Thrombopoietin receptor agonists as second-line therapy in splenectomy-eligible persistent immune thrombocytopenia: a case series.

: Thrombopoietin receptor agonists (TPO-RA) are currently approved to treat chronic immune thrombocytopenia (ITP) but there is increasing interest in considering these drugs earlier during the course of the disease. We present six patients with primary ITP resistant to corticosteroids and intravenous immunoglobulins, who received TPO-RA in the persistent phase and then underwent splenectomy in the chronic phase. Eltrombopag was administered as a second-line therapy in four patients, whereas two patients received romiplostim. Five out of six patients rapidly reached response or complete response (four and one, respectively) and steroid suspension. In one case, remission was obtained with steroid and TPO-RA. No significant side effects were reported. After splenectomy, complete response and response was reached in four and two patients, respectively. One relapse was recorded, rescued by steroid and eltrombopag. Postsplenectomy complication was registered in one patient (grade 4 intra-abdominal bleeding). TPO-RA could be a valuable choice in ITP patients in persistent phase candidates to splenectomy.

Activated Platelet-Derived and Leukocyte-Derived Circulating Microparticles and the Risk of Thrombosis in Heparin-Induced Thrombocytopenia: A Role for PF4-Bearing Microparticles?

BACKGROUND: Though the presence of platelets-derived microparticles (MPs) have previously been described in heparin-induced thrombocytopenia (HIT), the mechanism of thrombosis in HIT remains poorly understood. We aimed to assess the presence and origin of MPs in patients with HIT and their possible contribution to HIT with thrombosis (HITT). METHODS: Forty-five patients with HIT and 45 matched hospitalized patients with not confirmed HIT (HIT-negative) were enrolled. Twelve HIT patients (27%) developed HITT. MPs expressing phosphatidylserine (Annexin V-MP), activated platelet-derived (P-Selectin+), activated leukocyte-derived (L-Selectin+), PF4-bearing and tissue factor-bearing (TF+) MPs were measured by flow-cytometry. RESULTS: HIT patients showed significantly higher median levels of P-Selectin+, L-Selectin+, PF4-bearing, L-Selectin+/TF + MPs than HIT-negative; PF4-bearing MP showed the highest statistical difference. As compared to HIT patients, HITT patients showed a trend of higher median levels of all MP subtypes considered but the differences were not statistically significant. Only levels of activated-leukocyte/TF + MPs (L-Selectin + CD142+) were significantly higher (P = 0.015). Sensitive analyses showed that HIT patients with activated-leukocyte/TF + MPs above the cut-off (52 MP/µL) had an odds ratio (OR) for thrombosis of 3.78 (95%CI, 0.98-14.5, P = 0.045). The combination of activated-leukocyte/TF + MPs and PF4-bearing-MPs above the cut-off (1416 MP/uL) resulted in a higher risk of HITT (OR 4.49 (95% CI, 1.17-8.05, P = 0.014). CONCLUSIONS: We showed for the first time the presence of circulating PF4-bearing MPs derived from activated platelets in patients with HIT; activated leukocyte/TF + MPs are associated with an increased thrombotic risk. Our findings confirm that HIT antibodies complexes may determine a TF-driven prothrombotic state through the activation of platelets and leukocytes. © 2017 International Clinical Cytometry Society.

A family with factor-XI deficiency due to a compound heterozygosis between Gln 47 Pro (new mutation) in exon 3 and Leu 619 Pro in exon 15.

A new factor XI mutation (Gln 47 Pro) has been found in combination with another known mutation (Leu 619 Pro) in a female patient with FXI deficiency and a moderate bleeding tendency. FXI activity and antigen in the proposita were 2% activity and less than 5% of normal, respectively. The parents are not consanguineous and are asymptomatic. The father is heterozygote for the new mutation whereas the mother is heterozygote for the known mutation. Other family members are heterozygotes for either one of the two mutations. The new mutation is not a polymorphism as it was not found in the population of the area. The geographical area, north-east of Italy, of the present family is the same area where a cluster of another new mutation (Ile 436 Lys) was recently reported. No relation was found between the present family and those with the previous mutation.

Occurrence of thrombosis in congenital thrombocytopenic disorders: a critical annotation of the literature.

Patients with a low platelet count are prone to bleeding. The occurrence of a thrombotic event in congenital thrombocytopenic patients is rare and puzzling. At least nine patients with Glanzmann thrombasthenia have been reported to have had a thrombotic event, eight venous and one arterial (intracardiac, in the left ventricle). On the contrary, three patients with Bernard-Soulier syndrome have been shown to have had arterial thrombosis (myocardial infarction) but no venous thrombosis. Finally, seven patients with the familiar macrothrombocytopenia due to alterations of the MYH9 gene have been reported to have had thrombosis (five myocardial infractions, one ischemic stroke, one deep vein thrombosis and one portal vein thrombosis). The significance of these findings is discussed with particular emphasis on the discrepancy between venous and arterial thrombosis seen in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome.

Presence of anti-ADAMTS13 antibodies in obesity.

BACKGROUND: The low-grade chronic inflammation present in obesity has been recognized as a risk factor for thrombosis, atherosclerosis and cardiovascular complications. In this context, production by adipose organ of a number of inflammatory adipokines could play a crucial role. It has been reported that obesity represents a risk factor for acquired thrombotic thrombocytopenic purpura (TTP), a disease caused by ADAMTS13 deficiency because of anti-ADAMTS13 antibodies, but the pathophysiological link between obesity and TTP is still unknown. We aimed to investigate mechanisms linking obesity to risk of TTP. MATERIALS AND METHODS: Eighty obese patients consecutively admitted to Bariatric Unit of Padua between 2006 and 2009, and 39 lean subjects were characterized by anthropometric, metabolic and inflammatory parameters. ADAMTS13 autoantibodies, activity and antigen levels, and several cytokines including thrombospondin-1 were measured. RESULTS: 21.3% of obese patients were positive for noninhibitory ADAMTS13 autoantibodies, while all lean subjects were negative (P<0.01). No differences in ADAMTS13 activity and antigen levels were found. Thrombospondin-1 levels were significantly higher in obese than in lean subjects (974.4 ± 592.7 vs. 318.9 ± 202.1 ng/mL; P<0.001) and were inversely correlated with ADAMTS13 activity (R=-0.4853; P<0.001). Dot blot suggests that anti-ADAMTS13 antibodies in obese patients bind recombinant thrombospondin-1. CONCLUSIONS: We suggest that anti-ADAMTS13 antibodies are directed against thrombospondin domains shared between ADAMTS13 and thrombospondin-1 and that their generation may be sustained by high levels of thrombospondin-1. This phenomenon could be of relevance, because little is known on the pathogenesis of TTP and its possible link with obesity.