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Mark Crowther

Publications and source records attributed to Mark Crowther.

34 records · Page 2Linked to original sources
PubMed2005

Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population.

BACKGROUND: The use of anticoagulant therapy is expanding among the elderly population, in part because of the increasing prevalence of atrial fibrillation. Published data describing the warfarin maintenance dose requirements for this age group are limited. Because warfarin therapy is often initiated in the outpatient setting where significant barriers to daily monitoring exist for this patient population, a better understanding of the factors that predict lower dose requirements may reduce the risk of unanticipated over-anticoagulation and hemorrhage. OBJECTIVE: To define the effects of age and gender on the warfarin maintenance dose among ambulatory adult patients with an international normalized ratio target between 2.0 and 3.0. DESIGN: Prospective cohort study and retrospective cohort secondary data source. SETTING: One hundred one community-based physician practices with dedicated warfarin management systems and an academic medical center anticoagulation clinic. PATIENTS: A total of 4,616 patients comprised the prospective cohort, and 7,586 patients comprised the retrospective cohort. Of the 12,202 patients, 2,359 were > or = 80 years of age. MEASUREMENTS: Median weekly and daily maintenance warfarin dose. RESULTS: The warfarin dose was inversely related to age and was strongly associated with gender. The median weekly dose ranged from 45 mg (6.4 mg/d) for men who were < 50 years of age to 22 mg (3.1 mg/d) for women > or = 80 years of age. The weekly dose declined by 0.4 mg/yr (95% confidence interval [CI], 0.37 to 0.44; p < 0.001) and women required 4.5 mg less per week than men (95% CI, 3.8 to 5.3; p < 0.001). Among patients who were > 70 years of age, the often-suggested initiation dose of 5 mg/d will be excessive for 82% of women and 65% of men. CONCLUSIONS: Warfarin dose requirements decrease greatly with age. Older women require the lowest warfarin doses. These observations suggest that, when warfarin is being initiated, the commonly employed empiric starting dose of 5 mg/d will lead to over-anticoagulation for the majority of patients in the geriatric age group; lower initiation and maintenance doses should be considered for the elderly.

Adult↗
PubMed2005

Proficiency testing of reticulocyte counting in Ontario.

The reticulocyte count reflects the erythropoietic activity of the bone marrow and is thus useful in both the approach to the diagnosis of anemia and in monitoring bone marrow response to therapy. Traditionally, reticulocyte quantitation relied upon microscopic techniques; recently automated reticulocyte quantitation has become widely available. External quality assessment (EQA) of reticulocyte quantitation has not been widely reported; this paper presents data from reticulocyte EQA surveys conducted in Ontario between November 2000 and October 2004. Samples with normal and increased reticulocyte levels were obtained from adult donors and analyzed within 48 hours. We found that despite improved accuracy and precision, automated reticulocyte counting techniques do not translate into markedly improved inter-laboratory accuracy and precision. Further, we found that both microscopic and automated techniques can effectively differentiate between patients with normal and those with increased reticulocyte counts. Finally, we ascertained that reference intervals submitted with the initial surveys revealed that laboratories could have made erroneous clinical interpretations of their normal or elevated reticulocyte counts. The reestablishment of reference intervals by participants resulted in a marked improvement of the reference intervals submitted on subsequent surveys.

Adult↗
PubMed2004

Patients with severe sepsis vary markedly in their ability to generate activated protein C.

Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis.

APACHE↗
PubMed2004

Clinically important deep vein thrombosis in the intensive care unit: a survey of intensivists.

INTRODUCTION: Outside the intensive care unit (ICU), clinically important deep vein thrombosis (DVT) is usually defined as a symptomatic event that leads to objective radiologic confirmation and subsequent treatment. The objective of the present survey is to identify the patient factors and radiologic features of lower limb DVT that intensivists consider more or less likely to make a DVT clinically important in ICU patients. METHODS: Our definition of clinically important DVT was a DVT likely to result in short-term or long-term morbidity or mortality if left untreated, as opposed to a DVT that is unlikely to have important consequences. We asked respondents to indicate the likelihood that patient factors and ultrasonographic features make a DVT clinically important using a five-point scale (from 1 = much less likely to 5 = much more likely). RESULTS: Of the 71 Canadian intensivists who responded, 70 (99%) rated three patient factors as most likely to make a DVT clinically important: clinical suspicion of pulmonary embolism (mean score 4.6), acute or chronic cardiopulmonary morbidity that might limit a patient's ability to tolerate pulmonary embolism (score 4.5), and leg symptoms (score 4.2). Of the ultrasound features, proximal (score 4.7), large (score 4.2), and totally occlusive (score 3.9) thrombi were considered the three most important. CONCLUSION: When labeling a DVT as clinically important, intensivists rely on different patient specific factors and thrombus characteristics than are used to assess the clinical importance of DVT outside the ICU. The clinical importance of DVT is influenced by unique factors such as cardiopulmonary reserve among mechanically ventilated patients.

Adult↗
PubMed2004

Outcome of pregnancy in homozygous sickle cell disease.

OBJECTIVE: Previous reports on pregnancy in homozygous sickle cell (SS) disease are biased by hospital-based, more severely affected subjects and may have underestimated recurrent early pregnancy losses. We report pregnancy outcome in a representative sample of SS subjects subsequently referred to as "subjects" or "sickle cell subjects," and matched normal controls followed from birth. METHODS: The outcomes of 94 pregnancies in 52 subjects and 157 pregnancies in 68 controls followed in a cohort study from birth are presented. Outcome measures included the age at menarche, interval to first pregnancy, outcome of pregnancy, and maternal complications. Possible predictors of low birth weight are assessed. Outcomes were compared by the Kaplan-Meier analysis for interval to first pregnancy and by Student t test, chi(2) test, or Fisher exact test, as appropriate. Correction was made for multiple testing, and multiple linear regression was used for analysis of birth weight. RESULTS: Compared with controls, SS subjects had later menarche (median age 15.4 versus 13.0 years) and first pregnancy (median age 23.7 versus 20.1 years), and more spontaneous abortions (36% versus 10%). Babies of SS subjects had a lower gestational age (P <.001) and lower birth weight (P <.001), the latter being significantly affected by sickle-related events in pregnancy. There was no difference in pregnancy-induced hypertension, preeclampsia, or antepartum or postpartum hemorrhage, but a retained placenta was marginally more common in SS subjects (Fisher exact test, P =.007 after adjustment for multiple testing). Two SS subjects died, a mortality rate of 2.1%. CONCLUSION: The increased fetal loss and maternal morbidity in mothers with homozygous sickle cell disease is confirmed. LEVEL OF EVIDENCE: II-2

Abortion, Spontaneous↗
PubMed2004

Methodology for guideline development for the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This article describes the methodology for the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Guideline authors began by specifying the population, the intervention and alternative, and the outcomes for each clinical question, and defined the criteria for eligible articles, including methodological criteria, for each recommendation. Librarians, in collaboration with guideline authors and methodologists, conducted systematic searches for evidence. Guideline authors systematically evaluated the evidence, considered the full range of benefits, risks, inconvenience, and costs associated with alternative management strategies, considered patients' underlying values and preferences, and made recommendations accordingly. To increase the likelihood that the recommendations adequately represent patient values and preferences, the development process included a review of recommendations by research methodologists, practicing generalists, and specialists. Chapters are organized so that evidence is clearly linked to the relevant recommendations, and that recommendations particularly sensitive to underlying values and preferences are explicitly identified. Authors paid careful attention to the strength of the underlying evidence and to the balance between risks and benefits, which are both reflected in the grades of recommendations. Thus, improvements to the process of making recommendations for the ACCP guidelines include the explicit definition of questions, transparent eligibility criteria for including studies, and the specification of values and preferences underlying recommendations where they are particularly relevant. In combination with our previous practice of grading recommendations according to their strength, and the methodological quality of the supporting studies, these innovations establish our guidelines as, by and large, evidence based.

Bias↗
PubMed2004

New anticoagulants: an update.

There has been an explosion of new anticoagulants in recent years. new parenteral anticoagulants have been developed to overcome the limitations of heparin and low molecular weight heparin , whereas novel orally active anticoagulants have been designed to provide more streamlined therapy than vitamin K antagonists. Focusing on drugs in more advanced stages of clinical testing, this review identifies the molecular targets of new anticoagulants, describes the results of clinical trials, and provides perspective on the opportunities for new anticoagulants.

Anticoagulants↗
PubMed2003

A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis.

BACKGROUND: Because clinical diagnosis is inaccurate, objective testing is usually considered necessary when patients present with suspected deep venous thrombosis (DVT). OBJECTIVE: To determine whether a negative result on a quantitative latex D dimer assay eliminates the need for further investigation in patients with a low or moderate pretest probability of DVT. DESIGN: Prospective cohort study. SETTING: Three tertiary care hospitals in Canada. PATIENTS: 556 consecutive outpatients with suspected first DVT. INTERVENTION: Patients were categorized as having a low, moderate, or high pretest probability of DVT and then underwent D-dimer testing. Patients with low or moderate pretest probability and a negative D-dimer result had no further diagnostic testing and received no anticoagulant therapy. Serial compression ultrasonography was performed in all other patients. Patients who did not receive a diagnosis of DVT were followed for symptomatic venous thromboembolism. MEASUREMENTS: Objectively confirmed symptomatic venous thromboembolic events during 3 months of follow-up. RESULTS: 283 patients (51%) had low or moderate pretest probability and a negative D-dimer result. One of these patients had DVT during follow-up (negative likelihood ratio, 0.05 [CI, 0.01 to 0.23]). The negative likelihood ratio of the d -dimer test in all patients was 0.03 (CI, 0.01 to 0.16). CONCLUSION: A negative result on a quantitative latex d -dimer assay safely eliminates the need for further testing in patients with low or moderate pretest probability of DVT.

Fibrin Fibrinogen Degradation Products↗
PubMed2003

Fetal-maternal hemorrhage detection in Ontario.

The results from fetal-maternal hemorrhage (FMH) detection and quantitation external quality assessment surveys conducted in Ontario indicate that the rosette test had a sensitivity and specificity for an FMH of more than 10 mL of 1.0 and 0.75, respectively, compared with 0.96 and 0.92, respectively, for acid elution. With FMH quantitation, the percentage error of the mean from the target FMH was 20% or more in 7 of 8 surveys, and coefficients of variation ranged from 39.5% to 71.8%. Inadequate Rho(D) immune globulin prophylaxis could have occurred in 19.4% of the challenges with an FMH of more than 10 mL. The rosette and acid elution techniques are both effective for the detection or exclusion of FMH, but acid elution lacks adequate accuracy and precision for reliable FMH quantitation. Furthermore, a strategy of prescribing an extra 1,500-IU Rho(D) immune globulin dose, in addition to the dose required to treat the volume of fetal blood detected, is an effective strategy to overcome the limitations of FMH quantitation by acid elution.

Adult↗
PubMed2002

Direct thrombin inhibitors.

Thrombin plays a central role in thrombosis. Consequently, most current antithrombotic treatment strategies are aimed at blocking the activity of thrombin, or preventing its generation. Although heparin has been a cornerstone of treatment, it has limitations. Thus, the anticoagulant response to heparin is unpredictable, the heparin/antithrombin complex is unable to inhibit fibrin-bound thrombin, an important trigger of thrombus growth, and heparin is neutralized by platelet factor 4. Direct thrombin inhibitors were developed to overcome these limitations. Unlike heparin, direct thrombin inhibitors produce a predictable anticoagulant response that is unaffected by platelet factor 4, and they inhibit fibrin-bound thrombin. Three parenteral direct thrombin inhibitors--hirudin, bivalirudin and argatroban--are currently licensed for use in North America, and orally available direct thrombin inhibitors are under investigation. This review summarizes the clinical trial data with direct thrombin inhibitors and provides perspective on the role of direct thrombin inhibitors in the face of other new anticoagulants currently under development.

Anticoagulants↗
PubMedDate not supplied

Is impaired renal function a contraindication to the use of low-molecular-weight heparin?

BACKGROUND: Because of the risk of accumulation of anticoagulant effect, it has been suggested that patients with a creatinine clearance of 30 mL/min or less (< or =0.50 mL/s) should be excluded from treatment with low-molecular-weight (LMW) heparin, or have anti-factor Xa heparin level monitoring performed. OBJECTIVE: To assess the appropriateness of this recommendation. METHODS: We performed a systematic search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts to identify prospective articles comparing differences in the pharmacokinetics of LMW heparins in nondialyzed patients with varying degrees of renal function. Reference lists of retrieved reports were checked for additional articles. RESULTS: Three single-dose pharmacokinetic trials and 2 multiple-dose deep vein thrombosis (treatment trials met our selection criteria. The 3 trials that could address our primary objective did not support the use of a 30-mL/min (0.50-mL/s) cutoff of creatinine clearance to select individuals at risk of accumulation when LMW heparin is used. Four of the 5 trials support the notion that anti-factor Xa activity of some LMW heparin preparations accumulates in patients with impaired creatinine clearance. Tinzaparin sodium, an LMW heparin with a higher-than-average molecular weight distribution, appears to be the exception, since it did not exhibit accumulation in patients with creatinine clearances as low as 20 mL/min (0.33 mL/s). CONCLUSIONS: The use of a 30-mL/min (0.50-mL/s) cutoff is not justified, on the basis of currently available evidence, to select individuals at increased risk of accumulation when LMW heparin is used. The pharmacokinetic response to impaired renal function may differ among LMW heparin preparations.

Adult↗