Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions

Abstract

Background: Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16.

Results: Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard-Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each.

Conclusion: vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.

Keywords: Autosomal recessive; Bernard–Soulier syndrome; Coagulation factors; Glanzmann’s thrombasthenia; Inherited bleeding disorders; von Willebrand disease type 3.

Fig. 1

Flow diagram of patient recruitment, sample collection and its disposition at different levels of health care facilities/laboratories. a Initial presentation of patients with bleeding disorders at primary and/or secondary health care centers. b Referral of patients to the tertiary health care centers or laboratories for definitive diagnosis. Patients were recruited into the study at this point (c). Samples sent over to the central reference laboratory NIBD where the tests were repeated to establish reliability. CHL, Children Hospital Lahore; CL, Chughtai’s Laboratory; FFK, Fatimid Foundation Karachi; HMC, Hayatabad Medical Complex; KP, Khyber Pakhtunkhwa; LRH, Lady Reading Hospital; NIBD, National Institute of Blood Diseases; PAEC, Pakistan Atomic Energy Commission. N = number of patients with ARBD, () indicate total number of patients recruited from each center initially

Fig. 2

Comparative studies of different nationalities with ARBDs [7, 29, 36]