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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 37 records · Page 2Linked to original sources
PubMed2001

Use of antithrombotic agents during pregnancy.

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE; for the prevention and treatment of systemic embolism in patients with mechanical heart valves; and, often in combination with aspirin, for the prevention of pregnancy loss in women with APLAs or thrombophilia and previous pregnancy losses. Several questions concerning anticoagulant therapy remain unanswered. It appears that LMWH will largely replace UFH. Oral anticoagulants are fetopathic, but the true risks of the warfarin embryopathy and CNS abnormalities remain unknown. There is considerable evidence that warfarin embryopathy occurs only when oral anticoagulants are administered between the sixth week and the 12th week of gestation and that oral anticoagulants may not be fetopathic when administered in the first 6 weeks of gestation. Oral anticoagulant therapy should be avoided in the weeks before delivery because of the risk of serious perinatal bleeding caused by the trauma of delivery to the anticoagulated fetus. The safety of aspirin during the first trimester of pregnancy is still a subject of debate. There is a concern about the efficacy of UFH in the prevention of arterial embolism in pregnant women with mechanical heart valves. Finally, the optimum management of pregnant women with thrombophilia (and prior pregnancy loss and/or prior VTE) is unknown, but trials of anticoagulant therapy are ongoing. Because it is safe for the fetus, LMWH (or UFH) is the anticoagulant of choice during pregnancy for situations in which its efficacy is established. There is some doubt that heparin is effective for the prevention of systemic embolism in patients with mechanical heart valves. Low doses of heparin or poorly controlled heparin therapy are not effective in preventing systemic embolism in patients with mechanical heart valves.

Aspirin↗
PubMed2001

Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study.

To determine whether fibrinolytic testing predicts recurrent venous thrombosis, we have performed a prospective cohort study in which 303 patients with a first episode of venous thromboembolism underwent comprehensive fibrinolytic testing while receiving oral anticoagulants, and after anticoagulants had been discontinued. They were then followed for up to 3 years for recurrent venous thrombosis. No systematic differences in the levels or activity of type 1 plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (tPA) or euglobulin clot lysis times were detected between patients who did, or did not, suffer recurrent thrombosis. There were also no differences in these variables when patients whose initial thrombosis was idiopathic were compared to patients whose thrombosis occurred in the setting of a known thrombotic risk factor. Based on these results, neither measuring fibrinolytic parameters in patients with venous thromboembolism, nor modification of treatment based on the results of such testing, are justified. Our study also confirms that patients with idiopathic venous thromboembolism have a high risk of recurrence.

Anticoagulants↗
PubMed2000

Hypersulfated low molecular weight heparin with reduced affinity for antithrombin acts as an anticoagulant by inhibiting intrinsic tenase and prothrombinase.

In buffer systems, heparin and low molecular weight heparin (LMWH) directly inhibit the intrinsic factor X-activating complex (intrinsic tenase) but have no effect on the prothrombin-activating complex (prothrombinase). Although chemical modification of LMWH, to lower its affinity for antithrombin (LA-LMWH) has no effect on its ability to inhibit intrinsic tenase, N-desulfation of LMWH reduces its activity 12-fold. To further explore the role of sulfation, hypersulfated LA-LMWH was synthesized (sLA-LMWH). sLA-LMWH is not only a 32-fold more potent inhibitor of intrinsic tenase than LA-LMWH; it also acquires prothrombinase inhibitory activity. A direct correlation between the extent of sulfation of LA-LMWH and its inhibitory activity against intrinsic tenase and prothrombinase is observed. In plasma-based assays of tenase and prothrombinase, sLA-LMWH produces similar prolongation of clotting times in plasma depleted of antithrombin and/or heparin cofactor II as it does in control plasma. In contrast, heparin has no effect in antithrombin-depleted plasma. When the effect of sLA-LMWH on various components of tenase and prothrombinase was examined, its inhibitory activity was found to be cofactor-dependent (factors Va and VIIIa) and phospholipid-independent. These studies reveal that sLA-LMWH acts as a potent antithrombin-independent inhibitor of coagulation by attenuating intrinsic tenase and prothrombinase.

Anticoagulants↗
PubMed2000

Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group.

BACKGROUND: Women with a history of venous thromboembolism may be at increased risk for venous thromboembolic events during pregnancy. In these women, the decision to give or withhold heparin in the antepartum period is controversial, because accurate estimates of the frequency of recurrent thromboembolic events if antepartum heparin is withheld are not available. METHODS: We prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. Our primary objective was to determine the rate of antepartum recurrence of venous thromboembolism. Laboratory studies were performed to identify thrombophilia in 95 women. RESULTS: Three of the 125 women (2.4 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 0.2 to 6.9 percent). There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 1.2 to 16.2 percent). CONCLUSIONS: The risk of recurrent antepartum venous thromboembolism in women with a history of venous thromboembolism is low, and therefore routine antepartum prophylaxis with heparin is not warranted.

Adult↗
PubMed2000

Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial.

BACKGROUND: Warfarin-associated coagulopathy is a frequent clinical complication. We aimed to assess whether treatment with vitamin K is safe and more effective than placebo in rapidly lowering the international normalised ratio (INR) into the therapeutic range in over anticoagulated patients receiving warfarin. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised trial in five tertiary care hospitals. In this study, patients receiving warfarin who had an INR value between 4.5 and 10.0, and who did not have an indication for the immediate normalisation of their INR, had their warfarin withheld, and were randomly allocated to receive either 1 mg of vitamin K or placebo orally. The primary outcome measure was the INR value on the day after treatment. Secondary outcome measures included INR values on subsequent days, and the risk of haemorrhage and recurrent thrombosis over a 3 month follow-up period. FINDINGS: Patients given vitamin K had a more rapid decrease in the INR than those given placebo (25 of 45 (56%] vs nine of 44 [20%] patients with INR values of 1.8-3.2 on the day after treatment, respectively, p=0.001; odds ratio [OR] 0.21, 95% CI 0.07-0.57). Fewer patients given vitamin K had bleeding episodes during the follow-up period than those given placebo (two [4%] vs eight [17%] patients, respectively, p=0.050; OR 0.87, 95% CI 0.019-0.999). INTERPRETATION: Low dose oral vitamin K is more effective than placebo for the rapid lowering of raised INR values in patients taking warfarin.

Administration, Oral↗
PubMed2000

Effect of a preoperative intervention on preoperative and postoperative outcomes in low-risk patients awaiting elective coronary artery bypass graft surgery. A randomized, controlled trial.

BACKGROUND: In publicly funded health care systems, a waiting period for such services as coronary artery bypass graft surgery (CABG) is common. The possibility of using the waiting period to improve patient outcomes should be investigated. OBJECTIVE: To examine the effect of a multidimensional preoperative intervention on presurgery and postsurgery outcomes in low-risk patients awaiting elective CABG. DESIGN: Randomized, controlled trial. SETTING: A regional cardiovascular surgery center in a tertiary care hospital, southwestern Ontario, Canada. PATIENTS: 249 patients on a waiting list for elective CABG whose surgeries were scheduled for a minimum of 10 weeks from the time of study recruitment. INTERVENTION: During the waiting period, the treatment group received exercise training twice per week, education and reinforcement, and monthly nurse-initiated telephone calls. After surgery, participation in a cardiac rehabilitation program was offered to all patients. MEASUREMENTS: Postoperative length of stay was the primary outcome. Secondary outcomes were exercise performance, general health-related quality of life, social support, anxiety, and utilization of health care services. RESULTS: Length of stay differed significantly between groups. Patients who received the preoperative intervention spent 1 less day [95% CI, 0.0 to 1.0 day] in the hospital overall (P = 0.002) and less time in the intensive care unit (median, 2.1 hours [CI, -1.2 to 16 hours]; P = 0.001). During the waiting period, patients in the intervention group had a better quality of life than controls. Improved quality of life continued up to 6 months after surgery. Mortality rates did not differ. CONCLUSION: The waiting period for elective procedures, such as CABG, may be used to enhance in-hospital and early-phase recovery, improving patients' functional abilities and quality of life while reducing their hospital stay.

Anxiety↗
PubMed2000

Type II cAMP-dependent protein kinase-deficient Drosophila are viable but show developmental, circadian, and drug response phenotypes.

We identified a unique type II cAMP-dependent protein kinase regulatory subunit (PKA-RII) gene in Drosophila melanogaster and a severely hypomorphic if not null mutation, pka-RII(EP(2)2162). Extracts from pka- RII(EP(2)2162) flies selectively lack RII-specific autophosphorylation activity and show significantly reduced cAMP binding activity, attributable to the loss of functional PKA-RII. pka-RII(EP(2)2162) shows 2-fold increased basal PKA activity and approximately 40% of normal cAMP-inducible PKA activity. pka-RII(EP(2)2162) is fully viable but displays abnormalities of ovarian development and multiple behavioral phenotypes including arrhythmic circadian locomotor activity, decreased sensitivity to ethanol and cocaine, and a lack of sensitization to repeated cocaine exposures. These findings implicate type II PKA activity in these processes in Drosophila and imply a common role for PKA signaling in regulating responsiveness to cocaine and alcohol.

Amino Acid Sequence↗
PubMed2000

Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: The optimal duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. OBJECTIVE: To determine the efficacy and safety of extended out-of-hospital prophylaxis with low-molecular-weight heparin (ardeparin sodium). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 33 community, university, or university-affiliated hospitals. PATIENTS: 1195 adults who had elective total hip or knee replacement and completed 4 to 10 days of postoperative ardeparin prophylaxis. INTERVENTION: Daily subcutaneous ardeparin (100 anti-Xa IU/kg of body weight) or placebo from time of hospital discharge to 6 weeks after surgery. MEASUREMENTS: Symptomatic, objectively documented venous thromboembolism or death, along with major bleeding, from time of hospital discharge to 12 weeks after surgery. RESULTS: Patients who received ardeparin (n = 607) and those who received placebo (n = 588) did not differ significantly in the cumulative incidence of venous thromboembolism or death (9 cases [1.5%] compared with 12 cases [2.0%]; odds ratio, 0.7 [95% CI, 0.3 to 1.7]; P > 0.2; absolute difference, -0.56 percentage points [CI, -2.2 to 1.1 percentage points]) or major bleeding (2 cases [0.3%] compared with 3 cases [0.5%]). CONCLUSIONS: Among patients who had total knee or total hip replacement and received 4 to 10 days of postoperative ardeparin prophylaxis, the cumulative incidence of symptomatic venous thromboembolism or death after hospital discharge was not significantly reduced by extended out-of-hospital ardeparin prophylaxis. Extended ardeparin use could provide a maximum 2.2-percentage point true reduction in such events. The benefit of extended ardeparin use is not clinically important for most patients. Future research should identify high-risk patients who would benefit most from extended prophylaxis.

Adult↗
PubMed2000

Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study.

BACKGROUND: Although the incidence of the postthrombotic syndrome (PTS) has been addressed in patients with symptomatic deep vein thrombosis (DVT), less information is available on the incidence in patients who develop asymptomatic DVT after major hip or knee arthroplasty. OBJECTIVES: To determine whether symptomatic PTS occurs more frequently in patients who develop DVT after hip or knee arthroplasty than those who are free of DVT and to provide an estimate of the incidence of PTS in patients who had undergone major hip or knee arthroplasty and had proximal DVT, distal (calf) DVT, or no DVT. DESIGN AND SETTING: A cross-sectional study conducted at the Hamilton Health Sciences Corporation, Hamilton, Ontario, and the Academic Medical Centre, Amsterdam, the Netherlands. SUBJECTS AND METHODS: Two hundred fifty-five subjects who had undergone major hip or knee arthroplasty 2 to 7 years previously and had routine predischarge venography showing proximal DVT (n = 25), distal DVT (n = 66), or no DVT (n = 164) were enrolled from March 1993 through December 1998. The presence of symptomatic PTS confirmed by the presence of objectively confirmed venous valvular incompetence was ascertained. RESULTS: The rates of PTS were low and not significantly different among the 3 subgroups: 1 (4.0%, 95% confidence interval [CI] = 0.1%-20.4%) of 25 patients with proximal DVT, 4 (6.1%, 95% CI = 1.7%-14.8%) of 66 patients with distal DVT, and 7 (4.3%, 95% CI = 1.7%-8.6%) of 164 patients with no DVT. CONCLUSIONS: Symptomatic PTS is an uncommon complaint after major hip or knee arthroplasty. Patients who develop postoperative proximal or distal DVT and who receive 6 to 12 weeks of anticoagulant therapy are not predisposed to PTS.

Aged↗
PubMed2000

Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study.

BACKGROUND: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate. METHOD: Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study. RESULTS: Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P<.001) and 6 of 7 venous events occurred at lower than 2.0 INRs. CONCLUSIONS: A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.

Administration, Oral↗
PubMed2000

Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster.

Sensitization to repeated doses of psychostimulants is thought to be an important component underlying the addictive process in humans [1] [2] [3] [4]. In all vertebrate animal models, including humans [5], and even in fruit flies, sensitization is observed after repeated exposure to volatilized crack cocaine [6]. In vertebrates, sensitization is thought to be initiated by processes occurring in brain regions that contain dopamine cell bodies [2] [7]. Here, we show that modulated cell signaling in the Drosophila dopamine and serotonin neurons plays an essential role in cocaine sensitization. Targeted expression of either a stimulatory (Galpha(s)) or inhibitory (Galpha(i)) Galpha subunit, or tetanus toxin light chain (TNT) in dopamine and serotonin neurons of living flies blocked behavioral sensitization to repeated cocaine exposures. These flies showed alterations in their initial cocaine responsiveness that correlated with compensatory adaptations of postsynaptic receptor sensitivity. Finally, repeated drug stimulation of a nerve cord preparation that is postsynaptic to the brain amine cells failed to induce sensitization, further showing the importance of presynaptic modulation in sensitization.

Animals↗