Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran.

BACKGROUND: Rare bleeding disorders (RBDs) are heterogeneous disorders, mostly inherited in an autosomal recessive pattern. Iran is a Mideast country with a high rate of consanguinity that has a high rate of RBDs. OBJECTIVE: In this study, we present prevalence and clinical presentation as well as management and genetic defects of Iranian patients with RBDs. METHODS: For this study, all relevant publications were searched in Medlin until 2015. RESULTS AND DISCUSSION: Iran has the highest global incidence of factor XIII deficiency. Factor VII deficiency also is common in Iran, while factor II deficiency, with a prevalence of 1 per ∼3 million, is the rarest form of RBDs. Factor activity is available for all RBDs except for factor XIII deficiency, in which clot solubility remains as a diagnostic test. Molecular analysis of Iranian patients with RBDs revealed a few recurrent, common mutations only in patients with factor XIII deficiency, and considerable novel mutations in other RBDs. Clinical manifestations of these patients are variable and patients with factor XIII, factor X and factor VII more commonly presented severe life-threatening bleeding, while patients with combined factor V and factor VIII presented a milder phenotype. Plasma-derived products are the most common therapeutic choice in Iran, used prophylactically or on-demand for the management of these patients. CONCLUSION: Since Iran has a high rate of RBDs with life-threatening bleeding, molecular studies can be used for carrier detection and, therefore, prevention of the further expansion of these disorders and their fatal consequence.

Hemophilia in Iran.

BACKGROUND: Hemophilia A (HA) and B (HB) are common bleeding disorders, Iran having the ninth largest such population in the world. A considerable number of studies have been performed on different aspects of their disorder. OBJECTIVE: The aim of the study was to gather all obtainable data about Iranian patients with HA and HB, including molecular studies, clinical presentations and treatment, and development and management of patients with inhibitor, to help better understand the disease and its management in other parts of the world. METHODS: For this review study, we searched MEDLINE and Scientific Information Database for English and Persian sources until 2015. RESULTS AND DISCUSSION: There are 5369 patients with HA and HB in Iran among which 4438 patients have HA. About one-fifth of HA patients' genes were analyzed and their underlying defects detected. Hemarthrosis, epistaxis, ecchymosis, and post-dental extraction bleeding are the most common clinical presentations. Bleeding was mainly managed by on-demand replacement therapy with factor VIII/factor IX (FVIII/FIX) concentrates or cryoprecipitate in HA, and fresh frozen plasma in HB in the absence of factor concentrate. Mean per capita for FVIII in HA patients is 1.56 IU, which is higher than the global per capita mean. However, mean per capita for FIX (0.24 IU) is lower than the global mean but highest among eastern Mediterranean countries. Replacement with plasma-derived components has led to infection in a large number of patients as well as inhibitor development against exogenous infusion of coagulation factors. According to a World Federation of Hemophilia survey, 223 HA and 6 HB patients in Iran have developed inhibitor and have been mainly managed by recombinant FVII (rFVIIa) and activated prothrombin-complex concentrate. CONCLUSION: Although this study was performed in Iranian patients, the large number thereof gives confidence that the results can be used more widely for other countries, especially in the developing world.

First cases of severe congenital factor XIII deficiency in Southwestern Afghanistan in the vicinity of southeast of Iran.

Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with the highest global incidence in southeast of Iran. Southwestern Afghanistan (Nimruz Province) is located near the border with Iran in the vicinity of Sistan and Baluchestan Province in southeast Iran, and there seems to be a high prevalence of FXIIID in Nimruz. Thus, this cross-sectional study was designed to assess the prevalence of FXIIID, molecular basis as well as clinical manifestations of FXIIID in Southwestern Afghanistan. During the course of the study, all patients suspected of FXIIID were clinically examined and assessed by routine coagulation tests, including bleeding time, activated partial thromboplastin time, prothrombin time, as well as platelet count and clot solubility test. Patients with normal routine coagulation tests, but abnormal clot solubility test, underwent further investigations by FXIII activity, as well as molecular analysis for FXIII-A gene mutation (Trp187Arg) by PCR-restriction fragment length polymorphism that confirmed by sequencing. Patients with confirmed FXIIID deficiency were registered to receive prophylaxis treatment. All data including demographic information, clinical manifestations, as well as therapeutic response and type and duration of treatment, were recorded, and the data were analyzed by SPSS software. In this cross-sectional study, we found five patients with abnormal clot solubility test, among whom two patients abandoned the study, whereas three patients remained for a more precise study. All the patients were residents of Zaranj city, the capital of Nimruz Province. All these patients had undetectable activity of FXIII, which indicates a severe deficiency. Molecular analysis of patients showed mutation of Trp187Arg in all of them. Hematoma was the most common clinical presentation leading to diagnosis of FXIIID in these patients (100%). Epistaxis (67%), gum bleeding (33%), and hematuria (33%) were other recurrent clinical presentations of the patients. Three cases of death due to FXIIID were detected in the family of these patients. There was a high prevalence of FXIIID in Zaranj city with a population of 50 000, which was appropriately equal to the prevalence of the disorder in southeast of Iran, which seemed to have the highest global prevalence of FXIIID, and underlines that the same mutation (Trp187Arg) in both regions is same.

Congenital factor V deficiency: comparison of the severity of clinical presentations among patients with rare bleeding disorders.

BACKGROUND: Factor V deficiency (FVD) is a rare bleeding disorder (RBD) mostly present in regions with a high rate of consanguinity. FVD after FXIII deficiency is the next more prevalent RBD in Sistan and Baluchistan (S&B) in southeastern Iran. The aim of this study was to evaluate the clinical manifestations and severity of bleeding diathesis in patients with FVD. METHODS: This descriptive study was conducted on 23 patients with FVD in S&B province. FVD was diagnosed by clinical findings and routine laboratory tests. Bleeding diatheses were classified into three grades (I-III) depending on the severity of symptoms. The severity of bleeding episodes in our patients was compared with other RBDs. RESULT: Based on residual plasma FV activity, 6 (26%), 16 (69.5%) and 1 (4.5%) patients had mild, moderate and severe factor deficiency, respectively. 24% of the patients had grade III life-threatening bleeding episodes which in comparison with FVII deficiency (17.4%) and FI deficiency (21%) had a higher incidence, and in comparison with FX deficiency (41.7%) and FXIII deficiency (63.1) had a lower incidence. Grade II and grade I bleeding diathesis were observed in 56.2 and 16.7% of the patients, respectively. CONCLUSION: FVD is the second most common type of RBD in S&B province and grade II bleeding episodes were the major bleeding presentation and observed in more than half of the patients.

Central nervous system bleeding in pediatric patients with factor XIII deficiency: a study on 23 new cases.

BACKGROUND: Factor XIII (FXIII) deficiency is an extremely rare bleeding disorder, which has the highest incidence in Sistan and Baluchistan Province in Iran, compared to its overall incidence around the world. This disorder has different clinical manifestations ranging from mild bleeding tendency to lethal bleeding episodes including central nervous system (CNS) hemorrhage. The aim of this study was to evaluate the demographic data, pattern of CNS bleeding, and the role of plasminogen activator inhibitor-1 (PAI-1) (PAI-1) 4G/5G and thrombin activatable fibrinolysis inhibitor (TAFI) Thr325Ile polymorphisms in intracranial and extracranial hemorrhages in 23 new cases of FXIII-deficient subjects. METHODS: This case-control study was conducted on 23 FXIII-deficient patients with CNS bleeding episodes and 23 patients as the control group with FXIII deficiency but without any history of CNS bleeding. Initially, to confirm the molecular defect, both groups were evaluated for the most frequently reported mutation of FXIII (Trp187Arg mutation) in a previous study in Sistan and Baluchistan Province. Then, demographic data, clinical manifestations, and pattern of CNS bleeding were determined. Eventually, the patients were assessed for PAI-14G/5G and TAFI Thr325Ile polymorphisms. RESULTS: The results of this study revealed that all the subjects (including the case and control groups) were homozygous for Trp187Arg mutation. Nineteen patients (82.6%) had intracranial hemorrhage (ICH) and four patients (17.4%) had extracranial hemorrhage (ECH). Intraparenchymal hemorrhage was the most common form of ICH (89.5%), and epidural hemorrhage was observed in two patients (10.5%). Anatomic regions in patients with intraparenchymal hemorrhage were temporal in six (35.3%), occipital in four (23.5%), diffused intraparenchymal in four (23.5%), temporal-occipital in two (11.8%), and subdural with temporal in one (5.9%) patient. We found that in the case group, 14 patients (60.8%) were homozygous for TAFI Thr325Ile polymorphism and 8 cases (34.7%) were heterozygous. In the control group, 4 (17.4%) and 13 (56.5%) patients were homozygous and heterozygous, respectively (P < 0.001 vs. P < 0.01).We also found that an equal number of patients (two individuals) in the case and control groups (8.7% in each group) were heterozygous for PAI-14G/5G polymorphism. CONCLUSION: It seems that PAI-14G/5G polymorphism does not have any effect on occurrence of ICH and ECH in patients with FXIII deficiency, while TAFI Thr325Ile is a strong genetic risk factor (odds ratio:14.9, 95% confidence interval: 7.4-31.1).

Clinical manifestations and management of life-threatening bleeding in the largest group of patients with severe factor XIII deficiency.

Factor XIII (FXIII) deficiency is a rare hemorrhagic disorder for which the highest incidence occurs in southeast Iran. The aim of this study was to assess molecular characteristics, clinical manifestations and management of life-threatening diathesis in FXIII deficiency. This study was conducted on 190 patients with FXIII deficiency. Genotype analysis for the most frequent mutation of FXIII-A subunit gene in Iranian, Trp187Arg, was performed for all patients. Clinical manifestations and management of patients with intracranial hemorrhage (ICH), miscarriage and neonates with FXIII deficiency were documented. Neonates were divided in two groups: Group 1 received a standard dose of Fibrogammin P(®) (10-26 IU/Kg) and group 2 received a high dose of this drug (60-80 IU/Kg) for 36 months. Bleeding episodes in both groups were recorded, and neonates of group 2 were regularly checked for thrombotic events. Molecular analysis revealed that all patients were homozygous for Trp187Arg mutation. Umbilical bleeding, hematoma and prolonged wound bleeding were common presentations. ICH was another common presentation leading to behavioral and developmental disorders and aphasia. ICH was managed by Fibrogammin P(®) at a dose of 10-26 IU/Kg, and miscarriage was managed by Fibrogammin P(®) at a dose of 10 IU/Kg every 2 weeks during pregnancy, and the same dose administered as prophylaxis before gestation every 4 weeks. Neonates of group 2 received 60-80 IU/kg dose of Fibrogammin P(®). This higher dose did not trigger thrombotic events but significantly decreased bleeding episodes and prevented the occurrence of major bleeding. Trp187Arg is the most common mutation of FXIII-A subunit in Iran, and Fibrogammin P(®) is effective in the management of FXIII deficiency, and higher dose of this drug is safe and effective in neonates.

Evaluation of complement regulatory components in patients with atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, is associated with mutations and polymorphisms in various components and regulators of the complement alternative pathway (AP), including factor H, factor I, membrane cofactor protein (MCP or CD46) and factor B. This impaired regulation of the alternative pathway leads to a procoagulant state with microthrombi formation in the renal vasculature, which influences disease onset and progression. AIM OF THE STUDY: To evaluate the role of complement regulatory factors in occurrence of aHUS; we also included evaluation of ADAMTS13 activity and autoantibody against ADAMTS13 in order to exclude thrombotic thrombocytopenic purpura (TTP) cases, which might have overlapping clinical and laboratory findings. MATERIAL AND METHODS: This study was conducted on 273 individuals with aHUS. Diagnosis was based on clinical manifestations, kidney function tests, red blood cell count, morphology and reticulocyte count. Then, the ADAMTS 13 autoantibody and activity and also complement factor B, complement factor H (CFH) and complement factor-I (CIF) were analyzed. Finally, the statistical analysis was performed by SPSS software. RESULTS: The mean age of our patients was 27.3 years, 55% were female and 45% were male. The mean levels of urea and creatinine concentration were 92.9 mg/dl and 5.1 mg/dl, respectively. The mean levels of RBC count, Hb and HCT in these patients were lower than normal but the mean percentage of reticulocyte count was higher than normal (2.5%). The assessment of complement regulatory factors revealed that the B and H factors levels were normal except in two cases but the level of factor I was higher than normal. CONCLUSIONS: According to the results of this study, it seems that up regulation of factor I had a significant role in occurrence of aHUS in our study group.

A prospective study of tubular dysfunction in pediatric patients with Beta thalassemia major receiving deferasirox.

BACKGROUND: Beta thalassemia major is a lifelong transfusion-dependent disorder. Transfusion-dependent thalassemia patients are prone to develop renal dysfunction due to iron overload, chronic anemia, and/or chelation therapy. METHODS: In this prospective study, thalassemia patients who fitted inclusion and exclusion criteria received Deferasirox 20 mg/kg/day. A complete biochemistry analysis of serum and 24-hour-urine specimens was performed before and after treatment. Estimated glomerular filtration rate (eGFR), Fractional excretion of sodium (FENA), potassium (FEK), uric acid (FEUA), and the maximum ratio of tubular reabsorption of phosphorus to eGFR (TmP/GFR) at baseline and after treatment was calculated and compared. RESULTS: A total of 30 patients with mean age of 4.9 ± 3.2 years were recruited. The mean serum creatinine increased significantly after 6 months of treatment (0.54 ± 0.08 vs. 0.67 ± 0.16, P < .001) while eGFR was decreased (104.36 ± 19.62 vs. 86.00 ± 16.92, P < .001). Mean potassium level in serum was increased after treatment, while serum calcium, magnesium, and uric acid levels decreased significantly (P > .05). A significant increase was confirmed for mean urinary ß2-microglobulin (ß2-MG), protein, uric acid, calcium, and magnesium (P > .05). CONCLUSION: Our findings highlighted tubular nephropathy induced by Deferasirox in patients with beta thalassemia, and confirmed the necessity for diligent monitoring of renal function in thalassemia patients receiving Deferasirox.

Anemia and thrombocytopenia in acute and chronic renal failure.

BACKGROUND: Acute renal failure describes as a syndrome by rapid decline in the ability of the kidney to eliminate waste products, regulate acid-base balance, and manage water homeostasis. When this impairment is prolonged and entered chronic phase, erythropoietin secretion by this organ is decreasing and toxic metabolic accumulates and causes hematological changes include decrease of HCT, MCV and RBC and platelet counts. This study evaluates present of anemia and thrombocytopenia in patients with acute and chronic renal failure. MATERIALS AND METHODS: This study conducted on 132 patients with renal impairment and also 179 healthy individuals as two separated control groups. Initially patients with renal problem were tested and after confirmation of impairment, patients were divided in two groups, acute with less than 3 months and chronic with more than 3 months renal failure, based on duration of the disease. Then complete blood count performed for each patient and finally obtained data were analyzed by SPSS software. RESULTS: Comparison between 96 patients with acute and 36 patients with chronic renal failure revealed that severity of anemia (HCT, Hb and MCV) between these two groups were statistically high in comparison with control groups (P > 0.05) but thrombocytopenia in patients with chronic renal failure was statistically different from control and the acute ones (P < 0.001). CONCLUSION: It was recommended that in patients with chronic renal failure, to prevent the risk of bleeding, platelet count should be checked periodically.