Correlation of factor XIII subunit A with factor XIII activity in a population of parturient women.

BACKGROUND: The role of factor XIII in acute bleeding situations is gaining more and more importance. It has previously been shown that prepartum factor XIII activity has a significant impact on postpartum blood loss. Whether factor XIII antigen behaves in a similar manner is unknown. As postpartum hemorrhage is one of the leading causes of maternal morbidity and mortality worldwide and factor XIII antigen determination might be available more readily in some centers as compared to factor XIII activity, this is an important question to answer, especially in the emergency situation of a postpartum hemorrhage. OBJECTIVE: To assess the correlation of prepartum factor XIII antigen with prepartum factor XIII activity and to evaluate the correlation between prepartum factor XIII antigen on measured postpartum blood loss. METHODS: This is a secondary analysis of a prospective cohort study which analyzed the impact of prepartum blood coagulation factor XIII activity on postpartum blood loss in 1300 women at the University Hospital Zurich, Switzerland between October 2015 and November 2016 ("PPH-1300 study"). Blood loss was quantified using a previously validated technique. The association of factor XIII activity and factor XIII antigen was assessed by means of a Spearman rank correlation and differences were displayed using Bland-Altman plot and Passing-Bablok regression. The effect of the prepartum factor XIII antigen on blood loss was estimated by continuous outcome logistic regression. RESULTS: Prepartum factor XIII activity significantly correlated with prepartum factor XIII antigen (Spearman rank correlation coefficient for prepartum values 0.89, p < 0.001 and postpartum values 0.902, p < 0.001). Elevated values of prepartum factor XIII antigen showed a trend toward lower measured postpartum blood loss. CONCLUSION: The correlation of factor XIII activity with factor XIII antigen (subunit A) in a large real-world sample as well as an association of prepartum factor XIII antigen and postpartum blood loss is observed. Factor XIII antigen determination, a highly automatable test, could be useful in emergency situations such as a PPH (as well as other bleeding situations) if the determination of factor XIII activity is not possible. To evaluate whether FXIII replenishment reduces blood loss is the focus of ongoing studies.

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.

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.

[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.

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.

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.

[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.

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.

[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.

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.

Short activated partial thromboplastin times are related to increased thrombin generation and an increased risk for thromboembolism.

This prospective study was designed to investigate whether patients with short activated partial thromboplastin times (aPTTs) have increased thrombin generation and are at increased risk for thromboembolism. During a 4-month period, routine coagulation specimens were screened for the presence of a short or normal aPTT, and, accordingly, 250 specimens were collected. Prothrombin fragment F1 + 2 (F1 + 2) was measured to evaluate thrombin activation, and a second aPTT was performed with a different reagent. Diagnoses were obtained from medical records after conclusion of sample collection. Five to 9 months later, patients were questioned on thromboembolic events during the previous 18 months by questionnaire and telephone interview. F1 + 2 and the incidence of venous thromboses were elevated significantly in the short aPTT group. Unexpectedly, patients with acute bleeding had short aPTTs, but 36% of these also had thromboembolic events during the 18 months proximal to blood collection. These findings were confirmed with the second aPTT reagent. Patients with short aPTTs have increased thrombin generation and are at increased risk for thromboembolism, mainly venous thromboses, despite the fact that a short aPTT can occur in the acute setting of bleeding.

Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia.

Current guidelines suggest that anaemia due to erythropoietin deficiency almost exclusively occurs with creatinine concentrations of at least 177 micromol/l or above. The aim of this prospective case control pilot study was to evaluate whether borderline renal function or mild renal dysfunction with creatinine concentrations well below 177 micromol/l is sufficient to induce inadequate erythropoietin secretion. Patients referred for work-up of otherwise unexplained anaemia with mildly abnormal creatinine concentrations (104-129 micromol/l; study group: eight patients) and patients referred for work-up or therapy of other diseases who also presented with anaemia but normal creatinine levels (<100 micromol/l; control group: nine patients matched for gender, age and degree of anaemia) were included. All but two patients in the control group had bone marrow biopsies to exclude other pathologies. Mild renal dysfunction (as evidenced by creatinine concentrations between 100 and 140 micromol/l, median concentration 112 micromol/l) was found to be sufficient to induce inadequate erythropoietin secretion. The physiologic hemoglobin-dependent erythropoietin regulation demonstrated in the control group was abolished in the study group. Patients with mild renal dysfunction and unexplained anaemia should be investigated for erythropoietin concentration. If the erythropoietin concentration is found to be inadequate for the degree of anaemia, substitution therapy should be considered.

Multicentre evaluation of a new point-of-care test for the quantitative determination of D-dimer.

Imprecision studies, interference testing and multicentre method comparisons using patient samples were carried out with of a new point-of-care test for D-dimer (CARDIAC D-Dimer). The CV of the within-series and the day-to-day imprecision with blood samples and control materials were between 7% and 13%. Compared with Tina-quant D-Dimer, CARDIAC D-Dimer showed a good correlation and accuracy (n=353; r=0.91; y=1.06x-0.03), compared with STA LIATEST D-Dimer some poorer accuracy (n=304; r=0.91; y=1.12x-0.03). No interference was detected for different hematocrit values (16% to 51%) and in investigations with hemoglobin (up to 0.13 mmol/l), biotin (up to 30 microg/l), bilirubin (up to 340 micromol/l), intralipid (up to 31.1 mmol/l) and rheumatic factor (up to 79 IU/ml). Overdosing or underdosing by 10 microl did not affect the test result. The diagnostic sensitivity of CARDIAC D-Dimer for the detection of acute venous thromboembolic diseases was 100% in our study. With CARDIAC D-Dimer reliable quantitative D-dimer results can be easily obtained. Because of the good analytical and clinical agreement with Tina-quant D-Dimer, it should be suitable for ruling out venous thromboembolic diseases.

Day-to-day titration to initiate transdermal fentanyl in patients with cancer pain: short- and long-term experiences in a prospective study of 39 patients.

Initial dose finding in patients with cancer pain who are started on TTS fentanyl (Duragesic, TTS-F) is often unsatisfactory with currently recommended doses and intervals. Acknowledging that studies reveal a "psuedo steady state" 15 to 20 hr after application of TTS-F, we prospectively investigated an increased initial dose and day-to-day titration of TTS-F in 39 (evaluable) patients with uncontrolled cancer pain. Significant pain reduction (P = 0.001) was seen after 24 hr, and satisfactory analgesia was achieved within 48 h and maintained for the rest of the study. Significant increases in TTS-F were necessary during weeks 1 through 4 to maintain pain control. Forty-nine percent of the patients needed one or more early dose increases. Only one patient had side effects partially due to the specific properties of the TTS. Other side effects seemed to be less common compared with usual morphine treatment. TTS-F can be titrated effectively and safely on a day-to-day basis with an increased initial dose and adequate patient monitoring, thus avoiding more complicated approaches. TTS-F seemed to induce less constipation than might be expected.

Veno-occlusive disease of the liver after bone marrow transplantation: is hypercoagulability really part of the problem?

Patients undergoing bone marrow transplantation (BMT) experience changes in various proteins with important functions in the coagulation and fibrinolysis system. Veno-occlusive disease (VOD) of the liver is a leading cause of non-relapse mortality after BMT. Because of the concurrent occurrence of changes in the coagulation and fibrinolysis system and development of VOD, most authors assume a causative relationship between these two observations, but the results leading to this conclusion are not unequivocal. Data currently available do not allow the conclusion that coagulation activation and local excess fibrin generation are key factors in the pathogenesis of VOD. One approach to deciding whether there is, in fact, excessive local fibrin generation during the development of VOD might be the monitoring of high risk patients with tools that enable differentiation of local and systemic hypercoagulability (e.g. anti-D-dimer immunoscintigraphy). Screening of patients at risk for VOD with special coagulation parameters pretransplant does not seem appropriate at present. However, markedly increased plasminogen activator inhibitor-1 levels (from baseline) seem to be appropriate tool to confirm the diagnosis of VOD when clinical suspicion exists. More research is needed in order to advance our understanding of the disease and to improve outcomes in both the prophylaxis and treatment of VOD.

Rapid D-dimer testing and pre-test clinical probability in the exclusion of deep venous thrombosis in symptomatic outpatients.

We assessed the performance of three rapid D-dimer tests (Auto Dimertest, VIDAS and Tinaquant) in combination with a pretest clinical probability model for deep venous thrombosis (DVT) in 106 consecutive outpatients with suspected DVT. Contrast venography or colour-coded duplex ultrasonography demonstrated the presence of DVT in 47 patients (14 distal DVT and 33 proximal DVT). First, we assessed the accuracy indices for different cut-off levels of the rapid D-dimer tests. Sensitivity was found to be 97.9-100%, negative predictive value (NPV) was 96.3-100%, and the exclusion rate was 24.5-31.1%. Next, the patients were grouped according to the pre-test clinical probability model in categories with low, moderate or high probability. In patients with a low pre-test probability, DVT would have been directly ruled out and the patients would not have undergone further investigations. In patients with a moderate probability, D-dimer testing and, in the case of a positive result, objective testing would have been performed and, in the case of a negative result, they would have been ruled out of having DVT. Patients with high probability would directly have undergone objective tests for DVT. The combination with the pre-test clinical probability model improved the exclusion rate (43.5-44.6%), whereas sensitivity (97.5-100%) and NPV (97.6-100%) remained roughly unchanged. The combination of rapid D-dimer tests with a pre-test clinical probability model may help to reduce unnecessary work-up in patients with suspected DVT.

Degradation of three related bis(pyridinium)aldoximes in aqueous solutions at high concentrations: examples of unexpectedly rapid amide group hydrolysis.

The principal initial degradation products of two bis(pyridinium)aldoxime organophosphate-inhibited acetylcholinesterase reactivators, 1 (HI-6) and 3 (HS-6), in concentrated nonbuffered aqueous solutions approximating potential therapeutic dosage concentrations were found to be the carboxylic acid derivatives 2 and 4 formed from the hydrolysis of the amide functional group. Compounds 2 and 4 were prepared by heating 1 and 3 in the presence of high concentrations of hydroxylamine hydrochloride and characterized by 1H and 13C NMR, IR, and UV analyses. Estimates of the rates of hydrolysis of the amide groups in 1 and 3 and in model compounds 5, 7, and 8 under similar conditions were determined. The unexpectedly rapid hydrolysis of the amide groups in 1 and 3 was attributed to both the hydrogen ion catalysis of the concentrated aqueous solutions of the unusually acidic bis(pyridinium)aldoximes 1 and 3 and general acid catalysis by the aldoxime group.