Giovanni Di Minno

Measuring Plasma Fibrinogen to Predict Stroke and Myocardial Infarction An Update

Plasma fibrinogen is a major determinant of platelet aggregation and blood viscosity. The decrease in plasma fibrinogen by bezafibrate is associated with a decrease in the risk of reinfarctions. To strengthen the predictive value of plasma fibrinogen with respect to cardiovascular risk, we performed a meta-analysis of studies conducted between 1984 and 1998. Emphasis has been put on the relationship between high levels of plasma fibrinogen and fatal and/or nonfatal cardiovascular events in both the general population and in patients with previous cardiovascular events. Twenty-two studies (13 prospective, 5 cross-sectional, and 4 case-control) addressing the association between fibrinogen plasma concentrations and cardiovascular disease were analyzed. The overall estimate of risk of cardiovascular event in subjects with plasma fibrinogen levels in the higher tertile, was twice as high as that of subjects in the lower one (odds ratio, 1.99; 95% confidence interval, 1.85 to 2.13). High plasma fibrinogen levels were associated with an increased risk of cardiovascular disease in healthy as much as in high-risk individuals. A metaregression showed no confounding effects attributable to selected characteristics of retrieved studies. A subgroup analysis (study design, follow up, mean fibrinogen levels, percentage of smokers, and mean age) allowed us to conclude that fibrinogen is an independent risk factor for cardiovascular disease; that it interacts with major determinants of myocardial and cerebrovascular ischemia; and that, in secondary prevention studies, it enhances by 8% the prediction of future events by established risk factors. Thus, fibrinogen measurements should be encouraged to refine the overall risk profiles of individuals and to better tailor preventive interventions.

Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.

OBJECTIVE This studys objective was to evaluate the association between venous thromboembolism during pregnancy and the postpartum period and the factor V Arg 506 Gln (factor V Leiden), the prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphisms. STUDY DESIGN In this case-control study 42 case patients and 213 control subjects (parous age-matched women without history of thrombosis) were genotyped for all the polymorphisms. Moreover, antiphospholipid antibodies and protein C, protein S, and antithrombin III deficiencies were investigated in each case. RESULTS Ten case patients (23.8%) and 4 control subjects (1.9%; odds ratio 16.3, 95% confidence interval 4.8-54.9) carried the factor V Leiden mutation; 13 case patients (31.0%) and 9 control subjects (4.2%; odds ratio 10.2, 95% confidence interval 4.0-25.9) were carriers of the prothrombin G20210A allele. Finally, 12 case patients (28.6%) and 34 control subjects (16.0%; odds ratio 2.1, 95% confidence interval 1.0-4.5) were homozygotes for methylenetetrahydrofolate reductase C677T. Overall, mutations were found in 25 case patients (59.5%) and 47 control patients (22.2%; odds ratio 5.2, 95% confidence interval 4.9-19.6). One patient carried the antithrombin III deficiency and 1 the protein S deficiency, whereas 2 women had a primary antiphospholipid syndrome. CONCLUSIONS The significant risk estimates of having a pregnancy-related venous thromboembolism in the presence of the prothrombotic genetic risk factors analyzed suggest to screen for these mutations women with a personal history of thromboembolic events during pregnancy or the postpartum period.

Obesity and the prediction of minimal disease activity: A prospective study in psoriatic arthritis

We prospectively evaluated whether obesity impacts achievement of minimal disease activity (MDA) in subjects with psoriatic arthritis (PsA).

Carotid Intima-Media Thickness in Psoriatic Arthritis: Differences Between Tumor Necrosis Factor-α Blockers and Traditional Disease-Modifying Antirheumatic Drugs

Objective—Subjects with psoriatic arthritis (PsA) have an abnormally high prevalence of vascular risk factors (VRFs) and are predisposed to vascular mortality. Tumor necrosis factor (TNF)-&agr;, a major determinant of inflammation, is involved in atherosclerosis. Ultrasonographic carotid intima-media thickness (C-IMT) evaluation allows for subclinical atherosclerosis detection. Methods and Results—Two hundred twenty-four PsA patients (120 on TNF-&agr; blockers and 104 on traditional disease-modifying antirheumatic drugs [DMARDs]) underwent a C-IMT ultrasound assessment. As many as 305 matched subjects without any inflammatory/rheumatologic disease served as controls. The C-IMT of PsA subjects without VRFs was higher (P<0.0001) than that of controls, the C-IMT of PsA subjects with ≥1 VRF(s) was lower (P<0.0001) than that of controls, and the C-IMT was lower (P<0.0001) in those on TNF-&agr; blockers than in those on DMARDs. Carotid plaques were detected in 15.8% of those on TNF-&agr; blockers and in 40.4% of those on DMARDs (P<0.0001). Treatment duration inversely (&bgr;=−0.317, P<0.0001) predicted C-IMT in PsA subjects on TNF-&agr; blockers but not in those on DMARDs (P=0.313). Conclusion—Among PsA individuals, the C-IMT is higher in subjects on DMARDs than in those on TNF-&agr; blockers. The reduction of inflammation may hamper the cascade that causes the raised vascular risk in PsA patients.

Plasma Folate, Vitamin B12, and Total Homocysteine and Homozygosity for the C677T Mutation of the 5,10-Methylene Tetrahydrofolate Reductase Gene in Patients with Alzheimer’s Dementia

Background: Elevated total plasma homocysteine (tHcy) levels are considered a risk factor for cerebrovascular disease and may also play an important role in the pathogenesis of Alzheimer’s disease (AD). High values of plasma tHcy and low levels of vitamin B12 and folate are frequently present in AD patients. Moreover, the homozygous mutation (C677T) of the methylene tetrahydrofolate reductase (MTHFR) gene, related to a thermolabile type of the encoded enzyme, causes hyperhomocysteinemia by reducing the 5-methyltetrahydrofolate availability. Objective: The aim of the study was to investigate plasma levels of folate, vitamin B12 and tHcy in patients with AD. These values were also related to the severity and the duration of the disease and to the possible role of the MTHFR genotype (C677T). Method: Plasma tHcy levels, homozygosity for the C677T mutation of the MTHFR gene, and folate and vitamin B12 plasma levels were evaluated in 74 patients with AD (45 men, 29 women, mean age 68 years) and in 74 healthy matched controls (42 men, 32 women, mean age 68 years). Results: AD patients had higher mean (± SD) plasma levels of tHcy (20.9 ± 15 µmol/l compared to 11.8 ± 5 µmol/l, p < 0.001) and lower mean plasma folate (5.7 ± 2.1 ng/ml compared to 8.5 ± 3.2 ng/ml, p < 0.001) and vitamin B12 (491 ± 144 pmol/l compared to 780 ± 211 pmol/l, p < 0.001) concentrations. Homozygosity for the C677T mutation of the MTHFR gene had a similar prevalence among controls (18%) and AD patients (20%). Homozygous AD patients (n = 15) had higher plasma tHcy values than nonhomozygotes, in spite of similar mean plasma folate and vitamin B12 levels. This difference in plasma tHcy levels was not observed in controls. Patients with levels of plasma tHcy above and of plasma folate below the normal limits were more frequent in the homozygous AD group. The duration of the disease correlated with plasma levels of tHcy (r = +0.832, p < 0.001), plasma folate (r = –0.580, p < 0.05), and vitamin B12 (r = –0.460, p < 0.05). However, when all the data were corrected for age, serum creatinine levels, and duration of the disease, mean plasma tHcy, folate, and vitamin B12 levels were not statistically different between controls and AD patients. Conclusions: Our data suggest that rather than a risk factor for AD, hyperhomocysteinemia is related to its progression and increasing severity. This might be particularly relevant in homozygotes for the C677T mutation of the MTHFR gene and supports the possible need for continuous supplements in this setting.

Inherited Thrombophilia: Implications for Prevention and Treatment of Venous Thromboembolism

Inherited thrombophilia, defined as a genetically determined tendency to develop venous thromboembolism (VTE), contributes to the pathogenesis of approximately 40% of VTE episodes. About 50% of carriers of inherited thrombophilic traits develop VTE, but the impact of the different abnormalities is variable in terms of clinical penetrance. Some rare abnormalities (natural anticoagulant deficiencies, homozygous factor V Leiden, and combined defects) result in more severe thrombophilic phenotypes, characterized by early-onset events, more frequent recurrence, and positive family history, whereas the common polymorphisms (heterozygous factor V Leiden and prothrombin G20210A) are associated with lower VTE risk, often in association with triggering risk factors. Therefore, clinical implications of inherited thrombophilia should be assessed in the framework of coexisting and/or circumstantial risk factors involved in the multifactorial pathogenesis of VTE. These considerations should be taken into account when assessing the need and modalities of primary and secondary thromboprophylaxis in patients carrying inherited thrombophilic traits.

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received freshfrozen plasma. Prophylactic schedules clustered into “frequent” courses (three times weekly, n=23) and “infrequent” courses (≤2 times weekly, n=15). Excluding courses for menorrhagia, “frequent” and “infrequent” courses produced 18/23 (78%) and 5/12 (41%) “excellent” outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on “frequent” administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency (clinicaltrials.gov: NCT01269138).

Predictors of early minimal disease activity in patients with psoriatic arthritis treated with tumor necrosis factor-α blockers

Objective. To identify predictors of early minimal disease activity in patients with psoriatic arthritis (PsA) receiving tumor necrosis factor-α (TNF-α) antagonists. Methods. In total 146 consecutive patients with PsA eligible for anti-TNF-α therapy were enrolled. At baseline (T0) information about age, sex, PsA subset, disease duration, comorbidities, and treatments was collected. All subjects were tested for metabolic syndrome (MetS) and/or liver steatosis. A clinical and laboratory evaluation was performed at T0 and at 3 months (T3). Changes in all these variables were compared in subjects achieving minimal disease activity (MDA) and those who did not. Results. Among 146 PsA subjects, 10 discontinued therapy before 3-month followup because of adverse events; thus 136 concluded the study. All clinical outcome measures changed significantly from T0 to T3. Erythrocyte sedimentation rate showed a significant reduction (p < 0.001). C-reactive protein (CRP), serum cholesterol, and triglycerides showed no significant variation (p > 0.05). The prevalence of MetS and liver steatosis showed no significant differences between subjects achieving MDA and those who did not (p = 0.347 and 0.053, respectively). Patients achieving MDA at T3 were younger than those not achieving MDA (p = 0.001). A lower baseline tender joint count (p = 0.001), swollen joint count (p = 0.013), Bath Ankylosing Spondylitis Disease Activity Index (p = 0.021), and Ritchie index (p = 0.006) were found in subjects achieving MDA. Age (OR 0.896, p = 0.003) and Bath Ankylosing Spondylitis Functional Index (BASFI) (OR 0.479, p = 0.007) inversely predicted, whereas CRP (OR 1.78, p = 0.018) directly predicted, achievement of MDA at T3. Conclusion. In patients with PsA, age, CRP, and BASFI at the beginning of treatment were found to be reliable predictors of MDA after 3 months of TNF-α blocker therapy.

Glanzmann’s thrombasthenia (defective platelet integrin αIIb-β3): proposals for management between evidence and open issues

Glanzmanns Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder, characterized by a quantitative or qualitative defect of platelet surface alpha(IIb)-beta(3) integrin. Presently, no specific guideline/algorithm for clinical management for GT is available. Due to the rarity and heterogeneity of inherited platelet abnormalities, recommendations and guidelines are based on reports from opinions and clinical experience of panel of experts, and refer to the general management of platelet disorders. Based on the limited evidence in the area and on the strategies in clinical settings of inherited/acquired platelet defects, proposals for management of minor bleeding, moderate/major bleeding unresponsive to conservative management, major surgery, minor surgery and dental procedures for GT patients without, or with anti-platelet isoantibodies are reported. In addition to life-style advices and continuous patient education programs, when and how to employ/combine local measures, antifibrinolytic agents, hormone treatment, platelet transfusions and recombinant activated Factor VII is described. The prospective collection of treatments in GT patients recently established (Glanzmanns Thrombasthenia Registry, GTR), based on a careful definition of clinical settings and outcomes, is likely to provide newer insight for optimising clinical management in GT.

Cardiovascular risk in rheumatic patients: the link between inflammation and atherothrombosis.

In addition to a high prevalence of the metabolic syndrome and a significant under-diagnosis of vascular risk factors (VRFs), the effect of chronic inflammation also represents the cornerstone of the raised cardiovascular (CV) risk in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Moreover, the finding that among current anti-inflammatory treatments, the use of tumor necrosis factor (TNF)-α blockers is associated with optimal rheumatologic and CV outcomes further supports the impact of inflammation on the CV risk. However, up-to-date treatment guidelines suggest that TNF-α blockers should be used only after the failure of traditional disease-modifying antirheumatic drugs (DMARDs). Early predictors of the therapeutic efficacy of traditional DMARDs are needed to identify candidates for TNF-α blocker treatment. Furthermore, whether the CV risk should be taken into account while choosing antirheumatic treatments is an emerging issue to be addressed. Common educational programs for specialists and general practitioners and appropriate CV prevention programs, taking into consideration traditional VRFs as well as the inflammatory status, should be planned to prevent ischemic events and to achieve optimal inflammation control in rheumatic patients.