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BACKGROUND: As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. PATIENTS AND METHODS: We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT. RESULTS: No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03). CONCLUSIONS: Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.

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Transfusion of platelet concentrates (PC) reduced the incidence of fatal hemorrhages in several thrombocytopenic conditions. Unfortunately, long-term platelet supportive care may be complicated by the development of a state of refractoriness, resulting in inadequate recovery of functional platelets. PC handling, clinical conditions of the patients and alloimmunization are the main factors affecting refractoriness. We evaluated the post-transfusion platelet increase in 25 patients (M=6, F=19) with hypomegakaryocytic thrombocytopenia receiving random ABO-compatible PC within 24 h after collection. Quality of PC was assessed by platelet count, pH measuring, LDH release, glycocalicin levels, CD-62 and CD-42b expression. Besides history, clinical status and therapy, we searched for the presence of anti-HLA class 1 and anti-HPA 1-4-5 antibodies. Only six patients (24%) were refractory to PC transfusion, as assessed by a corrected count increment (CCI)<5000. Four of such six patients (67%) had anti-HLA antibodies, as compared to zero of 19 responders (P<0.02). No other investigated clinical or laboratory feature was significantly different in refractory and responsive patients. Although post-transfusion bleeding time was shorter in responders than in refractory patients (297.33+/-249.95 versus 673.33+/-409.96; P<0.02), it did not significantly change even in patients with adequate correct count increment. Our data confirm the importance of anti-HLA antibodies in determining adequate post-transfusion recovery or refractoriness.

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The pathogenesis of thrombocytopenia associated with TAD and the occurrence of overlapping traits between TAD and AITP are still a matter of debate. For this reason, we investigated for the presence and specificity of platelet and thyroid autoantibodies in 18 TAD patients with thrombocytopenia, 19 TAD patients without thrombocytopenia and in 22 patients with primary AITP without clinical signs of TAD. Platelet-associated IgG and/or specific circulating platelet autoantibodies were detected in 83% of patients with TAD and thrombocytopenia, in 10% of patients with TAD without thrombocytopenia and in 86% of patients with primary AITP. The reactivity of serum autoantibodies, assayed by MoAb immobilization of platelet antigens (MAIPA), was directed against platelet glycoproteins Ib and/or IIb/IIIa in 50% of the patients with TAD and thrombocytopenia, as in 46% of the patients with primary AITP. Thyroid autoantibodies were found in 89% of patients with TAD and thrombocytopenia, in 95% of patients with TAD without thrombocytopenia, and in 18% of patients with primary AITP. Thyrotropin (TSH) levels determined in three of four AITP patients with thyroid autoantibodies revealed a subclinical hyperthyroidism in one patient. The present study supports the autoimmune aetiology of thrombocytopenia associated with TAD, since the prevalence and specificity of platelet autoantibodies are similar in TAD and primary AITP. The results indicate also that there exists an overlap between thyroid and platelet autoimmunity with or without clinical manifestations.

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Myeloproliferative disorders (MPD) are prone to modification and evolution during the progression of the disease. While post-polycythemia myeloid metaplasia and chronic myelogenous leukemia following polycythemia vera have been frequently described, no report is available about the evolution of polycythemia vera into essential thrombocythemia. Our case is probably the first report on this occurrence. In the course of a fortuitous observation of electrocardiographic alterations, a diagnosis of polycythemia vera was ruled out in accordance with polycythemia vera study group criteria. At the time of diagnosis, RBC was 6 x 10(12)/L, WBC 15 x 10(9)/L, Ht 59% and platelets 1000 x 10(9)/L. The patient was treated with phlebotomies and radioactive phosphorus achieving a good remission or the disease. Five years later, platelets rose to over 3300 x 10(9)/L without significant modification or RBC, WBC and Ht. The restaging or the disease was consistent for an essential thrombocythemia. In particular, RBC mass was within normal levels. During the last ten years, the patient has been followed recurrently and the blood picture remained stationary, without an increase in the hematocrit but with a platelet count between 658 and 800 x 10(9)/L. We conclude that this report may complete data concerning the evolution of MPD in others.

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