Pathogenesis and treatment of the antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is one of the most important causes of thrombophilia, presenting most often as venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. Both the lupus anticoagulant and anticardiolipin antibody are associated with APS. The mechanism of the prothrombotic state is not understood, but may involve beta-2 glycoprotein 1 (a naturally occurring anticoagulant), platelet aggregation, the protein C pathway, or endothelial cell function. The current treatment recommendation, after a venous or arterial thrombosis, is high-intensity, long-term warfarin therapy.     

Thromboembolic disease developing during oral contraceptive therapy in young females with antiphospholipid antibodies

The role of oral contraceptives as a triggering factor for thrombosis in patients with lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA) has not yet been established. We describe the cases of three women aged 19, 29 and 48 years who developed venous thrombosis after 16 +/- 3.4 (mean +/- SD) cycles of oral contraceptives. They were all asymptomatic before taking the pill. Two patients subsequently developed venous and/or arterial recurrence of thrombosis. Laboratory studies performed after the diagnosis of thrombosis, showed the presence of LA and elevated levels of ACA (IgG and IgM) in all three patients. None of these patients had autoimmune diseases and therefore appeared to have a primary antiphospholipid antibody syndrome. The three patients belonged to a group of 45 young females who experienced their first thrombotic event while taking the pill. This group had a similar prevalence (8%) for antithrombin deficiency and antiphospholipid antibodies. We surmise that some of the women who developed venous thrombosis while taking the pill might have an undetected primary antiphospholipid syndrome.     

Recurrence of venous thromboembolism in patients with familial thrombophilia

BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.     

Identification of arg-30 as the essential residue for the enzymatic activity of Taiwan cobra phospholipase A2

Three cohorts of patients with the factor V Leiden mutation were recruited independently (heterozygotes, homozygotes and combined thrombophilia). The antithrombotic efficacy of oral anticoagulation and the predictive value for recurrence of an idiopathic as opposed to a precipitated first event were determined. Idiopathic first events occurred at an older age than precipitated events (43 v 26 years, LR = 23.31, P < 0.001). None of the patients had a recurrent event while on warfarin but the median time to recurrence after stopping warfarin was 9 years (95% CI 0.7-17.3 years). The time to recurrence was shorter when the first event was idiopathic as opposed to precipitated (3.5 v 13 years, LR = 4.76, P = 0.029). A calculation of benefit to risk of oral anticoagulation with a target INR of 2.5 does not support the use of long-term therapy in all patients with the factor V Leiden mutation following a first thrombotic event.     

Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study

OBJECTIVE: To examine the relationship between plasma homocysteine, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism, and the risk of arterial and/or venous thrombosis in systemic lupus erythematosus (SLE). METHODS: Plasma homocysteine and MTHFR polymorphism were determined in a retrospective cohort of 175 patients with SLE. Associations between homocysteine levels and antiphospholipid antibodies, renal function, and drug therapy were analyzed. RESULTS: Patients with arterial thrombosis had higher homocysteine concentration than nonthrombotic patients (20.6+/-10.2 vs 13.2+/-6.8 micromol/l; p < 0.001). The crude odds ratio for arterial thrombosis for the highest versus lowest quartile of homocysteine was 4.4 (95% CI 1.3-14.9). After adjustment for other risk factors the odds ratio remained significant (3.7; 95% CI 1.2-13.0). Increased plasma homocysteine was not associated with venous thrombosis. A significant correlation was found between homocysteine and creatinine (r=0.57, p < 0.0001) or the use of methotrexate. Homocysteine levels were higher in patients using corticosteroids and lower in patients using oral contraceptive drugs. This finding may be biased by impaired renal function in patients using corticosteroids and the advice to stop estrogen-containing contraceptives in female patients upon an episode of thrombosis. The distribution of MTHFR genotypes was 50% for homozygous wild type, 42% for heterozygous, and 8% for homozygous mutant, with a similar distribution among patients with or without a history of thrombosis. CONCLUSION: Raised levels of homocysteine are associated with arterial thrombosis in patients with SLE. Mutation in the MTHFR gene does not explain the raised levels, and renal failure is by far the most frequent cause.     

Doppler-derived left ventricular rate of pressure rise and inotropic requirements during mitral valve surgery

OBJECTIVE: Inherited resistance to activated protein C (APC resistance), which is caused by a single point mutation in the factor V gene, is a frequent risk factor for venous thromboembolism. The aim of this study was to determine the prevalence of APC resistance and other coagulation disorders in fertile women with venous thromboembolism and also the risk factors these women had been exposed to in connection with thromboembolic events. DESIGN: A retrospective, case-control study of 36 month duration. SETTING: The study was carried out at Blekinge Hospital, Karlskrona, Sweden. SUBJECTS: The study population comprised 27 fertile women age 16-47 years with thromboembolic complications, referred to the department of Internal Medicine at Blekinge Hospital in Karlskrona during a 36-month period. RESULTS: APC resistance was found in 10 out of 27 women. APC resistance was associated with treatment with oral contraceptives in five out of six women and with pregnancy in one of seven women. All women with resistance to APC developed venous thrombosis in association with a predisposing situation (risk situation) such as surgery, trauma, immobilization, pregnancy, inflammatory state or the use of oral contraceptives. Amongst women not resistant to APC, all but one developed thrombosis in connection with a risk situation. CONCLUSION: APC resistance was found to be highly prevalent amongst fertile women with a history of thromboembolic complication occurring during their use of oral contraceptives.     

Vascular dopamine-I receptors and atherosclerosis

Four hundred and ninety-three consecutive patients referred for arterial or venous thrombosis were screened for congenital and acquired abnormalities of blood coagulation predisposing to thrombosis, and were compared to 341 age- and sex-matched controls. The aim of the study was to determine the prevalence and clinical characteristics of resistance to activated protein C (APC), a defect shown to have different prevalences in different ethnic groups and to be associated with an increased risk of thrombosis. Seventy-three (15%) patients had both APC resistance and the 1691 G to A factor V gene mutation, compared to 6/341 (2%) controls. Seven patients had antithrombin deficiency (1.4%), 11 had protein C deficiency (2.2%), and 4 had protein S deficiency (0.8%). The relative risk of thrombosis in APC-resistant patients was 9.4. Resistance to APC was associated mainly with venous thrombosis, the most frequent being deep-vein thrombosis of the lower limbs. Fifty-eight percent of APC-resistant patients had an associated risk factor at the first thrombotic event: pregnancy and oral contraceptive intake were associated with the first thrombotic episode in 35% and 30% of women, respectively. APC resistance is the most frequent defect of blood coagulation in the general population and in the unselected thrombotic population studied by us.     

Preventing the cardiotoxic effects of anthracyclines with Cardioxane]

An immune response to heparin, which is clinically manifested by the development of thrombocytopenia with or without thrombosis, is stimulated by a complex of heparin with platelet factor 4 (PF4). The primary thrombotic events in patients with heparin-induced thrombocytopenia (HIT) are more frequently venous than arterial. The development of antibodies, however, does not always result in thrombocytopenia or in catastrophic events. The antibodies, which are of the IgG, IgM, and IgA isotypes, can be easily measured by an ELISA that contains a complex of heparin-platelet factor 4 (PF4). Initial antibody formation can be greatly reduced by limiting the exposure to unfractionated heparin or by the use of low-molecular-weight heparin. For those patients who require anticoagulation and who have antibodies to heparin-PF4, danaparoid (Orgaran), a low-molecular weight heparinoid that does not react with the antibodies, is now commercially available; argatroban, a thrombin-specific inhibitor, can also be obtained for compassionate use. The use of these agents during anticoagulation with warfarin is preferable to the simple discontinuation of heparin and intitiation of warfarin, because the latter treatment can result in ongoing thrombosis.     

Risk of thrombosis with oral contraceptives: value of a thrombophilia screening test

Oral contraceptives increase the natural incidence of venous thrombosis of 1-2/10,000 women per year 3- to 4-fold. Recent studies have shown that desogestrel or gestodene containing formulations bear twice the risk of older low-dose ovulation inhibitors. During pregnancy, the incidence of thrombosis rises to 10/10,000 women-years and post partum up to 40/ 10,000. For 60% of thromboses no causal explanation can be found. In approximately 40% of the patients an inherited thrombophilia can be presumed. Among the hereditary types of thrombophilia, a resistance to activated protein C (APC-resistance) represents nearly 50%, while in 15 to 20% a deficiency of antithrombin III, protein C or protein S is found. APC-resistance, with a prevalence of 3-5% in the general population, increases the risk of thrombosis 8-fold and in users of oral contraceptives 35-fold. Antithrombin III-deficiency carries a comparable risk. Protein C-deficiency increases the risk of thrombosis 9-fold and in users of oral contraceptives 15-fold. Ovulation inhibitors do not influence the risk of thrombosis in women with protein S-deficiency. Anti-phospholipid-antibodies increase during treatment with oral contraceptives and represent a considerably enhanced risk of thrombosis. Inherent thrombophilia is suspected in a patient with a positive history or family history of thrombosis, especially with thrombosis before the age of 40 or with atypical localisation. Even in these risk groups, the cost-benefit ratio of selective screening is unfavorable, as today at most 70% of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few of the patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder. At present, it is unclear whether a selective screening process is superior to a careful assessment of individual and family history. A general screening, however, cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an increased risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombo-embolic event, cannot be identified in advance. If oral contraceptives represent a particularly high risk in patients with thrombophilic disorders and/or other risk factors, other contraceptive methods should be considered. If a patient with risk factors decides on the use of oral contraceptives, she must be informed that in the case of symptoms indicating a thrombosis, a physician should be consulted immediately. The earlier an appropriate therapy is initiated, the more effectively pulmonary thrombo-embolism and permanent damage, such as the post-phlebitic syndrome, can be prevented.     

Anti-phospholipid syndrome: from patient's bedside to experimental animal models and back to the patient's bedside

The availability of animal models of the APS has provided a lot of experimental data which might be considered in trying to unravel several questions concerning this complicated disease. The main clinical manifestations associated with this disorder are repeated pregnancy loss, thrombocytopenia and thrombotic events. Other manifestations have been reported in relation to APS. However, the association with anti-phospholipid antibodies (aPL) are still uncertain. In the APS murine models presented here, both the Lupus-prone mice and the naive mice with induced APS, fetal resorption (parallels to embryo loss) and reduced fecundity rate were prominent features strongly associated with pathogenic aCL antibodies, making these models appropriate for investigating the human disease. Utilizing these models for APS have enabled to show the pathogenicity of aPL in pregnancy loss, neurological and behavioral changes, renal involvement and thrombus formation. Antiphospholipid antibodies from patients with APS, as well as natural aCL antibodies exerted pathogenic effects in naive mice, and in an in vivo thrombosis model. Several therapeutic modalities were found promising for application in the clinics. These include the antithrombotic and anticoagulant treatments using aspirin or LMWH, IL-3, or immunomodulation by high dose IVIG, specific anti-idiotypic or anti-CD4 antibodies, cyprofloxacin or bromocriptin administration.     

Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors

A cooperative, retrospective study was performed on data from 8 coagulation laboratories and thrombosis units in Austria, Germany, and Switzerland to assess the risk for thrombosis in patients with hereditary antithrombin III (AT-III), protein C (PC), and protein S (PS) deficiencies; to compare the clinical manifestations of these 3 deficiency states; and to estimate the risk for development of thrombosis in high-risk situations. Two hundred thirty patients from 71 families with a documented hereditary deficiency of a natural coagulation inhibitor were included in the study. The patient group comprised 69 patients from 25 families with AT-III deficiency, 86 patients from 27 families with PC deficiency, and 75 patients from 19 families with PS deficiency. Diagnosis of the deficiency state was made at each participating center. Clinical data were documented in a questionnaire that was completed during each patient's visit to the participating center. The questionnaires were sent to the coordinating center (Vienna) and analyzed centrally. The probability of developing thrombosis was 80% to 90% for all deficiency states by 50 to 60 years of age, and this figure did not change considerably after data from the propositi were excluded. AT-III-deficient females developed thrombosis earlier in life compared with PC- and PS-deficient females due to a high thrombotic risk during pregnancy (40% in patients with AT-III deficiency) and oral contraceptive use. The clinical features of thromboembolism were similar in the three deficiency states except for a higher frequency of superficial thrombophlebitis in patients with PC and PS deficiencies. Mesenteric vein thromboses occurred in 4% to 10% of patients and in 2 of 8 patients as a recurrent event. The recurrence rate was 63% (60% of recurrent events occurred spontaneously) and did not differ significantly among the three deficiency states. Before 14 years of age only 1 of 80 surgical procedures and 0 of 21 leg injuries were followed by thrombosis. After 14 years of age thromboembolic events occurred after abdominal surgery or leg injury in one third of patients. Between 40% and 50% of symptomatic patients reported that they felt handicapped by a postthrombotic syndrome. We conclude that diagnosis of a coagulation inhibitor deficiency state should be made before 14 years of age. During childhood thrombosis prophylaxis cannot be regularly recommended but should be instituted after 13 years of age during/after abdominal surgery, including appendectomy, and after leg injury in AT-III-, PC-, and PS-deficient patients. The high recurrence rate (60% spontaneous recurrence) and the relatively high frequency of mesenteric vein thrombosis as a recurrent event favor introduction of long-term oral anticoagulant treatment after the first thrombotic event in patients with a documented hereditary deficiency of AT-III, PC, or PS.     

Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is defined by the presence of anti-phospholipid antibodies (aPLs) and venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The syndrome can be either primary or secondary to an underlying condition, most commonly systemic lupus erythematosus (SLE). Echocardiographic studies have disclosed heart valve abnormalities in about a third of patients with primary APS. SLE patients with aPLs have a higher prevalence of valvular involvement than those without these antibodies. Valvular lesions associated with aPLs occur as valve masses (nonbacterial vegetations) or thickening. These two morphological alterations can be combined and are thought to reflect the same pathological process. Both can be associated with valve dysfunction, although such association is much more common with the latter alteration. The predominant functional abnormality is regurgitation; stenosis is rare. The mitral valve is mainly affected, followed by the aortic valve. Valvular involvement usually does not cause clinical valvular disease. The presence of aPLs seems to further increase the risk for thromboembolic complications, mainly cerebrovascular, posed by valve lesions. Superadded bacterial endocarditis is rare but may be difficult to distinguish from pseudoinfective endocarditis. The current therapeutic guidelines are those for APS in general. Secondary antithrombotic prevention with long-term, high-intensity oral anticoagulation is advised. The efficacy of aspirin, either alone or in combination, is yet to be assessed. Corticosteroids are not beneficial and may even facilitate valve damage. Immunosuppressive agents should only be used for the treatment of an underlying condition. Current data suggest a role for aPLs in the pathogenesis of valvular lesions. aPLs may promote the formation of valve thrombi. These antibodies may also act by another mechanism, as indicated by the finding of subendothelial deposits of immunoglobulins, including anticardiolipin antibodies, and of colocalized complement components in deformed valves from patients with APS.     

Antiphospholipid antibodies, haemostatic variables and thrombosis--a survey of 144 patients

Several clotting abnormalities have been put forth to explain the thrombotic tendency of the antiphospholipid syndrome, but a possible role for fibrinogen and von Willebrand factor has been poorly investigated. The present cross-sectional retrospective study evaluated the relationship of IgG anticardiolipin antibodies, lupus anticoagulants, fibrinogen and von Willebrand factor with the occurrence of arterial and venous thromboses in patients with antiphospholipid antibodies. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell's viper venom time correlated with a history of venous thrombosis more strongly than activated partial thromboplastin time (p < 0.0002 vs p < 0.009) and was the only test which correlated with a history of arterial thrombosis (p < 0.01), also at low levels of IgG anticardiolipin antibodies (p = 0.003). By regression analysis, and after correction for confounders, serum levels of IgG anticardiolipin antibodies were found to be positively associated with the number of venous events (p < 0.001). Plasma levels of fibrinogen and von Willebrand factor were associated with each other (p < 0.0001; r: 0.48) and with the occurrence of arterial and venous thromboses (p < 0.001). Moreover, plasma levels of fibrinogen and von Willebrand factor in thrombotic patients with antiphospholipid antibodies were significantly higher than those of a control group of thrombotic patients who suffered thrombosis for other reasons (p < 0.0001 and p = 0.0008 respectively). Titres of IgG anticardiolipin antibodies correlated with plasma levels of von Willebrand factor (p < 0.0001; r: 0.42).(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiological study of angioedema and ACE inhibitors

A total 30,040 pregnancies were reviewed at one institution over 5 years to determine the incidence of venous thrombotic complications. Thirty-one patients experienced such complications related to pregnancy (incidence 0.1%); 13 had deep venous thrombosis and 14 had superficial venous thrombophlebitis diagnosed by duplex ultrasound. Four had pelvic vein thrombophlebitis diagnosed by computed tomography scan; three patients (one from each group) sustained a non-fatal pulmonary embolus. Of those with deep venous thrombosis, 10 (77%) were left-sided, and three (23%) were right-sided. Three had a prior history of deep venous thrombosis and one of pulmonary embolism. Of those with superficial venous thrombophlebitis, seven (50%) were left-sided, six (43%) were right-sided, and one (7%) was bilateral. Most with deep venous thrombosis presented later in pregnancy; three in the first trimester, two in the second, three in the third, and five early postpartum. Most (10/14) with superficial venous thrombophlebitis presented within 48 hours of delivery. Distribution of thrombi in those with deep venous thrombosis was compared with 643 non-pregnant women with a similar condition. A pattern of proximal involvement on the left was found, with left common femoral vein (54% versus 28%, P = 0.03) and superficial femoral vein (62% versus 26%, P = 0.006) more often involved in pregnant patients. The average number of vein segments involved was greater on the left than the right (5.3 versus 3.7). Symptoms of chronic venous insufficiency developed in three with deep venous thrombosis (25%) and in three with superficial venous thrombophlebitis (27%). None had recurrence of deep venous thrombosis. It is concluded that venous thrombotic complications associated with pregnancy are not necessarily benign, with the risk of pulmonary embolism and chronic venous insufficiency not limited to patients with deep venous thrombosis only.     

Weakness of biochemical markers of nutritional and inflammatory status as prognostic indices for growth retardation and morbidity of young children in central Africa

BACKGROUND: Recurrent fetal loss has been well described in women with antiphospholipid antibodies. Such women also often have other autoantibodies commonly found in patients with systemic lupus erythematosus. Treating them with prednisone and aspirin may reduce the risk of fetal loss. METHODS: We screened 773 nonpregnant women who had the unexplained loss of at least two fetuses for antinuclear, anti-DNA, antilymphocyte, and anticardiolipin antibodies and for the lupus anticoagulant. Of 385 women with at least one autoantibody, 202 who later became pregnant were randomly assigned in equal numbers to receive either prednisone (0.5 to 0.8 mg per kilogram of body weight per day) and aspirin (100 mg per day) or placebo for the duration of the pregnancy. The women were stratified according to age (18 to 34 years or 35 to 39 years) and the week of gestation at which the previous fetal losses had occurred (< or = 12 or > 12 weeks). The primary outcome measure was a successful pregnancy. RESULTS: Live infants were born to 66 women in the treatment group (65 percent) and 57 women in the placebo group (56 percent, P=0.19). More infants were born prematurely in the treatment group than in the placebo group (62 percent vs. 12 percent, P<0.001). The major side effects of therapy in the mothers were hypertension (treatment group, 13 percent; placebo group, 5 percent; P=0.05) and diabetes mellitus (15 percent and 5 percent, P=0.02). CONCLUSIONS: Treating women who have autoantibodies and recurrent fetal loss with prednisone and aspirin is not effective in promoting live birth, and it increases the risk of prematurity.     

Risk factors for deep venous thrombosis of the upper extremities

BACKGROUND: Hypercoagulable states and triggering factors (surgery, trauma, immobilization, pregnancy, and use of oral contraceptives) are associated with an increased risk for deep venous thrombosis of the lower extremities. In contrast, risk factors for deep venous thrombosis of the upper extremities have not been identified. OBJECTIVE: To evaluate the prevalence of hypercoagulable states and triggering factors in patients with primary deep venous thrombosis of the upper extremities. DESIGN: Frequency-matched case-control study. SETTING: Hemophilia and thrombosis center at a university hospital. PATIENTS: 36 patients who had primary deep venous thrombosis of the upper extremities, 121 patients who had primary deep venous thrombosis of the lower extremities, and 108 healthy controls. Patients who had deep venous thrombosis of the lower extremities and study controls were frequency-matched by age, sex, geographic origin, and social status with patients who had deep venous thrombosis of the upper extremities. MEASUREMENTS: Resistance to activated protein C was evaluated by a clotting method based on the activated partial thromboplastin time. If test results were abnormal or borderline, DNA analysis for substitution in coagulation factor V gene was done. Antithrombin, protein C, protein S, antiphospholipid antibodies, and total plasma homocysteine levels were also measured. RESULTS: Prevalences of abnormalities of the natural anticoagulant system (9%) and hyperhomocysteinemia (6%) in patients who had deep venous thrombosis of the upper extremities were similar to prevalences of both factors in controls (6% and 7%, respectively) but lower than in patients who had deep venous thrombosis of the lower extremities (31% and 14%, respectively). Antiphospholipid antibodies were found only in patients who had venous thrombosis of the lower extremities (7%). The overall prevalence of hypercoagulable states in patients who had thrombosis of the upper extremities (15%) was similar to that in controls (12%) but was significantly lower than that in patients who had thrombosis of the lower extremities (56%). A recent history of strenuous exercise of muscles in the affected extremity was the most frequent triggering factor for patients who had deep venous thrombosis in the upper extremities (33%). CONCLUSIONS: This preliminary study indicates that the prevalence of hypercoagulable states is low in patients who have primary deep venous thrombosis of the upper extremities.     

The factor V Leiden mutation increases the risk of venous thrombosis in patients with inflammatory bowel disease

BACKGROUND & AIMS: Thromboembolic disease is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). The aim of this study was to determine the incidence and possible association of the factor V Leiden mutation with the development of thrombosis in patients with IBD. METHODS: This retrospective study included 11 patients with IBD and arterial or venous thrombosis and 51 patients with IBD and no history of thrombosis who were matched for age, sex, ethnic/racial origin, and type of IBD (controls). The presence of the factor V Leiden mutation was determined by coagulation assay and confirmed by a polymerase chain reaction method. RESULTS: Four of 11 IBD patients (36%) with thrombosis and 2 of 51 IBD controls (4%) were heterozygotes for the factor V Leiden mutation (relative risk, 14.00; 95% confidence interval, 1.55-169.25; P = 0.009, Fisher exact test). All thrombotic events in the patients with activated protein C resistance were venous with a calculated prevalence of 50% (4 of 8 patients) and a relative risk of venous thrombosis in IBD patients with factor V Leiden of 23 (95% confidence interval, 2-294; P = 0.005). CONCLUSIONS: In patients with IBD, inheritance of the factor V Leiden mutation results in a significant increased risk of venous thrombosis.     

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group

OBJECTIVE: To investigate whether users of oral contraceptives and in [corrected] carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. DESIGN: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. SETTING: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). SUBJECTS: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). MAIN OUTCOME MEASURE: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. RESULTS: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. CONCLUSION: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.     

Incidence and characteristics of fall-related emergency department visits

BACKGROUND: Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies. METHODS AND RESULTS: In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004). CONCLUSIONS: Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.     

Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone

OBJECTIVE: The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome. STUDY DESIGN: A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by chi(2) analysis and Fisher's exact test. RESULTS: Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 +/- 2.1 vs 37.2 +/- 3.4 weeks), number of cesarean sections (18% vs 20%), or complications. CONCLUSION: Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss.