7% (89.4, 95.1), and 94.8% (91.1, 97.0), respectively (specificities 82.2%, 93.7%, and 94.4%). In conclusion, the clinical performance of a universal, edoxaban-calibrated anti-Xa assay was solid and most drug concentrations were predicted correctly