Interaction of duloxetine and warfarin causing severe elevation of international normalized ratio.
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Adult↗
Biomedical subjects
Charles J Glueck
Publications and source records attributed to Charles J Glueck.
Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
BACKGROUND: Patients with high levels of low-density lipoprotein cholesterol (LDL-C) might not tolerate 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") because of adverse effects (AEs) and might not respond well enough to nonstatin lipid-lowering therapies (LLTs) to meet LDL-C goals. OBJECTIVE: The purpose of this study was to assess the acceptability, effectiveness, and safety profile of rosuvastatin 5 and 10 mg/d in consecutively referred patients with primary high LDL-C who were unable to tolerate other statins because of myalgia and, subsequently in some cases, unable to reach LDL-C goals with nonstatin LLT. METHODS: This prospective, open-label pilot study was conducted in consecutively referred male and female patients aged 38 to 80 years with primary high LDL-C (mean, 177 mg/dL) at The Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. Patients were instructed in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) therapeutic lifestyle changes diet. Rosuvastatin 5 mg/d was administered to patients categorized by NCEP ATP III risk stratification as moderately high risk, and rosuvastatin 10 mg/d was administered to patients categorized as high or very high risk. End points included acceptability (assessed using patient-initiated discontinuation of rosuvastatin), effectiveness (absolute and percentage reductions in LDL-C and triglycerides), and safety profile (aspartate and alanine aminotransferases [AST and ALT, respectively] >3 times the laboratory upper limit of normal [xULN] or elevations in creatine kinase [CK]>10xULN). RESULTS: A total of 61 patients were enrolled (41 women, 20 men; mean [SD] age, 60 [10] years; 5-mg/d dose, 25 patients; 10-mg/d dose, 36 patients). Myalgia, a predominant AE, had caused 50 patients to previously discontinue treatment with atorvastatin; 30, simvastatin; 19, pravastatin; 5, fluvastatin; 2, ezetimibe/simvastatin; and 1, lovastatin. Eighteen patients subsequently failed to reach LDL-C goals with nonstatin LLT(s) alone (colesevelam, 10 patients; ezetimibe, 8; niacin extended release, 2; and fenofibrate, 1). After a median treatment duration of 16 weeks, rosuvastatin 5 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 75 (34) mg/dL (mean [SD] %Delta, -42% [18%]) (P<0.001 vs baseline). After a median treatment duration of 44 weeks, rosuvastatin 10 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 79 (49) mg/dL (mean [SD] %Delta, -42% [24%]) (P<0.001 vs baseline). Of the 61 patients, 1 receiving the 10-mg/d dose discontinued rosuvastatin treatment because of unilateral muscular pain after 4 weeks; no AST or ALT levels were >3xULN, and no CK levels were >10xULN. CONCLUSION: In these 61 hypercholesterolemic patients unable to tolerate other statins and, subsequently in some cases, unable to meet LDL-C goals while receiving nonstatin LIT monotherapy, these preliminary observations suggest that rosuvastatin at doses of 5 and 10 mg/d+diet was well tolerated, effective, and had a good safety profile.
Adult↗
Beyond bisphosphonates: thrombophilia, hypofibrinolysis, and jaw osteonecrosis.
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Bone Density Conservation Agents↗
Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome.
OBJECTIVES: To test the hypothesis that metformin during lactation versus formula feeding would have no adverse effects on infants' growth, motor-social development, or intercurrent illness. STUDY DESIGN: Growth, motor-social development, and illness requiring a pediatrician visit were assessed in 61 nursing infants (21 male, 40 female) and 50 formula-fed infants (19 male, 31 female) born to 92 mothers with polycystic ovary syndrome (PCOS) taking a median of 2.55 g metformin per day throughout pregnancy and lactation. RESULTS: Within sex, at 3 and 6 months of age, weight, height, and motor-social development did not differ (p > or = .06) between breast- and formula-fed infants. No infants had retardation of growth, motor, or social development. Intercurrent illnesses did not differ. CONCLUSIONS: Metformin during lactation appears to be safe and effective in the first 6 months of infancy.
Adult↗
Plasminogen activator inhibitor activity, 4G5G polymorphism of the plasminogen activator inhibitor 1 gene, and first-trimester miscarriage in women with polycystic ovary syndrome.
We assessed whether hypofibrinolytic plasminogen activator inhibitor 1 (PAI-1 activity) showed an independent association with first-trimester miscarriage in the 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies (from a cohort of 967 women with PCOS). Prospectively, we hypothesized that Glucophage (Bristol-Myers Squibb, Princeton, NJ) promotes successful live births in women with PCOS by lowering PAI-1 activity before conception and maintaining further reductions of PAI-1 activity during the first trimester of pregnancy. We also assessed whether PAI-1 activity levels were independently related to PAI-1 genotype and to modifiable risk factors body mass index (BMI), insulin, and triglyceride. By stepwise logistic regression, with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208]; both > or =1 live birth and > or =1 first-trimester miscarriage [n = 111]; or first-trimester miscarriages only [n = 71]) and explanatory variables PAI-1 genotype, PAI-1 activity, insulin, homeostasis model assessment of insulin resistance, BMI, and triglyceride, PAI-1 activity was positively associated with first-trimester miscarriage (P = .004). For each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage category increased (odds ratio, 1.12; 95% confidence interval, 1.04-1.20). Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-1 activity fell 44%, but rose 19% in 23 women with first-trimester miscarriage (P = .03). In the 30 women with live birth pregnancies, median PAI-1 activity fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), whereas PAI-1 activity was either unchanged or rose in women with first-trimester miscarriage. Of the 921 women with PCOS who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87 (69%) of 126 normal female controls (chi(2) = 4.95, P = .026). The 4G allele frequency was 53% in women with PCOS vs 46% in controls (chi(2) = 4.3, P = .04). Of the 866 women with PCOS who had PAI-1 activity data, by stepwise regression, positive independent determinants of PAI-1 activity included BMI (partial R(2) = 10.6%, P < .0001), insulin (partial R(2) = 2.8%, P < .0001), triglyceride (partial R(2) = 1.1%, P = .0009), and the 4G4G-4G5G genotype (partial R(2) = 1%, P = .0011). The PAI-1 gene 4G polymorphism is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity. Preconception and first-trimester decrements in PAI-1 activity on Glucophage are associated with live births, whereas increments or no change in PAI-1 activity despite Glucophage appears to be associated with first-trimester miscarriage.
Abortion, Spontaneous↗
Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents.
Adolescent girls with polycystic ovary syndrome (PCOS) have increased levels of factors constituting the metabolic syndrome: centripetal obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and hyperinsulinemia. Given the strong association reported between early, persistent obesity and development of metabolic syndrome 10 years later in girls, we speculated that if adolescent girls without PCOS had obesity measures similar to girls with PCOS, they would exhibit similar metabolic syndrome-cardiovascular disease risk factors. Within this context, we compared 37 adolescent girls with PCOS and 2 samples of normal, regularly cycling adolescent girls (controls) of similar ages, selected from the Cincinnati Clinic of the National Heart, Lung, and Blood Institute Growth and Health Study. The first sample included 157 controls selected using a stratified random sample based on age. As expected, girls with PCOS had higher body mass index (BMI), waist circumference, insulin, systolic blood pressure (SBP) and diastolic blood pressure, triglycerides (TGs), lower HDL-C, and higher low-density lipoprotein cholesterol (LDL-C) and free testosterone (FT) than controls. A second sample consisted of girls matched one to one with girls with PCOS for BMI and age. Comparisons of group differences were not significant for insulin, lipids, or blood pressure; girls with PCOS had a trend toward higher values for waist circumference (median, 92.7 vs 87.5 cm; P = .07) and much higher median FT (4.25 vs 1.42 ng/mL, P = .0001). After matching for BMI and age, by conditional regression analysis, we showed that the groups were not differentiated (P > .15) by insulin, HDL-C, LDL-C, TG, SBP, or diastolic blood pressure, but were differentiated by higher FT (P = .0024) and waist circumference (P = .0024) in PCOS than in controls. Prospective longitudinal analyses of NHGS controls showed that changes in BMI from ages 9 to 10 years to ages 15 to 16 years were positively associated with changes in waist circumference (P < .0001), LDL-C (P = .01), TG (P = .008), and SBP (P = .002). These findings suggest that if adolescent girls achieve adiposity equal to girls with PCOS, they then acquire major components of the metabolic syndrome, and excluding high FT and waist circumference, comparable increased cardiovascular disease risk.
Adolescent↗
Sustainability of 8% weight loss, reduction of insulin resistance, and amelioration of atherogenic-metabolic risk factors over 4 years by metformin-diet in women with polycystic ovary syndrome.
In 74 women with polycystic ovary syndrome, treated for 4 years with metformin (MET) and diet, we prospectively assessed whether, and to what degree, weight loss, reduction of insulin resistance, and amelioration of coronary heart disease risk factors could be sustained. We hypothesized that response to MET-diet would not differ by pretreatment body mass index (BMI) classes <25 (normal), > or =25 to <30 (overweight), > or =30 to <40 (obese), and > or =40 (extremely obese). [table: see text] Metformin-diet was successful in producing stable approximately 8% weight reduction for all 4 years (trend P < .0001). Percentage of reductions in weight on MET-diet was significant (P < .05) and did not differ among the 3 highest BMI categories (> or =40, > or =30 to <40, > or =25 to <30), but were not significant in the normal-weight category (BMI, <25). On MET-diet, median homeostasis model assessment of insulin resistance (HOMA-IR) was 33% lower than entry at 1 year, 50% at 2 years, 51% at 3 years, and 50% at 4 years (trend, P < .0001). On MET-diet, median low-density lipoprotein cholesterol (LDL-C) was 6% lower than entry at year 1, 6% at year 2, 7% at year 3, and 11% at year 4 (trend P < .0001). On MET-diet, median high-density lipoprotein cholesterol (HDL-C) was 3% higher than entry at year 2, 8% higher at year 3, and 11% higher at year 4 (trend P < .0001). Percentage of reductions in HOMA-IR, LDL-C, triglyceride, and systolic blood pressure, and increments in HDL-C did not differ (P > .1) in the 4 BMI categories. By stepwise regression, weight loss was a significant (P < or = .01) positive explanatory variable for reduction in HOMA-IR for all 4 follow-up years. Metformin-diet in women with polycystic ovary syndrome effectively and safely reduces weight and LDL-C while raising HDL-C, and maintains these outcomes stable over 4 years.
Atherosclerosis↗
Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia.
The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS. Changes in weight, papilledema, headache, visual fields, and overall life status were prospectively assessed in response to 6 to 14 months on 2.25 g/day MET-diet or diet alone in 36 women with IIH, 23 with PCOS, selected by baseline body mass index (BMI) > or = 25, and no previous surgery for IIH. Overall life status was graded using a self-reported 1-5 scale (1 = well, normal activities; 2 = unwell, usual activities; 3 = poor, usual activities; 4 = poor, no usual activities; 5 = totally disabled). Conventional treatment for IIH was maintained unchanged during MET-diet intervention. The diet was hypocaloric (1500 calories/day), high protein (26% of calories), and low carbohydrate (44%). Of the 23 women with PCOS, 20 received MET-diet and 3 diet only (could not tolerate MET). Of the 13 women without PCOS, 7 were hyperinsulinemic and received MET-diet and 6 received diet alone. The 3 treatment groups (diet only [n = 9], PCOS-MET-diet [n = 20], and hyperinsulinemia-MET-diet [n = 7]) did not differ by median entry BMI (33.3, 37.6, and 35.7 kg/m(2)) or by duration of treatment (10.2, 11.4, and 10.9 months). Median percent weight loss was greatest in the PCOS-MET group (7.7%, P = 0.0015), was 3.3% in the diet only group, and 2.4% (P = 0.04) in the hyperinsulinemia-MET group. Papilledema significantly improved in the diet-alone group from 100% at baseline to 13% (P = 0.03), and in the PCOS-MET group from 95% to 30% (P = 0.002). If headache persisted on therapy, it was less intense-less frequent (P = 0.03) in the diet-only group and in the PCOS-MET group (P = 0.04). As many women with IIH have PCOS, and because weight loss is central to IIH treatment, diet-MET is a novel approach to treat IIH in women with concurrent PCOS or hyperinsulinemia without PCOS.
Adolescent↗
Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease.
Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.
DNA↗
Response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia.
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Diet Therapy↗
Obesity and extreme obesity, manifest by ages 20-24 years, continuing through 32-41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy.
OBJECTIVES: Document obesity-extreme obesity in most 20-24, 25-29, and 32-41 years old women with PCOS as a stimulus for physicians to consider the diagnosis of PCOS, an underlying reversible endocrinopathy. STUDY DESIGN: In matched age groups 20-24, 25-29, and 32-41 years, we compared BMI in 84, 129, and 188 Caucasian women with PCOS versus 956, 815, and 815 women in NHANES I (general population), and 25, 36, and 45 non-pregnant women (community obstetrics practice). RESULTS: At ages 20-24, 25-29, and 32-41 years, mean+/-S.D. BMIs in women with PCOS (35.3+/-7.7, 36.0+/-9.4, 36.7+/-8.2) were much greater than NHANES I (22.8+/-4.6, 23.3+/-5.0, 24.5+/-5.6; p < .0001), and community (26.1+/-6.8, 26.9+/-6.6, 25.2+/-5.2; p < .0001). Classifying BMI <25 (normal), > or =25-30 (overweight), > or =30-40 (obese), > or =40 (extremely obese), at ages 20-24, 25-29, and 32-41 years: 76, 73, and 78% of PCOS women were obese-extremely obese, versus 7, 11, and 14% of NHANES I, and 20, 28, and 15% of community women. At ages 20-24, 25-29, and 32-41 years, only 10, 12, and 7% PCOS women had BMIs <25, versus 78, 74, and 66% NHANES I, and 48, 47, and 58% of community women. CONCLUSIONS: Obesity-extreme obesity in women, manifest by ages 20-24 years, continuing through 32-41 years, should alert physicians to the likelihood of PCOS, an underlying, heritable, potentially reversible, insulin resistant endocrinopathy that promotes obesity.
Adult↗
Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia.
We studied thrombophilia, hypofibrinolysis, and polycystic-ovary syndrome (PCOS) in 65 women consecutively referred because of idiopathic intracranial hypertension (IIH) as a means of better understanding the origin of IIH, with the ultimate goal of developing novel medical therapies for IIH. Our hypothesis: IIH results in part from inadequate drainage of cerebrospinal fluid (CSF) resulting from thrombotic obstruction to CSF resorption-outflow, favored by thrombophilia-hypofibrinolysis. We conducted the polymerase chain reaction (PCR) and assessed serologic coagulation measures in 65 women (64 of them white) with IIH, PCR in 102 healthy white female controls (72 children, 30 age-matched adults), and serologic measures in the 30 adults. Of the 65 patients, 37 (57%) were found to have PCOS; 16 (43%) were obese (BMI > or = 30 to < 40), and 19 (51%) were extremely obese (BMI > or = 40). Of the 65 women with IIH, 25 (38%) were homozygous for the thrombophilic C677T MTHFR mutation, compared with 14% of controls (14/102) ( P = .0002). Thrombophilic high concentrations of factor VIII (>150%) were present in 9 of 65 (14%) IIH cases, compared with 0 of 30 controls (0%) (Fisher's p [p f ] = .053). An increased concentration of lipoprotein A (> or = 35 mg/dL), associated with hypofibrinolysis, was present in 19 of 65 IIH cases (29%), compared with 3 of 30 controls (10%) (p f = .039). IIH occurred in 18 of 65 IIH patients taking estrogen-progestin contraceptives (28%), in 6 patients taking hormone-replacement therapy (9%), and in 5 pregnant subjects (8%). We speculate that PCOS, associated with obesity and extreme obesity, is a treatable promoter of IIH. We also speculate that if thrombophilia-hypofibrinolysis and subsequent thrombosis are associated with reduced CSF resorption in the arachnoid villi of the brain, thrombophilia and hypofibrinolysis-often exacerbated by thrombophilic exogenous estrogens, pregnancy, or the paradoxical hyperestrogenemia of PCOS-are treatable promoters of IIH.
Adolescent↗
Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance.
We prospectively assessed whether metabolic and menstrual benefits of metformin-diet were equally realized in women with polycystic ovary syndrome (PCOS), categorized by pretreatment top (n = 32) and bottom (n = 35) quintile homeostasis model assessment insulin resistance (IR). Effects of metformin (2.55 g/d) and diet (6300-8400 J/d [1500-2000 cal/d], 26% protein, 44% carbohydrate) were prospectively assessed for 12 months. Pretreatment, the bottom and top insulin-resistant quintile groups differed by median weight (84 vs 121 kg), insulin (7.8 vs 40.5 I(1/4) U/mL), IR (1.62 vs 9.28), homeostasis model assessment insulin secretion (131 vs 416), glucose (82 vs 98 mg/dL), sex hormone-binding globulin (40 vs 15 nmol/L), (all P < .0001), free androgen index (2.76 vs 10.8) ( P < .001), triglyceride (92 vs 131 mg/dL), high-density lipoprotein (46 vs 39 mg/dL), systolic blood pressure (116 vs 128 mm Hg), and diastolic blood pressure (76 vs 84 mm Hg), (all P < .01). After 12 months on metformin-diet, weight fell by 7% in both insulin-resistant groups (P < .0001), insulin, IR, and insulin secretion fell in the top insulin-resistant group by 60%, 64%, and 39% (all P < .0001), with smaller reductions in the bottom insulin-resistant group of 18%, 13% (P > .05 for both), and 22% (P < .01), respectively. The free androgen index fell 39% (P > .01) in the top insulin-resistant group. The pretreatment percentage of expected menses in the top insulin-resistant quintile (26 +/- 39%) was 1.6 times less than in the bottom insulin-resistant quintile (41 +/- 38%) (P = .026). Over the 12-month treatment period, the percentage of spontaneous regular normal menses increased to 72 +/- 27% in the top insulin-resistant quintile group (P < .0001) and to 77 +/- 31% in the bottom quintile group (P < .0001), with no group difference (P = .33). Metformin-diet metabolic effects were much more marked in women in the top vs the bottom quintile for IR. Women with PCOS in the bottom insulin-resistant quintile, conventionally thought not to respond optimally to metformin-diet, nevertheless experience significant metabolic and menstrual benefits. Metformin-diet should benefit most women with PCOS, even those with normal serum insulin, without IR.
Blood Pressure↗
The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage.
We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common significant cause of sporadic first trimester miscarriage. We compared thrombophilia and hypofibrinolysis in 92 women (85 white, 5 black, 2 other) with 1 or more pregnancies and 1 miscarriage (143 live births, 92 miscarriages) (cases) and in 380 female controls (355 white, 21 black, 4 other) with 1 or more pregnancies and 0 miscarriages (964 live births). We used polymerase chain reaction techniques to characterize thrombophilic gene mutations (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic gene mutations (plasminogen activator inhibitor [PAI-1] activity 4G4G). We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]). Of the 380 controls, 6 (1.6%) had FV heterozygosity vs 12 heterozygous and 2 homozygous FV cases (15.2% [14/92]; P < .0001). Plasminogen activator inhibitor activity was high (> or =21.1 U/mL) in 21 (33%) of 63 cases vs 27 (18%) of 152 controls (P = .013). Factor VIII was high (>150%) in 15 (31%) of 48 cases vs 19 (18%) of 103 controls (P = .079). By logistic regression, with age and factor VIII (categorical [< or =150%, >150%]) as explanatory variables and group (cases, controls) as the dependent variable, after adjusting for age, high factor VIII was a significant predictor for miscarriage (odds ratio, 3.28; 95% confidence interval, 1.34-8.04; P = .01). There were no other group differences (P > .05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic first trimester miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and factor VIII, etiologies for sporadic miscarriage.
Abortion, Spontaneous↗
Enoxaparin prevents progression of stages I and II osteonecrosis of the hip.
UNLABELLED: In a prospective pilot study, we hypothesized that enoxaparin (60 mg/day for 12 weeks) would prevent progression of Stages I and II osteonecrosis of the hip associated with thrombophilia or hypofibrinolysis or both over > or = 108 weeks of followup versus untreated historic controls, with different treatment responses in primary versus corticosteroid-associated secondary osteonecrosis. Patients with one or more thrombophilic-hypofibrinolytic disorder and Ficat Stages I or II osteonecrosis of at least one hip were included. A blinded committee interpreted anteroposterior and frog-leg lateral radiographs at entry in the study and every 36 weeks to > or = 108 weeks. Maintenance of the disease at Stages I and II versus progression of the osteonecrosis to Stages III and IV requiring total hip replacement was the major end point. Sixteen patients had primary osteonecrosis (25 hips; 13 Stage I, 12 Stage II), and 12 had secondary osteonecrosis (15 hips; five Stage I, 10 Stage II). With no Enoxaparin-related complications, 19 of 20 hips (95%) with primary osteonecrosis were unchanged from Stages I and II osteonecrosis at > or = 108 weeks; 12 of 15 hips (80%) with secondary osteonecrosis progressed to Stages III and IV osteonecrosis. In primary osteonecrosis at > or = 108 weeks, survival of 95% hips, or 76% (19/25 hips, based on intent to treat), compared favorably with untreated historical controls (approximately 20% 2-year survival), comparable to 20% survival in secondary hip osteonecrosis. Enoxaparin may prevent progression of primary hip osteonecrosis, decreasing the incidence of total hip replacement. LEVEL OF EVIDENCE: Therapeutic study, II-1 (prospective cohort study).
Arthroplasty, Replacement, Hip↗
The John Charnley Award: heritable thrombophilia and development of thromboembolic disease after total hip arthroplasty.
UNLABELLED: We retrospectively assessed whether heritable thrombophilia-hypofibrinolysis was more common in patients developing venous thromboembolism after total hip replacement than among control patients who did not develop venous thromboembolism, as an approach to better identify causes of venous thromboembolism after total hip arthroplasty. Twenty patients with proximal deep venous thrombosis after THA and 23 patients with symptomatic pulmonary embolism were compared with 43 control patients who did not have postoperative venous thromboembolism. Five of 42 patients with venous thromboembolism (12%) and 0 of 43 control patients (0%) had antithrombin III deficiency (< 75%). Nine of 42 patients with venous thromboembolism (21%) and 2 of 43 control patients (4.7%) had protein C deficiency (< 70%). Ten of 43 patients with venous thromboembolism (9 heterozygous, 1 homozygous; 23%) and 1 of 43 control patients (heterozygous; 2%) had the prothrombin gene mutation. Patients who had venous thromboembolism after total hip arthroplasty were more likely than matched control patients to have heritable thrombophilia with antithrombin III or protein C deficiency, or homo-heterozygosity for the prothrombin gene mutation. Screening for these three tests of heritable thrombophilia before total hip arthroplasty should improve the identification of patients with a reduced risk of venous thromboembolism who may need only mild thromboprophylaxis, and of those patients with heritable thrombophilia in whom prophylaxis should be more aggressive. LEVEL OF EVIDENCE: Prognostic study, Level II-1 (lesser-quality RCT). See the Guidelines for Authors for a complete description of levels of evidence.
Adult↗
Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion.
We prospectively assessed whether thrombophilia and hypofibrinolysis, amplified by thrombophilic hormone replacement therapy (HRT), were associated with retinal vein occlusion (RVO). We studied 44 cases (18 men, 26 women), > or = 3 months after RVO, 42 with central RVO, 2 with branch RVO, in the consecutive order of their referral by 2 community-based ophthalmologists. PCR and serologic coagulation assays were compared to 83 and 40 healthy adult normal controls, respectively. The 4G allele frequency of the plasminogen activator inhibitor-1 (PAI-1) gene, associated with hypofibrinolysis, was 56 of 88 (64%) in cases vs 79 of 166 (48%) in controls, X(2) = 5.95, p = .015. The PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx), was higher in cases than controls (age-race-sex- adjusted mean 12.2 U/mL vs 6.3, p = .013). By stepwise logistic regression, the PAI-1 gene 4G allele was associated with RVO, odds ratio 1.94, 95% CI 1.12-3.34, p = .018. Thrombophilic resistance to activated protein C (RAPC) was present in 6 of 32 (19%) of cases vs 0 of 40 (0%) controls, Fisher's p [p(f)] = .006. Thrombophilic high factor VIII (> 150%) was present in 3 of 30 (10%) cases vs 0 of 40 (0%) controls, p = .041, p(f) = .07. Comparing 23 RVO cases < or = age 55 and controls < or = age 55 (n = 44 for PCR, n = 40 for serologic measures), RAPC was present in 17% of cases vs 0% controls (p(f) = .026), high Factor VIII in 17% vs 0% (p(f) = .026), heterozygosity for the G1691A Factor V Leiden mutation in 13% vs 2% (p(f) = 0.11), and the 4G allele frequency of the PAI-1 gene 74% vs 39% (p = .0001). PAI-Fx was higher in cases than controls (age-race-sex adjusted mean 12.7 U/mL vs 6.7, p = .016). The case-control odds ratio for the PAI-1 4G allele was 5.54, 95% CI = 1.86-16.7, p = .002. Of the 26 women, 9 (35%) took HRT; 4 of the 9 had PAI-1 gene 4G4G homozygosity, 2 had thrombophilic high anticardiolipin antibody (IgG), 1 was heterozygous for the G1691A Factor V Leiden mutation, and 2 were heterozygous for the thrombophilic PL A1/A2 mutation of the platelet glycoprotein IIb/IIIa gene. Associations between heritable coagulation disorders and RVO, most marked in cases < or = age 55, and often amplified in women by thrombophilic HRT, are, speculatively, causal.
Adult↗
Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men.
The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.
Adolescent↗