Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: A prospective cohort study

Abstract

Introduction: Diagnostic evaluation of patients with a bleeding tendency remains challenging, as no disorder is identified in approximately 50% of patients. An impaired interplay of several haemostatic factors might explain bleeding phenotype in these patients. Objective: To investigate whether global haemostasis assays are able to identify haemostatic abnormalities in patients with a bleeding tendency unexplained by current diagnostic laboratory tests. Materials and methods: Patients of ≥12 years with a bleeding tendency were included from a tertiary outpatient clinic. Bleeding phenotype was assessed with the ISTH-BAT. Patients were classified as having bleeding of unknown cause (BUC) or a mild bleeding disorder (MBD) based on abnormalities assessed by routine haemostatic tests. Global haemostasis tests (rotational thromboelastometry (ROTEM), thrombin generation test (TG) and plasma clot lysis time (CLT)) were measured in all patients. The results were compared with 76 controls. Results: One hundred and eighty-one patients were included, and 60% (109/181) was classified as having BUC. BUC patients demonstrated a significantly prolonged lag time in TG (median 7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5 minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM variables were found. Patients with MBD showed an impaired thrombin generation with a significantly decreased ETP (median 1024 nmol/L*min, IQR 776-1355) and peak height (median 95 nmol/L, IQR 76-138), compared to BUC patients and controls. Conclusion: No major differences were found in ROTEM and TG variables in BUC patients compared to controls. BUC patients did have a significantly prolonged clot lysis time. The underlying mechanism for this finding is unknown. K E Y W O R D S bleeding, bleeding of unknown cause, fibrinolysis, haemostasis, mild bleeding disorder, thrombin generation, thromboelastometry | e107 VEEN Et al.

FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects

“…Based on the retrospective nature of this study, this study was not subject to the Medical Research Involving Human Subjects Act and a waiver for informed consent was granted for the patient group (MEC-2020-0507). As part of the Crescendo study (Clinical Relevance and Significance of New Diagnostic Options in patients with Unexplained Bleeding) healthy individuals were recruited between July 2016 and March 2018 among employees and students of the Erasmus MC University Medical Center [9]. The Crescendo study was subject to the Medical Research Involving Human Subjects Act and approved by the Medical Ethics Committee of the Erasmus University Medical Center Rotterdam (MEC-2016-218).…”

Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management

“…Veen et al (2020) prospectively investigated 121 BUC/UBD patients with ROTEM (EXTEM, INTEM and FIBTEM). Thromboelastometry was within the reference range for patients with BUC 30 . Another study in 217 consecutive patients, investigated for a mild bleeding disorder, showed that ROTEM (EXTEM, INTEM and FIBTEM) was not associated with abnormal results compared to those without a mild bleeding disorder, with results mostly in the reference range, although only 4 patients had BUC/UBD in the cohort 1 …”

“…29 However, the opposite result was found in a study by Veen et al (2000), where clot lysis time was significantly longer in BUC/UBD patients compared to healthy controls. 30 shown to be a risk factor for bleeding, with a level of < 1.0 U/ml −1 found in 23% of a series of 586 consecutive patients referred for investigation of a bleeding tendency compared to 13% of controls and 10% of bloods donors (odds ratio and 95% CI, 2.04; 1.11-3.77 and 2.75; 1.39-5.42, respectively). 44 A follow-up study confirmed higher levels of plasmin-antiplasmin complexes in patients with PAI-1 < 1 U/ ml versus those with levels > 1 U/ml suggesting increased in vivo fibrinolysis in the presence of low PAI-1.…”

“…Recurrent, spontaneous, painful ecchymosis, frequently preceded by a prodrome of pain or itching of the skin Pathology unclear but lesions reproduced when autologous red cells injected intra-dermally [69,70] Exercise induced purpura Purpuric patches on the lower limbs after exercise 20,[26][27][28][29][30] Tissue factor pathway inhibitor (TFPI) has been investigated for its role in bleeding in a study of 13 patients (12 female) who had been diagnosed with BUC/UBD and that had either decreased endogenous thrombin potential or increased lag time on thrombin generation with either high-dose tissue factor (5 pM) or low-dose (1.5 pM)…”

“…There have been several studies which have compared thrombin generation (in platelet poor plasma) in BUC/UBD patients. These are summarized in supplementary Table 1 but in summary, studies have not shown reproducible abnormalities within the BUC/UBD patients and no diagnostic patterns from these studies have emerged; however, studies have been heterogenous in methodology and patients included so they are difficult to compare 20,26‐30 …”