Myeloperoxidase (MPO) is a microbicidal and reactive species-generating enzyme. It traditionally is considered to be stored mostly within polymorphonuclear leukocytes and is strongly implicated in the pathogenesis of numerous diseases. MPO also has been studied for at least 20 years as a marker of hemodialysis procedure biocompatibility and oxidative stress generation; research yielded discordant and inconclusive results. In this review, a novel and growing body of evidence indicating that MPO also is a potent blood vessel-bound enzyme that can be mobilized rapidly and extensively into circulating blood by exogenous heparin is discussed. Beneficial consequences of such evoked arterial wall MPO depletion that may be counterbalanced in part by the harmful effects of circulating MPO on polymorphonuclear leukocyte activation and thus atherosclerosis propagation also are presented. Potential clinical implications of these undervalued phenomena in commonly atherosclerotic maintenance hemodialysis patients regularly administered large doses of heparin for temporary blood anticoagulation (frequently over years) are stressed, including the challenging issue of morbidity and mortality. In view of the plausible clinical importance of the novel MPO-oxidative stress-heparin interaction in this population, the need for additional studies assessing different dialyzer membranes, various heparin types (unfractionated heparin versus low-molecular-weight heparins versus pentasaccharides), as well as different anticoagulation regimens, is emphasized.

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment.

Massive pulmonary embolism (PE) is a life-threatening condition with a high early mortality rate due to acute right ventricular failure and cardiogenic shock. As soon as the diagnosis is suspected, an IV bolus of unfractionated heparin should be administered. In addition to anticoagulation, rapid initiation of systemic thrombolysis is potentially life-saving and therefore is standard therapy. Many patients with massive PE cannot receive thrombolysis because of an increased bleeding risk, such as prior surgery, trauma, or cancer. In these patients, catheter or surgical embolectomy are helpful for rapidly reversing right ventricular failure. Catheter thrombectomy appears to be particularly useful if surgical embolectomy is not available or the patient has contraindications to surgery. Although no controlled clinical trials are available, data from cohort studies indicate that the clinical outcomes after surgical and catheter embolectomy may be comparable.

BACKGROUND

Patients undergoing gastric bypass surgery are at risk for postoperative venous thromboembolism. Thromboprophylaxis often includes fixed doses of some type of heparin. However, it is unlikely that the same dose of subcutaneous heparin will be optimal for all patients, because heparin pharmacokinetics depend on a number of patient variables, including thickness of the adipose layer.

METHODS

An adjusted-dose, unfractionated heparin protocol was developed using pharmacokinetic data from 245 medical and surgical patients. Heparin doses were adjusted to achieve subtherapeutic peak anti-factor Xa heparin activity levels of 0.11-0.25 units/mL. This protocol was then applied to a prospective series of 700 patients undergoing laparoscopic Roux-en-Y gastric bypass who had no history of thromboembolism. Heparin prophylaxis was begun the evening of the day of surgery.

RESULTS

No patients were diagnosed with a deep venous thrombosis, but 3 (0.4%) were diagnosed with a non-fatal pulmonary embolism. Heparin therapy was halted because of bleeding in 2.3% of patients but only half of these required blood transfusions (1% of total). No patient required reoperation. Minor wound hematomas occurred in 0.6%. There were no deaths from any cause in this series.

CONCLUSIONS

Use of a monitored, adjusted-dose unfractionated heparin prophylactic protocol in a laparoscopic gastric bypass patient population resulted in doses greater than those used in traditional fixed-dose protocols. However, bleeding and thromboembolism rates were very low and no patients died.

BACKGROUND

Venous thromboembolism (VTE) often complicates the clinical course of cancer disease. The risk is further increased by chemotherapy but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain.

OBJECTIVE

To assess the efficacy and safety of primary thromboprophylaxis in ambulatory cancer patients receiving chemotherapy.

METHODS

The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 3 May 2011) and CENTRAL (2011, Issue 2). The authors searched clinical trials registries and reference lists of relevant studies.

METHODS

Randomised controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), direct thrombin inhibitors, direct factor Xa inhibitors or mechanical intervention to no intervention or placebo; or comparing two different anticoagulants.

METHODS

Data were extracted on methodological quality, patients, interventions and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.

RESULTS

Nine RCTs with a total of 3538 patients were considered. None of the RCTs tested UFH, fondaparinux, direct factor Xa inhibitors or mechanical interventions. Overall, the risk of bias was low in most of the studies. LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.41 to 0.93) with no evidence of heterogeneity (I(2) = 0%). The number needed to treat to prevent a symptomatic VTE was 60. LMWH was associated with a 60% increase in major bleeding when compared with inactive control, although this was not statistically significant (RR 1.57, 95% CI 0.69 to 3.60; I(2) = 10%). There was a 45% reduction in overall VTE (RR 0.55, 95% CI 0.34 to 0.88; I(2) = 0%) while for symptomatic pulmonary embolism, asymptomatic VTE, minor bleeding and one-year mortality the differences between the LMWH and control groups were not statistically significant. The effect of the vitamin K antagonist warfarin on preventing symptomatic VTE, measured in only one study, was not statistically significant (RR 0.15, 95% CI 0.02 to 1.20). In one RCT of patients with myeloma, LMWH was associated with a 67% reduction in symptomatic VTE (RR 0.33, 95% CI 0.14 to 0.83) compared with warfarin, with no differences in major bleeding. Antithrombin, evaluated in one study on paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control.

CONCLUSIONS

Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. However, the lack of power hampers definite conclusions on the effects on major safety outcomes, which mandates additional studies to determine the risk to benefit ratio of LMWH in this setting.

Heparin-induced thrombocytopenia (HIT) is the most common drug-induced, antibody-mediated cause of thrombocytopenia and thrombosis. HIT is caused by IgG antibodies that bind to epitopes on platelet factor 4 (PF4) released from activated platelets that develop when it forms complexes with heparin. Anti-PF4/antibodies develop in over 50% of patients undergoing surgery involving cardiopulmonary bypass (CPB), an incidence 20-fold higher than HIT. Why might this occur? Binding of HIT IgG occurs only over a narrow molar ratio of reactants, being optimal at 1 mol PF4 tetramer to 1 mol unfractionated heparin (UFH). At these ratios, PF4 and UFH form ultralarge (>670 kD) complexes that bind multiple IgG molecules/complex, are highly antigenic, and promote platelet activation. Low molecular weight heparin (LMWH), which is less antigenic, forms ultralarge complexes less efficiently and largely at supratherapeutic concentrations. In transgenic mice that vary in expression of human PF4 on their platelets, antigenic complexes form between PF4 and endogenous chondroitin sulfate. Binding of HIT IgG to platelets and induction of thrombocytopenia in vivo is proportional to PF4 expression. Heparin prolongs the duration and exacerbates the severity of the thrombocytopenia. High doses of heparin, as used in CPB, or protamine, which competes with PF4 for heparin, disrupts antigen formation and prevents thrombocytopenia induced by HIT antibody. These studies may help explain the disparity between the incidence of antibody formation and clinical disease and may help identify patients at risk for HIT (high platelet PF4). They also demonstrate that this autoimmune disease can be modulated at the level of autoantigen formation and point to rational means to intervene proximal to thrombin generation.

BACKGROUND

Prophylaxis for venous thromboembolism (VTE) in head injured patients has avoided heparin products because of concern for exacerbating intracranial bleeding. The purpose of this study was to evaluate the safety of unfractionated heparin (UFH) for VTE prophylaxis after traumatic brain injury.

METHODS

We retrospectively evaluated the early use of UFH in patients sustaining a severe closed head injury (Abbreviated Injury Scale score>> 3) from January 1, 2000, through December 31, 2000. Two groups were formed on the basis of the timing of UFH administration: within 72 hours of admission (Early group), or after the third day of hospitalization (Late group), if at all. Intracranial bleeding related to UFH administration was assessed by computed tomographic scan of the head and/or clinical examination.

RESULTS

Sixty-four of 76 patients with intracranial blood on admission head computed tomographic scan fulfilled study criteria. Seventy-three percent (n = 47) were in the Early group and 27% (n = 17) were in the Late group. None of the Early group had an increase in intracranial bleeding or deterioration on neurologic examination as a result of UFH administration. However, there was no statistical difference in VTE events between the two groups.

CONCLUSIONS

Early use of UFH in the severe head injured patient does not increase bleeding complications.

Enoxaparin is a low-molecular-weight heparin (LMWH) that differs substantially from unfractionated heparin (UFH) in its pharmacodynamic and pharmacokinetic properties. Some of the pharmacodynamic features of enoxaparin that distinguish it from UFH are a higher ratio of anti-Xa to anti-IIa activity, more consistent release of tissue factor pathway inhibitor, weaker interactions with platelets and less inhibition of bone formation. Enoxaparin has a higher and more consistent bioavailability after subcutaneous administration than UFH, a longer plasma half-life and is less strongly bound to plasma proteins. These properties mean that enoxaparin provides a more reliable anticoagulant effect without the need for laboratory monitoring, and also offers the convenience of once-daily administration. Clinical studies have confirmed that these pharmacological advantages translate into improved outcomes. There are important pharmacokinetic and pharmacodynamic differences between enoxaparin, other LMWHs and UFH, and therefore these molecules cannot be regarded as interchangeable.

The acute respiratory illnesses caused by severe acquired respiratory syndrome corona Virus-2 (SARS-CoV-2) is a global health emergency, involving more than 8.6 million people worldwide with more than 450,000 deaths. Among the clinical manifestations of COVID-19, the disease that results from SARS-CoV-2 infection in humans, a prominent feature is a pro-thrombotic derangement of the hemostatic system, possibly representing a peculiar clinicopathologic manifestation of viral sepsis. The severity of the derangement of coagulation parameters in COVID-19 patients has been associated with a poor prognosis, and the use of low molecular weight heparin (LMWH) at doses registered for prevention of venous thromboembolism (VTE) has been endorsed by the World Health Organization and by Several Scientific societies. However, some relevant issues on the relationships between COVID-19, coagulopathy and VTE have yet to be fully elucidated. This review is particularly focused on four clinical questions: What is the incidence of VTE in COVID-19 patients? How do we frame the COVID-19 associated coagulopathy? Which role, if any, do antiphospolipid antibodies have? How do we tackle COVID-19 coagulopathy? In the complex scenario of an overwhelming pandemic, most everyday clinical decisions have to be taken without delay, although not yet supported by a sound scientific evidence. This review discusses the most recent findings of basic and clinical research about the COVID-associated coagulopathy, to foster a more thorough knowledge of the mechanisms underlying this compelling disease.

Keywords: Antiphospholipid antibodies; COVID-19; Coagulopathy; D-dimer; Disseminated intravascular coagulation; Low molecular weight heparin; Sepsis-induced coagulopathy; Unfractionated heparin; Venous thromboembolism.

Background: Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness has recently been initiated in the United States. To date, there remains a paucity of high-quality evidence to inform clinical practice world-wide. Therefore, the objective of this scientific statement is to provide consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses, and to identify priorities for future research.

Methods: We surveyed 20 pediatric hematologists and pediatric critical care physicians from several continents who were identified by Pediatric/Neonatal Hemostasis and Thrombosis Subcommittee leadership as having experience and expertise in the use of anticoagulant thromboprophylaxis and/or the management of COVID-19-related illness in children. A comprehensive review of the literature on COVID-19 in children was also performed.

Results: Response rate was 90%. Based on consensus of expert opinions, we suggest the administration of low-dose low molecular weight heparin subcutaneously twice-daily as anticoagulant thromboprophylaxis (in the absence of contraindications, and in combination with mechanical thromboprophylaxis with sequential compression devices, where feasible) in children hospitalized for COVID-19-related illness (including the multisystem inflammatory syndrome in children [MIS-C]) who have markedly elevated D-dimer levels or superimposed clinical risk factors for hospitalassociated VTE. For children who are clinically unstable or have severe renal impairment, we suggest the use of unfractionated heparin by continuous intravenous infusion as anticoagulant thromboprophylaxis. In addition, continued efforts to characterize VTE risk and risk factors in children with COVID-19, as well as to evaluate the safety and efficacy of anticoagulant thromboprophylaxis strategies in children hospitalized with COVID-19-related illness (including MIS-C) via cooperative multicenter trials, were identified among several key priorities for future research.

Conclusion: These consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses and priorities for future research will be updated as high-quality evidence emerges.

Keywords: COVID‐19; SARS‐CoV‐2; children; thromboprophylaxis; venous thromboembolism.

Due to various side effects of heparin, such as heparin-induced thrombocytopenia type I or type II, alternative anticoagulants are in clinical development to optimize the anticoagulant regimes in patients requiring low or high anticoagulation dosages. Sulodexide is a highly purified preparation containing a fast-moving heparin fraction as well as dermatansulfate. The pharmacological effects of sulodexide differ substantially from unfractionated heparin and are mainly characterized by a prolonged half-life and reduced effect on global coagulation and bleeding parameters. The lipolytic activity of sulodexide is increased in comparison to unfractionated heparin. Clinical studies demonstrate the safety and efficacy of sulodexide. Specially, oral administration leads to fibrinolytic activities in contrast to oral administration of other glycosaminoglycans. Thus, sulodexide releases tissue plasminogen activator and decreases fibrinogen levels as well as HDL and total cholesterol levels and blood viscosity. Clinical efficacy is demonstrated in peripheral arterial disease, cardiovascular events, in postphlebitic syndrome and on albuminuria in nephropathy.

BACKGROUND

Venous thromboembolism (VTE) confers considerable morbidity and mortality in hospitalized patients, although few studies have focused on the critically ill population. The objective of this study was to understand current approaches to the prevention and diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) among patients in the intensive care unit (ICU).

METHODS

Mailed self-administered survey of ICU Directors in Canadian university affiliated hospitals.

RESULTS

Of 29 ICU Directors approached, 29 (100%) participated, representing 44 ICUs and 681 ICU beds across Canada. VTE prophylaxis is primarily determined by individual ICU clinicians (20/29, 69.0%) or with a hematology consultation for challenging patients (9/29, 31.0%). Decisions are usually made on a case-by-case basis (18/29, 62.1%) rather than by preprinted orders (5/29, 17.2%), institutional policies (6/29, 20.7%) or formal practice guidelines (2/29, 6.9%). Unfractionated heparin is the predominant VTE prophylactic strategy (29/29, 100.0%) whereas low molecular weight heparin is used less often, primarily for trauma and orthopedic patients. Use of pneumatic compression devices and thromboembolic stockings is variable. Systematic screening for DVT with lower limb ultrasound once or twice weekly was reported by some ICU Directors (7/29, 24.1%) for specific populations. Ultrasound is the most common diagnostic test for DVT; the reference standard of venography is rarely used. Spiral computed tomography chest scans and ventilation-perfusion scans are used more often than pulmonary angiograms for the diagnosis of PE. ICU Directors recommend further studies in the critically ill population to determine the test properties and risk:benefit ratio of VTE investigations, and the most cost-effective methods of prophylaxis in medical-surgical ICU patients.

CONCLUSIONS

Unfractionated subcutaneous heparin is the predominant VTE prophylaxis strategy for critically ill patients, although low molecular weight heparin is prescribed for trauma and orthopedic patients. DVT is most often diagnosed by lower limb ultrasound; however, several different tests are used to diagnose PE. Fundamental research in critically ill patients is needed to help make practice evidence-based.

BACKGROUND

Dysregulation of coagulation and local fibrinolysis found in patients with acute lung injury often results in the need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and suppression of fibrinolytic activity, but the mechanisms are unclear. We hypothesized that subcutaneous injections of unfractionated heparin and enoxaparin would decrease neutrophil infiltration, lung edema, and plasminogen-activator inhibitor-1 (PAI-1) production in mice exposed to high-tidal-volume ventilation.

METHODS

Male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume (30 ml/kg) or low-tidal-volume (6 ml/kg) mechanical ventilation with room air for 1 to 5 hours after 200 IU/kg or 400 IU/kg unfractionated heparin and 4 mg/kg or 8 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet- to dry-weight ratio, histopathologic grading of epithelium, myeloperoxidase, and gene expression of PAI-1 were measured. The expression of PAI-1 was studied by immunohistochemistry.

RESULTS

High-tidal-volume ventilation induced increased microvascular permeability, neutrophil influx, PAI-1 mRNA expression, production of PAI-1 protein, and positive staining of PAI-1 in epithelium in a dose-dependent manner. Lung injury induced by high-tidal-volume ventilation was attenuated with PAI-1-deficient mice and pharmacologic inhibition of PAI-1 activity by low-dose unfractionated heparin and enoxaparin.

CONCLUSIONS

We conclude that high-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx, lung PAI-1 mRNA expression, production of active PAI-1. The deleterious effects were attenuated by low-dose unfractionated heparin or enoxaparin treatment. Understanding the protective mechanism of unfractionated heparin and enoxaparin related to the reduction of PAI-1 may afford further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.

BACKGROUND

We evaluated venous thromboembolism (VTE) prophylaxis rates in hospitalized medical patients in a teaching hospital, the State University of New York-Downstate Medical Center-University Hospital of Brooklyn, before and after implementation of a multifaceted VTE prophylaxis quality improvement intervention that combined regular education, dissemination of a decision support tool, and regular audit-and-feedback to resident physicians.

METHODS

The charts of 312 hospitalized medical patients were retrospectively reviewed to assess baseline rates of appropriate VTE prophylaxis. Rates of appropriate VTE prophylaxis were then determined 12 and 18 months after implementation of the quality improvement intervention. Data collected included risk factors for VTE, contraindications to anticoagulant prophylaxis, type of VTE prophylaxis prescribed, and whether the prophylaxis was appropriate.

RESULTS

Most of the hospitalized medically ill patients had 3 or more risk factors for VTE. At baseline, the proportion of patients receiving any form of VTE prophylaxis, primarily unfractionated heparin, was 47%. The proportion of patients for whom a physician provided appropriate prophylaxis was 43%. After the intervention, the proportion of patients receiving prophylaxis significantly increased, to 86% at 12 months, and this level was maintained at 18 months. The rate of appropriate prophylaxis increased to 68% and 85% after 12 and 18 months, respectively.

CONCLUSIONS

The proportion of hospitalized medical patients receiving appropriate VTE prophylaxis as recommended by evidence-based guidelines can be increased significantly by combining regular education, a decision support tool, and regular audit-and-feedback.

BACKGROUND

Pulmonary embolism after acute ischemic stroke (AIS) is associated with a high in-hospital mortality. The benefit from pharmacological prophylaxis for venous thromboembolism (VTE) is uncertain probably due to doubts about the optimal agent and dose. We evaluated the benefit/risk ratio of different anticoagulant regimens in the prevention of VTE in patients with AIS.

METHODS

The MEDLINE, EMBASE, and Cochrane Library databases were searched up to January 2005. Randomized controlled trials (RCT) comparing early administration of either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) with control were included. Endpoints were objectively diagnosed deep-vein thrombosis (DVT), pulmonary embolism, intracranial hemorrhage (ICH), and extracranial hemorrhage (ECH). Low-dose UFH was arbitrarily defined as < or =15,000 IU/day, low-dose LMWH as < or =6000 IU/day or weight-adjusted dose of < or =86 IU/kg/day.

RESULTS

Sixteen trials involving 23,043 patients with AIS met the inclusion criteria. The number of events was small and different doses of anticoagulant treatment were used. Compared to control, high-dose UFH was associated with a reduction in pulmonary embolism (OR=0.49, 95% confidence interval (CI)=0.29-0.83), but also with an increased risk of ICH (OR=3.86, 95% CI=2.41-6.19) and ECH (OR=4.74, 95% CI=2.88-7.78). Low-dose UFH decreased the thrombosis risk (OR=0.17, 95% CI=0.11-0.26), but had no influence on pulmonary embolism (OR=0.83, 95% CI=0.53-1.31); the risk of ICH or ECH was not statistically significant increased (OR=1.67, 95% CI=0.97-2.87 for ICH; and OR=1.58, 95% CI=0.89-2.81 for ECH, respectively). High-dose LMWH decreased both DVT (OR=0.07, 95% CI=0.02-0.29) and pulmonary embolism (0.44, 95% CI=0.18-1.11), but this benefit was offset by an increased risk for ICH (OR=2.01, 95% CI=1.02-3.96) and ECH (OR=1.78, 95% CI=0.99-3.17). Low-dose LMWH reduced the incidence of both DVT (OR=0.34, 95% CI=0.19-0.59) and pulmonary embolism (OR=0.36, 95% CI=0.15-0.87), without an increased risk of ICH (OR=1.39, 95% CI=0.53-3.67) or ECH (OR=1.44, 95% CI=0.13-16). For low-dose LMWH, the numbers needed to treat were 7 and 38 for DVT and pulmonary embolism, respectively.

CONCLUSIONS

Indirect comparison of low and high doses of UFH and LMWH suggests that low-dose LMWH have the best benefit/risk ratio in patients with acute ischemic stroke by decreasing the risk of both DVT and pulmonary embolism, without a clear increase in ICH or ECH.

The risk for venous thromboembolism (VTE) is high in hospitalized cancer patients, and is associated with an elevated risk for recurrent thrombosis, bleeding complications, and use of health care resources. Thromboembolism is the second leading cause of death in hospitalized cancer patients. Thromboprophylaxis with unfractionated heparin or low-molecular-weight heparins has been clinically proven to reduce the risk for VTE and improve outcomes. However, VTE prophylaxis continues to be underprescribed in cancer patients. Recognizing the clinical burden of VTE in cancer patients, the National Comprehensive Cancer Network (NCCN) recently released guidelines for VTE prevention and management. These NCCN guidelines recommend evidence-based prophylactic anticoagulant therapy for all patients admitted to hospital with a diagnosis of cancer who do not have contraindications to anticoagulant use. However, there continue to be barriers to the implementation of clinical practice guidelines and appropriate use of VTE prophylaxis. Multifaceted active educational and electronic interventions are necessary to raise awareness and reduce the burden of cancer-associated thrombosis and its attendant consequences.

OBJECTIVE

To determine the extent of 15 hospital-based clinical pharmacy services, 51 different drugs managed under protocol by pharmacists, medication errors, and pharmacy technology in United States hospitals.

METHODS

A survey was mailed, as well as sent electronically, to pharmacists in 2893 hospitals.

RESULTS

A total of 1125 surveys were returned (38.9% response rate). The 1125 hospitals had 14,315,506 patients admitted, which represented 45.7% of the 31,324,496 admissions to all U.S. hospitals in 2006. The proportion of clinical pharmacy services provided by Veterans Affairs (VA) hospitals was higher compared with non-VA hospitals. In all hospitals, the clinical pharmacy services with the greatest growth from 1989-2006 were pharmacist-provided admission drug histories (300% increase), pharmacist participation on medical rounds (292.3% increase), drug protocol management (208% increase), pharmacist-conducted clinical research (166.7% increase), pharmacist-provided drug information (150% increase), and pharmacist-provided pharmacokinetic consultation (117.5% increase). A total of 864 hospitals (76.8%) had pharmacists providing drug protocol management (collaborative drug management). Pharmacists managed a mean +/- SD of 9.18 +/- 10.23 different drugs/hospital (7932 protocols). Drugs commonly managed included aminoglycosides (64.4% of hospitals), vancomycin (63.8%), warfarin (37.8%), low-molecular-weight heparins (32.7%), unfractionated heparin (30.0%), fluoroquinolones (30.0%), antiparkinsonian drugs (22.8%), proton pump inhibitors (22.7%), human immunodeficiency virus drugs (21.9%), and cephalosporins (19.7%). The mean number of medication errors reported/hospital increased by 151.4% between 1995 and 2006. The percentage of patients who experienced a medication error increased from 4.7% to 6.5% between 1995 and 2006 (a 38.3% increase). A total of 220 hospitals (19.6%) had computerized prescriber order entry systems, 263 (23.4%) had bar coding for drug administration, and 439 (39.0%) used robotics for dispensing.

CONCLUSIONS

This study provides continuing evidence of the growth and value of clinical pharmacy services and clinical pharmacists in our nation's hospitals. These data will guide hospital pharmacy directors and clinical coordinators in allocating resources to optimally meet their patients' needs.

As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low-molecular-weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect-acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin-induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available-lepirudin, bivalirudin, and argatroban-with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5-2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short-term efficacy and safety appear promising. Further research is needed regarding long-term safety and efficacy for other anticoagulation indications.

BACKGROUND

Venous thromboembolic disease has been extensively studied in surgical patients. The benefit of thromboprophylaxis is now generally accepted, but it is medical patients who make up the greater proportion of the hospital population. Medical patients differ from surgical patients with regard to their health and the pathogenesis of thromboembolism and the impact that preventative measures can have. The extensive experience from thromboprophylaxis studies in surgical patients is therefore not necessarily applicable to non-surgical patients.

OBJECTIVE

To determine the effectiveness and safety of heparin thromboprophylaxis in general medical patients.

METHODS

The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 24 April 2009) and the Cochrane Central Register of Controlled Trials in The Cochrane Library (last searched Issue 2, 2009)We handsearched meeting abstracts, and consulted with colleagues and investigators as well as the manufacturers of the various LMWH preparations to identify unpublished or missed studies.

METHODS

Randomised controlled trials comparing unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with placebo or no treatment, or comparing UFH with LMWH.

METHODS

One author identified possible trials, and the other author confirmed eligibility for inclusion in the review. Both authors extracted the data. Disagreements were resolved by discussion. We performed the meta-analysis as a fixed-effect model with relative risks.

RESULTS

A significant risk reduction in deep vein thrombosis (DVT) by 60% (relative risk (RR) 0.40; 95% confidence interval CI 0.31 to 0.53; P < 0.00001) and pulmonary embolism (PE) by 42% (RR 0.58; 95% CI 0.43 to 0.80; P = 0.0007) was observed with heparin compared with placebo or no treatment. However, heparin resulted in a significant increase in major haemorrhage (RR 2.18; 95% CI 1.28 to 3.72; P = 0.004) and minor haemorrhage (RR 1.74; 95% CI 1.26 to 2.41; P = 0.0008). There was no statistically significant difference in efficacy between LMWH and UFH. There was a statistically significant 72% risk reduction in major bleeding when LMWH was compared with UFH (RR 0.28; 95% CI 0.10 to 0.78; P = 0.02).

CONCLUSIONS

The data from this review support the use of heparin thromboprophylaixs in medical patients presenting with an acute medical illness. Although the analysis found no significant difference in efficacy between LMWH and UFH, it did note differences in the incidence of DVT and clinical PE with a significantly reduced risk of bleeding in favour of LMWH.

Unfractionated heparin (UF-H) has been the drug of choice for the treatment of thromboembolic disorders during pregnancy. Low molecular weight heparin (LMW-H) preparations may present some advantages over UF-H. They have longer half-lives and a better bioavailability after subcutaneous (s. c.) injection and may cause less bleeding. It has not yet been established whether LMW-H Novo (LHN-1) crosses the placenta. 17 women admitted for abortion during the second trimester of pregnancy (induced by application of prostaglandine PGE2 gel at a concentration of 0.25 mg/ml into the cervix) were given s. c. 35 anti-Xa units per kg of body weight of LHN-1 (Novo). 10 patients not receiving LHN-1 and their fetuses served as a control group. 7 women in whom the time interval between injection of LHN-1 and expulsion of the fetus was less than 3 h or more than 7 h were excluded from further study. In one fetus blood collection failed. Anti-Xa and anti-IIa levels increased approximately ten-fold in women receiving LHN-1 [anti-Xa units/ml from 0.02 +/- 0.01 (mean +/- SD) to 0.17 +/- 0.01, p less than 0.001; anti-Ha units/ml from less than 0.01 +/- 0.01 to 0.07 +/- 0.03], but remained below the detection limit in their fetuses as well as in the women and fetuses of the control group. We conclude that LHN-1 at these doses does not cross the placenta during the second trimester of pregnancy to suggest that LHN-1 may be a safe alternative to heparin in the management of the thromboembolic complications during pregnancy.

Low molecular weight heparins are significantly superior to unfractionated heparin or warfarin in the prevention of thromboembolic episodes associated with orthopaedic surgery. Therapeutic doses of heparin and warfarin have been shown to delay bone repair in a rabbit model. The current study investigated the effect of prophylactic administration of a low molecular weight heparin, enoxaparin, on the healing of a closed rabbit rib fracture. Fracture healing was assessed using histomorphometric, histologic, and immunohistochemical methods at 3, 7, and 14 days, and biomechanical testing with torsional loading was assessed after 21 days. Bone repair was significantly attenuated at all times in animals receiving subcutaneous enoxaparin compared with that of the control animals. Numerous putative mechanisms for this phenomenon are discussed, and additional studies are proposed to elucidate the effects of this pharmacologically diverse group of compounds on all aspects of bone physiology and repair.

Forty-eight patients with acute proximal deep vein thrombosis (DVT) were randomised to intravenous infusions for 4 to 6 days with melagatran, a novel synthetic low molecular weight thrombin inhibitor, or unfractionated heparin adjusted by the activated partial thromboplastin time (APTT). The aim of the study was to investigate the pharmacokinetics, pharmacodynamics and the safety of melagatran therapy at three different doses. Steady-state plasma concentrations were rapidly achieved and maintained throughout the infusion period. The mean plasma concentrations in the low, medium and high dose groups were 0.17, 0.31 and 0.53 micromol/l, respectively. The prolongation of APTT was stable during the melagatran infusions and correlated to the plasma concentration. Phlebographically verified regression of thrombus size measured as decrease in Marder score was seen after 4 to 6 days in 8 of 12 patients, 6 of 12 patients and 5 of 11 patients in the low, medium and high dose groups of melagatran and in 5 of the heparin-treated patients. In the low dose group with melagatran, thrombus extension was seen in one patient. At the dose levels studied, melagatran was well tolerated with no clinically significant bleeding problems, suggesting that melagatran could safely be given to patients suffering from DVT.

BACKGROUND

Acquired antithrombin III (AT) deficiency may induce heparin resistance and premature membrane clotting during continuous renal replacement therapy (CRRT). The purpose of this study was to evaluate the effect of AT supplementation on filter lifespan in critically ill patients with septic shock requiring CRRT.

METHODS

We conducted a retrospective case-control analysis based on a 4-year observational study with prospectively collected data in two medical intensive care units in a university hospital. In all, 106 patients with septic shock underwent CRRT during the study period (55 during 2001 to 2002 and 51 during 2003 to 2004). Of these, 78 had acquired AT deficiency (plasma level below 70%) at onset of renal supportive therapy, 40 in the first 2-year period and 38 in the last 2-year period. In the latter intervention period, patients received AT supplementation (50 IU/kg) during CRRT each time that plasma AT activity, measured once daily, fell below 70%.

RESULTS

In a case-control analysis of the 78 patients with acquired AT deficiency, groups were similar for baseline characteristics, except in severity of illness as assessed by a higher Simplified Acute Physiology Score (SAPS) II after 2002. In comparison with controls, cases had a significantly greater AT level after AT supplementation, but not at baseline, and a smaller number of episodes of clots, without excess bleeding risk. The median hemofilter survival time was longer in the AT group than in the heparin group (44.5 versus 33.4 hours; p = 0.0045). The hemofiltration dose, assessed by the ratio of delivered to prescribed ultrafiltration, increased during intervention. AT supplementation was independently associated with a decrease in clotting rate, whereas femoral angioaccess and higher SAPS II were independent predictors of filter failure. However, mortality did not differ between periods, in the control period the observed mortality was significantly higher than predicted by the SAPS II score, unlike in the treatment period.

CONCLUSIONS

In sepsis patients requiring CRRT and with acquired AT deficiency, anticoagulation with unfractionated heparin plus AT supplementation prevent premature filter clotting and may contribute to improving outcome, but the cost-effectiveness of AT remains to be determined.

OBJECTIVE

In patients on oral anticoagulation (OAC) undergoing coronary stenting (PCI-S), procedural management and in-hospital outcome have never been specifically and prospectively investigated. Also, the contribution of early bleeding to the relevant hemorrhagic rate reported at follow-up with triple therapy of OAC, aspirin, and clopidogrel is largely unknown.

METHODS

Consecutive patients with indication for OAC undergoing PCI-S at 5 centers were enrolled and prospectively evaluated.

RESULTS

Out of 3410 patients undergoing PCI-S in the study period, indication for OAC was present in 4.8%. Femoral approach and bare metal stents were the most frequently used. During PCI-S, OAC was continued in about 30% of patients, whereas in about 20% heparin bridging was carried out. Glycoprotein IIb/IIIa inhibitors were rarely used (11%), whereas a standard bolus of unfractionated heparin was given in 93% of cases. Major adverse cardiovascular events (MACE) occurred in 4.8% of patients and major bleeding in 4.3%. No predictors of MACE or bleeding were identified, although the femoral approach was of borderline significance for major bleeding (OR 4.6, 95% CI 1.0-20.8; P = 0.05). A history of previous hemorrhage (OR 5.3, 95% CI 1.6-18.1; P = 0.007) predicted Carbofilm-coated stent implantation.

CONCLUSIONS

A limited, albeit clinically relevant, proportion of patients undergoing PCI-S has indication for OAC. Procedural management appears not substantially different from that of common patients. In-hospital major bleeding is relevant and should be taken into account when evaluating the overall hemorrhagic rate at a medium- to long-term follow-up.