Claudia Santarossa

Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms An European Leukemia Net study

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN‐CVT) to 87 with MPN and other venous thrombosis (group MPN‐VT) and 178 with MPN and no thrombosis (group MPN‐NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN‐CVT and MPN‐VT than in MPN‐NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN‐VT, MPN‐CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow‐up period (6.1 vs. 10.3 years, P = 0.019), a higher long‐term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN‐CVT than in MPN‐VT group (8.8% and 4.2% patient‐years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05–3.72 and 2.09, 1.09–4.00, respectively). Am. J. Hematol. 89:E200–E205, 2014.

Prevalence of bleeding manifestations in 128 heterozygotes for Factor X deficiency, mainly for FX Friuli, matched versus 128 unaffected family members, during a long sequential observation period (23.5 years)

The main objective of the study was to evaluate the incidence of bleeding manifestations in heterozygotes for FX deficiency vs. unaffected family members. Secondary objective was to compare the prevalence of arterial or venous diseases found in the two groups.

Acquired Isolated FVII Deficiency An Underestimated and Potentially Important Laboratory Finding.

Objective: To investigate all cases of isolated factor VII (FVII) deficiency as gathered from personal files or by a PubMed search. Patients and Methods: Personal files dealing with patients studied in Padua during the years 1970 to 2010 were reevaluated. The PubMed search was time unlimited and was carried on 2 occasions during 2014. Cross-checking of the references, listed in every article, was also carried out to avoid omissions. Inclusion criteria were isolated FVII defect of less than 40% of normal, negative coagulation pattern in the family, normal level of other vitamin K-dependent clotting factors, and normalization of the clotting factor after the therapeutic procedures, unless the patient died. Results: Twenty-nine patients met the inclusion criteria (18 male and 9 female, in 2 cases gender was unreported). This number included 1 personal case. Mean age was 37.9 (range 3-80). Underlying diseases were the following: neoplasia, infections, polytrauma, penicillin administration, nephrotic syndrome Wiskott Aldrich syndrome, and left heart failure (1 case, each); 2 patients had no underlying disease. Bleeding was variable but usually mild. There were 11 fatalities. Conclusions: Isolated FVII deficiency is a rare defect, which appears to be a finding associated with several morbid conditions, especially sepsis and tumors. This indicates the need for a careful investigation of even a mild prolongation of prothrombin time, especially when fibrinogen and partial thromboplastin time are normal.

Drug-Induced Thrombophilic or Prothrombotic States: An Underestimated Clinical Problem That Involves Both Legal and Illegal Compounds.

Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.

Bleeding manifestations in heterozygotes with prothrombin deficiency or abnormalities vs. unaffected family members as observed during a long follow-up study

&NA; To investigate the prevalence of bleeding in heterozygotes for prothrombin deficiencies. Homozygotes or compound heterozygotes with Factor II (FII) levels of less than 10% of normal are always severely symptomatic. On the contrary little is known about the heterozygous population who have FII levels around 40–50% of normal. Forty-four patients heterozygous for this defect, in comparison with age and sex matched 44 unaffected family members, have been followed during a mean observational period of 22.5 years (range 4–35 years). The study was carried out in Padua between the years 1971 and 2010. The mean prothrombin activity was 0.49 IU/dl (range 0.38–0.62) and 0.91 IU/dl (range 0.81–1.10) in the heterozygotes and in the normal counterparts, respectively. In total, 14 patients showed bleeding manifestations vs. only three among the controls. Bleeding was sometimes spontaneous but more frequently occurred after tooth extractions, surgery, or delivery. Some heterozygous patients had also to be given replacement therapy to control the bleeding. No substitution therapy was ever needed for the normal counterparts. The prothrombin activity levels in the patients who were symptomatic tended to be lower than in those who remained asymptomatic. The difference in the frequency of bleeding and in the bleeding score between patients and unaffected family members was statistically significant (P = 0.007 and 0.0007). Prothrombin levels of about 40–50% of normal may not represent well tolerated hemostatic levels in case of surgical procedures, tooth extraction, or delivery. These data may have general clinical significance even for patients who have acquired defects.

Effect of busulfan on JAK2V617F allele burden.

We read with interest the paper from Kuriakose et al .[1][1] regarding the dramatic decrease of JAK2 V617F allele burden (AB) observed in 5 patients with polycythemia vera (PV) treated with busulfan (BU). Interestingly, a patient with 100% AB obtained the disappearance of the mutation within three

Factor X Friuli Coagulation Disorder: Almost 50 Years Later

The story of factor X (FX) Friuli. Factor X Friuli was discovered in 1969 to 1970. However, the story of that disease was an international event since patients with this defect were studied in France and in Italy, and different diagnoses were reached—FVII; FX; combined prothrombin complex; and combined FII, FVII, and FX deficiencies. The diagnostic difficulties were due to the peculiar clotting pattern presented by these patients, namely, prolonged partial thromboplastin time, prolonged prothrombin time but normal Russell viper venom clotting time. Only suitable anti-FX antisera clarified the pattern. Altogether 12 homozygotes and 102 heterozygotes have been followed during 4 decades. Six homozygotes died, 2 of them due to HIV infection and 1 due to hepatitis B liver cirrhosis. The other 3 died of nontransfusion-related morbidity. Bleeding tendency has been moderate in agreement with the extrinsic or intrinsic system assay results—FX level of 4% to 5% is considered normal. Heterozygotes may present occasional bleeding manifestations usually during surgery or delivery. Molecular analysis have shown that the mutation responsible for the defect is a Pro343Ser substitution in exon 8. Chimeric FX Friuli mice have been useful in studying the effect of FX levels on embryonic or natal mortality of these animals. No new homozygote but several heterozygotes have been recently seen. The study of FX Friuli has revolutionized the diagnostic approach to FX deficiencies. The FX should be assayed by all assay systems. The FX Friuli has never been described in any other country, and all patients studied come from the Friuli Meduna River Valley.

Thrombotic Events in Asymptomatic FXII Deficiency versus Symptomatic FXI Deficiency: Surprising Observations

Objective: To evaluate the impact of an asymptomatic congenital clotting defect (FXII deficiency) versus that of a similar but symptomatic defect (FXI deficiency) on protection from thrombosis. Patients and Methods: All patients with FXII or FXI deficiency and thrombosis were gathered from a time-unlimited PubMed search that was carried out twice and from personal records. Combined defects were excluded. The defect had to be proven by the demonstration of a suited hereditary pattern and by a specific clotting assay. Only patients with a factor activity level of <30% of normal were selected. Results: Twenty-eight patients with an FXII deficiency presented with arterial thrombosis, mainly myocardial infarction, and 29 showed venous thrombosis; for FXI deficiency, these figures were 43 and 10, respectively. The ratio of arterial and venous thrombosis was 0.96 and 4.3, respectively, for FXII and FXI deficiency. Conclusions: Factor FXII deficiency supplies no protection from arterial or venous thrombosis. FXI deficiency shows no protection from arterial thrombosis but appears to guarantee protection from venous thrombosis. A symptomatic, namely bleeding, condition (FXI deficiency) provides protection from venous thrombosis whereas an asymptomatic one (FXII deficiency) does not.