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

Abstract

Introduction There is an unmet need to characterize the diagnosis and management of patients with an unclassified bleeding disorder (UBD). Methods Retrospective review of registered patients with UBD at our centre. Assessment including rotational thromboelastometry (ROTEM) and thrombin generation (TG) were used. Results A total of 124 patients were identified; 91% female. Mean age of presentation was 38.3 years. Mean bleeding score was 8.8 (standard deviation [SD] 3.8); 6.6 in men (SD 1.4) and 9.7 in women (SD 3.3), which was significantly different (P < .05). In women, after deduction of scores for menorrhagia and postpartum haemorrhage, the mean score was 6.4 which was not significantly different to the male score (P = .11). Twenty‐three percent of patients have been transfused, 61% women had treatment for menorrhagia and 17% for epistaxis. TxA and desmopressin were effective at preventing bleeding in 69 procedures and 13 deliveries. TG revealed 26% patients with a long lag time and 19% with a decreased endogenous thrombin potential but no diagnostic pattern was seen. ROTEM (NATEM) was unable to characterize patients; 9% had a prolonged clot time or maximum lysis. ThromboGenomics was normal in 45 tested patients. Conclusions We provide data which shows the bleeding score is biased towards gynaecological bleeding but which remains elevated even when the bleeding score is deducted. Tranexamic acid and desmopressin are effective as haemostatic prophylaxis but there is an urgent need for clinical trials. In conclusion, we describe the use of the bleeding score in these patients and phenotype, diagnosis (including ThromboGenomic testing) and management with practice recommendations.

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

“…36 There is an unmet need for therapeutic advances in UBD, with only two series describing the use of tranexamic acid and desmopressin to manage haemostatic challenges. 20,37 In summary, we describe patients with UBD and abnormalities in physiological coagulation inhibitors including raised TFPI activity with partial correction of thrombin generation with an anti-TFPI antibody. No patients had a pathological variant in the TFPI gene.…”

“…A previous study with concizumab in spiked haemophilia A and B patients and administration in healthy volunteers demonstrated near normalization of ETP/peak thrombin generation and increased ETP/peak thrombin generation in the respective groups . There is an unmet need for therapeutic advances in UBD, with only two series describing the use of tranexamic acid and desmopressin to manage haemostatic challenges …”

“…This was previously described in a study from our centre. 20 About 13 currently registered patients with UBD agreed to participate in the current study that had an initial test showing either a prolonged lag time or decreased ETP (when performed as routine clinic blood tests) but without a haemostatic deficiency to adequately explain the bleeding phenotype.…”

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)…”

“…53,55 There are only 2 published retrospective case series about the HMB is a significant women's health issue within the BUC/UBD patient group (found in more than 50% of these women) and can impair quality of life. 18,20,58 Patients should be managed by a gynaecologist and guidance for HMB has been published, which may be of help with BUC/UBD patients. 59 Management with tranexamic acid and desmopressin has been described as being of symptomatic benefit, but patient numbers are limited.…”