Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case-control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02-3.27, P = 1.64 × 10 ). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10 to 7.60 × 10 ). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10 ). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease.
Blends of polystyrene and polyethylene (PS/PE), including belnds in which a styrene/ethylene‐butylene/styrene (SEBS) terpolymer was employed as a compatibilizer, were studied. Their rheology showed that the effect of the addition of SEBS to PS/PE blends was strongly affected by the blend composition and the shear rates involved in the blending and post‐forming processes. The addition of PE to PS led to a reduction of fracture toughness compared with that of PS. This effect was attributed to the fine minor phase morphology of the blends obtained after extrusion blending and injection molding. The fatigue crack propagation (FCP) results showed that the fatigue crack growth rates were significantly reduced at low and moderate range of stress intensity factor (ΔK) by the presence of PE. Performance was enhanced when SEBS was present. The results also showed that both the fracture toughness and the FCP behavior of the blends were strongly dependent on the loading direction, the minor phase morphology, the composition of the blend, and, to a lesser degree, the presence of a compatibilizer. This study demonstrates that the fracture toughness and the FCP performance of such polymer blends can vary inversely.
We prospectively evaluated the effect of anagrelide (ANA) on platelets, PF4, F1+2, PAP, PAI-1, and TFPI and erythromelalgia in patients with essential thrombocythemia (ET) receiving anti-aggregants both pre-and post-ANA. At first, we observed a successful reduction of platelets, which was associated with normalization of platelet coagulant and endothelial function and disappearance of erythromelalgia. Secondly, we found a correlation between PF4 and TFPI and between TFPI and thrombosis, suggesting that erythromelalgia may be caused by platelet-mediated endothelial activation. These data may indicate that ANA may be efficacy in the treatment of symptomatic patients with ET. Am. J. Hematol. 80:81-83, 2005. ª 2005 Wiley-Liss, Inc.Key words: anagrelide; erythromelalgia; essential thrombocythemia Erythromelalgia frequently complicates the essential thrombocythemia (ET) [1]. Thrombocytosis and platelet coagulant activation are risk factors for this microvascular complication [1,2]. Its management includes cytoreduction and anti-aggregants [1]. It has been demonstrated that ET patients receiving cytoreduction and anti-aggregants show normal platelet count but still present platelet coagulant activation and thrombosis [3]. Anagrelide (ANA) is a platelet-lowering drug that inhibits platelet aggregation [4]. Therefore, we evaluated the effect of ANA on platelets and markers of platelet coagulant activation, such as platelet factor 4 (PF4), prothrombin fragment 1+2 (F1+2), plasmin/a 2 -antiplasmin complex (PAP), and plasminogen activator inhibitor-1 (PAI-1) in patients with ET and erythromelalgia. Platelet endothelial activation releases tissue factor pathway inhibitor (TFPI), which is a marker of microvascular damage [5]. Thus we also determined TFPI. All measurements were performed before ANA and when complete response (CR), defined as platelets < 500 Â 10 9 /L for more than 1 month, was achieved. The study comprised 17 patients [10 men, 7 women; mean age 48 years (range 24-72 years)] with ET diagnosed according to criteria defined by the Polycythemia Vera Study Group [6]. The mean duration of disease was 4 years (range 1-14 years). All patients were on anti-aggregants, such as aspirin (ASA) (9 patients), indobufen (IND) (7 patients), or dipyridamole (DYP) (1 patient). Nine of 17 patients suffered from erythromelalgia. These patients typically presented with painful burning and red congested extremities [1]. After a median time from diagnosis of 3 years, all patients were started on ANA. ANA was initially administered at a dose of 0.5 mg/day. Subsequently, the dose was increased by 0.5 mg/day every week until the platelets had decreased to below 500 Â 10 9 /L. The average maintenance dose was 2.1 mg/day (range 0.5-6 mg/day). Therapy was well tolerated. None of the patients had acquired thrombotic or inherited risk factors. Twenty healthy subjects served as controls. Platelets were determined on the Sysmex XE-21300 (Dasit, Milan, Italy). PF4, F1+2, PAP, PAI-1, and TFPI were measured by enzyme- Published online in Wiley In...
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