Efficacy of the National Thalassaemia and Sickle Cell Disease Prevention Programme in Northern Greece: 15-Year Experience, Practice and Policy Gaps for Natives and Migrants.

Hemoglobinopathies constitute the most frequent monogenic disorders worldwide and in Greece. In Greece, carrier frequency is estimated at about 8.0%, resulting in a heavy disease burden in the past. Therefore, the implementation of a national prevention program of the disease was an urgent necessity. Moreover, due to migration flow from different geographic areas in the last two decades, the observed spectrum of underlying mutations was expanded, leading to the adaptation of diagnostic approaches. We report the results of the National Thalassaemia Prevention Programme in Northern Greece, over a 15-year period (2001-2015). In total 33,837 healthy at-risk individuals (individuals or couples, 91.0% Greeks) were screened. We have screened 1598 pregnancies in 371 (23.0%) (10.0% non Greeks), of whom both parents carried gene defects and were offered genetic counseling. Seventy-six fetuses (23.0%) were predicted to be affected by severe forms of the disease. Following informed parental choices, 73 of the above pregnancies were terminated. Meanwhile, within the study period, 58 new thalassemic babies (five non Greeks) were referred to the Thalassaemia and Sickle Cell Disease Care Unit of Northern Greece, reflecting mostly parental unawareness, choice or the program failure. Based on the region's population, the birth rate and the prevalence of the disease, the anticipated number of new cases is about 45 annually. According to our data, four thalassemic newborns were registered annually at a stable rate in the last 15 years, reaching a reduction of 90.0% of new affected births. Overall, the National Thalassaemia Prevention Programme effectively decreased the incidence of affected newborns in our region.

Successful Outcome of Hyperhemolysis in Sickle Cell Disease following Multiple Lines of Treatment: The Role of Complement Inhibition.

Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in patients with sickle cell disease, characterized by difficulties in diagnosis and management. Certain reports have suggested successful salvage treatment with the terminal complement inhibitor, eculizumab. We here report evidence of complement activation and successful complement inhibition with one dose of eculizumab in an adult sickle cell disease patient presenting DHTR with hyperhemolysis. A 21-year old female sickle cell disease patient [Hb S (HBB: c.20A>T)/ß-thalassemia (ß-thal)] presented at our Adult Thalassaemia Unit, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece, with headaches, perioral numbness and pain in both antibrachia. The patient was admitted with the diagnosis of vaso-occlussive crisis (VOC) and treated symptomatically. On her third day of admission, due to hemoglobin (Hb) value of 6.9 g/dL with increase in reticulocytes, the patient was transfused with one unit of compatible leukodepleted red blood cells (RBC). The following day, hemolytic parameters increased, although Coombs, panel antibodies and screening tests were negative. Five days later, she again received a unit of RBCs, resulting in another increase of hemolytic parameters. During the following 2 days, there was a dramatic decrease of Hb levels to 5.4 g/dL with reticulocytes at 6.0%, negative Coombs testing and negative alloantibodies. Based on these findings, we recognized the syndrome of DHTR with hyperhemolysis. Given the lack of immediate access to other treatment, we administered intravenous rituximab, immunoglobulins and corticosteroids. As there was no response, one dose of eculizumab (900 mg) was then administered with ciprofloxacin as prophylaxis. The patient remains well 6 months post treatment.

Presence of the IVS-I-6-Mutated Allele in Beta-Thalassemia Major Patients Correlates with Extramedullary Hematopoiesis Incidence.

Extramedullary hematopoiesis (EMH) results from the extension of hematopoietic tissue beyond the confines of the bones. Since the initiation of regular transfusion programs from an early age for all thalassemia major (ΤΜ) patients, EMH has not been considered a clinical issue anymore. The present study aims to record the prevalence of EMH in chronically transfused ΤΜ patients followed at our institution and to investigate possible risk factors associated with its occurrence. The project was designed as a retrospective, nonexperimental, descriptive, exploratory study. In total, the study enrolled 104 patients. EMH was revealed in 15/104 (14%) patients. The presence of intravening sequence (IVS)-I-6 was significantly related with the development of EMH (p < 0.05). No other demographic or biological factor studied was found to be related with the presence of EMH. The study stresses a profound incidence of asymptomatic EMH in a solid group of well-transfused ΤΜ patients. Given the high incidence of the IVS-I-6 allele in the Mediterranean and Middle Eastern region, high-quality, prospective, multicenter studies could confirm the association of EMH occurrence with the presence of the IVS-I-6 mutation and further evaluate the exact role of this mutation in the EMH process.

Thrombin generation assay identifies individual variability in responses to low molecular weight heparin in pregnancy: implications for anticoagulant monitoring.

Low molecular weight heparin (LMWH) given to inhibit coagulation and reduce the risk of thrombosis, is typically monitored by anti-Xa assay. However, anti-Xa levels may not necessarily provide an accurate measure of coagulation inhibition. Moreover, pregnancy is associated with hypercoagulability, which may compromise the efficacy of LMWH. We looked at the association between anti-Xa levels and parameters of thrombin generation assay [TGA; area under the curve (AUC), peak height (PH) and time to peak (ttP)] using samples from 41 pregnant women receiving LMWH and 40 normal pregnant women controls. TGA results confirmed the physiological hypercoagulability of normal pregnancy (mean normalised values: AUC 119%; PH 157%; ttP 72%). Although anti-Xa measures correlated with all three TGA parameters, this group correlation masked significant inter-individual variability, demonstrated by the R(2) value or coefficient of determination. Anti-Xa levels contributed to 74% of variation in AUC values, 63% of variation in PH values and only 53% of variation in ttP values. The remainder reflects the contribution of patients' intrinsic coagulation status. Hence, some patients with 'safe' anti-Xa levels may potentially be under-anticoagulated, particularly in pregnancy. Measuring coagulability directly with TGA may lower the risk of adverse events due to under-anticoagulation in selected patients.

Thrombotic thrombocytopenic purpura or immune thrombocytopenia in a sickle cell/ß+-thalassemia patient: a rare and challenging condition.

The diagnosis of thrombotic thrombocytopenic purpura is one of the possible diagnosis when a patient is admitted with unexpected micro-angiopathic hemolytic anemia and thrombocytopenia. The combination of sickle cell/ß(+)-thalassemia and thrombotic thrombocytopenic purpura is rare and triggering. This article describes the poor outcome of a patient with sickle cell/ß(+)-thalassemia presenting with gingival bleeding, severe thrombocytopenia and anemia. The patient had normal renal function, no neurological deficit and he was initially treated as immune thrombocytopenic purpura. He eventually died due to multi-organ failure and brain hemorrhage even though he had started plasma exchange sessions. The co-existence of thrombotic thrombocytopenic purpura and sickle cell anemia is making the diagnosis of the former difficult. Early and rapid intervention is critical to the outcome.