Thrombin‐generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause

Abstract

BackgroundIn a large proportion of patients with a mild to moderate bleeding tendency no diagnosis can be established (bleeding of unknown cause, BUC).ObjectivesTo investigate possible dysfunctions in thrombin generation and plasma clot formation and lysis in patients with BUC from the Vienna Bleeding Biobank (VIBB).Patients and MethodsThrombin generation and plasma clot properties of 382 BUC patients were compared to those of 100 healthy controls and 16 patients with factor VIII (FVIII) activity ≤50%.ResultsThrombin generation was significantly impaired in BUC patients compared to healthy controls, exhibiting a prolonged lag time and time to peak and decreased maximum thrombin generation, velocity index, and area under the curve (AUC). The assessment of clot formation and lysis in BUC patients revealed a lower clot formation rate (Vmax), resulting in a longer TTP, increased absorbance (ΔAbs), and a shorter clot lysis time (CLT) than in healthy controls. Comparing patients with FVIII activity ≤ 50% to those with BUC, parameters of thrombin generation and clot formation and lysis were either stronger or comparably impaired. Bleeding severity did not correlate with parameters of thrombin generation, clot formation, or clot lysis.ConclusionPatients with BUC have an impaired hemostatic capacity reflected by a lower thrombin‐generation potential, a lower clot formation rate, increased clot turbidity, and shorter clot lysis time, which might contribute to their increased bleeding tendency. Assays monitoring these parameters can alert physicians of hemostatic impairment and should be considered in situations where traditional hemostatic lab tests fail to reveal the clinical bleeding tendency.

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

“…In two other studies with relatively large patient numbers, TG was unable to discern a difference between patients with UBD and controls . Recently, the VBB has identified TG abnormalities including prolonged lag time, time to peak, decreased maximum TG, velocity index and area under the curve but these did not correlate with bleeding severity . Routinely, we cannot recommend TG for routine use but we propose it may be of use in a research setting to further investigate these patients.…”

“…34,35 Recently, the VBB has identified TG abnormalities including prolonged lag time, time to peak, decreased maximum TG, velocity index and area under the curve but these did not correlate with bleeding severity. 36 Routinely, we cannot recommend TG for routine use but we propose it may be of use in a research setting to further investigate these patients. A limitation is that the tests were done over a long period of time with some changes in our laboratory protocols, reagents, equipment and reference ranges.…”

Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity

“…Recently, the Vienna Bleeding Biobank described abnormal thrombin generation in patients with bleeding of unknown cause, including an increased lag time and decreased area under the curve. 24 It is known that abnormalities in tissue factor pathway inhibitor, thrombomodulin and fibrinogen-γ (a fibrinogen isoform that can effect thrombin generation) can cause abnormal thrombin generation profiles. [11][12][13][14]25,26 Our data provides in-vitro evidence that blocking TFPI inhibition can partially correct thrombin generation; however, we have not provided definitive proof; this is the cause of the bleeding disorder.…”

“…In addition, thrombin generation is not likely to be abnormal in all patients with UBD as many may have vascular/collagen, platelet or fibrinolytic defects which thrombin generation would not show. Recently, the Vienna Bleeding Biobank described abnormal thrombin generation in patients with bleeding of unknown cause, including an increased lag time and decreased area under the curve . It is known that abnormalities in tissue factor pathway inhibitor, thrombomodulin and fibrinogen‐γ (a fibrinogen isoform that can effect thrombin generation) can cause abnormal thrombin generation profiles .…”

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

“…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)…”