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Thrombosis and Haemostasis 04/2013; 110(1). · 5.04 Impact Factor
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ABSTRACT: We sequenced the SERPINC1 gene in 26 patients (11 males) with antithrombin (AT) deficiency (22 type I, 4 type II), belonging to 18 unrelated families from Southern Italy. Heterozygous mutations were identified in 15/18 (83.3%) families. Of them, eight were novel mutations, each being identified in one family. Seven clearly cause impaired protein synthesis (four frameshift, one non-stop, one splicing and one 21bp deletion). One, present in a single patient, is a missense mutation thought to be causative because: a) it is absent in 100 chromosomes from controls; b) it involves a highly conserved amino acid, whose change is predicted to impair AT activity; c) no other mutation is present in the propositus. Severe mutations (i.e. nonsense, frameshift, deletions) were invariably identified in type I patients. In type II patients, 3/4 were missense mutations; the fourth leads to a 19 nucleotides shift in the stop codon. In addition to the type of mutation, the co-existence of other predisposing factors in most patients helps explain the severity of the present type I cases (age at first event, recurrence during prophylaxis). In the five families in which there was more than one member affected, the same genotype and a concordant clinical expression of the disease were found. We conclude that the molecular bases of AT deficiency in Southern Italy are different as compared to other geographic areas, and that molecular analysis and the study of the effect of the mutation may help predict the clinical expression of the disease.
Thrombosis and Haemostasis 03/2012; 107(4):673-80. · 5.04 Impact Factor
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ABSTRACT: Although patients with idiopathic VTE are at higher than normal risk of asymptomatic atherosclerosis and of cardiovascular events, the impact of cardiovascular risk factors on VTE is poorly understood.
To assess the prevalence of the metabolic syndrome and of its components in patients with early-onset idiopathic VTE.
As many as 323 patients referred to our Thrombosis Ward for a recent (<6-months) early-onset idiopathic venous thromboembolism (VTE), were compared with 868 gender- and age-matched subjects, in whom a history of venous thrombosis had been excluded, referred during the same period time to our Ward. All had undergone a clinical assessment for smoking habits and for the presence of the components of the metabolic syndrome.
The metabolic syndrome was detected in 76/323 cases (23.5%) and in 81/868 controls (9.3%) (p<0.001; OR:2.990; 95%C.I.:2.119-4.217). Smoking was more common in patients with idiopathic VTE than in controls. In addition to the metabolic syndrome as a whole, its major individual determinants (arterial hypertension, impaired fasting glucose plasma levels, abdominal obesity, hypertriglyceridemia, low HDL-cholesterol) significantly correlated with idiopathic VTE (p always <0.05). The prevalence of thrombotic events was lower in females than in males (p=0.000; OR:2.217), the latter being most often hypertensives, smokers, hypertriglyceridemics, carriers of a metabolic syndrome and of impaired fasting glucose than females. In a multivariate analysis, arterial hypertension, impaired fasting glucose, abdominal obesity, and hypercholesterolemia independently predicted idiopathic venous events.
Both metabolic syndrome as a whole and its major components individually considered, independently predict early-onset idiopathic VTE.
Thrombosis Research 03/2011; 127(3):193-7. · 2.44 Impact Factor
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ABSTRACT: Diabetes mellitus (DM) is associated with macrovascular and microvascular complications. Platelets have a "key role" in atherogenesis and its thrombotic complications in subjects with DM. Moreover, the concomitant presence of multiple "classical" cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk. Antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis (cardiovascular events, ischaemic stroke, and peripheral arterial occlusive disease). The role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention, and, also in diabetic patients, the decision to give primary prophylaxis should be taken on an individual-patient basis, after a careful evaluation of the balance between the expected benefits and the risk of major bleedings. Although, currently, treatment has proven useful in reducing vascular events, diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients. This paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs, and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development.
International journal of vascular medicine 01/2011; 2011:250518.
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Thrombosis and Haemostasis 03/2010; 103(6):1270-2. · 5.04 Impact Factor
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ABSTRACT: Antiphospholipid antibodies are a heterogeneous group of auto-antibodies against phospholipids-binding proteins. The antiphospholipid syndrome is an autoimmune disorder characterized by the clinical association of antiphospholipid antibodies with a condition of hypercoagulability that can affect any blood vessel. Involvement of larger vessels, such as arteries or veins, manifests in the form of thrombosis or thromboembolism, whereas involvement of small vessels manifests as thrombotic micro-angiopathy. The antiphospholipid syndrome is also characterized by the presence of recurrent fetal loss. Patients who are persistently positive for antiphospholipid tests, and who have an arterial thrombosis or venous thrombosis history, are at increased risk of recurrence. Oral anticoagulant therapy is the mainstay of treatment for the thrombotic manifestations of the syndrome. Therapy with anticoagulant drugs should be long-term. On the other hand, although the thromboembolic potential of antiphospholipid antibodies has been well documented, there is still no general consensus on the prophylactic treatment of antiphospholipid antibodies carriers who have never developed vascular/obstetric manifestations. The effect of primary prophylaxis in antiphospholipid antibodies positive individuals is not well known and no evidence-based recommendations exist for thrombosis prevention in these individuals. However, the presence of risk factors for thrombosis increases the risk of first event of antiphospholipid antibodies positive patients. In conclusion, there is still much to learn on primary prophylaxis of asymptomatic antiphospholipid antibodies carriers. Hopefully, evidence-based guidelines will be available in the future.
Nutrition, metabolism, and cardiovascular diseases: NMCD 02/2010; 20(4):217-23. · 3.52 Impact Factor
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ABSTRACT: Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvements in the quality of life and life expectancy of individuals with this disorder. However, because injected FVIII has a short half-life in vivo, this strategy has major limitations for highly demanding regimens (e.g. prophylaxis, immune tolerance induction, surgery). Newer formulations of longer-acting FVIII are presently under investigation. The use of low molecular weight polyethylene glycol (PEG)-containing liposomes as carriers for recombinant FVIII (rFVIII) results in the prolongation of haemostatic efficacy. Data from preclinical experiments in mice, early clinical evaluations, and pharmacokinetics and pharmacodynamics results indicate that an rFVIII pegylated liposomal formulation may provide potential clinical benefit to patients with severe haemophilia A by prolonging the protection from bleeding. In light of this potential clinical benefit, a multicentre, randomized, active-controlled, non-inferiority phase II trial with two parallel treatment arms and equal randomization after stratification for the presence or absence of target joints in patients and for ages >/=18 years vs. <18 years is currently being conducted. The study will test the hypothesis that rFVIII-Lip once-weekly prophylaxis is not inferior to rFVIII-water for injection thrice-weekly prophylaxis. A total of 250 patients will be enrolled with severe haemophilia A (<1% FVIII) on on-demand or secondary prophylaxis treatment and with documented bleeds or injections during the 6 months before study entry. Sixty-four centres in 14 different countries are involved in the study; recruitment is underway. In Italy, six centres have already included 15 patients (no screening failure). Eight of these patients have completed the run-in phase and have begun the home treatment. No unexpected serious adverse events have been reported thus far. Data emerging from this phase II study will help collect relevant data to overcome current limitations in haemophilia management by employing treatment with longer-acting rFVIII.
Haemophilia 01/2010; 16 Suppl 1:2-6. · 2.60 Impact Factor
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ABSTRACT: Prophylaxis with von Willebrand factor (VWF)-containing concentrates is considered to be a potential approach for patients with von Willebrand disease (VWD) and severe bleeding tendency. We report the case of a 57-year-old man with type 3 VWD and a history of recurrent melaena. Bleeding frequency and severity had progressively increased and the patient showed chronic anaemia and persistent haemoglobin in the stools. Endoscopic examinations revealed multiple vascular mucosal abnormalities (MVA) of the stomach and large bowel. Photocoagulation of some actively bleeding lesions and octreotide did not significantly affect his clinical conditions: six red cell transfusions and >400 000 IU of intermediate-purity factor VIII (FVIII) concentrate (Haemate P) on-demand were needed during 2002. Prophylaxis with Haemate P 40 IU kg(-1) (102 IU kg(-1) VWF:RCo) thrice weekly was associated with improvement of his mean haemoglobin levels, cessation of clear-cut melaena and red cell transfusions and reduction of total Haemate P requirements (-20% over 2003-04). Prophylaxis with Haemate P is still ongoing without any adverse event over a 30-month period. Clinical course and pharmacokinetic evaluations led to administer Haemate P each 72-96 h. Possible vascular complications were excluded by a careful clinical follow up, as the patient suffered from arterial hypertension and diabetes mellitus; thrombophilic abnormalities were previously excluded and no signs of abnormal coagulation activation or FVIII:C levels >150% were detected thereafter. Long-term prophylaxis with Haemate P has been shown to be safe, effective (also in terms of quality of life) and cost saving in this patient with severe gastrointestinal bleeding due to MVA and VWD.
Haemophilia 02/2006; 12(1):90-4. · 2.60 Impact Factor
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ABSTRACT: To assess the prevalence of risk factors for venous thromboembolism (VTE) and the prevalence of recent (<1 year) VTE [including superficial vein thrombosis (SVT), deep vein thrombosis (DVT) and pulmonary embolism (PE)] amongst patients attending general practitioner (GP) surgeries.
Multicentre, cross-sectional, observational study.
A total of 1536 GP surgeries.
A total of 15 180 adult, co-operative subjects, who had consulted their GP for a health disorder and signed the informed consent form.
None.
Prevalence of known VTE risk factors graded according to importance and prevalence of recent (<1 year) VTE events (including SVT), based on interviews.
About 1:5 patients had at least one strong risk factor and about 1:20 had at least two risk factors, with no difference between sexes. The prevalence of strong risk factors increased with age. Most were related to medical conditions: history of SVT and/or DVT/PE, heart failure and malignancy. About 3:4 women and 2:3 men had at least one moderate to weak risk factor; nearly 1:2 women and 1:3 men had at least two moderate to weak risk factors. The most common were: history of VTE, smoking, history of miscarriage, estrogen therapy, obesity, and varicose veins. Overall, 80% women and 67% men had at least one risk factor, and 50% women and 35% men had at least two risk factors. The prevalence of recent (<1 year) VTE was 3.4% in women and 2.4% in men, and increased with age. The majority of cases were SVT in both sexes (2.5% in women and 1.5% in men).
The prevalence of risk factors for VTE amongst patients attending GP surgeries is high. GPs should bear this in mind during their daily practice.
Journal of Thrombosis and Haemostasis 07/2005; 3(7):1459-66. · 5.73 Impact Factor
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ABSTRACT: In clinical practice there are several conditions that are at relatively high risk of venous thromboembolism (VTE). However, not all patients included in the high risk category will actually develop VTE, and not all patients in the low risk category are protected against this eventuality. A high risk of VTE is associated with orthopedic or major surgery; a relative risk is associated with laparoscopic surgery, intermediate risk is associated, for instance, with oncology. In conclusion, individuals with deficiencies of natural anticoagulants, homozygotes due to mutation of Factor V Leiden or prothrombin and individuals with multiple risk factors may be defined as "high risk".
Acta bio-medica: Atenei Parmensis 02/2005; 76 Suppl 1:31-2.
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ABSTRACT: Aging itself is a risk factor for venous thromboembolism, and the prevalence in the elderly of additional risk factors (e.g. cancer, orthopedic surgery, immobility) increase its intrinsic risk. Many in the medical community are reluctant to prescribe anticoagulation (for primary and secondary prevention of venous thromboembolism) to their geriatric patients for the fear that bleeding complications may outweigh the benefits. A thorough analysis of the data support the concept that the under-use of heparin in primary prevention in the elderly is more related to medical beliefs than to facts. The risk of bleeding due to oral anticoagulants (secondary prevention) is greatly reduced by keeping the International Normalized Ratio (INR) values within therapeutic ranges and carefully avoiding conditions/drugs that may interfere with such treatment. The oral direct thrombin inhibitor ximelagatran has been studied for primary (hip and knee replacement surgery) and for secondary prophylaxis of venous thromboembolism, and for acute venous thromboembolism treatment. The selective factor Xa inhibitor fondaparinux has been approved for primary prophylaxis of venous thromboembolism in hip and knee replacement surgery and in hip fracture surgery. Studies on the latter drugs, where most of the patients were > 65 years of age, further show that the fear of bleeding complications due to anticoagulation in the elderly is largely unjustified.
Journal of Thrombosis and Haemostasis 08/2004; 2(8):1292-8. · 5.73 Impact Factor
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ABSTRACT: A 75-year-old woman with Glanzmann's thrombasthenia was admitted because of persistent melaena. Endoscopic examination showed multiple angiodysplastic lesions, with active bleeding in small and large bowel. Electro-coagulation of some lesions, octreotide, conjugated oestrogens and selective embolization of jejunal vessels did not change transfusion requirements. After 8 month-transfusions, ethinylestradiol + norethisterone in association with octreotide was started, leading to no transfusion over the following 9 months. Bleeding recurred after withdrawing octreotide and substituting ethinylestradiol + norgestrel for the ethinylestradiol + norethisterone combination. Re-introduction of octreotide did not improve bleeding; however, a reduction of transfusion requirement was observed when the ethinylestradiol + norethisterone pill was re-administered. The association of octreotide and of an oestrogen-progesterone combination was helpful in the difficult management of recurrent bleeding in this patient with diffuse gastrointestinal vascular abnormalities and a severe condition predisposing to bleeding.
Journal of Internal Medicine 10/2002; 252(3):271-5. · 5.48 Impact Factor
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ABSTRACT: Older individuals (subjects aged >65 years) largely contribute to the percentage deaths due to myocardial infarction (MI) and stroke. The incidence of venous thromboembolism (VTE) is also higher >65 years old patients. However, the risk of bleeding complications in patients on antithrombotic drugs increases with age and with clinical conditions, as cognitive/psychiatric diseases, traumas, hypertension, poor compliance with medications, common in the elderly. Thus the risk-benefit ratio of antithrombotics should be carefully evaluated in older individuals. To prevent the risk and the recurrence of ischemic stroke and MI in the older patients with stable/ unstable angina, MI, TIA/stroke or peripheral arterial disease, antiplatelet drugs are of choice. Aspirin is the most widely used antiplatelet drug. Clopidogrel is safer and more effective than aspirin in this respect. The combination of heparin and aspirin is the treatment of choice for unstable angina and non-Q wave MI, also in the elderly. Low molecular weight heparins (LMWHs) proved to be as effective as standard heparin in this indication. In the absence of contraindications, thrombolysis for treatment of acute MI may be considered in the elderly. For the treatment of acute venous thromboembolism (VTE), intravenous standard heparin, subcutaneous standard heparin or LMWHs are effective. Because of the limited risk/benefit ratio, thrombolytic agents are not recommended for treating deep vein thrombosis (DVT) in the elderly. They should be limited to young patients and to patients with massive pulmonary embolism (PE). For chronic treatment of VTE, warfarin is the treatment of choice (INR 2.0-3.0), also in the elderly. Because of hypersensitivity to oral anticoagulants, lower dosages of warfarin are needed in the old patient. As to prophylaxis of VTE in surgery, in subjects at low-moderate risk, or in medical patients, low-dose heparin or low-dose LMWHs are effective. As to prophylaxis of VTE in surgery in subjects at high risk, adjusted-dose heparin or high-dose LMWHs are recommended. Finally, as to prevention of stroke in patients older than 75 with atrial fibrillation (AF), warfarin is of choice.
Minerva medica 02/2002; 93(1):13-26. · 0.90 Impact Factor
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Haematologica 12/2001; 86(11 Suppl 2):8-11. · 6.42 Impact Factor
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G Davì,
G Di Minno,
A Coppola,
G Andria,
A M Cerbone,
P Madonna, A Tufano,
A Falco,
P Marchesani,
G Ciabattoni,
C Patrono
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ABSTRACT: Severe hyperhomocysteinemia due to cystathionine beta-synthase deficiency (CbetaSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F(2alpha), a platelet-active product of arachidonic acid peroxidation, is enhanced in CbetaSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion.
Urine and blood samples were obtained from patients with homozygous CbetaSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF(2alpha) excretion was significantly higher in CbetaSD patients than in control subjects (640+/-384 versus 213+/-43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (rho=0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB(2) excretion was enhanced in CbetaSD (1166+/-415 versus 324+/-72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF(2alpha) (rho=0.362, P=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6+/-4.6 to 40.4+/-8.7 micromol/L, P=0.0002) and with reductions in 8-iso-PGF(2alpha) (from 790+/-159 to 559+/-111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB(2) (from 1273+/-383 to 913+/-336 pg/mg creatinine, P=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF(2alpha) and plasma vitamin E levels (rho=-0.745, P=0.0135).
The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F(2)-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CbetaSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.
Circulation 10/2001; 104(10):1124-8. · 14.74 Impact Factor
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ABSTRACT: Older individuals contribute heavily to the percentage of deaths due to myocardial infarction (MI) and stroke. The incidence of venous thromboembolism (VTE) is highest in subjects > 65 years. Prospective intervention trials involving groups of clinically comparable subjects > or = 60 allow the following statements to be made with regard to the use of antithrombotic drugs in the elderly. Antiplatelet agents. To prevent recurrence of ischaemic stroke and MI in stable/unstable angina, MI, TIA/stroke or peripheral arterial disease, aspirin is the drug of choice. Clopidogrel is more effective than aspirin in this respect. Heparin. For the treatment of acute deep venous thrombosis (DVT) and pulmonary embolism (PE), intravenous standard heparin or subcutaneous standard heparin are effective (aPTT 1.5-2.0 times baseline values). As the risk of bleeding increases with age, low-molecular-weight heparins (LMWH) are preferable in the elderly. For the prophylaxis of VTE in general surgery in subjects at low-moderate risk, low-dose heparin or low doses of LMWH are effective. In subjects at high risk, adjusted-dose heparin plus physical devices or high-dose LMWH are recommended. The combination of heparin and aspirin is the standard treatment for unstable angina and non-Q wave MI. LMWH are as active as standard heparin in this indication. Vitamin K antagonists. For the chronic treatment of VTE, warfarin is also the treatment of choice (INR 2.0-3.0) in the elderly, though lower doses are needed due to their hypersensitivity to oral anticoagulants. For the prevention of thromboembolic stroke in patients > 75 with atrial fibrillation, warfarin is the drug of choice. Patients aged 65-75 may receive warfarin or aspirin. Thrombolytic agents. Thrombolytic agents are not recommended for treating DVT in the elderly because of their limited risk/benefit ratio and should be confined to massive PE. In the absence of contraindications, thrombolysis for MI may be considered in the elderly.
Nutrition Metabolism and Cardiovascular Diseases 02/2001; 11(1):41-62. · 3.73 Impact Factor
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ABSTRACT: Homocysteine is involved in a complex and dynamic system of vascular injury and repair and may thus contribute to the development of diabetic microangiopathy. This still debated issue has important scientific and clinical implications, since hyperhomocysteinemia can be corrected nutritionally.
1) To evaluate the association between fasting plasma homocysteine, type 1 diabetes and its microvascular complications; 2) to elucidate the basis of this association by investigating the major determinants of plasma homocysteine in relation to diabetic microangiopathy.
We studied sixty-six consecutive patients with type 1 diabetes mellitus of > 10 years duration and normal serum creatinine (< 115 mumol/L, 1.3 mg/dL), and free from clinically detectable cardiovascular diseases. Forty-four non-diabetic controls were also studied. Plasma concentrations of homocysteine, folate and vitamin B12 were investigated together with the C677T mutation in the gene coding for methylenetetrahydrofolate reductase (MTHFR), a key enzyme in homocysteine metabolism. Renal and retinal diabetic complications were evaluated as albumin/creatinine ratio on early-morning, urine spot collection and fundus photographs.
Fasting plasma homocysteine levels were very similar in patients and controls. Patients with microalbuminuria or proliferative retinopathy had significantly higher values than those without: 9.4 +/- 3.1 vs 7.4 +/- 2.8 mumol/L, p < 0.02 and 9.5 +/- 2.6 vs 7.3 +/- 3.0 mumol/L, p < 0.05. This difference was not attributable to confounders, such as age, sex and smoking, nor to dissimilar plasma folate and vitamin B12 concentrations. In contrast, homozygosity for the C677T mutation in the MTHFR gene--the commonest genetic defect linked to moderately increased plasma homocysteine--was significantly more frequent in patients with microalbuminuria and/or proliferative retinopathy (50% vs 13%, p < 0.004), odds ratio 6.7 (95% CI 1.7-27.6).
Type 1 diabetes as such is not associated with increased plasma homocysteine levels, though patients with microalbuminuria and/or proliferative retinopathy display significantly higher values than those without. This difference is not attributable to obvious confounders, nor to differences in vitamin status, and may be partly mediated by genetic factors. Plasma homocysteine, together with other diabetes-related noxae, may thus be in a position to contribute to the development of nephropathy and the progression of retinopathy.
Nutrition Metabolism and Cardiovascular Diseases 12/2000; 10(6):297-304. · 3.73 Impact Factor
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Diabetes Care 08/2000; 23(7):1026-7. · 8.09 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.
Diabetes 08/1999; 48(7):1466-8. · 8.29 Impact Factor
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Circulation 03/1998; 97(12):1213-4. · 14.74 Impact Factor
