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Pattern of bleeding and response to therapy in Glanzmann thrombasthenia

Glanzmann Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder affecting the megakaryocyte lineage. The incidence of this disorder is higher in communities where consanguinity is prevalent like Jordan, Iran, South India and Iraqi Jews [1,2]. The molecular basis shows the quantitative and/or qualitative abnormalities of the platelet fibrinogen receptor, the aIIbb3 integrin (glycoprotein (GP) IIb/IIIa, CD41/CD61) which mediates the incorporation of platelets into an aggregate or thrombus at the sites of vessel injury [3]. Clinical manifestations in GT usually start in childhood and have clinical variability; ranging from minimal bruising to severe and potentially fatal haemorrhages. Diagnosis is associated with mucocutaneous bleeding with no platelet aggregation in response to all physiologic stimuli, a normal platelet count and morphology. Deficient or non-functional platelet aIIbb3 should be confirmed using flow cytometry. Genetic studies reveal multiple mutations that can affect the GPIIb/IIIa complex assembly on the platelet membrane. Standard treatment includes platelet transfusion to stop bleeding when conservative measures fail, but repeated transfusions may result in the development of antibodies (alloimmunization) against GPIIb/IIIa and/or human leucocyte antigen (HLA), resulting in refractoriness to further platelet transfusion [4]. In Pakistan, consanguineous unions continue to be extremely common as in SouthWest Asia. The Pakistan Demographic and Health Survey (DHS) shows that two-thirds of marriages in Pakistan are consanguineous. As a result of consanguineous marriages, rare autosomal recessive disorders run in close families and tribes [5]. Therefore, the specific aim of this study was to assess the frequency of GT, to see the pattern of bleeding and their response to therapy in our patients by comparing them over worldwide presentation. This is a retrospective study of GT patients who were diagnosed and followed at the National Institute of Blood Disease & Bone Transplantation (NIBD), Karachi, Pakistan from October 2008 to November 2011. The study was approved by the Institutional ethics committee, informed consent was obtained from all adult subjects, parents or legal guardians. The data were taken from hospital medical records which included outpatient files, emergency department notes, operative reports and inpatient charts. Information for each clinical encounter was recorded and tabulated. Patients were diagnosed on the basis of clinical suspicion of the disease, normal platelet count on complete blood counts (CBC), prolonged bleeding time (BT), normal prothrombin time (PT), activated partial thromboplastin time (APTT), normal to suboptimal platelet aggregation in the presence of ristocetin and defective aggregation with collagen, ADP and epinephrine. Patients with other coagulation and platelet function disorders were excluded from this study. Platelet aggregation studies were done on platelet-rich plasma (PRP) with a count adjusted to 200–250 9 10 L 1 by Helena Agg RAM using ristocetin, adenosine diphosphate (ADP), epinephrine and collagen. The following demographic and clinical data were obtained: age, gender and type of bleeding symptoms i.e. epistaxis, bruising, gum bleeding, bleeding at circumcision (in males), bleeding at dental extraction, muscle bleed, haematoma, subcutaneous bleed, haematuria, haematemesis, gastrointestinal(GI) bleeding, ear bleeding and menorrhagia (in females). Information was also obtained on the number of bleeding episodes, hospital visits, requiring or not requiring admission, duration of bleeds between two consecutive episodes were recorded and responses of the symptoms to different treatment modalities were observed. The initial treatment offered for minor bleeds was local haemostatic measures such as pressure bandage, ice therapy and antifibrinolytic agents such as tranexamic acid. Platelet transfusions were used if bleeding failed to stop and in the presence of severe bleeding, dental procedures and surgery. Response was assessed and when no response was observed another treatment modality such as DDAVP or rFVIIa was added to the treatment regimen and the response assessed. Female patients presented with episodes of menorrhagia were treated with oral contraceptives, tranexamic acid, iron supplements and if needed with platelet transfusions. If a patient required any other treatment modality, they were considered as non-responders for the previously offered treatments. The response to treatment was measured from the initiation of treatment until complete cessation of bleeding in less than 6 h, in more than 6 h, less than 24 h and more than 24 h and labelled as responders. Patients were considered as non-responders when they continued to bleed for more than 36 h from the start of the initial treatment. The statistical package SPSS-13 was used to analyse the data. Frequency and percentage were computed for categorical variables and mean and standard deviation (SD) were estimated for quantitative variables. A total of 43 GT patients were diagnosed at NIBD hospital of the 123 congenital platelet function disorders (35%). These patients were followed in OPD, inpatient and emergency department. There were 20 males with a mean age of 12.1 years (range, 6 months– 30 years) and 23 females with a mean age of 10.5 years (range, 1–17 years). Parents of 34 (79%) patients were first or second cousins. Positive family history of bleeding was noted in 26 (60%) patients, no history of bleeding in 7 (16.2%) patients and unknown in 10 (23%) patients. A total of 245 bleeding episodes were identified during different time periods requiring visit to hospital, but only 173 bleeding episodes could be evaluated because of the availability of complete details. The average number of medical visits per patient was 12 (range, 2–66). Hospitalization was required in 147/173 (85%) of these visits for a mean of 31 days spent as an inpatient Correspondence: Dr. Munira Borhany, National Institute of Blood Disease and Bone Marrow Transplantation (NIBD), Karachi, Pakistan,: ST 2/A Block 17, Gulshan-e-Iqbal KDA Scheme 24 Karachi, Pakistan 75300. Tel.: +0092-21-34821502-3; fax: +0092-21-34821504; e-mail: drmunirashoaib@yahoo.com