Francesca Gianniello

Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism

Summary.u2002 Background:u2002 Inherited deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) are risk factors for venous thromboembolism (VTE). They are usually defined by laboratory cut‐offs (in our setting 81, 70 and 63u2003IUu2003dL−1, respectively), which give only a rough idea of the VTE risk associated with plasma levels of these proteins.

The JAK2 V617F mutation in patients with cerebral venous thrombosis.

Summary.u2002 Background:u2002 It is currently unclear whether or not cerebral venous thrombosis, such as splanchnic venous thrombosis, can be the first manifestation of an underlying myeloproliferative neoplasm.

Global coagulation in myeloproliferative neoplasms

In spite of their recognized risk of thrombosis, patients with myeloproliferative neoplasms (MPN) show little or no abnormalities of traditional coagulation tests, perhaps because these are unable to represent the balance between pro- and anticoagulants nor the effect of platelets and blood cells. We investigated whether global tests such as thrombin generation in platelet-rich plasma (PRP) or thromboelastometry in whole blood were able to detect signs of procoagulant imbalance in MPN. The endogenous thrombin potential (ETP) of 111 patients and 89 controls was measured in PRP with platelet count adjusted to the original patient- or control-count. Testing was performed with and without thrombomodulin (the physiological protein C activator) and results were expressed as ETP ratios (with/without thrombomodulin). High ETP ratios reflect resistance to thrombomodulin and were taken as indexes of procoagulant imbalance. Patients were also investigated by thromboelastometry that provides such parameters as the clot formation time (CFT) and maximal clot firmness (MCF). Short CFT or high MCF were taken as indexes of procoagulant imbalance. ETP ratios were higher in patients than in controls and were directly correlated with platelet counts and inversely with the plasma levels of free protein S, protein C and antithrombin. Patients on hydroxyurea had lower ETP ratios than those on other treatments. CFT was shorter and MCF was greater in patients than controls; CFT and MCF were correlated with platelet counts. In conclusion, patients with MPN display a procoagulant imbalance detectable by thrombin generation and thromboelastometry. These tests might be useful in the frame of clinical trials to assess their association with the occurrence of thrombosis and with the effect of therapeutic strategies in MPN.

Risk factors for idiopathic sudden sensorineural hearing loss and their association with clinical outcome

BACKGROUNDnSudden sensorineural hearing loss (ISSHL) is idiopathic in 85% of cases and cochlear micro-thrombosis has been hypothesized as pathogenic mechanism. The role of thrombophilia and cardiovascular risk factors in ISSHL is controversial and whether these risk factors influence the clinical outcome of ISSHL is unknown.nnnMETHODSnand patients To investigate the role of thrombophilia and cardiovascular risk factors in ISSHL and to evaluate their influence on clinical outcome of the disease, 118 patients with a first episode of ISSHL and 415 healthy controls were investigated. Thrombophilia screening included measurements of antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, fibrinogen, factor VIII and homocysteine.nnnRESULTSnDeficiencies of antithrombin, protein C or S taken together, high factor VIII and hyperhomocysteinemia were significantly associated with ISSHL (OR [95%CI]: 7.55 [1.05-54.47], 2.91 [1.31-6.44] and 2.69 [1.09-6.62], respectively), whereas no association was found with the remaining thrombophilia markers. A 2-fold increased risk of poor clinical outcome was observed for every 5 μmol/L increase of fasting homocysteine levels (adjusted OR [95%CI]) 2.13 [1.02-4.44]) until levels of approximately 15 μmol/L, then the risk increased slowly. Cardiovascular risk factors (arterial hypertension, hyperlipidemia, diabetes and smoking) were associated with an increased risk of ISSHL (OR [95%CI] 1.88 [1.17-3.03]) and with a poor clinical outcome (OR [95%CI] 2.22 [0.93-5.26]).nnnCONCLUSIONSnHyperhomocysteinemia, high factor VIII and, with more uncertainty, deficiencies of antithrombin, protein C or S and cardiovascular risk factors increase the risk of ISSHL. Hyperhomocysteinemia and cardiovascular risk factors are associated with a poor clinical outcome of ISSHL.

Hemostatic Abnormalities in Noonan Syndrome

BACKGROUND: A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated. METHODS: The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group. RESULTS: The study population included 39 patients and 28 controls. Bleeding score was ≥2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and ≥4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score ≥2 (93.3%) but also in 21 (87.5%) of those with bleeding score <2. The prothrombin time and activated partial thromboplastin time were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K–dependent factors, was the most frequent coagulation abnormality. Moreover, platelet aggregation and secretion were reduced in 29 of 35 patients (82.9%, P < .01 for all aggregating agents). CONCLUSIONS: Nearly 40% of patients with the Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients.

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Summary.u2002 We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype ‐52T was associated with an increased bleeding severity score (Pu2003<u20030.01). This association remained statistically significant when the three type 2B pedigrees were excluded (Pu2003=u20030.012) or when gender‐specific bleeding categories were excluded (Pu2003<u20030.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit α2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.

Pregnancy outcome after a first episode of cerebral vein thrombosis

Essentials Little is known about recurrences and pregnancy outcome after cerebral vein thrombosis (CVT). We studied a cohort of pregnant women with CVT. Women with CVT appear at increased risk of late obstetrical complications despite prophylaxis. Risks of recurrent thrombosis and bleeding in women on heparin prophylaxis while pregnant are low.

Antithrombotic prophylaxis in a patient with nephrotic syndrome and congenital protein S deficiency

BackgroundNephrotic syndrome confers an acquired prothrombotic phenotype due to the urinary loss of anticoagulant proteins.Patients with reactivation of nephrotic syndrome may develop thrombosis.Case presentationWe report the case of a life-threatening cerebral venous thrombosis in a 13 year-old boy affected by a relapse of nephrotic syndrome during a P. aeruginosa otitis/mastoiditis. Due to the worsening general conditions and the severe neurological impairment, a course of systemic thrombolysis was successfully administered, followed by anticoagulant therapy. In the present case severe inherited thrombophilia (inherited dysfunctional protein S deficiency) was identified as an important additional risk factors for thrombosis.ConclusionsA careful evalutaion of risk factos for thrombosi during reactivation of nephrotic syndrome include measurement of plasma anticaogulant proteins. When low, antithrombotic prophylaxis with heparin should be considered to prevent thrombotic episodes.

Recurrent thrombosis in patients with antiphospholipid antibodies treated with vitamin K antagonists or rivaroxaban

Antiphospholipid antibodies (aPL) include lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-β2 glycoprotein I antibodies (aβ2-GPI). This condition is a severe acquired thrombophilia associated with an increased risk of venous and arterial thrombosis and adverse pregnancy outcome

Duration of oral contraceptive use and the risk of venous thromboembolism. A case-control study

INTRODUCTIONnOral contraceptive (OC) use increases the risk of venous thromboembolism (VTE), but the effect of duration of use remains to be elucidated.nnnPATIENTS AND METHODSnThis case-control study was aimed to investigate the duration of OC use on the risk of VTE according to women age, periods of use, prevalence of other risk factors and the role of thrombophilia abnormalities. Seven-hundred patients and 209 controls who used OC were stratified into short users (≤1year), long users (1 to 5years), and very long users (>5years).nnnRESULTS AND CONCLUSIONSnCompared to non-users, the odds ratio (OR) for VTE was 9.0 (95% CI 6.9-12.2) in short, 6.5 (95% CI 4.8-83.7) in long and 5.9 (95% CI 4.4-8.1) in very long users. The risk of VTE in short users was highest in women ≤30years and in the first year of use (OR 13.1, 95% CI 7.7-22.4) and decreased afterward (OR 7.7, 95% CI 5.0-11.9). This trend was not observed in women >30years. Compared to non-carriers and non-users, a joint effect of thrombophilia abnormalities and OC use on VTE risk was observed particularly in short users (OR 62.2, 95% CI 29.8-129.6), but also afterward (OR 25.4, 95% CI 16.5-39.2). Other transient risk factors for VTE were present in 25% of very long and 16% of short users. In conclusion, the risk of VTE in OC users decreases over time only before 30years and in first users. Thrombophilia abnormalities strongly interact with the duration of OC use in determining VTE.