Tailored prophylaxis in children with severe hemophilia: A four-year Iranian study.

BACKGROUND: Prophylaxis the current standard care for patients with severe hemophilia should be planned to optimize the replacement therapy and minimize bleeding. We report our single-center experience of tailored prophylaxis in children affected by hemophilia A (HA) and hemophilia B (HB). METHODS: This study was conducted on 55 patients, under 15 years, with HA (PWHA, n: 46) and HB (PWHB, n: 9) between 2015 and 2019. According to the phenotype, three prophylaxis regimens: 25-50 unit/kg once, twice, or three-times a week for PWHA, and two: 30-50 unit/kg once or twice a week for PWHB were administered. Following the occurrence of > 3 joint bleeding, or > 4 soft tissue bleeding, or one spontaneous major bleeding in the last 3 months, the prophylaxis regimen is changed. Annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), target joints development, inhibitor development, and hemophilia joint health score (HJHS) also were assessed. RESULTS: A mean ± SD of 2520 ± 1045 IU/kg/yr coagulation factor (F) VIII was used to reduce ABR and AJBR from 1.02 ± 1.11 and 0.8 ± 1.3 (in the first year of the study) to 0.27 ± 0.44 (P < 0.001) and 0.19 ± 0.38 (P = 0.004) (at the end of the study) in PWHA, respectively. Furthermore, in PWHB, in the first year of the study, with using 2168 ± 1216 IU/kg coagulation FIX, ABR and AJBR were 0.19 ± 0.39 and 0.06 ± 0.1. At the end of the study, ABR and AJBR were 0.02 ± 0.05 (p = 0.156) and 0.01 ± 0.03 (p = 0.361), respectively. During the study period, the mean number of the target joints and mean HJHS were 0.25 ± 0.57 and 7.6 ± 2.1 for PWHA and 0 and 6.3 ± 1.8 for PWHB, respectively. Finally, 5 PWHA (11 %) did not need dose-escalation in their prophylaxis regimen, whereas 31 (67 %) and 10 (21 %) PWHA needed two and three infusions a week, respectively. In PWHB, 7 (78 %) and 2 (22 %) were adjusted to receive a once and twice weekly regimen, respectively. CONCLUSION: Our results suggest that tailored prophylaxis is an effective strategy to reduce the rate of bleeding and optimize the replacement therapy in children with hemophilia.

Congenital Combined Bleeding Disorders, a Comprehensive Study of a Large Number of Iranian Patients.

Congenital combined bleeding disorders (CBDs) are extremely rare disorders which mainly occur in regions with a high rate of consanguineous marriage. These disorders can present with a variety of symptoms ranging from mucocutaneous bleeding to life-threatening episodes. This study aims to evaluate the prevalence and clinical course of Iranian patients with congenital CBDs. This study is conducted on 450 patients with CBDs who were referred to the Iranian Comprehensive Hemophilia Care Center (ICHCC) between 2010 and 2020. All these patients were diagnosed through evaluation of past medical history and coagulation laboratory investigation. Out of 450 patients, 33 were entered in this study. Having excluded cases with factor (F) V and FVIII deficiency, as well as those with hereditary combined Vitamin K dependent clotting factor deficiency (VKCFD), We found the most common CBDs to be FV-FVII deficiency (n: 6, 18.1%), together with FVII and FX deficiency (n: 6, 18.1%). The most common reason for referral of these patients to ICHCC was postoperative bleeding (14.3%). The mean of The International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) and condensed MCMDM-1VWD bleeding assessment tool were 9.6 ± 4.79 and 9.1 ± 4.87, respectively (P < 0.005). In 10 females of reproductive age, the mean of Pictorial Bleeding Assessment Chart (PBAC) score was 649.3 ± 554. Among all patients, 23 (69.7%) received on-demand replacement therapy, whereas 5 patients (15.1%) received prophylaxis. In Iran, the coinheritance of bleeding disorders is surprisingly higher than expected. Moreover, patients with congenital CBDs may experience serious bleeding manifestations.

Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience.

Type 2 von Willebrand disease (VWD) is the most common congenital bleeding disorder, with variable bleeding tendency and a complex laboratory phenotype. In the current study, we report the clinical and molecular profile of a large number of Iranian patients with type 2 VWD. All exons, intron-exon boundaries, and untranslated regions were sequenced by Sanger sequencing for direct mutation detection. All identified mutations were confirmed in family members and by relevant bioinformatics studies. A total of 136 patients with type 2 VWD were diagnosed, including 42 (30.9%), 32 (23.6%), 38 (27.9%), and 24 (17.6%) patients with type 2A, type 2B, type 2M, and type 2N, respectively. Epistaxis (49%), gum bleeding (30.2%), ecchymosis (23.2%), and menorrhagia (16.3%) were the most common clinical presentations, while miscarriage (2.3%) and umbilical cord bleeding (0.8%) were the rarest. Thirty mutations were identified within the VWF gene, nine (30%) being novel, with p.Arg1379Cys (n = 20), p.Val1316Met (n = 13), p.Arg1597Trp (n = 13), p.Arg1374Cys (n = 10), p.Ser1506Leu (n = 10), and p.Arg1308Cys (n = 9) the most common. Type 2 VWD is a hemorrhagic disorder with variable bleeding tendency and a heterogeneous molecular basis in patients in Iran.

Molecular characterization of Glanzmann's thrombasthenia in Iran: identification of three novel mutations.

: Quantitative and/or qualitative defects of the platelet membrane glycoprotein IIb/IIIa complex lead to the clinical entity of Glanzmann's thrombasthenia. A large variety of mutations and polymorphisms are responsible for the aberrant expression and defective activity of this heterodimeric complex. The current study aimed to determine the pattern of mutations among Iranian population with Glanzmann's thrombasthenia. A total of 20 patients with Glanzmann's thrombasthenia have been evaluated. All exons and splice sites of ITGA2B and ITGB3 genes were amplified using touchdown PCR. Mutation screening was analyzed using conformation sensitive gel electrophoresis heteroduplex PCR, and DNA sequencing. In addition to finding one previously identified mutation and polymorphism, the experimenters explored 3 and 2 novel mutations and polymorphisms, respectively. One substitution mutation, two deletions of a single nucleotide, one insertion of a single nucleotide, two synonymous polymorphisms, and one missense polymorphism were found using Sanger sequencing method. All detected mutations were homozygous which will most likely contribute to the pathogenesis of Glanzmann's thrombasthenia. Furthermore, it suggested ITGB3 as the mainly affected gene impaired in the patients with Glanzmann's thrombasthenia. As expected, the molecular results were consistent with the phenotypic findings so that GPIIb/IIIa complex was disrupted due to mutations in all type-I Glanzmann's thrombasthenia patients. It is concluded that intronic alterations or epigenetic regulations could be responsible for aberrant expression and/or defective activity of GPIIb/IIIa complex among other patients.

A novel D235Y mutation in the GP1BA gene enhances platelet interaction with von Willebrand factor in an Iranian family with platelet-type von Willebrand disease.

Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder with an intrinsic defect in platelets rather than von Willebrand factor (VWF), but has clinical and laboratory features similar to the more common type 2B VWD. The intriguing nature of the pathophysiology and molecular genetics of PT-VWD has created lengthy debate in literature regarding its discrimination from type 2B VWD, and essentially confirming DNA analysis as the gold standard in diagnosis and revealing pathologic mutations. In this report we identify a novel Asp235Tyrmutation in the GP1BA gene of two Iranian patients showing the PT-VWD phenotype who were originally misdiagnosed as type 2B VWD. By structural modelling of the mutant by introducing Tyr235 into the available crystal structure of the glycoprotein (GP)Ibα N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended ß-switch loop of GPIbα. Further modelling of the resulting complex with VWFA1 indicates this could result in an enhanced interface compared to wild-type Asp235. This data provides an update to the present knowledge about this rare disorder, and confirms the necessity of genetic testing for accurate diagnosis, and the importance of studying natural mutations to better understand molecular aspects of GPIbα-VWFA1 interaction.

External financial aid to blood transfusion services in sub-Saharan Africa: a need for reflection.

Jean-Pierre Allain and colleagues argue that, while unintended, the foreign aid provided for blood transfusion services in sub-Saharan Africa has resulted in serious negative outcomes, which requires reflection and rethinking.

Impact of inherited bleeding disorders on pregnancy and postpartum hemorrhage.

Inherited bleeding disorders are caused by various genetic defects in the proteins involved in haemostasis. Female patients or carriers are faced with the risk of haemorrhage throughout life. During pregnancy and postpartum, this complication affects the health of either the mother or the baby, or both. This retrospective cohort study was designed to assess the occurrence of obstetric bleeding in the three trimesters of pregnancy, along with primary and secondary postpartum haemorrhage among 100 women with inherited bleeding disorders. A questionnaire was designed in order to collect historical data. The patients were evaluated in three groups: haemophilia carriers, von Willebrand disease (VWD) and rare bleeding disorders. In comparison with normal women, significantly severe bleeding was observed among patients in all of the five stages. VWD patients showed a higher frequency of bleeding in first trimester but the rate of miscarriage was lower. Haemophilia carriers were threatened with bleeding complications during the prenatal period, but they also had the highest frequency of postpartum haemorrhage. Based on our results, vaginal bleeding is a serious threat in all three patient groups, especially during the first trimester of pregnancy and in the postpartum period.

Hemophilia treatment in developing countries: products and protocols.

The most important aspect of management of hemophilia is to provide adequate replacement of safe clotting factor concentrates to prevent or treat bleeding episodes. There has been considerable progress in many countries in the developing world with regard to this aspect of care. However, very little data are available in the literature on the types of products being used for factor replacement and the doses being administered for control or treatment of bleeding in different countries. These data are important to document because only then can data from different centers be compared. This article provides data from seven countries: Korea, Malaysia, Thailand, Venezuela, Argentina, Iran, and India. It shows that there is wide variability not only in the types of products used (plasma to recombinant factor concentrates) but also in the doses administered (minimal to very high) for similar indications. Prospective documentation of data on musculoskeletal outcome at these centers and correlation with dose of factor replacement could help identify different models of care. Comparing such data and collating the experience in different countries could be useful for optimizing care and establishing cost-effective models. The combined experience in the developing world in providing hemophilia services should be used to define standards of care that are practical and to set achievable goals.