Paul R. J. Ames

Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.

OBJECTIVES AND METHODS:Splanchnic vein thrombosis (SVT), not associated with cancer or liver cirrhosis, is a rare event and scanty data are available on its natural history, long-term prognosis, and treatment. In this study 121 SVT patients consecutively seen from January 1998 to December 2005 were included and 95 of them were followed up for a median time of 41 months. Screening for thrombophilic factors was performed in 104 patients. New thrombotic or bleeding episodes were registered and anticoagulant therapy was performed according to preestablished criteria.RESULTS:SVT was an incidental finding in 34 (28.1%) patients; 34 (28.1%) presented with abdominal infarction; 39 (32.2%) had bowel ischemia or acute portal vein thrombosis; 14 (11.6%) had bleeding from portal hypertensive sources. Survival rates at 1, 3, and 7 yr were 95%, 93.3%, and 89.6%, respectively; 87.5% of deaths occurred at onset of SVT as complications of intestinal infarction. Patients with isolated portal vein thromboses had symptoms and intestinal infarction in 16/41 (39%) and 0/41 (0%) of the cases, respectively, whereas superior mesenteric vein thromboses, isolated or not, were associated with symptoms and intestinal infarction in 69/75 (92%) and 34/75 (45%), respectively.During the follow-up 14 (14.7%) suffered from 39 episodes of gastrointestinal bleeding with no deaths. A previous gastrointestinal bleed was associated with new hemorrhagic events during follow-up.New venous thrombotic episodes occurred in 10 of 95 patients (10.5%), of which 73% were in the splanchnic area. Seven out of these 10 patients had a chronic myeloproliferative disease (MPD) and none was on anticoagulation.CONCLUSIONS:Anticoagulant therapy was effective to obtain recanalization of acute SVT in 45.4% of patients and preserved patients from recurrent thrombosis when given lifelong.

Eosinophilia and Thrombophilia in Churg Strauss Syndrome: A Clinical and Pathogenetic Overview

During the past decade, there has been an increased description of Churg Strauss syndrome (CSS) characterized by vascular occlusions possibly linked to the thrombogenic potential of the eosinophil that is poorly appreciated. The purpose of this overview is 3-fold: the first to evaluate the available prevalence of thrombosis in Churg Strauss series, the second to demonstrate that any vascular district may be affected, and the third to describe the pathogenesis of thrombosis in CSS. A Pubmed, EMBASE, and Google search of CSS series from 1951 to date revealed a prevalence of arterial occlusion ranging between 3.1% and 18.7% and a prevalence of venous occlusion between 5.8% and 30%, whereas a specific survey for venous thromboembolism in CSS yielded a prevalence of 8.1%. Eosinophils store and release tissue factor as well as other cationic proteins: the former initiates coagulation while the latter inhibits natural anticoagulant activity and activate platelets eventually culminating in excessive thrombin generation and clot formation. In addition, antineutrophil cytoplasmic antibodies may shift the endothelial lining to proadhesive and prothrombotic surface. It is hoped that the review will represent a basis to foster novel research on this topic.

Subclinical atherosclerosis in primary antiphospholipid syndrome

Abstract:  To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 ± 12 years), in 25 patients with inherited thrombophilia (mean age 40 ± 10 years), and in 34 normal controls (mean age 38 ± 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P= 0.01), at the bifurcation (P= 0.003), and at the internal carotid (P= 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.

Bleeding and re-thrombosis in primary antiphospholipid syndrome on oral anticoagulation An 8-year longitudinal comparison with mitral valve replacement and inherited thrombophilia

The aim of this study was to compare bleeding and re-thrombosis in primary antiphospholipid syndrome (PAPS), mitral valve replacement (MVR) and inherited thrombophilia (IT) at different oral anticoagulation intensities. It entailed a prospective 8-year follow-up on 67 patients with PAPS, 89 with IT and 24 with MVR. Anticardiolipin (aCL) antibodies detected by Elisa and lupus anticoagulant by clotting assays. At INR 2-3 minor bleeding rate was higher in MVR (33.3) than PAPS (10.9) and IT (4.2)(p<0.0001). At INR 3-4 minor bleeding rate was higher in PAPS (142) than IT (33.3) and MVR (5.8)(p<0.0001). At either INR major bleeding rate were not significantly different across the three groups, but in PAPS major and minor bleeding rates were superior at INR 3-4 than INR 2-3 (p=0.02 and p<0.0001). Re-thrombosis rate was higher in PAPS than IT at INR 2-3 (4.0 vs 0.35) (p=0.01) and at INR 3-4 (10.5 vs. nil). The hazard ratio for re-thrombosis between PAPS and IT was 13 (95% IC 1.6-102.2, p=0.015). By regression analysis, baseline IgG aCL titre (>80 GPL) p=0.001) and male sex (p=0.03) independently predicted re-thrombosis. In conclusion, in PAPS, high intensity oral anticoagulation was not superior to conventional intensity in preventing re-thrombosis but was offset by greater bleeding rates. Male sex and elevated baseline IgG aCL predicted rethrombosis in PAPS that is 13-fold more re-thrombogenic than IT.

Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome.

Objective. To assess the role of nitrite (NO2−), nitrate (NO3−), and nitrative stress in thrombotic primary antiphospholipid syndrome (PAPS). Methods. We investigated 46 patients with PAPS: 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE), and 29 healthy controls (CTR). IgG anticardiolipin (aCL), IgG anti-beta2-glycoprotein I (anti-ß2-GPI), IgG anti-high density lipoprotein (aHDL), IgG anti-apolipoprotein A-I (aApoA-I), crude nitrotyrosine (NT) (an indicator of nitrative stress), and high sensitivity C-reactive protein (CRP) were measured by immunoassays. Plasma nitrite (NO2−), nitrate (NO3−), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays. Results. Average plasma NO2− was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO3− was highest in SLE (p < 0.0001), whereas average NT was higher in PAPS and SLE (p = 0.01). In thrombotic PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO2− (p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO3− (p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO3− (p = 0.03). In the SLE group IgG aCL negatively predicted NO2− (p = 0.03) and NO3− (p = 0.02). Conclusion. PAPS is characterized by decreased NO2− in relation to type and number of vascular occlusions and to aPL titers. Nitrative stress and low grade inflammation are linked phenomena in PAPS and may have implications for thrombosis and atherosclerosis.

Impact of plasma homocysteine and prothrombin G20210A on primary antiphospholipid syndrome

The prevalence of prothrombin (PT) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677 ← T was assessed in 40 patients with primary antiphospholipid syndrome (APS) (14 male, 26 female; mean age, 37 ± 14 years) and in 27 persistent carriers of antiphospholipid antibodies (aPL) (five male, 22 female; mean age, 40 ± 16 years) without underlying diseases. Non-APS thrombotic patients (n = 100; 47 female, 53 male; mean age, 40 ± 10 years) and healthy subjects (n = 100; 46 female, 54 male; mean age, 56 ± 16 years) served as control groups. Plasma homocysteine (HC) (enzyme-linked immunosorbent assay) was measured in all aPL patients and in 51 subjects from the healthy control group (mean age, 38 ± 16 years). Heterozygous prothrombin PT G20210A was more frequent in the thrombotic group without APS (18%) than in the control (4%), APS (12%) or aPL (11%) groups, whereas homozygous MTHFR C677 ← T was equally distributed. After genotype sub-grouping, plasma HC was higher in APS patients with homozygous MTHFR C677 ← T compared with non-homozygous APS patients (22 ± 5.4 versus 11 ± 1.3 μmol/l;P < 0.01) and with homozygous MTHFR C677 ← T controls (22 ± 5.4 versus 15 ± 2.0 μmol/l). In the APS group, mean age at first event was lower in homozygous MTHFR C677 ← T patients than in non-homozygous patients (26 ± 7.5 versus 36 ± 13 years;P = 0.008). In the same group, homozygous MTHFR C677 ← T patients suffered an increased average number of events per person than non-homozygous patients (1.9 versus 1.3;P = 0.04). Heterozygous PT G20210A contributes little to the thrombotic tendency of primary APS whereas plasma HC may influence age at first event and number of events. Measurement of plasma HC in aPL subjects may identify patients at increased thrombotic risk requiring HC lowering.

Increased plasma prothrombin concentration in cirrhotic patients with portal vein thrombosis and prothrombin G20210A mutation

It was the aim of the present study to investigate factor II levels in liver cirrhosis (LC) patients with portal vein thrombosis (PVT) carrying the heterozygous G20210A prothrombin (PT) mutation. Plasma concentrations of factor II, VII, X, V, protein C (PC) total protein S (tPS) antithrombin (AT) and D-dimers (DD) were measured in 13 LC patients with PVT heterozygous for PT G20210A, in 13 LC patients with PVT without PT G20210A and in 13 LC controls matched by age, sex and Child-Pugh score. Crude factor II and factor II/DD ratio were highest in LC patients with PVT heterozygous for PT G20210A (p = 0.03 and p = 0.02 respectively). The factor II/PC ratio, expression of a procoagulant/anticoagulant imbalance was highest in the same group (p = 0.0008). Plasma factor II levels are elevated in LC patients heterozygous for PT G20210A and may favour PVT.

Sumatriptan therapy for headache and acute myocardial infarction

Importance of the field: Migraine is a common, debilitating, chronic neurovascular disorder. Triptans are considered the drugs of choice to treat migraine attacks; however, their use is limited owing to concerns about cardiovascular safety. Areas covered in this review: The aim of this review is to describe: the mechanisms of action of triptans; the case-reports of acute myocardial infarction (AMI) associated with sumatriptan use; and the results of studies evaluating its tolerability and safety. What the reader will gain: Sumatriptan administration can be followed, in close temporal relationship, by AMI in young or adult migraine patients. Some of these cases have developed in subjects taking their first dose. Based on the results of prospective studies, the risk of severe cardiovascular adverse events after the use of a triptan is estimated at 1:100,000 treated attacks. These adverse events, albeit very infrequent, highlight the importance of careful adherence to the sumatriptan prescribing information. Take home message: Inherent in its mechanism of action, sumatriptan could produce (coronary) vasospasm sometimes followed by AMI. The drug should not be prescribed to patients with history, symptoms or signs of ischemic vascular disease; an in-depth evaluation should be carried out in subjects at intermediate cardiovascular risk.

Role of thrombophilia in adverse obstetric outcomes and their prevention using antithrombotic therapy.

A series of case-control studies in the last decade have shown the role of inherited thrombophilia in the occurrence of adverse obstetric outcomes. In small series of cases, it has been proven that rare inherited causes of thrombophilia such as natural anticoagulant deficiencies can be associated with fetal losses. The confirmed presence of antiphospholipid antibodies in plasma, representing an acquired thrombophilic condition, is also an established cause of fetal losses, although other studies with a smaller sample size have found an association with other obstetric complications, namely preeclampsia, fetal growth restriction, and abruption placentae. Case-control studies have been performed regarding the potential association between unexplained fetal losses and mild hyperhomocysteinemia. Although case-control and prospective studies are also available regarding hyperhomocysteinemia and other gestational vascular complications, published data are conflicting. Intervention studies have been performed to prevent adverse obstetric outcomes in women with inherited or acquired thrombophilia and previous adverse outcomes. There is much debate in the literature regarding the need for treatment of women with thrombophilia during pregnancy. Although in most cases these are not randomized controlled trials, all studies found significantly better outcomes in treated pregnancies compared with those of untreated pregnancies.

Eosinophilia and Thrombosis in Parasitic Diseases: An Overview

It is known that peripheral blood eosinophilia (PBE) is a normal hematopoietic response to several parasitic diseases, but it is less known that PBE promotes a hypercoagulable state that may favor thrombosis. Scope of this article is to explore which parasitic infestations are most likely to be complicated by thrombosis and to highlight the pathogenetic contribution of PBE to vascular occlusions in this setting. A review of the world literature revealed 18 cases in which PBE was associated with vascular occlusion though no specific surveys were dedicated to this topic. The eosinophil exerts its thrombogenic potential by inhibition of the natural anticoagulant pathways and release of tissue factor with enhanced coagulation activation leading to vascular occlusion. It is hoped that this review contributes to the awareness of the link between PBE and thrombosis in parasitic disorders to foster research in this area.