Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.

Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria.

In an international study of 1104 patients with essential thrombocythemia (ET), a histological review according to the 2008 World Health Organization (WHO) criteria confirmed ET in 891 patients (WHO-ET, 81%), and revised the diagnosis to prefibrotic primary myelofibrosis (PMF) in 180 patients (PMF, 16%). Major bleeding during follow-up occurred in 55 (6%) WHO-ET and 21 (12%) PMF patients (P = 0.009), at a rate of 0.79 and 1.39% patients per year, respectively, (P = 0.039). In a multivariable analysis, predictors of bleeding included diagnosis of PMF (P = 0.05; hazard ratio (HR) 1.74), leukocytosis (P = 0.04; HR 1.74), previous hemorrhage (P = 0.025; HR 2.35) and aspirin therapy (P=0.001; HR 3.16). The analysis restricted to patients with WHO-ET confirmed previous hemorrhage (P = 0.043; HR 1.92) and aspirin (P=0.027; HR 2.24) as independent risk factors. The current study reveals that major bleeding associated with thrombocytosis might be relatively specific to PMF, as opposed to WHO-defined ET. Furthermore, it shows that low-dose aspirin exacerbates these hemorrhagic events of PMF. In contrast, thrombocytosis per se was not a risk factor for bleeding; however, low-dose aspirin had a synergistic hemorrhagic effect unmasking the bleeding tendency of patients with extreme thrombocytosis. These observations carry significant therapeutic implications in these two WHO entities.

Blood oxidative status and selectins plasma levels in healthy donors receiving granulocyte-colony stimulating factor.

Recombinant human G-CSF (rHuG-CSF) is used for hematopoietic progenitor cells (HPC) mobilization and collection. Activation of polymorphonuclear leukocytes (PMN) is present during rHuG-CSF treatment and is associated with endothelial cell dysfunction and hypercoagulation. We evaluated whether PMN activation by rHuG-CSF may alter the blood oxidative status and subsequently affect the vascular cell function. Fourteen healthy individuals received rHuG-CSF for HPC harvesting. Blood was drawn before starting rHuG-CSF (T0), on the last day of rHuG-CSF (T1) and 1 week after stopping rHuG-CSF (T2). Levels of CD11b, myeloperoxidase (MPO), hydroperoxides, nitric oxide (NO), and soluble endothelium (sES), leukocyte (sLS), and platelet (sPS) selectins were measured. During rHuG-CSF, CD11b, MPO and hydroperoxides significantly increased, while NO levels significantly decreased, compared with T0. At T2 all these markers returned to baseline values. Significant increments of all selectins were observed during rHuG-CSF. At T2 sES and sEP significantly decreased back to pre-treatment values, whereas sLS remained significantly high. These data show that rHuG-CSF induces a transient inflammatory status characterized by circulating activated PMN, which release reactive oxygen species and intracellular proteases, promoting the onset of an abnormal oxidative status. This process may modify the hemostatic balance towards a pro-thrombotic state.

Monoclonal gammopathy in human leishmaniasis.

A 64-year-old female with IgGk monoclonal components (total 45 g/l) and 30% abnormal plasma cells and plasmoblasts in bone marrow is reported. After the identification of leishmania in the bone marrow, liposomal amphotericin B was used and a progressive resolution of the gammopathy was documented.

Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemaophilia B: a critical evaluation of reported cases.

Myocardial infarction and other arterial thrombosis are commonly maintained to be rare in hemophilia patients. This, in general, seems true but the occurrence of a thrombotic event in hemophilia B is not exceptional. A thorough search of the literature has yielded 13 patients with myocardial infarction and 1 patient with a cerebrovascular accident. There were three fatalities. In five cases MI occurred after infusion of Prothrombin Complex Concentrates. In three additional patients the event occurred after infusion of plasma, Feiba or cryoprecipitate supernatant. Four patients had an antero-lateral infarction. Two had a non-Q infarction and one each showed a multiple or a posterior-inferior form. Several therapeutic coronary procedures (GABG and PTCA) were carried out in hemophilia B patients without undue complication providing adequate level of FIX were maintained. Heparin prophilaxis was used in all patients but one. The analysis of the literature indicates that (1) MI may occur in hemophilia B patients and (2) that invasive coronary artery therapeutic procedures may be carried out without complications.

Normal thrombopoietin and its receptor (c-mpl) genes in children with essential thrombocythemia.

BACKGROUND: Following the observation of thrombopoietin (TPO) gene abnormalities as the cause of familiar cases of thrombocythemia similar derangements of TPO and/or its receptor (c-mpl) might be surmised to be at the root of increased platelet count also in non-familiar (sporadic) cases. Although this was not demonstrated in adults, little data exist about childhood. PROCEDURES: We studied the molecular biology of TPO and c-mpl in seven children with non-familiar essential thrombocythemia (ET) and one child with secondary thrombocytosis (ST). Plasma TPO content was measured using a commercially available kit. Genomic DNA was extracted from whole blood by standard methods and TPO and c-mpl genes were amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: Plasma TPO levels were normal in all our patients. No alteration was detected in either coding region, including the flanking intronic sequences of TPO and c-mpl genes. As compared to the published normal sequence of the TPO gene, one allelic base change in a non-coding region of intron 1 was found in all children with ET and ST, but this was reported as a common finding in normal subjects as well. CONCLUSIONS: High platelet count in our series of sporadic ET of childhood is not due to an abnormality either of TPO or c-mpl gene.

Thrombosis-free surgical procedures in severe (Homozygote) factor XII deficiency: report of four additional cases and literature review.

The outcome of various surgical procedures carried out in patients with severe (homozygote) factor XII deficiency were investigated for the appearance of blood coagulation-related complications with particular emphasis on thrombotic complications. The surgical procedures were total mastectomy, tonsillectomy and adenoidectomy, placement of a hip prosthesis, and double hernia repair. None of the patients slowed any complication. Several other reported cases of surgical procedures carried out in several patients ware found in the literature. Bleeding or thrombotic complications were noted in none of these cases. The surgical procedures in some cases were minor such as adenoidectomy, tonsillectomy, or nasal polyp removal. However several major surgical procedures were carried out in some patients (cholecystectomy, gastrectomy, repair of atrial septal defect, coronary bypass). All patients remained asymptomatic. In some cases whole blood and/or plasma were used as requested by the caring surgeons. In a few patients, the plasma was given prophylactically because of the long partial thromboplastin time. Finally, three patients (two for cardiac surgery and one after hip replacement) received heparin prophylaxis as foreseen by accepted procedures without the undue sequels. These data supply further evidence that factor XII deficiency does not only show any bleeding tendency but also can withstand even major surgical procedures without thrombotic complications.

The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature.

According to our personal experience and to the study of the literature, 11 cases of venous thrombosis have been described as sporadic reports in patients with severe (homozygous) factor XII (FXII) deficiencies. In every cases but 4, associated risk factors were found to be present (pregnancy, post-partum period, surgery, trauma, in dwelling catheter, AT deficiency, heterozygous factor V Leiden, Burger's disease). In some instances more then one condition was present. The four patients for whom no information is supplied, were cases gathered from old and logically incomplete files and therefore the existence of associated risk factors cannot be excluded. The papers which investigated the presence of venous thrombosis in cohorts of patients with homoxygous FXII deficiency demonstrated the occurrence of venous thrombosis in 2 additional cases out of a total of 63 patients investigated. In these latter cases thrombosis occurred during pregnancy. This brings the total number of patients with FXII deficiency who showed a venous thrombosis to 13. Only a few of these patients were investigated for the presence of concomitant congenital prothrombotic conditions. The conclusion of the study seem to suggest that the role played by FXII deficiency in the pathogenesis of venous thrombosis is minor, if any.

Association of monoclonal gammopathy and polycythemia vera or essential thrombocythemia: study of a large cohort of patients.

Concomitant cases of monoclonal gammopathies with polycythemia vera (PV) and essential thrombocythemia (ET) have been described. We report our experience in a large cohort of patients with ET and PV and the occurrence of M protein in such a population. Retrospective evaluation of clinical and laboratory records of 164 patients with PV and 218 with ET was performed, and 500 subjects matched for sex and age were used as controls. The patients were divided into group A (younger than 55 years), group B (55-70 years), and group C (over 70 years), and the presence of M protein was sought at the time of diagnosis and later during follow-up. M protein was found in 14 patients with myeloproliferative disorders (MPDs), representing 3.6% of patients both with ET and PV, and in 10 subjects of the control group (2%). M protein was detected in 2.1% of MPD patients of group A, in 4.8% of group B, and in 5.7% of group C and in 1.6% of controls of group A, 2.7% of group B, and 2% of group C. No significant statistical difference was observed. The occurrence of M protein in PV and ET does not seem to differ from that observed in the control group. A more relevant increase in the incidence of M protein in MPDs than in the controls was observed by dividing patients and controls by age. However, no statistical significant difference was documented.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia.

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.

Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura.

Sixty-one consecutive patients undergoing splenectomy for chronic immune thrombocytopenia were retrospectively evaluated. Platelet response was considered as complete (CR) when platelet count rose to > 100 x 109/l, partial (PR) when 30-100 x 109/l or absent (NR) if otherwise. Follow-up (mean time 7.6 years) was possible in 54 patients. Forty-eight patients (88%) had an immediate response to splenectomy (39 CR, 9 PR) whereas six (12%) were NR. Thirty-six responders (67%) had sustained remission (31 CR; 5 PR) without further treatment; thrombocytopenia recurred in 12 patients (33%). The probability curve of continued remission showed a constant relapse-rate during the first 36 months; a further step of relapse was observed beginning 70 months after surgery. The only positive predictive factor for the long-term response to splenectomy was age < 40 (P < 0.005). Neither duration of thrombocytopenia nor previous response to medical treatment (steroids and/or intravenous immunoglobulins) were related to splenectomy response.

Clinical and laboratory factors that affect the post-transfusion platelet increment.

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.