Hamostaseologie最新文献

We report the case of a 59-year-old multiple myeloma patient in whom an anti-human thrombin IgA antibody led to prolonged in vitro coagulation times, suggesting inhibitors to all intrinsic coagulation factors in the absence of spontaneous bleeding.Routine and extensive special coagulation tests, in vivo bleeding time, and specific antibody testing were performed.Although the patient did not suffer from spontaneous bleeding and had a normal in vivo bleeding time, the anti-human thrombin IgA autoantibody affected all coagulation assays involving human thrombin in vitro, mimicking inhibitors to intrinsic coagulation factors. As the IgA paraprotein and the IgA antibody virtually disappeared after autologous stem cell transplantation, the coagulation tests also largely normalized.Antibodies to human thrombin may interfere with all coagulation assays involving thrombin, imitating a severe coagulopathy. However, in vivo they do not necessarily lead to strongly increased bleeding tendency. Complex and ambiguous coagulation abnormalities should be evaluated and treated in an interdisciplinary setting, including a highly specialized coagulation laboratory, from the beginning.

The Timed Up and Go (TUG) test is frequently used to assess patients' functional mobility. However, its psychometric characteristics in patients with haemophilia (PwH) are unknown. This study's primary aim was to determine the validity, reliability, standard error of measurement (SEM), and minimal detectable change (MDC) of the TUG in PwH. The secondary aim was to determine predictors for the TUG time.A total of 40 PwH were included. Test-retest reliability was assessed by the same rater at two time points and inter-rater reliability was assessed by two raters. Construct validity was tested via correlation analyses between the TUG and the haemophilia joint health score (HJHS), the short physical performance battery (SPPB), the HEP-Test-questionnaire, and the Haemophilia Activity List (HAL). SEM and MDC were calculated. Multiple linear regression analyses with several patient-specific predictors were performed.Test-retest and inter-rater reliability analyses revealed excellent ICCs of 0.990 (95% CI: 0.972-0.995) and 0.929 (95% CI: 0.870-0.962), respectively. The SEM and MDC of the TUG were 0.34 and 1.52 seconds, respectively. Large correlations (r > 0.5) were observed between the TUG and the HJHS, SPPB, HEP-Test-Q, and HAL. Regression analysis revealed the HJHS as the sole significant predictor, with the full model explaining 37.0% of the variance in TUG performance.In PwH, the TUG is a reliable test possessing an excellent test-retest and inter-rater reliability, while showing a high validity. TUG times can mainly be predicted by HJHS. The TUG can therefore be considered a suitable tool to evaluate mobility in adult PwH.

Emicizumab is a bispecific monoclonal antibody that mimics the cofactor function of activated factor VIII (FVIIIa). It is approved for routine prophylaxis in patients with severe or moderate congenital hemophilia A (HA), both with and without FVIII inhibitors, and is increasingly used as a first-line treatment in acquired HA (AHA). Owing to its predictable pharmacokinetic profile, emicizumab monitoring is generally limited to cases with suspected reduced efficacy, such as due to poor adherence or the development of anti-drug antibodies (ADAs). However, emicizumab interferes with standard clotting assays, particularly by shortening activated partial thromboplastin times (APTT). To address this, modified FVIII one-stage clotting assays (mOSA), which use higher sample pre-dilution and emicizumab-specific calibration, are commonly employed to estimate plasma levels, although other assay formats like emicizumab-calibrated chromogenic substrate assays based on human factors or liquid chromatography tandem mass spectrometry are also available. Additionally, global assays such as in vitro thrombin generation testing are being explored to better reflect clinical hemostatic efficacy. This review summarizes current knowledge on assay interferences caused by emicizumab, challenges in functional measurement of plasma levels, and strategies to ensure reliable laboratory assessment. We also discuss the relevance and methods for ADA detection and provide an overview of current and emerging strategies for thrombin generation measurement as a global indicator of treatment effectiveness.

Inherited deficiencies of coagulation factors are rare and exhibit variable associations with severe bleeding phenotypes. Although conventional hemostatic assays serve as useful screening tools, they often fail to accurately predict clinical bleeding severity. Disease management is further complicated by poor correlation between residual factor levels and the overall symptom severity in affected patients and limited clinical experience. In this review, we evaluate the utility of global coagulation tests, such as the thrombin generation assay, plasmin generation assay (PGA), and rotational thromboelastometry (ROTEM), in assessing the severity of rare coagulation factor deficiencies and their clinical manifestations.Overall, thrombin generation, plasmin generation, and ROTEM were impaired in most rare coagulation factor deficiencies. Furthermore, significantly reduced coagulation factor activity and consequently decreased thrombin generation potential correlated with the clinical bleeding severity in deficiencies of prothrombin and factors V, VII, X, and XI. PGA was significantly impaired in fibrinogen and prothrombin deficiency and variably reduced in FV- and FX-deficient patients, but did not correlate with the presence or severity of bleeding manifestations. Lastly, ROTEM parameters were able to discriminate between asymptomatic FX-, FXI-, and fibrinogen-deficient patients and those with a history of bleeding.Although these studies are mostly limited to small sample sizes and prospective data are lacking, the available literature suggests that TGA, PGA, and ROTEM may be useful in stratifying patients according to their overall bleeding severity, as well as their risk of major bleeding complications in some of the rare coagulation factor deficiencies.

Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by low FXI levels, resulting in bleeding after trauma or surgery. Genetic variants affecting FXI structure and function often result in bleeding diatheses.This study aimed to estimate the variant detection rate (VDR), and assess its correlation with FXI activity (FXI:C) in a large cohort of FXI-deficient patients.Genetic defects in the F11 gene were analyzed in 316 index patients (IPs) using Sanger or next-generation sequencing. Multiplex ligation-dependent probe amplification or copy number variation analysis was used to detect duplications and deletions.Genetic defects were identified in 249 IPs (VDR of 79%). A strong negative correlation (Pearson coefficient: -0.891) was found between FXI:C levels and VDRs: higher FXI:C levels corresponded to a lower likelihood of detecting genetic alterations, with a significant decline in VDR beyond 60 IU/dL. A total of 286 genetic variants were identified in F11 gene: 56% missense, 24% nonsense, 11% small deletions/insertions, and 6% splice-site variants. Large deletions were rare (3%). A total of 48 novel variants were detected. Ashkenazi Jewish founder variants were the most frequent (14.3%). Variants p.Gln134Ter, p.Ile215_Asp216del, and p.Glu315Lys (27% of cases) were recurrent. In four cases, large deletions extended beyond the F11 gene and included the neighboring KLKB1 gene, encoding prekallikrein.This study demonstrated a significant negative correlation between FXI:C levels and VDRs, underscoring the importance of genetic testing. Findings included combined deficiencies in FXI and prekallikrein due to large deletions affecting both F11 and KLKB genes.