We performed a meta-analysis of modern total joint replacement (TJR) to determine the post-operative mortality and the cause of death using different thromboprophylactic regimens as follows: 1) no routine chemothromboprophylaxis (NRC); 2) Potent anticoagulation (PA) (unfractionated or low-molecular-weight heparin, ximelagatran, fondaparinux or rivaroxaban); 3) Potent anticoagulation combined (PAC) with regional anaesthesia and/or pneumatic compression devices (PCDs); 4) Warfarin (W); 5) Warfarin combined (WAC) with regional anaesthesia and/or PCD; and 6) Multimodal (MM) prophylaxis, including regional anaesthesia, PCDs and aspirin in low-risk patients. Cause of death was classified as autopsy proven, clinically certain or unknown. Deaths were grouped into cardiopulmonary excluding pulmonary embolism (PE), PE, bleeding-related, gastrointestinal, central nervous system, and others (miscellaneous). Meta-analysis based on fixed effects or random effects models was used for pooling incidence data. In all, 70 studies were included (99 441 patients; 373 deaths). The mortality was lowest in the MM (0.2%) and WC (0.2%) groups. The most frequent cause of death was cardiopulmonary (47.9%), followed by PE (25.4%) and bleeding (8.9%). The proportion of deaths due to PE was not significantly affected by the thromboprophylaxis regimen (PA, 35.5%; PAC, 28%; MM, 23.2%; and NRC, 16.3%). Fatal bleeding was higher in groups relying on the use of anticoagulation (W, 33.8%; PA, 9.4%; PAC, 10.8%) but the differences were not statistically significant. Our study demonstrated that the routine use of PA does not reduce the overall mortality or the proportion of deaths due to PE.

BACKGROUND

Adequate anticoagulation is a precondition to prevent extracorporeal blood clotting and to improve biocompatibility during hemodialysis. In this study, we performed a morphologic analysis by using scanning electron microscopy to compare three modes of anticoagulation-conventional unfractionated heparin (UFH), low molecular weight heparin (LMWH; dalteparin sodium), or sodium citrate during hemodialysis-on membrane-associated coagulation activation.

METHODS

Fifteen patients on regular hemodialysis therapy were investigated. Five patients received UFH, five patients LMWH, and five patients sodium citrate as an anticoagulant during a standardized hemodialysis protocol using a single-use polysulfone capillary dialyzer. Membrane-associated clotting was evaluated using a scanning electron microscope. A dialyzer clotting score was used for quantitative description of coagulation activation on membrane segments.

RESULTS

Using UFH as an anticoagulant revealed the most pronounced cell adhesion and thrombus formation and the highest dialyzer clotting score (11.5 +/- 1.3 of a maximal 20 points). LMWH had a lower dialyzer clotting score than UFH (10.4 +/- 1.2 of 20 points). During the use of sodium citrate, a negligible thrombus formation and the lowest dialyzer clotting score (1.6 +/- 0.6 of 20 points, P < 0.05) were observed.

CONCLUSIONS

The results of this investigation indicate that using sodium citrate as an anticoagulant during hemodialysis induces a lower activation of coagulation than both conventional and fractionated heparin, which might contribute to an improvement of biocompatibility of hemodialysis extracorporeal circulation.

Thanks to their predictable pharmacokinetics and ease of use, low-molecular-weight heparins (LMWHs) have established uses in the prevention and treatment of thrombotic diseases and as a replacement for unfractionated heparin (UFH). Although LMWHs as a class have similar antithrombotic effects, they comprise a diverse group of agents with distinct biochemical and pharmacological profiles. In light of the ongoing pressure to contain pharmacy costs, the diversity among the LMWHs and their benefits over UFH are important considerations in clinical practice.

OBJECTIVE

According to guidelines from the American College of Chest Physicians, low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) should be prescribed to medical (nonsurgical) patients at high risk of venous thromboembolism. Thromboprophylaxis and mortality rates were determined in medical inpatients with indications for thromboprophylaxis. Cost differences between patient groups were investigated and are discussed.

CONCLUSIONS

Using Solucient's ACTracker Inpatient Database, medical discharges between January 2001 and December 2004 were extracted and patients who had indications for thromboprophylaxis (acute myocardial infarction, ischemic stroke, cancer, heart failure, or severe lung disease) were identified. Patients < 40 years or with deep-vein thrombosis or pulmonary embolism, active peptic ulcer, malignant hypertension, blood disease, HIV infection, or intubation of gastrointestinal or respiratory tract were excluded. Rates of thromboprophylaxis and mortality were compared between groups. Mean total drug costs and hospital costs per patient discharge were compared between patient groups. Of 12,887,080 medical discharges extracted from 330 hospitals, there were 2,367,362 patients with indications for thromboprophylaxis. Patients were subdivided on the basis of whether they received thromboprophylaxis (n = 717,850) or not (n = 1,649,512). The thromboprophylaxis rate was low, despite increasing from 26% to 33% over the study period. Patients receiving thromboprophylaxis had significantly lower risk-adjusted mortality rates than those who did not (p < 0.001), except those with ischemic stroke. The mean total drug cost per patient receiving LMWH and UFH ($791 and $569, respectively) was higher than for patients not receiving thromboprophylaxis ($372) (p < 0.001). The mean total hospital cost per patient receiving UFH ($7615) was higher than for LMWH ($6866, p < 0.001).

CONCLUSIONS

The thromboprophylaxis rate among medical patients was low, with no significant improvement between 2001 and 2004. Thromboprophylaxis can impact patient mortality rates. Economic evaluation revealed that the use of LMWH for thromboprophylaxis in at-risk medical patients was associated with higher total drug costs but lower total hospital costs than UFH. Efforts should be made to increase clinicians' awareness of clinical guidelines.

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Among children, newborn infants are most vulnerable to development of thrombosis and serious thromboembolic complications. Amongst newborns, those neonates who are critically ill, both term and preterm, are at greatest risk for developing symptomatic thromboembolic disease. The most important risk factors are inflammation, DIC, impaired liver function, fluctuations in cardiac output, and congenital heart disease, as well as exogenous risk factors such as central venous or arterial catheters. In most clinically symptomatic infants, diagnosis is made by ultrasound, venography, or CT or MRI angiograms. However, clinically asymptomatic vessel thrombosis is sometimes picked up by screening investigations or during routine imaging for other indications. Acute management of thrombosis and thromboembolism comprises a variety of approaches, including simple observation, treatment with unfractionated or low molecular weight heparin, as well as more aggressive interventions such as thrombolytic therapy or catheter-directed revascularization. Long-term follow-up is dependent on the underlying diagnosis. In the majority of infants, stabilization of the patients' general condition and hemodynamics, which allows removal of indwelling catheters, renders long-term anticoagulation superfluous. Nevertheless, in certain types of congenital heart disease or inherited thrombophilia, long-term prophylaxis may be warranted. This review article focuses on pathophysiology, diagnosis, and acute and long-term management of thrombosis in critically ill term and preterm neonates.

Non-ST elevation acute coronary syndromes are responsible for approximately 1 million admissions to U.S. hospitals and twice as many to European hospitals each year. Thus, they are among the most common serious illnesses in adults, and are associated with an in-hospital mortality of approximately 5%. The most common cause is rupture of an atherosclerotic coronary plaque, resulting in subtotal coronary occlusion. Diagnosis is based on the clinical picture of retrosternal chest pain, aided by electrocardiographic findings of ST segment deviations and biomarker abnormalities (elevation of troponin and natriuretic peptides) and cardiac imaging (myocardial scans showing perfusion defects). Treatment involves antiischemic agents (nitrates and β blockers), antiplatelet drugs (aspirin, P2Y(12), and glycoprotein IIb/IIIa receptor blockers), and anticoagulants (unfractionated and low-molecular-weight heparins). Patients should undergo risk stratification, and those with high-risk factors should undergo coronary arteriography promptly with the intent to carry out coronary revascularization. Those at low risk should continue to receive intensive antiischemic and antithrombotic therapy. At discharge, patients should receive intensive lipid-lowering therapy with high doses of a statin, as tolerated.

Intravenous unfractionated heparin (UFH) remains an important therapeutic agent, particularly in the inpatient setting, for anticoagulation. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. The aPTT test has evolved since the 1950s, and the historical goal range of 1.5-2.5 times the control aPTT, which first gained favor in the 1970s, has fallen out of favor due to a high degree of variability in aPTT readings from one laboratory to another, and even from one reagent to another. As a result, it is now recommended that the aPTT goal range be based on a corresponding heparin concentration of 0.2-0.4 unit/ml by protamine titration or 0.3-0.7 unit/ml by antifactor Xa assay. Given that several biologic factors can influence the aPTT independent of the effects of UFH, many institutions have transitioned to monitoring heparin with antifactor Xa levels, rather than the aPTT. Clinical data from the last 10-20 years have begun to show that a conversion from aPTT to antifactor Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments. Given the minimal increased acquisition cost of the antifactor Xa reagents, it can be argued that the antifactor Xa is a cost-effective method for monitoring UFH. In this review, we discuss the relative advantages and disadvantages of the aPTT, antifactor Xa, and protamine titration tests, and provide a clinical framework to guide practitioners who are seeking to optimize UFH monitoring within their own institutions.

BACKGROUND

In ulcerative colitis, a state of hypercoagulation has frequently been observed. Unfractionated heparin has shown beneficial effects as an adjuvant treatment of steroid refractory ulcerative colitis in open trials and in one placebo-controlled trial. Low molecular weight heparin (LMWH) offers advantages in the method of administration, but it has not been evaluated in severe ulcerative colitis. We therefore assessed the tolerability, safety and potential therapeutical effects of LMWH in hospitalized patients with steroid refractory ulcerative colitis.

METHODS

Twenty-five patients with severely active ulcerative colitis were included in an open-labelled trial. All patients had a flare-up of disease under glucocorticosteroid treatment. Nadroparine calcium 5.700 IE anti-Xa/0.6 mL s.c. was self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events, and changes in clinical symptoms and in laboratory, endoscopical and histological results were analysed.

RESULTS

Tolerability and compliance were excellent and no serious adverse events occurred. In 20 of 25 patients, a good clinical and laboratory response was observed. Also, the endoscopic and histological signs of inflammation were found to be significantly improved. However, this was not accompanied by a significant reduction in the number of mucosal microvascular thrombi after 8 weeks of LMWH treatment.

CONCLUSIONS

LMWH may be a safe adjuvant therapy for patients with active, glucocorticosteroid refractory ulcerative colitis.

BACKGROUND

Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.

METHODS

We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome "dead or dependent" in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.

RESULTS

Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59-0·67) and for haemorrhagic events was 0·60 (0·55-0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.

CONCLUSIONS

There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.

BACKGROUND

MRC.

Heparin is frequently used in the treatment of cancer-associated thromboembolism. Accumulating clinical evidence indicates that cancer patients treated with unfractionated and low-molecular weight heparin (LMWH) survive longer than patients treated by other anticoagulants, especially patients in the early stage of the disease. Experimental analysis from a number of animal models constantly provides evidence for the ability of heparin to attenuate metastasis. The non-anticoagulant activity of heparin on metastasis includes the ability to inhibit cell-cell-interaction through blocking of P- and L-selectin, to inhibit extracellular matrix protease heparanase, and to inhibit angiogenesis. This chapter summarizes current experimental evidence on the biology of heparin during cancer progression, with the focus on potential mechanism of heparin antimetastatic activity.

BACKGROUND

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction presenting as a prothrombotic disorder related to antibody-mediated platelet activation. It is a poorly understood paradoxical immune reaction resulting in thrombin generation in vivo, which leads to a hypercoagulable state and the potential to initiate venous or arterial thrombosis. A number of factors are thought to influence the incidence of HIT including the type and preparation of heparin (unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) and the heparin-exposed patient population, with the postoperative patient population presenting a higher risk.Although LMWH has largely replaced UFH as a front-line therapy, there is evidence supporting a lack of superiority of LMWH compared with UFH regarding prevention of deep vein thrombosis and pulmonary embolism following surgery, and similar frequencies of bleeding have been described with LMWH and UFH. The decision as to which of these two preparations of heparin to use may thus be influenced by adverse reactions such as HIT. We therefore sought to determine the relative impact of UFH and LMWH specifically on HIT in postoperative patients receiving thromboembolism prophylaxis.

OBJECTIVE

The objective of this review was to compare the incidence of HIT and HIT complicated by thrombosis in patients exposed to UFH versus LMWH in randomised controlled trials (RCTs) of postoperative heparin therapy.

METHODS

The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (March 2012) and CENTRAL (2012, Issue 2). In addition, the authors searched LILACS (March 2012) and additional trials were sought from reference lists of relevant publications.

METHODS

We were interested in comparing the incidence of HIT occurring during exposure to UFH or LMWH after any surgical intervention. Therefore, we studied RCTs in which participants were postoperative patients allocated to receive UFH or LMWH, in a blinded or unblinded fashion. Eligible studies were required to have as an outcome clinically diagnosed HIT, defined as a relative reduction in the platelet count of 50% or greater from the postoperative peak (even if the platelet count at its lowest remained>> 150 x 10(9)/L) occurring within five to 14 days after the surgery, with or without a thrombotic event occurring in this timeframe. Additionally, circulating antibodies associated with the syndrome were required to have been investigated through laboratory assays.

METHODS

Two review authors independently extracted data and assessed the risk of bias. Disagreements were resolved by consensus with participation of a third author.

RESULTS

In total two studies involving 923 participants met all the inclusion criteria and were included in the review. Pooled analysis showed a statistically significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.07 to 0.82; P = 0.02). This result suggests that patients treated with LMWH would have a relative risk reduction (RRR) of 76% in the probability of developing HIT compared with patients treated with UFH.Venous thromboembolism (VTE) complicating HIT occurred in 12 of 17 patients who developed HIT. Pooled analysis showed a statistically significant reduction in HIT complicated by VTE with LMWH compared with UFH (RR 0.20, 95% CI 0.04 to 0.90; P = 0.04). This result indicates that patients using LMWH would have a RRR of 80% for developing HIT complicated by VTE compared with patients using UFH. Arterial thrombosis occurred in only one patient who received UFH and there were no amputations or deaths documented.

CONCLUSIONS

There was a lower incidence of HIT and HIT complicated by VTE in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. This is consistent with the current clinical use of LMWH over UFH as front-line heparin therapy. However, conclusions are limited by a scarcity of high quality evidence. We did not expect the paucity of RCTs including HIT as an outcome as heparin is one of the most commonly used drugs worldwide and HIT is a life-threatening adverse drug reaction. To address the scarcity of clinically-relevant information on the topic of HIT as a whole, HIT should be included as an outcome in future RCTs of heparin, and HIT as an adverse drug reaction should be considered in clinical recommendations regarding monitoring of the platelet count for HIT.

During the past decade, a large number of new anticoagulant and antithrombotic drugs have been developed. These agents represent a wide variety of substances that are derived using natural sources, biotechnology-based methods, and synthetic approaches. Because of the structural and molecular characteristics, these agents exhibit physicochemical and functional diversities. Thus, each of these classes of drugs controls thrombogenesis by way of distinct mechanisms. The main classes of these new drugs include peptides, peptidomimetics, heparinomimetics, and recombinant proteins. Despite these significant developments, heparin and heparin-derived drugs have continued to play a major role in the management of thrombotic and cardiovascular disorders.

Venous thromboembolism (VTE) occurs roughly in one out of five cancer patients and is the second cause of death in this population. When all cancer patients are considered together, a sevenfold increased risk for VTE has been calculated. Over the last 20 years, a number of risk factors have been recognized. These have been used in several risk assessment models aimed at identifying high-risk patients who are therefore candidates for thromboprophylaxis. An easily applicable and reliable risk score is based on the cancer site, hemoglobin levels, pre-chemotherapy platelet and leukocyte counts as well as body mass index. The additional measurement of two biomarkers, namely D-dimer and soluble P-selectin, may improve estimates of the cumulative VTE probability. A variable incidence of VTE has been determined in patients with specific types of malignancy, with the highest odds in those with pancreatic cancer followed by head and neck tumors. In terms of histotype, the risk of VTE is significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma and in patients with high-grade versus low-grade tumors. Cancer therapy may also be responsible for VTE; specifically, the presence of an indwelling central venous catheter, immunomodulatory drugs such as thalidomide and lenalidomide, monoclonal antibodies, such as bevacizumab, erythropoiesis-stimulating agents and hormonal therapy with tamoxifen place patients at higher risk. The pathogenesis of cancer-related VTE is poorly understood but is likely to be multifactorial. "Virchow's triad," comprising stasis consequent to a decreased blood flow rate, an enhanced blood clotting tendency such as accompanies inflammation and growth factor expression, and structural modifications in blood vessel walls, is thought to play a central role in the induction of VTE. The prophylaxis and treatment of VTE are based on well-established drugs such as vitamin K antagonists and unfractionated and low-molecular-weight heparins as well as on an expanding group of new oral anticoagulants, including fondaparinux, rivaroxaban, apixaban and dabigatran. Furthermore, aspirin has been shown to prevent arterial thrombosis and to reduce the rate of major vascular events. Guidelines for the general management of VTE in cancer patients and in those with an indwelling central venous catheter have been recently developed with the aim of selecting the most rational therapeutic approach for each clinical situation. The main features of VTE based on our own observations of 92 cancer patients and 159 patients with non-neoplastic disease are briefly described herein.

BACKGROUND

Despite advances in hospital management in recent years, it is not clear whether mortality after acute pulmonary embolism (PE) has decreased over time.

OBJECTIVE

This study describes the trends in the management and outcomes of acute symptomatic PE.

METHODS

We identified adults with acute PE enrolled in the registry between 2001 and 2013. We assessed temporal trends in length of hospital stay and use of pharmacological and interventional therapies. Using multivariable regression, we examined temporal trends in risk-adjusted rates of all-cause and PE-related death to 30 days after diagnosis.

RESULTS

Among 23,858 patients with PE, mean length of stay decreased from 13.6 to 9.3 days over time (32% relative reduction, p < 0.001). For initial treatment, use of low-molecular-weight heparin increased from 77% to 84%, whereas the use of unfractionated heparin decreased from 22% to 8.4% (p < 0.001 for trend for all comparisons). Thrombolytic therapy use increased from 0.7% to 1.0% (p = 0.07 for trend) and surgical embolectomy use doubled from 0.3% to 0.6% (p < 0.01 for trend). Risk-adjusted rates of all-cause mortality decreased from 6.6% in the first period (2001 to 2005) to 4.9% in the last period (2010 to 2013) (p = 0.02 for trend). Rates of PE-related mortality decreased over time, with a risk-adjusted rate of 3.3% in 2001 to 2005 and 1.8% in 2010 to 2013 (p < 0.01 for trend).

CONCLUSIONS

In a large international registry of patients with PE, improvements in length of stay and changes in the initial treatment were accompanied by a reduction in short-term all-cause and PE-specific mortality.

Glycosylation is the most common form of post-translational modifications by which oligosaccharide side chains are covalently attached to specific residues of the core protein. Especially O-linked glycan structures like the glycosaminoglycans were found to contribute significantly to many (patho-)biological processes like inflammation, coagulation, cancer and viral infections. Glycans exert their function by interacting with proteins thereby changing the structure of the interacting proteins and consequently modulating their function. Given the complex nature of cell-surface and extracellular matrix glycan structures, this therapeutic site has been neglected for a long time, the only exception being the antithrombin III-glycan interaction which has been successfully targeted by unfractionated and low-molecular weight heparins for many decades. Due to the recent breakthrough in the '-ome' sciences, among them proteomics and glycomics, protein-glycan interactions became more amenable for therapeutic approaches so that novel inhibitors of this interaction are currently in preclinical and clinical studies. An overview of current approaches, their advantages and disadvantages, is given and the promising potential of pharmacologically interfering with protein-glycan interactions is highlighted here.

OBJECTIVE

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that paradoxically is associated with a brief but dramatically increased risk for thrombosis (transient acquired thrombophilia). The objective of this article is to provide practical recommendations for platelet count monitoring in patients receiving heparin, as well as for selection of laboratory assays to detect pathogenic HIT antibodies.

METHODS

Relevant literature that focused on frequency and timing of HIT in various clinical settings and that dealt with laboratory testing for HIT antibodies was critically appraised.

METHODS

The author prepared a preliminary manuscript including recommendations that was presented to participants at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia (November 10, 2001). Support of at least 70% of conference participants was required for recommendations to be adopted.

CONCLUSIONS

The risk of immune HIT varies depending on the type of heparin (unfractionated heparin greater than low-molecular-weight heparin) and patient population (surgical greater than medical). Thus, the intensity of platelet count monitoring should be stratified depending on the clinical situation. Platelet count monitoring should focus on the period of highest risk (usually days 5 to 10 after starting heparin) and should use an appropriate platelet count baseline (generally, the highest platelet count beginning 4 days after start of heparin). However, earlier platelet count monitoring is appropriate if the patient received heparin within the past 100 days, as already circulating HIT antibodies can cause rapid-onset HIT with heparin reexposure. Although both antigen and (washed platelet) activation assays are very sensitive for detecting clinically significant HIT antibodies, activation assays have greater diagnostic specificity for clinical HIT.

OBJECTIVE

Major bleeding complications from pharmacologic deep venous thrombosis (DVT) prophylaxis are infrequent.

METHODS

Systematic review of the MEDLINE database from 1965 to August 2005, using the terms DVT, prophylaxis, general surgery, and heparin.

METHODS

Randomized controlled trials evaluating pharmacologic DVT prophylaxis in patients undergoing general surgery.

METHODS

Eight complication categories: injection site bruising, wound hematoma, drain site bleeding, hematuria, gastrointestinal tract bleeding, retroperitoneal bleeding, discontinuation of prophylaxis, and subsequent operation.

RESULTS

Fifty-two randomized controlled trials studied DVT prophylaxis; 33 randomized controlled trials with 33 813 patients undergoing general surgery evaluated pharmacologic prophylaxis and quantified bleeding complications. Of the minor complications, injection site bruising (6.9%), wound hematoma (5.7%), drain site bleeding (2.0%), and hematuria (1.6%) were most common. Major bleeding complications, such as gastrointestinal tract (0.2%) or retroperitoneal (<0.1%) bleeding, were infrequent. Discontinuation of prophylaxis occurred in 2.0% of patients and subsequent operation in less than 1% of patients. When analyzed by high- vs low-dose unfractionated heparin, the lower dose had a smaller rate of discontinuation of prophylaxis (P = .02) and subsequent operation (P = .06).

CONCLUSIONS

Knowledge of bleeding complication rates is important for surgeons because DVT prophylaxis may soon be implemented by Medicare as a quality measure. This level 1 evidence report shows that bleeding complications requiring a change in care occur less than 3% of the time and seem reduced with lower-dose prophylaxis. Given these findings, most patients undergoing general surgery could receive pharmacologic prophylaxis safely.

Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a century. Besides an effective anticoagulant, this drug has been used in several additional indications. Despite the development of newer anticoagulant drugs, unfractionated heparin has remained the drug of choice for surgical anticoagulation and interventional cardiology. In the area of hematology and transfusion medicine, unfractionated heparin has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent a class of depolymerized heparin derivatives with a distinct pharmacologic profile that is largely determined by their composition. These drugs produce their major effects by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic mediators from the blood vessels. The cumulative effects of each of the different LMWHs differ and each product exhibits a distinct profile. Initially these agents were developed for the prophylaxis of postsurgical deep-vein thrombosis. However, at this time these drugs are used not only for prophylaxis, but also for the treatment of thrombotic disorders of both the venous and arterial type. To a large extent, the LMWHs have replaced unfractionated heparin in most subcutaneous indications. With the use of these refined heparins, outpatient anticoagulant management has gone through a dramatic evolution. For the first time, patients with thrombotic disorders can be treated in an outpatient setting. Thus, the introduction of LMWHs represents a major advance in improving the use of heparin. The development of the oral formulation of heparin and LMWHs also provides an important area that may impact on the use of heparin and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated the development of newer methods to identify patients at risk of developing this catastrophic syndrome. Furthermore, a strong interest has developed in alternate drugs or the management of patients with this syndrome. Despite the development of alternate anticoagulants that are mostly antithrombin derived (hirudins, hirulog), these agents have failed to provide similar clinical outcome as heparin in many indications. However, antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. The FDA has approved a recombinant hirudin (Refludan) and a synthetic antithrombin agent, argatroban (Novastan), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa agents may have an impact on the prophylaxis of thrombotic disorders. However, these monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore, these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting not only factor Xa and thrombin, but other serine proteases in the coagulation network. The only way the newer drugs can mimic the actions of heparin is in combination modalities (polytherapeutic approaches). It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions. While these drugs may exhibit weak effects on thrombin generation, none of the currently available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely that heparins synergize or augment the effects of the new antiplatelet drugs. Currently, combination approaches are used to anticoagulate patients in these studies. The dosage of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional clinical studies are needed to study these combinations where the alterations of these drugs are compared. Such combinations will require newer monitoring approaches. The development of oral thrombin agents, GP IIb

OBJECTIVE

A landmark Canadian randomized controlled clinical trial compared treatment of acute proximal vein thrombosis via low-molecular-weight heparin (LMWH) [enoxaparin] administered primarily at home with IV unfractionated heparin (UH) in the hospital. Results demonstrated equivalent safety and efficacy for home care with enoxaparin with a reduction in cost. Our objective was to validate these findings in the routine practice setting of a US health maintenance organization.

METHODS

Retrospective analysis of medical and administrative records of health-plan members meeting inclusion-exclusion criteria of the Canadian trial during the period from 1995 to 1998.

METHODS

Staff-model health maintenance organization serving New Mexico.

METHODS

Persons presenting as outpatients from 1995 to 1996 or from 1997 to 1998 with acute, proximal deep vein thrombosis (DVT) diagnosed by duplex ultrasonography.

METHODS

Initial anticoagulant therapy of IV UH administered in the hospital (from 1995 to 1996 group, n = 64) or subcutaneous LMWH (enoxaparin) administered primarily at home (from 1997 to 1998 group, n = 65), followed by warfarin therapy.

RESULTS

No statistically significant differences were observed in the number of recurrent venous thromboembolic events (p = 0.36) or bleeding events (p = 1.0). Mean +/- SD cost per patient was 9,347 dollars +/- 8,469 in the enoxaparin group compared with 11,930 dollars +/- 10,892 in the UH group, a difference of - 2,583 dollars (95% bootstrap-adjusted asymmetrical confidence interval, - 6,147 dollars, + 650 dollars).

CONCLUSIONS

Retrospective replication of the Canadian study in a US routine (managed) care setting found similar clinical and economic outcomes. Treatment of acute proximal DVT with enoxaparin in a primarily outpatient setting can be accomplished safely and yields savings through avoidance or minimization of inpatient stays.

BACKGROUND

The management of venous thromboembolism (VTE) requires an initial treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), followed by oral anticoagulants (OA) for at least 3 months. OA treatment however, requires laboratory monitoring of anticoagulation, carries a definite risk of bleeding, and may be contraindicated in some patients. As an alternative to vitamin K antagonists, subcutaneous LMWH has been proposed and evaluated in randomized clinical trials, but they are all small studies that lack the power to establish if these two treatment modalities are equivalent in efficacy or safety.

OBJECTIVE

The objective of this review was to evaluate the efficacy (VTE recurrence) and safety (bleeds and deaths) of long-term treatment of VTE with LMWH compared with OA. A secondary endpoint was to evaluate the effect of LMWH on cancer mortality.

METHODS

Computerized searches of MedLine and EmBase were performed. In addition, randomized clinical trials were located through personal communication with colleagues, and through the manual scanning of meeting proceedings and reference lists of relevant studies. When necessary, the authors of the selected papers were called to obtain additional information. Two reviewers (AI and FG) reviewed and extracted data independently using a standard form. The primary analysis was performed for efficacy and safety endpoints on an intention-to-treat basis for the study period of randomized treatment. A meta-regression analysis was used to investigate the relationship between daily dose and clinical outcome.

RESULTS

Seven studies that fulfillled our predefined criteria were identified, for a total of 1379 patients. When all studies were combined, a statistically non-significant reduction in the risk of VTE (OR 0.66; 95% confidence interval [CI] 0.41, 1.07) and in the risk of major bleeding (OR 0.45; 95% CI 0.18, 1.11) in favor of LMWH treatment was found. No difference in total mortality (OR 1.19; 95% CI 0.78, 1.83) or in cancer-related mortality was observed between the LMWH and the OA treatment.

CONCLUSIONS

The results of this meta-analysis indicate that a 3-month course of LMWH is as effective and safe as a corresponding period of OA treatment, and may thus be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic.

OBJECTIVE

We tested the hypothesis that different anticoagulant treatments may produce different platelet effects and von Willebrand factor (vWf) release in unstable angina.

BACKGROUND

The early increase of vWf has been reported to be a risk factor for adverse outcome in unstable angina. Anticoagulant drugs play a key role in stabilization of unstable angina, but they may not have the same efficacy and the same effects on acute vWf release.

METHODS

We studied 154 patients enrolled in several clinical trials testing four different anticoagulant treatments in unstable angina or non-Q-wave myocardial infarction. Patients were treated during at least 48 h by either intravenous unfractionated heparin, one of two different low molecular weight heparins (enoxaparin or dalteparin) or the direct thrombin inhibitor PEG-hirudin. All patients received aspirin but no Ib/IIIa inhibitors.

RESULTS

The release of vWf over the first 48 h (delta vWf) did not relate to the baseline clinical characteristics. At 30 days of follow-up, delta vWf was sevenfold higher in patients with an end point (death, myocardial infarction, revascularization) than in patients free of events (+53 +/-7% vs. +7 +/-14%, p = 0.004). The same trend was present for each component of the composite end point with the highest levels for one-month mortality (+87 +/- 32% vs. +26 +/- 8%, p = 0.09). The vWf values did not increase over 48 h in patients receiving either enoxaparin or PEG-hirudin (+10 +/- 9% and -5 +/- 20%, respectively). A serious rise ofvWf was measured in unfractionated heparin-treated patients (+87 +/- 11%), which differed significantly from the enoxaparin group (p = 0.0006) and PEG-hirudin group (p < 0.0001). In dalteparin-treated patients, delta vWf was elevated (+48 +/- 8%) and did not differ from the unfractionated heparin group (NS).

CONCLUSIONS

We confirm that, in unstable angina patients, a rise of vWf over the first 48 h is associated with an impaired outcome at 30 days. Moreover, the four different anticoagulant treatments tested here do not provide the same protection with regards to vWf release, which may have important prognostic implications and explain different results observed in recent clinical trials.

BACKGROUND

Previous meta-analyses comparing low molecular weight heparin (LMWH) and unfractionated heparin for thrombosis prophylaxis after surgical interventions need updating.

METHODS

This is a publication-based meta-analysis of 36 double-blind studies including 16583 patients. Main outcome measures are incidence of deep vein thrombosis (efficacy) and wound haematoma (safety).

RESULTS

In general surgery there is no increased efficacy in favour of LMWH (odds ratio (OR) 0.88, 95 per cent confidence interval (c.i.) 0.60-1.30) but there exists a higher incidence of bleeding complications (OR 1.47, 95 per cent c.i. 1.07-2.01). Low-dose LMWH is equally efficacious (OR 1.03, 95 per cent c.i. 0.85-1.26) but safer than unfractionated heparin (OR 0.68, 95 per cent c.i. 0.56-0.82). In orthopaedic surgery there is a trend towards an increased efficacy for LMWH (OR 0.83, 95 per cent c.i. 0.68-1.02) with equivalent safety (OR 0.96, 95 per cent c.i. 0.68-1.36).

CONCLUSIONS

A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.

OBJECTIVE

Our purpose was to investigate the use of low-molecular-weight heparin (enoxaparin, Clexane) for thromboprophylaxis in pregnancy.

METHODS

A prospective consecutive cohort of 61 pregnant women at high risk of thromboembolism receiving antenatal thromboprophylaxis with enoxaparin (usually 40 mg, subcutaneously daily) in a total of 69 pregnancies was identified from the obstetric medicine clinic at Queen Charlotte's Hospital. Bone density measurements of the hip and lumbar spine were taken in 26 women after 28 pregnancies within 16 months post partum. Nonparametric statistics were used for comparisons.

RESULTS

There were no episodes of antenatal thromboembolism. One woman (1.6%) (receiving 20 mg of enoxaparin) had a pulmonary embolus post partum. Heparin levels (anti-Xa assay) were greater with the 40 mg dose (median 0.09 U/ml) than with the 20 mg dose (median 0.03 U/ml) (p = 0.0006) but were not affected by gestational age (r = -0.1, p = 0.14). Enoxaparin had no effect on platelet count or on in vitro coagulation tests. Nine (32%) women had bone density in the spine or hip>> 1 SD below the mean for age- and sex-matched controls.

CONCLUSIONS

This, the largest study to date of low-molecular-weight heparin use in pregnancy, confirms previous reports that it is a safe and effective alternative to unfractionated heparin for obstetric thromboprophylaxis in high-risk women. Effects on bone demineralization require further investigation.