[Peripartum hemorrhage, diagnostics and treatment : Update of the S2k guidelines AWMF 015/063 from August 2022]. / Peripartale Blutungen, Diagnostik und Therapie : Update der S2k-Leitlinie AWMF 015/063 vom August 2022.

The current S2k guidelines on the diagnostics and treatment of peripartum hemorrhage are summarized in this article from the perspective of anesthesiology based on a fictitious case report. The update of the guidelines was written under the auspices of the German Society of Gynecology and Obstetrics with the participation of other professional societies and interest groups from Germany, Austria and Switzerland and published by the AWMF in 2022 under the register number 015/063.

Accuracy and consistency of anti-Xa activity measurement for determination of rivaroxaban plasma levels.

Essentials Accurate determination of anticoagulant plasma concentration is important in clinical practice. We studied the accuracy and consistency of anti-Xa assays for rivaroxaban in a multicentre study. In a range between 50 and 200 µg L-1 , anti-Xa activity correlated well with plasma concentrations. The clinical value might be limited by overestimation and intra- and inter-individual variation. SUMMARY: Background Determining the plasma level of direct oral anticoagulants reliably is important in the work-up of complex clinical situations. Objectives To study the accuracy and consistency of anti-Xa assays for rivaroxaban plasma concentration in a prospective, multicenter evaluation study employing different reagents and analytical platforms. Methods Rivaroxaban 20 mg was administered once daily to 20 healthy volunteers and blood samples were taken at peak and trough levels (clinicaltrials.gov NCT01710267). Anti-Xa activity was determined in 10 major laboratories using different reagents and analyzers; corresponding rivaroxaban plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Findings Overall Pearson's correlation coefficient of anti-Xa levels and HPLC-MS results was 0.99 for Biophen® Heparin (95% CI, 0.99, 0.99), Biophen® DiXaI (95% CI, 0.99, 0.99) and STA® anti-Xa liquid (95% CI, 0.99, 1.00). Correlation was lower in rivaroxaban concentrations below 50 µg L-1 and above 200 µg L-1 . The overall bias of the Bland-Altman difference plot was 14.7 µg L-1 for Biophen Heparin, 17.9 µg L-1 for Biophen DiXal and 19.0 µg L-1 for STA anti-Xa liquid. Agreement between laboratories was high at peak level but limited at trough level. Conclusions Anti-Xa activity correlated well with rivaroxaban plasma concentrations, especially in a range between 50 and 200 µg L-1 . However, anti-Xa assays systematically overestimated rivaroxaban concentration as compared with HPLC-MS, particularly at higher concentrations. This overestimation, coupled with an apparent interindividual variation, might affect the interpretation of results in some situations.

The PiCT® test is a reliable alternative to the activated partial thromboplastin time in unfractionated heparin therapy management: results from a multicenter study.

Essentials Activated partial thromboplastin time (APTT) or anti-Xa tests are used to monitor heparin. Prothrombinase-induced Clotting Time (PiCT) was compared to APTT in a clinical study. PiCT shows higher correlation to anti-Xa than APTT does and is more comparable between centers. PiCT demonstrates significantly higher accuracy and reliability than APTT in heparin monitoring. SUMMARY: Background Unfractionated heparin (UFH) is still a commonly used anticoagulant for prevention and treatment of thromboembolism in a variety of situations. Increasingly, chromogenic anti-Xa assays are used for UFH monitoring given the high variability of the activated partial thromboplastin time (APTT) in this setting. On the other hand, and despite the known variability, the APTT test remains the most frequently used monitoring tool in UFH therapy because of its broad availability, lower costs and wide acceptance. Various guidelines continue to recommend the use of the APTT as an anti-Xa surrogate, but this approach remains controversial. Objective To assess the prothrombinase-induced clotting time (PiCT® ) test, reported in seconds, as an alternative to the APTT in the management of UFH-mediated anticoagulation. Methods Plasma samples from patients receiving UFH were obtained in three different centers in the USA and Europe. Samples were analyzed for PiCT, APTT and anti-Xa activities with conditions set to allow comparability. Target-ranges in seconds for PiCT and APTT were established for a UFH concentration of 0.3-0.7 IU mL-1 , derived from anti-Xa results as suggested by the ACCP guidelines. Results PiCT demonstrated better correlation with anti-Xa IU mL-1 than APTT, higher ability to identify samples within target range and, importantly, comparable target-ranges between different centers. Conclusion Accuracy and reliability of PiCT are significantly better than those of APTT in monitoring UFH for anticoagulant therapy.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium.

Intestinal infection with the mouse pathogen Citrobacter rodentium induces a strong local Th17 response in the colon. Although this inflammatory immune response helps to clear the pathogen, it also induces inflammation-associated pathology in the gut and thus, has to be tightly controlled. In this project, we therefore studied the impact of Foxp3(+) regulatory T cells (Treg) on the infectious and inflammatory processes elicited by the bacterial pathogen C. rodentium. Surprisingly, we found that depletion of Treg by diphtheria toxin in the Foxp3(DTR) (DEREG) mouse model resulted in impaired bacterial clearance in the colon, exacerbated body weight loss, and increased systemic dissemination of bacteria. Consistent with the enhanced susceptibility to infection, we found that the colonic Th17-associated T-cell response was impaired in Treg-depleted mice, suggesting that the presence of Treg is crucial for the establishment of a functional Th17 response after the infection in the gut. As a consequence of the impaired Th17 response, we also observed less inflammation-associated pathology in the colons of Treg-depleted mice. Interestingly, anti-interleukin (IL)-2 treatment of infected Treg-depleted mice restored Th17 induction, indicating that Treg support the induction of a protective Th17 response during intestinal bacterial infection by consumption of local IL-2.

Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).

There is a need to validate risk assessment tools for hospitalised medical patients at risk of venous thromboembolism (VTE). We investigated whether a predefined cut-off of the Geneva Risk Score, as compared to the Padua Prediction Score, accurately distinguishes low-risk from high-risk patients regardless of the use of thromboprophylaxis. In the multicentre, prospective Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE) cohort study, 1,478 hospitalised medical patients were enrolled of whom 637 (43%) did not receive thromboprophylaxis. The primary endpoint was symptomatic VTE or VTE-related death at 90 days. The study is registered at ClinicalTrials.gov, number NCT01277536. According to the Geneva Risk Score, the cumulative rate of the primary endpoint was 3.2% (95% confidence interval [CI] 2.2-4.6%) in 962 high-risk vs 0.6% (95% CI 0.2-1.9%) in 516 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.5% vs 0.8% (p=0.029), respectively. In comparison, the Padua Prediction Score yielded a cumulative rate of the primary endpoint of 3.5% (95% CI 2.3-5.3%) in 714 high-risk vs 1.1% (95% CI 0.6-2.3%) in 764 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.2% vs 1.5% (p=0.130), respectively. Negative likelihood ratio was 0.28 (95% CI 0.10-0.83) for the Geneva Risk Score and 0.51 (95% CI 0.28-0.93) for the Padua Prediction Score. In conclusion, among hospitalised medical patients, the Geneva Risk Score predicted VTE and VTE-related mortality and compared favourably with the Padua Prediction Score, particularly for its accuracy to identify low-risk patients who do not require thromboprophylaxis.

First report of sandfly fever virus infection imported from Malta into Switzerland, October 2011.

We report the first documented cases of sandfly fever virus infection in travellers returning from Malta to Switzerland in autumn 2011. These cases illustrate the importance of considering sandfly-borne viral infection in the differential diagnosis of febrile patients from the Mediterranean island Malta. Raising awareness among physicians is relevant especially now at the beginning of the summer tourist season.

Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories.

INTRODUCTION: Rivaroxaban (RXA) is licensed for prophylaxis of venous thromboembolism after major orthopaedic surgery of the lower limbs. Currently, no test to quantify RXA in plasma has been validated in an inter-laboratory setting. Our study had three aims: to assess i) the feasibility of RXA quantification with a commercial anti-FXa assay, ii) its accuracy and precision in an inter-laboratory setting, and iii) the influence of 10mg of RXA on routine coagulation tests. METHODS: The same chromogenic anti-FXa assay (Hyphen BioMed) was used in all participating laboratories. RXA calibrators and sets of blinded probes (aim ii.) were prepared in vitro by spiking normal plasma. The precise RXA content was assessed by high-pressure liquid chromatography-tandem mass spectrometry. For ex-vivo studies (aim iii), plasma samples from 20 healthy volunteers taken before and 2 - 3hours after ingestion of 10mg of RXA were analyzed by participating laboratories. RESULTS: RXA can be assayed chromogenically. Among the participating laboratories, the mean accuracy and the mean coefficient of variation for precision of RXA quantification were 7.0% and 8.8%, respectively. Mean RXA concentration was 114±43µg/L .RXA significantly altered prothrombin time, activated partial thromboplastin time, factor analysis for intrinsic and extrinsic factors. Determinations of thrombin time, fibrinogen, FXIII and D-Dimer levels were not affected. CONCLUSIONS: RXA plasma levels can be quantified accurately and precisely by a chromogenic anti-FXa assay on different coagulometers in different laboratories. Ingestion of 10mg RXA results in significant alterations of both PT- and aPTT-based coagulation assays.

Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. The SWIss Venous ThromboEmbolism Registry (SWIVTER) II.

In patients with acute cancer-associated thrombosis, current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Among 1,247 patients with acute venous thromboembolism (VTE) enrolled in the prospective Swiss Venous Thromboembolism Registry (SWIVTER) II from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, 83 (26%) prior cancer surgery, and 63 (20%) recurrent VTE. Long-term anticoagulation treatment for >12 months was more often planned in patients with versus without cancer (47% vs. 19%; p<0.001), with recurrent cancer-associated versus first cancer-associated VTE (70% vs. 41%; p<0.001), and with metastatic versus non-metastatic cancer (59% vs. 31%; p<0.001). In patients with cancer, recurrent VTE (OR 3.46; 95%CI 1.83-6.53), metastatic disease (OR 3.04; 95%CI 1.86-4.97), and the absence of an acute infection (OR 3.55; 95%CI 1.65-7.65) were independently associated with the intention to maintain anticoagulation for >12 months. In conclusion, long-term anticoagulation treatment for more than 12 months was planned in less than half of the cancer patients with acute VTE. The low rates of long-term anticoagulation in cancer patients with a first episode of VTE and in patients with non-metastatic cancer require particular attention.

Peri-operative management of antiplatelet therapy in patients with coronary artery disease: joint position paper by members of the working group on Perioperative Haemostasis of the Society on Thrombosis and Haemostasis Research (GTH), the working group on Perioperative Coagulation of the Austrian Society for Anesthesiology, Resuscitation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society for Cardiology (ESC).

An increasing number of patients suffering from cardiovascular disease, especially coronary artery disease (CAD), are treated with aspirin and/or clopidogrel for the prevention of major adverse events. Unfortunately, there are no specific, widely accepted recommendations for the perioperative management of patients receiving antiplatelet therapy. Therefore, members of the Perioperative Haemostasis Group of the Society on Thrombosis and Haemostasis Research (GTH), the Perioperative Coagulation Group of the Austrian Society for Anesthesiology, Reanimation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society of Cardiology (ESC) have created this consensus position paper to provide clear recommendations on the perioperative use of anti-platelet agents (specifically with semi-urgent and urgent surgery), strongly supporting a multidisciplinary approach to optimize the treatment of individual patients with coronary artery disease who need major cardiac and non-cardiac surgery. With planned surgery, drug eluting stents (DES) should not be used unless surgery can be delayed for ≥12 months after DES implantation. If surgery cannot be delayed, surgical revascularisation, bare-metal stents or pure balloon angioplasty should be considered. During ongoing antiplatelet therapy, elective surgery should be delayed for the recommended duration of treatment. In patients with semi-urgent surgery, the decision to prematurely stop one or both antiplatelet agents (at least 5 days pre-operatively) has to be taken after multidisciplinary consultation, evaluating the individual thrombotic and bleeding risk. Urgently needed surgery has to take place under full antiplatelet therapy despite the increased bleeding risk. A multidisciplinary approach for optimal antithrombotic and haemostatic patient management is thus mandatory.

The uncalibrated prothrombinase-induced clotting time test. Equally convenient but more precise than the aPTT for monitoring of unfractionated heparin.

The activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT's dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

[Chronic subdural hematoma - assessment and management]. / Chronisches Subduralhämatom - Beurteilung und Management.

Subdural hematomas (SDH) are associated with an increased morbidity and mortality and generally occur as chronic SDH among older patients. The most frequent signs and symptoms - like headache, alteration of consciousness, gait impairment and hemiparesis - are also prevalent among other diseases, which has to be taken into account in the differential diagnosis. In the case of symptomatic patients with focal neurological deficits, a surgical intervention should be considered, whereas in case of asymptomatic patients or patients with only slight headaches, also a conservative treatment with a clinical and radiological follow-up might be a possibility. Also after surgical intervention, the recurrence rate is between 5 and 33%. Therefore, all patients with chronic SDH depict, irrespective of the indication for an oral anticoagulation, a challenge for the treating physicians.

Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the SWIss Venous ThromboEmbolism Registry (SWIVTER).

BACKGROUND: Venous thromboembolism (VTE) prophylaxis remains underutilized, particularly in cancer patients. We explored clinical predictors of prophylaxis in hospitalized cancer patients before the onset of acute VTE. METHODS: In the SWiss Venous ThromboEmbolism Registry, 257 cancer patients (61 +/- 15 years) with acute VTE and prior hospitalization for acute medical illness or surgery within 30 days (91% were at high risk with Geneva VTE risk score > or =3) were enrolled. RESULTS: Overall, 153 (60%) patients received prophylaxis (49% pharmacological and 21% mechanical) before the onset of acute VTE. Outpatient status at the time of VTE diagnosis [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.18-0.53], ongoing chemotherapy (OR 0.51, 95% CI 0.31-0.85), and recent chemotherapy (OR 0.53, 95% CI 0.32-0.88) were univariately associated with the absence of VTE prophylaxis. In multivariate analysis, intensive care unit admission within 30 days (OR 7.02, 95% CI 2.38-20.64), prior deep vein thrombosis (OR 3.48, 95% CI 2.14-5.64), surgery within 30 days (OR 2.43, 95% CI 1.19-4.99), bed rest >3 days (OR 2.02, 95% CI 1.08-3.78), and outpatient status (OR 0.38, 95% CI 0.19-0.76) remained the only independent predictors of thromboprophylaxis. CONCLUSIONS: Although most hospitalized cancer patients were at high risk, 40% did not receive any prophylaxis before the onset of acute VTE. There is a need to improve thromboprophylaxis in cancer patients, particularly in the presence of recent or ongoing chemotherapy.

[Managing perioperative haemostasis]. / Perioperative Gerinnungsstörungen, perioperatives Gerinnungsmanagement.

Managing perioperative haemostasis starts with the diligently taken patient history. Unfortunately, classic global tests such as the PT and aPTT have no predictive value with regard to an acquired intra- or postoperative bleeding diathesis. However, new assays for preoperative risk stratification are in clinical development. An attribute of good perioperative haemostasis management is the early, multidisciplinary problem assessment. With a preoperatively existing anticoagulation or antiplatelet therapy, perioperative bridging therapy needs to be carefully planned as cardiovascular risk patients have an increased risk of morbidity and mortality when their current anticoagulative therapy is simply stopped. If a haemorrhagic diathesis is known, a specific therapy should be scheduled early preoperatively. When excessive intra- and postoperative bleeding occurs, point of care diagnostics can help to determine the underlying pathophysiology. A predefined validated algorithm reduces the need for blood products. To establish an evidence based approach for the use of blood components and other procoagulants in such a situation requires prospective clinical trials. The actual knowledge on the pathophysiology of such incidents (e. g. cross linking defects by use of colloids, dilutional effects of volume therapy, repeated use of FFP, of antifibrinolytics, frequency of unwanted effects) should also be considered.

[Fibrin monomer and factor XIII: a new concept for unexplained intraoperative coagulopathy]. / Fibrinmonomer und Faktor XIII: neues Konzept bei ungeklärter intraoperativer Blutungsneigung.

Unexplained intraoperative coagulopathies continue to be a diagnostic and therapeutic dilemma. The pathophysiology behind unexplained intraoperative coagulopathies is of great variety and complexity (preexisting coagulopathies, dilutional coagulopathy, interactions of medications etc.). We have shown in prospective studies that patients undergoing elective surgery who develop "unexplained" intraoperative coagulopathies have significantly less FXIII per unit thrombin available at any point in time (i.e. already preoperatively) than patients without such coagulopathies. The consequence is a significant loss of clot firmness associated with an increase in intraoperative blood loss. Thus, these patients have less cross-linking capacity to begin with, which explains their preoperatively increased fibrin monomer concentration. The association of increased preoperative fibrin monomer and increased intraoperative blood loss was prospectively evaluated and confirmed in a separate clinical study. It is important to note that the acquired or (compared to the amount of thrombin generated) relative F. XIII deficiency in situations with surgical stress shows early clinical relevance (even if only mild to moderate changes are present); this differs from the experiences with patients with inborn FXIII deficiency, where a pronounced deficiency must be present to have clinically significant spontaneous bleeding. Patients undergoing elective surgery, without clinically obvious coagulopathy but increased preoperative fibrin monomer concentration (as a marker of decreased crosslinking capacity) are at risk for increased intraoperative blood loss. This new concept helps to explain the pathophysiology behind unexplained intraoperative coagulopathies and thus allows for corresponding treatment strategies. Further clinical studies for early detection and interventions in patients with such coagulopathies are necessary.

[Treatment of bleeding due to anticoagulants]. / Behandlung der Blutung unter Antikoagulation.

The increased incidence in cardiovascular diseases has initiated research that finally led to improvements in prophylactic therapies that aim to prevent the occurrence of occlusive thromboses. Nowadays, the post interventional prophylaxis in the arterial system is mainly achieved by using antiplatelet drugs; in this setting, the combination of drugs with different mechanisms allow to achieve a maximum effect. This is important since patients with cardiovascular diseases often use multiple medications which by themselves can already induce a platelet dysfunction, increasing the potential for bleeding due to side effects. Prophylaxis for venous thromboembolism or in patients with heart valve replacements is still performed with coumarin derivatives in most instances. It is crucial to target an INR of 2.5 as close and as stable as possible, since INRs below 2.0 are associated with increased incidences of thromboses and those above 3.0 show an increased bleeding tendency. In cancer patients, prophylaxis of thromboembolism with low molecular weight heprin seems more efficient than with coumarin derivatives; this might be due to the fact that low molecular weight heparin not only seems to have an antithrombotic but also an anti-tumor effect. From a pharmacokinetic point of view, renal insufficiency is always to be considered and looked for in (especially elderly) patients undergoing LMWH therapy in order to avoid cumulation. In patients suffering from a thrombotic event during heparin therapy or in patients with a significant drop in platelet count during heparin therapy, heparin-induced thrombocytopenia should be considered as a differential diagnosis; in his case, vitally important diagnostic or therapeutic steps might have to follow. This review discusses the most frequent indications for anticoagulant therapy, potential side effects of this therapy and the management of these side effects.

[Paroxysmal nocturnal hemoglobinuria--consequences of a missing anchor]. / Paroxysmale nächtliche Hämoglobinurie--Folgen eines fehlenden Ankers.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder characterized by the clonal expansion and differentiation of a multi-potent hematopoietic stem cell carrying a somatic mutation in the X-linked PIG-A gene. As a consequence of this mutation, glycosylphosphatidylinositol (GPI)-anchored proteins are lacking on the surface of blood cells derived from the mutated stem cell. This may result clinically in hemolytic anemia and a tendency for venous thrombosis and serious infection. Bone marrow failure is a frequently observed phenomenon associated with PNH. Reliable diagnosis of PNH is currently best achieved by flow cytometric analysis of GPI-anchored proteins on peripheral blood cells. Both the clinically relevant size of the PNH clone and type of GPI deficiency (complete or partial) can be reproducibly determined by this method. Most patients will benefit from supportive measures, albeit that allogeneic hematopoietic stem cell transplantation is currently considered the only potentially curative therapy. The development of a new therapeutic monoclonal antibody that reduces intravascular hemolysis and progress in diagnostic flow cytometry using a new GPI-specific marker may provide further benefit for PNH patients in the future.

An audit of red cell and blood product use after the institution of thromboelastometry in a cardiac intensive care unit.

Cardiac surgery is estimated to use 20% of the UK blood supply. However, there has been much interest recently in decreasing red cell and blood product use not only to ease strain on blood stocks or avoid potential transmission of infection but also to decrease post-operative transfusion-related complications. Coagulopathies are not uncommon in cardiac surgical patients, but the time lapse for reporting conventional laboratory results has been highlighted as an obstacle to the appropriate use of blood products. Accordingly, much interest has arisen in rapid near-patient testing of coagulation and, in January 2002, a thromboelastometer (ROTEM, Pentapharm, Germany) was purchased for our unit. This audit sought to assess its impact by retrospective analysis of 990 sequential patients' demographic data and transfusion details covering 6 months prior to its introduction and 6 months after. In the 6 months prior to its introduction, red cells were used in 60% of patients and fresh frozen plasma (FFP) and platelets used in 17 and 16% of patients, respectively. In the following 6 months, red cell use had fallen to 53% and FFP and platelets to 12 and 11%, respectively (P < 0.05). Introduction of thromboelastometry has significantly decreased our use of red cells and blood products.