Pregnancy-associated venous thrombosis.

Pregnant women are at an increased risk of venous thromboembolism (VTE) and the consequences of an acute event in pregnancy can be debilitating, long-lasting or fatal. Screening for risk factors early in pregnancy and the provision of thromboprophylaxis are useful ways of preventing VTE in some women, but even when performed diligently, acute events are likely to remain common for the foreseeable future. It is therefore important for obstetric and non-obstetric clinicians to recognize the symptoms and signs of deep vein thrombosis and pulmonary embolism in pregnancy, to understand how a diagnosis can be reached in an effective yet safe manner and to be aware of the available treatment modalities.

Impact of biomarkers for endothelial dysfunction and procoagulant state on 10-year cardiovascular risk in Type 2 diabetes.

AIMS: To estimate the coronary heart disease and cardiovascular disease risk associated with novel biomarkers in Type 2 diabetes mellitus. METHODS: We measured baseline peripheral blood concentrations of soluble E-selectin, factor XIIa, thrombin-antithrombin III complex and plasminogen activator inhibitor-1 in 86 patients with Type 2 diabetes free of known coronary heart disease. We used Cox proportional hazard models to estimate multivariable-adjusted hazard ratios associated with biomarker levels for 10-year coronary heart disease risk (n = 33 events) or total cardiovascular disease risk (n = 45 events). RESULTS: At baseline, mean (sd) age was 62 years (7 years); 62 were men; and 43 had microalbuminuria. Soluble E-selectin demonstrated cross-sectional relationships with glucose and factor XIIa was related to plasminogen activator inhibitor-1 and triglycerides (all P < 0.05). Baseline log soluble E-selectin was significantly related to incident coronary heart disease and cardiovascular disease. Hazard ratios (95% CIs) associated with a 1-unit increase in log soluble E-selectin in age- and sex-adjusted models were: coronary heart disease : 4.6 (95% CI 1.9-11.3), P = 0.001; cardiovascular disease: 3.6 (95% CI 1.7-7.4, P = 0.001); and in multivariable-adjusted models were: coronary heart disease: 2.9 (95% CI 1.2-7.1, P = 0.02); cardiovascular disease: 2.3 (95% CI 1.1-4.8), P = 0.02. Factor XIIa was significantly related to incident cardiovascular disease. The hazard ratios associated with a 1-unit increase in factor XIIa in age- and sex-adjusted models was 1.5 (95% CI 1.1-1.9, P = 0.003) and in a multivariable-adjusted model was 1.3 (95% CI 1.0-1.6, P = 0.047). Plasminogen activator inhibitor-1 and thrombin-antithrombin III complex were not related to cardiovascular disease events. CONCLUSIONS: In our study, soluble E-selectin and factor XIIa were significantly related to 10-year incident macrovascular events in patients with Type 2 diabetes. These preliminary findings call for replication in larger studies.

Early discharge of patients with pulmonary embolism: a two-phase observational study.

The aim of the present study was to assess whether patients with pulmonary embolism (PE) could be managed as outpatients after early discharge from hospital using low molecular weight heparin instead of remaining as in-patients until effective oral anticoagulation was achieved. Phase 1 of the study identified criteria for the safe discharge of selected patients; phase 2 treated a cohort of low-risk patients with PE as outpatients with tinzaparin using existing deep venous thrombosis services. In phase 1, 127 (56.4%) of 225 patients were considered unsuitable for outpatient management. Reasons included: admission for another medical reason; additional monitoring or requirement for oxygen; bleeding disorders; previous PE/further PE while on warfarin; co-existing major deep venous thrombosis; likelihood of poor compliance; significant immobility; and pregnancy. In phase 2, 157 patients with PE received outpatient anticoagulation therapy. There were no deaths, bleeding or recurrent thromboembolic events during acute treatment with low molecular weight heparin. The median (range) length of hospital stay was 1.0 (1-4) day, with a median saving of 5.0 (1-42) bed-days per patient. Patients were highly satisfied with outpatient management; 144 (96.6%) indicated that they would prefer treatment as outpatients for a subsequent pulmonary embolism. Early discharge and outpatient management of pulmonary embolism appears safe and acceptable in selected low-risk patients, and can be implemented using existing outpatient deep venous thrombosis services.

Localized reactive angioendotheliomatosis.

We present a unique case of a woman with multiple painful dermal lesions localized to the left upper quadrant of the body. Histological investigation revealed microvascular thrombosis with capillary-wall proliferation. Further investigation revealed a very high anticardiolipin IgG titre and a left subclavian stenosis, presumably providing the reduced blood flow and relative hypoxia to allow microthromboses to occur in the presence of a thrombophilic tendency. Similar clinical and histological features have been reported in patients with the antiphospholipid syndrome and cases of reactive angioendotheliomatosis (RAE). This case represents a unique variant of RAE.

Dietary vitamin K influences intra-individual variability in anticoagulant response to warfarin.

The relationship between dietary intake of vitamin K, fat, plasma vitamin K concentrations and anticoagulation response to warfarin within individuals, as well as the contribution of dietary vitamin K to differences in warfarin dose requirements between individuals were investigated in 53 patients on warfarin therapy who had stably controlled anticoagulation. Each patient completed a dietary record of all foods consumed on a daily basis for 4 weeks. Each week a blood sample was taken for measurement of the international normalized ratio (INR), plasma vitamin K, triglycerides and warfarin enantiomer concentrations. The patients' genotype for CYP2C9 was also determined. Regression analysis of the data showed that, for each increase of 100 microg in the daily dietary intake of vitamin K averaged over 4 d, the INR was reduced by 0.2. There was no correlation between warfarin daily dose and average daily dietary vitamin K intake when calculated over 28 d. The regression model for warfarin dose showed that, while dietary vitamin K had no effect, CYP2C9 genotype (P = 2%) and age (P < 1%) significantly contributed to inter-patient variability in warfarin dose requirements. A consistent intake of vitamin K could reduce intrapatient variability in anticoagulation response and thus improve the safety of warfarin therapy.

A systematic review of outcome measures reported for the therapeutic effectiveness of oral anticoagulation.

AIMS: To evaluate the evidence of therapeutic international normalised ratio (INR) control reporting and to provide recommendations for future reporting, particularly for research and audit purposes. METHODS: A systematic review of literature published over a five year period describing therapeutic INR control. Papers were identified from the Medline electronic database, and those that met the quality criteria were reviewed independently by an academic general practitioner and a consultant haematologist. RESULTS: Fifteen papers were identified that met the quality criteria for review. The sample size of studies ranged from 53 to 2545 (mean, 483.9) patients. Follow up ranged from three months to 13 years. Twelve studies reported results from secondary care only, one from primary care only, and two from both primary and secondary care. Seven of the 15 papers reported percentage time in range, five of 15 papers reported mean INR, six of 15 papers reported the proportion of tests in range, and five of 15 papers reported mean warfarin dose. Additional methods of presenting INR results were: dose changes each month, distribution of INR results, deviation of INR value from mean, percentage dose changes, time between visits, and median INR value. Six papers reported only one outcome measure, six reported two outcomes, two papers reported three outcomes, and one paper reported five outcomes. CONCLUSIONS: It is recommended that at least two outcome measures should be reported and measures should be selected so that both the INR determinations and dosing advice are monitored.

Incidence of symptomatic thrombosis in a stable population of 650,000: travel and other risk factors.

Despite recent intensive media interest, the incidence of traveler's thrombosis is unknown. We have undertaken a study of all symptomatic cases of venous thrombosis, presenting to a hospital, in a fixed population of 650,000. There were 1,250 cases of venous thromboembolism diagnosed over a 2-yr period. Of these, only 47 (3.8%) answered positively to the question" did you make a journey of more than 100 mi in the 4 wk prior to diagnosis?" Among the travelers, 60% had traveled by air, 36% by road, and the remainder by rail. At least one medical risk factor for venous thrombosis was present in all but three of our cohort. We conclude that, taking into consideration the enormous number of passengers who travel, the relative risk of traveler's thrombosis is likely to be low. The incidence of this complication in the North East of England is 1 per 27,660 of the whole population.

Expression of chemokine receptors CXCR1 and CXCR2 during cardiopulmonary bypass.

OBJECTIVE: This study investigated the effects of cardiopulmonary bypass on neutrophil expression of chemokine receptors, CXCR1 and CXCR2, and the beta2 integrin CD11b. METHODS: Ten patients undergoing coronary artery grafting with cardiopulmonary bypass were studied. Blood samples were collected preoperatively, before bypass, at termination of bypass, and 12 to 18 hours postoperatively. In vitro studies were performed on control subjects to determine changes in the surface expression of CXCR1, CXCR2, and CD11b on stimulation with interleukin 8. Receptor expression was measured by flow cytometry. Plasma levels of interleukin 8 from the patients were determined by enzyme-linked immunoassay. RESULTS: After bypass, CXCR2 expression fell by 66% (P <.0001) and remained low postoperatively (P <.0001). CXCR1 expression persisted at preoperative levels. CD11b expression increased significantly after bypass (P <.0001), returning to prebypass levels postoperatively. In vitro studies showed a dose-related fall of both CXCR1 (P <.0001) and CXCR2 expression (P <.0001) and a significant rise in CD11b expression (P <.0001). Plasma interleukin 8 increased significantly after bypass (P <.0001), remaining elevated 12 to 18 hours postoperatively (P =.02). Correlations between interleukin 8 levels and CXCR2 expression (P <.0001) and CD11b expression (P <.03) were demonstrated. CONCLUSIONS: CXCR2 expression is significantly down-regulated after bypass; in contrast, CXCR1 expression remains unchanged. In addition, whereas interleukin 8 is an important determinant of both CXCR1 and CXCR2 expression in vitro, it only correlates with CXCR2 and CD11b expression in vivo. This has implications in the search for antagonists against CXC chemokines and their receptors.

Clinical risk factors for venous thrombosis associated with air travel.

BACKGROUND: Recent reports have linked air travel with venous thrombo-embolism (VTE). Risk factors and associated features of this link are poorly understood. We have accumulated clinical data from a relatively large cohort of patients with traveler's thrombosis. METHODS: A total of 86 patients who developed venous thromboembolism within 28 d of flying were questioned concerning traveling habits, medical history (including risk factors for VTE) and characteristics of the index flight. RESULTS: Of the patients, 72% had at least one risk factor for VTE (excluding thrombophilia) prior to their flight. Of interest, 87% of VTE cases occurred following either a return trip or after an outward journey involving long trips made up of sequential flights. In only two cases could no identifiable risk factor or earlier journey be found. Duration of flights ranged from 2 to 30 h. Of responders, 38% presented with chest symptoms; 92% with VTE developed symptoms within 96 h of their flight. CONCLUSION: We conclude that the majority of VTE associated with air travel occur in those with identifiable risk factors prior to their flight, and that sequential flights may increase this risk.

Model for assessment of endothelial cell function and viability using the MTT dye test and [3H].

OBJECTIVES: To establish a reproducible in vitro model for evaluating endothelial cell function in clinical disease states. DESIGN: A prospective study of human umbilical vein endothelial cells (HUVEC) isolated and cultured. SETTING: Department of Haematology, University of Yaounde I, Cameroon and Department of Medicine University of Newcastle-upon-Tyne, England. RESULTS: The optimum initial cell seeding concentration, for maximal conversion of the formazan dye was 40 x 10(3) cells/well, after 24 hours incubation. At concentrations above 40 x 103 cells/well some inhibition of dye conversion occurred. The conversion of formazan dye was directly proportional to cell numbers for the first 48 hours only, at all cell concentrations. Thereafter, cell metabolism appeared to be inhibited. Third passage endothelial cells (ECs) were exposed to a range of lipopolysaccharide (LPS) concentrations for one and 24 hours, prior to performing the MTT dye test. Dye conversion was observed after one hour at even the lowest concentration of LPS (0.1 microgram/ml), to 49.9% +/- 5.6% of unperturbed control EC, with 10 x 10(3) initial seeding numbers. After 24 hours perturbation a small but statistically significant further inhibition was observed. [3H] thymidine incorporation studies indicated that the lowest LPS concentration tested (0.1 microgram/ml) had a stimulatory effect on DNA synthesis at the higher cell concentration (20 x 10(3) cells/well). In the range of 1 to 100 micrograms/ml of the LPS tested, there was increased DNA synthesis at all cell numbers. CONCLUSION: The model may be used to monitor the effects of other agents which are known to, or could be associated with, alterations in endothelial cell function and will serve in mimicking clinical situations including hyper coagulable states.

Temporal variations in plasma vitamin K and lipid concentrations and clotting factor activity in humans.

There is no information available on temporal variability in plasma vitamin K concentrations and its relationship to coagulation processes. We investigated the possible existence of temporal changes in plasma vitamin K and lipid concentrations and activity of clotting factors II, VII, IX, and X and relationships between these variables. Plasma vitamin K and lipid concentrations and clotting factor activity were measured at four-hour intervals for 28 hours in a group of healthy volunteers. Temporal variations existed in plasma vitamin K concentrations, with a mean maximum at 22:00 hr and a mean minimum (32% of the maximum) at 10:00 hr. Plasma triglycerol concentrations mirrored the changes in vitamin K concentrations. Mean factor VII activity was positively correlated with mean total plasma cholesterol concentrations (r = 0.714; P < 0.0001) and with mean plasma low density lipoprotein (LDL) cholesterol concentrations (r = 0.461; P < 0.0001). No distinct correlations were found between plasma vitamin K concentrations and either high density lipoprotein (HDL) or LDL cholesterol concentrations, or between triglycerol, HDL, or LDL cholesterol concentrations and functional activity of factors II, IX, and X. Plasma vitamin K concentrations did not correlate with the functional activity of any of the clotting factors. The presence of a correlation between plasma cholesterol concentrations and factor VII activity for blood samples collected at four-hour intervals suggests that plasma cholesterol concentrations may have a more acute effect on factor VII activity. Temporal variations in plasma vitamin K concentrations indicate that a single time point measurement may be an inappropriate method of establishing vitamin K status in an individual.

Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.

BACKGROUND: The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. METHODS: Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. FINDINGS: The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. INTERPRETATION: We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.

Rescue thrombolysis: alteplase as adjuvant treatment after streptokinase in acute myocardial infarction.

BACKGROUND: In acute myocardial infarction patients who do not reperfuse their infarct arteries shortly after thrombolytic treatment have a high morbidity and mortality. Management of this high risk group remains problematic, especially in centres without access to interventional cardiology. Additional thrombolytic treatment may result in reperfusion and improved left ventricular function. METHODS: Failure of reperfusion was assessed non-invasively as less than 25% reduction of ST elevation in the electrocardiographic lead with maximum ST shift on a pretreatment electrocardiogram. 37 patients with acute myocardial infarction who showed electrocardiographic evidence of failed reperfusion 30 minutes after 1.5 MU streptokinase over 60 minutes were randomly allocated to receive either alteplase (tissue type plasminogen activator (rt-PA) 100 mg over three hours) (19 patients) or placebo (18 patients). 43 patients with electrocardiographic evidence of reperfusion after streptokinase acted as controls. Outcome was assessed from the Selvester Q wave score of a predischarge electrocardiogram and a nuclear gated scan for left ventricular ejection fraction 4-6 weeks after discharge. RESULTS: Among patients in whom ST segment elevation was not reduced after streptokinase, alteplase treatment resulted in a significantly smaller electrocardiographic infarct size (14% (8%) v 20% (9%), P = 0.03) and improved left ventricular ejection fraction (44 (10%) v 34% (16%), P = 0.04) compared with placebo. This benefit was confined to patients who failed fibrinogenolysis after streptokinase (fibrinogen > 1 g/l). In patients in whom ST segment elevation was reduced after streptokinase, infarct size and left ventricular ejection fraction were not significantly different from those in patients treated with additional alteplase. CONCLUSION: Patients without electrocardiographic evidence of reperfusion after streptokinase may benefit from further thrombolysis with alteplase.

Do patients with epistaxis have drug-induced platelet dysfunction?

Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) are being used increasingly. A positive correlation has been shown between epistaxis and the use of NSAID in the over 50s. This prospective study compared the NSAID intake and platelet function in 50 patients with epistaxis and 50 controls. Standard haematological parameters and the platelet response to collagen and arachidonic acid aggregation and adenosine triphosphate release were measured. The patients showed a significant increase in NSAID intake (P < 0.01, 95% confidence for the difference in the medians = 4-36%) and hypertension (for diastolic blood pressure > 100 mmHg, P < 0.01, 95% confidence for the difference in the medians = 5.9-16.1). The patients showed a significant reduction in platelet aggregation to collagen (P = 0.025). Non-steroidal anti-inflammatory drugs produce a significant platelet dysfunction which should be considered in the multifactorial aetiology of epistaxis.

A comparison of five commercial thromboplastins: ISI re-evaluation on an automated coagulometer.

Five commercial rabbit brain thromboplastins were compared with an International Reference Preparation on an ACL coagulometer, using 90 patients stabilized on warfarin and 22 normal individuals. The prothrombin times were converted to INRs using the thromboplastin manufacturers' quoted ISI. The quoted ISIs were reassigned using orthogonal regression analysis and then used to recalculate INRs for patient and commercial INR control plasmas. This showed that the manufacturers' quoted ISIs and the INR control plasma results were inconsistent. With one thromboplastin the manufacturers quoted ISI changed from 1.17 to 1.05 whilst the control plasma results changed from an INR of 4.3 to an INR of 3.7 (manufacturer's INR, 3.3). In most routine laboratories ISI reassignment is not practical. We conclude that the availability of a reliable plasma calibrant is essential for the accurate calculation of INRs at a local level.

Autotransfusion after coronary artery bypass surgery: is there any benefit?

Postoperative salvage autotransfusion of shed mediastinal blood, using the cardiotomy reservoir, is an inexpensive technique whose efficacy and safety are evaluated in this study. We randomized 75 consecutive patients into two groups. The autotransfusion group (n = 42) received autotransfusion after the completion of the coronary artery bypass grafting (CABG) until the drainage was < or = 50 mL per hour for 2 consecutive hours. The control group (n = 33) was treated with standard chest drainage. Both groups received homologous blood transfusion when the hematocrit fell below 30%. Packed red cells were required post-operatively in 84.8% of the control group and 80.9% of the autotransfusion group (p = NS). Postoperative colloid fluid replacement (excluding autotransfusion fluid) did not differ significantly between the groups. The prothrombin time was significantly higher in the autotransfusion group 24 hours postoperatively (p = 0.03). The fibrin degradation products were elevated only in the serum of the autotransfusion patients (p < 0.002). More febrile patients were seen in the autotransfusion group although not significantly more than the controls. The autotransfusion group received more red cells than the control group, but it lost more red cells in the mediastinal drains. In conclusion, the autotransfusion of shed mediastinal blood has not proved beneficial in reducing the postoperative requirements in homologous blood in patients undergoing coronary artery bypass grafting (CABG).