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Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therapy

Summary Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therapy.

Background: Thromboelastometry is a whole blood assay performed to evaluate the viscoelastic properties during blood clot formation and lysis. Rotation thromboelastography (ROTEM((R)), Pentapharm GmbH, Munich, Germany) has overcome some of the limitations of classic thromboelastography. So far, no clinical validation on reproducibility (inter- and intra-assay variability) and sample stability over time has been published. Methods: To evaluate the pre-analytic aspects, sample stability over time was assessed in 48 patients in eight age groups. Citrated blood was stored at room temperature. Tests measured every 30min from T 0min up to T 120min on two ROTEM((R)) devices were INTEM (ellagic acid activated intrinsic pathway), EXTEM (tissue factor-triggered extrinsic pathway) and FIBTEM (with platelet inhibitor (cytochalasin D) evaluating the contribution of fibrinogen to clot formation). Precision by intra- and inter-assay variability was evaluated at two points of time in 10 volunteers. Finally, reference intervals and effect of age and sex were evaluated. Results: Blood was stable over 120min and no significant differences in ROTEM((R)) results were found. Maximum clot firmness measurements had a coefficient of variation of <3% for EXTEM, <5% for INTEM and <6% for FIBTEM. For clot formation time, the coefficient of variation was <4% for EXTEM and <3% for INTEM. Coefficient of variation for angle alpha was <3% for EXTEM and <6% for INTEM. The coefficient of variation for clotting time was <15% for both EXTEM and INTEM. Small but significant differences between ROTEM((R)) devices were found for maximum clot firmness in FIBTEM and INTEM as well as clot formation time and alpha angle in INTEM. Conclusions: ROTEM((R)) yields stable results over 120min with a minimal variability on the same ROTEM((R)) device. However, small but significant differences between ROTEM((R)) devices were observed. Analysis should be performed on the same ROTEM((R)) device if small differences are

Factor XIII (F XIII) is an essential parameter for final clot stability. The purpose of this study was to determine the impact of the addition of factor (F)XIII on clot stability as assessed by Rotation Thromboelastometry (ROTEM(R)). In 90 intensive care patients ROTEM(R) measurements were performed after in vitro addition of F XIII 0.32 IU, 0.63 IU, 1.25 IU and compared to diluent controls (DC; aqua injectabile) resulting in approximate F XIII concentrations of 150, 300 and 600%. Baseline measurements without any additions were also performed. The following ROTEM(R) parameters were measured in FIBTEM and EXTEM tests: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis (ML), maximum clot elasticity (MCE) and a-angle (aA). Additionally, laboratory values for FXIII, fibrinogen (FBG), platelets and haematocrit were contemporaneously determined. In the perioperative patient population mean FBG concentration was elevated at 5.2 g/l and mean FXIII concentration was low at 62%. The addition of FXIII led to a FBG concentration-dependent increase in MCF both in FIBTEM and EXTEM. Mean increases in MCF (FXIII vs. DC) of approximately 7 mm and 6 mm were observed in FIBTEM and EXTEM, respectively. F XIII addition also led to decreased CFT, increased aA, and reduced ML in FIBTEM and EXTEM. In vitro supplementation of FXIII to supraphysiologic levels increases maximum clot firmness, accelerates clot formation and increases clot stability in EXTEM and FIBTEM as assayed by ROTEM(R) in perioperative patients with high fibrinogen and low FXIII levels.

Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54+/-0.9427%, n=5, P<0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0%+/-4.031, n=9, P=0.0004 versus control) as well as a decreased maximal aggregation (-6.388+/-2.212%, n=6, P=0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

BACKGROUND: Less is known about the influence of hematocrit detection methodology on transfusion triggers. Therefore, the aim of the present study was to compare two different hematocrit-assessing methods. In a total of 50 critically ill patients hematocrit was analyzed using (1) blood gas analyzer (ABLflex 800) and (2) the central laboratory method (ADVIA(R) 2120) and compared. FINDINGS: Bland-Altman analysis for repeated measurements showed a good correlation with a bias of +1.39% and 2 SD of +/- 3.12%. The 24%-hematocrit-group showed a correlation of r2 = 0.87. With a kappa of 0.56, 22.7% of the cases would have been transfused differently. In the-28%-hematocrit group with a similar correlation (r2 = 0.8) and a kappa of 0.58, 21% of the cases would have been transfused differently. CONCLUSIONS: Despite a good agreement between the two methods used to determine hematocrit in clinical routine, the calculated difference of 1.4% might substantially influence transfusion triggers depending on the employed method.

AIM: This pilot study seeks to determine whether contact system activation (CSA) occurs in human sepsis patients and to characterise blood levels of the 47kD light chain of high-molecular weight kininogen (47kD HK). METHODS: Six consecutive patients with clinical suspicion of sepsis were evaluated on days 1, 2, 3 and 6-8 for 47kD HK blood levels expressed in U/ml of whole blood and as percent of total HK. 47kD HK was measured in whole blood by quantitative immunoblot analysis. RESULTS: On study day 1 or 2, analysis of 47kD HK in U/ml of whole blood identified CSA in 3/6 patients.When 47kD HK levels were expressed as percent of total HK, 4/6 patients were identified with CSA before day 3. The degree of CSA as assayed by the presence of 47kD HK correlated with the severity of the systemic inflammatory syndrome (SIRS), i.e. mean CSA increased progressively from basal levels in healthy controls (0.08 U/ml or 10.4%) to patients without SIRS (0.10 U/ml or 15.1%), to patients with sepsis (0.12 U/ml or 15.0%), and finally to patients in a combined category of severe sepsis and septic shock (0.13 U/ml or 17.4%). CONCLUSION: CSA, defined by increased 47kD HK, occurred early on in the course of sepsis in a subset of sepsis patients. 47kD HK levels, an indicator of bradykinin release, correlated with sepsis severity. Future larger studies will need to evaluate the role of 47kD HK as a biomarker for both prognosis and treatment response in human sepsis.

The clinical relevance of heparin-induced antibodies (HIA) in the absence of thrombocytopenia remains to be defined. The aims of this study were (i) to determine the prevalence of HIA in patients treated by dialysis, (ii) to determine the prevalence of thrombocytopenia and heparin-induced thrombocytopenia (HIT), and (iii) to test whether HIA are associated with adverse outcomes. Sera from 740 patients treated by hemodialysis (HD, n=596) and peritoneal dialysis (PD, n=144) were tested for HIA (IgG, IgA or IgM) by masked investigators at approximately six months after enrolment in the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study. We assessed, with time-to-event Cox proportional hazards models, whether the presence of HIA predicted any of four clinical outcomes: arterial cardiovascular events, venous thromboembolism, vascular access occlusion and mortality. HIA prevalence was 10.3% overall. HIA positivity did not predict development of thrombocytopenia or any of the four clinical outcomes over a mean follow-up of 3.6 years, with hazard ratios for arterial cardiovascular events of 0.98 (95% confidence interval 0.70-1.37), venous thromboembolism 1.39 (0.17-11.5), vascular access occlusion 0.82 (0.40-1.71), and mortality 1.18 (0.85-1.64). Chronic intermittent heparin exposure was associated with a high seroprevalence of HIA. In dialysis patients these antibodies were not an independent risk factor for cardiovascular events and mortality. Our data do not suggest that dialysis patients should be monitored for HIA antibodies in the absence of thrombocytopenia.

QUESTION UNDER STUDY: In most countries hypersensitivity to vitamin K antagonists (VKA) is considered to be a rare congenital bleeding diathesis. It occurs in patients with FIX propeptide mutations at locus -10. We present a Swiss family with two patients who suffered major bleedings under oral anticoagulant treatment in the presence of therapeutic or subtherapeutic INR levels and abnormally prolonged aPTT. In both patients a mutation in the propeptide of FIX at locus -10 with substitution of alanine by threonine (Ala-10Thr) was found. In one patient FIX clotting activity was found to be severely reduced (2%). The observed bleeding tendency is related to this--compared to the other vitamin K dependent factors (FII, FVII, FX)--excessively and disproportionately low level of FIX. Three generations of this family were tested for propeptide mutations, which are transmitted in an X-chromosomal recessive mode of inheritance. Apart from the two symptomatic male patients we found another male with the mutation who has not been exposed to VKA, six female carriers and four potential male carriers in the fourth generation who have not been tested. A founder effect for this mutation has been previously described for cases in Switzerland and Germany. CONCLUSION: FIX propeptide mutation-associated hypersensitivity to VKA is a rare occurrence in Switzerland. The severity of associated bleeding complications and the reversible nature of the bleeding diathesis may nonetheless warrant increased awareness on the part of primary care physicians in Switzerland.

Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therapy