Mehran Karimi

Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study

Despite recent advances in understanding the pathophysiologic mechanisms behind the thalassemia intermedia (TI) phenotype, data on the effects of treatment are deficient. To provide such data, we evaluated 584 TI patients for the associations between patient and disease characteristics, treatment received, and the rate of complications. The most common disease-related complications were osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, and cholelithiasis, followed by thrombosis, pulmonary hypertension (PHT), abnormal liver function, and leg ulcers. Hypothyroidism, heart failure, and diabetes mellitus were less frequently observed. On multivariate analysis, older age and splenectomy were independently associated with an increased risk of most disease-related complications. Transfusion therapy was protective for thrombosis, EMH, PHT, heart failure, cholelithiasis, and leg ulcers. However, transfusion therapy was associated with an increased risk of endocrinopathy. Iron chelation therapy was in turn protective for endocrinopathy and PHT. Hydroxyurea treatment was associated with an increased risk of hypogonadism yet was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis. Attention should be paid to the impact of age on complications in TI, and the beneficial role of splenectomy deserves revisiting. This study provides evidence that calls for prospective evaluation of the roles of transfusion, iron chelation, and hydroxyurea therapy in TI patients.

ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission

Acquired thrombotic thrombocytopenic purpura (TTP) is often due to anti-ADAMTS13 antibodies that inhibit the proteolytic activity of the plasma metallo-protease and/or accelerate its clearance. Survivors of an acute episode of TTP with severely reduced levels of ADAMTS13 and /or with anti-ADAMTS13 antibodies during remission are at high risk of developing another epidode of TTP. Background From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established. Design and Methods In 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients. Results Median values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p=0.007; antigen: 36% vs. 58%; p=0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p=0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p=0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p=0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence. Conclusions Survivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Factor XIII Deficiency.

Factor XIII (FXIII) is a tetrameric zymogen (FXIII-A (2)B (2)) that is converted into an active transglutaminase (FXIIIa) by thrombin and Ca (2+) in the terminal phase of the clotting cascade. By cross-linking fibrin chains and alpha (2) plasmin inhibitor to fibrin, FXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Severe deficiency of the potentially active A subunit (FXIII-A) is a rare but severe hemorrhagic diathesis. Delayed umbilical stump bleeding is characteristic, and subcutaneous, intramuscular, and intracranial bleeding occurs with a relatively high frequency in nonsupplemented patients. In addition, impaired wound healing and spontaneous abortion in women are also features of FXIII deficiency. The extremely rare B subunit deficiency results in milder bleeding symptoms. FXIII concentrate is now available for on-demand treatment and primary prophylaxis. A quantitative FXIII activity assay is recommended as a screening test for the diagnosis of FXIII deficiency. For classification purposes, FXIII-A (2)B (2) antigen in the plasma is first determined, and if decreased, further measurement of the individual subunits is recommended in the plasma and FXIII-A in platelet lysate. Analytical aspects of FXIII activity and antigen assays are discussed in this article. There are no hot-spot mutations in the F13A1 and F13B genes, and the majority of causative mutations are missense/nonsense point mutations.

Splenectomy and thrombosis: the case of thalassemia intermedia

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51.

Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran.

Hydroxyurea (HU) is a well-known chemotherapeutic agent that has been used largely for the treatment of various myeloproliferative conditions over the past 20 years. In β-thalassemia, the role for HU is much less clear and remains controversial. This study was undertaken to describe the hematologic and clinical responses of thalassemia intermedia patients to HU treatment during 6 years in Southern Iran. One hundred sixty-three thalassemia intermedia patients were selected among the 3,000 cases of β-thalassemia in Southern Iran from 1998 to 2003. All patients underwent laboratory tests and quantitative hemoglobin electrophoresis. Group 1 comprised patients receiving regular blood transfusions (after age 2 years old). Group 2 comprised those without any history of blood transfusions suffering from chronic anemia or long-interval transfusions. The state of energy, fatigability, and mood were recorded before the trial. Facial change was compared before and after treatment with HU. Electrocardiogram and echocardiography were carried out before and during treatment with HU. All patients were treated with HU; the starting dose was 8 to 12 mg/kg/d given orally once a day. Of the 163 patients, 149 tolerated the HU well and showed a dramatic response to the drug. Eighty-three of 106 transfusion-dependent patients (group 1) became completely transfusion-free, and 23 had one or two transfusions throughout the study. Sixteen of 43 patients (group 2) who were on long-interval transfusions became transfusion-free and 27 group 2 patients were transfusion-free, with developing acceptable hemoglobin levels. After treatment, 97% of patients described an increase in exercise tolerance, and no significant facial change was observed after therapy. No change in spleen size was observed in 83% of the patients. HU therapy was also associated with a marked increase in hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. HU may be administered in thalassemia intermedia patients to minimize or even obviate the need for regular transfusions and concomitant iron overload, and HU therapy appears to be safe and effective when administered in thalassemic patients.

Splenectomy and thrombosis: The case of thalassemia intermedia

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51.

Spectrum of the Mutations in Bernard–Soulier Syndrome

Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb‐IX‐V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

β-THALASSEMIA INTERMEDIA FROM SOUTHERN IRAN: IVS-II-1 (G→A) IS THE PREVALENT THALASSEMIA INTERMEDIA ALLELE

The preliminary results of a pilot study are reported, intended as an initiation of a research plan, focused on the prevention of β-thalassemia in Iran. The aims of this study are: (i) to improve the knowledge of the molecular background of β-thalassemia intermedia in Southern Iran; (ii) to verify the role of the −158 Gγ (C→T) (Xmn I) polymorphism as a modulating factor in thalassemia intermedia; (iii) to test the validity of the multiplex and single mutation specific amplification refractory mutation system in analyzing the molecular defects causing β-thalassemia in multiethnic populations; and (iv) to develop suitable strategies for the application of prevention protocols in Iran. To accomplish the task we have selected 87 β-thalassemia intermedia patients and adapted the DNA methodology to detect the following 11 frequent mutations in Iran: codon 5 (−CT); frameshift codons (FSC) 8/9 (+G); codon 30 (G→C); IVS-I-1 (G→A); IVS-I-5 (G→C); IVS-I-6 (T→C); IVS-I-110 (G→A); codons 36/37 (−T); codon 44 (−C); IVS-II-1 (G→A); IVS-II-745 (C→G). Because of the multiethnicity of the population we have also included the Indian IVS-I (25 bp deletion) and the Mediterranean IVS-I-130 (G→C) and codon 39 (C→T) mutations. Forty-eight patients were randomly studied for the Xmn I polymorphism together with 50 healthy volunteers as a control group. The molecular analysis conducted in Iran, identified only 31% of the alleles that were presumed to be thalassemic, revealing either a strategic or a technical insufficiency of the chosen method. However, the mutations with the highest prevalence in the country (IVS-II-1, IVS-I-110, IVS-I-1 and FSC 8/9) were found. As expected the IVS-II-1 defect, being the most frequent in south Iran, was present at the highest rate (24%). The Xmn I polymorphism was found in association with this prevalent mutation and was detected in the homozygous state in 87.5% of the patients homozygous for the IVS-II-1 (G→A) mutation. The overall positivity for Xmn I was found in 40.6% of the thalassemic alleles vs. 14% in the non-thalassemic, confirming the hypothesis of an older event, antecedent to the IVS-II-1 mutation. In trying to assess a more suitable molecular detection method we intend to continue this study in collaboration with the European centers involved, applying more effective technologies and better defining the molecular spectrum of β-thalassemia in the sub-populations. We also intend to verify the effect of α-thalassemia in the genotype/phenotype correlation of β-thalassemia intermedia.

Premarital screening for β-thalassaemia in Southern Iran: options for improving the programme

Background: β-thalassaemia is a preventable disease. Iran has about 20,000 homozygote β-thalassaemia patients and 3,750,000 carriers. Objective: To assess the 10-year results of the screening programme, which has been operating in Southern Iran since 1995. Methods: All couples wanting to marry were required to be checked for β-thalassaemia by their red blood cell indices in order to receive a permit for marriage registration. The results were reported to the nearest counselling team. If the results were conspicuous, haemoglobin A2(HbA2) and, in some subjects, Hb electrophoresis was performed. Couples in which both partners were carriers received counselling. For those who, in spite of the recommendation, decided to marry, prenatal diagnosis and termination of pregnancy in case of an affected fetus was offered. The latter was offered only in the last three years. Results: In 1995, 1999 and 2004, 296, 94 and 56 β-thalassaemia homozygotes, respectively, were born (2.53, 1.07 and 0.82 patients per 1000 births). Discussion: This programme has decreased the birth prevalence of β-thalassaemia, but has unfortunately not eliminated the disease altogether. The reasons for the birth of new cases, in spite of the screening programmes, are: (i) premarital screening programme started in 1995; therefore, carrier couples who married before this did not receive counselling and gave birth to homozygote β-thalassaemia children; (ii) unwanted pregnancy among the carrier couples; (iii) the couples knew about their problem, but they married for cultural and religious causes (illegal marriages).