BACKGROUND

The beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. However, the mechanisms underlying the therapeutic benefits of heparin in these conditions have not yet been clearly elucidated. The purpose of this study was to confirm the effect of heparin of neutralizing histone toxicity.

METHODS

Rat models of histone H3-induced organ dysfunction were administered in a low or high dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or argatroban, and the therapeutic effects of each anticoagulant were examined. In another series, the survival of the histone H3-administered animals was evaluated. Furthermore, the effect of each of the aforementioned anticoagulants on cell death induced by histone H3 was examined in cultured vascular endothelial cells and leukocytes.

RESULTS

Although UFH, LMWH, and argatroban significantly suppressed the histone-induced decrease of the WBC and platelet counts in the animal models of organ dysfunction, only UFH and LMWH attenuated hepatic and renal dysfunction. In addition, the mortality was significantly reduced only by high-dose UFH and LMWH. The in vitro study revealed that both vascular endothelial cell death and leukocyte cell death were significantly attenuated by UFH and LMWH but not by argatroban.

CONCLUSIONS

The histone-neutralizing effect of heparin may contribute to the beneficial effects of heparins observed in the animal study. The results of the in vitro study further confirmed the above contention and suggested that heparin binds to histones to attenuate the cytotoxic actions of the latter. Since heparin has been demonstrated to protect animals from the organ damage induced by histones and consequently reduce the mortality, administration of heparin could become a treatment of choice for patients suffering from severe sepsis.

The anticoagulant response to fixed doses of unfractionated heparin is variable in patients with acute illness, and some patients with venous thromboembolism require high doses of heparin to achieve a therapeutic anticoagulant response. To investigate the mechanism responsible for the variable anticoagulant response to heparin in acute illness, heparin clearance and nonspecific protein binding were compared in control and endotoxin-treated rabbits. The plasma half-life (t 1/2) of radiolabeled heparin increased in a dose-dependent fashion. At all doses of heparin studied, the t 1/2 of radiolabeled heparin was unaffected by experimental endotoxemia when compared with control animals. In contrast, the amount of heparin recovered was lower in the plasma of endotoxemic animals because of increased binding to plasma proteins. A chemically modified heparin with low affinity for antithrombin III was added ex vivo or in vivo to displace heparin bound nonspecifically to plasma proteins. The proportion of heparin bound to plasma proteins was significantly greater in the plasma of endotoxemic animals than in controls. These findings indicate that acute inflammation alters heparin recovery but does not affect heparin clearance. The variability of the anticoagulant response to heparin seen in patients with thromboembolism may, in part, be due to this effect of the underlying disease process.

The prothrombotic and hemostatic-altering environment that characterizes cardiac surgery in general and cardiopulmonary bypass (CPB) in particular is unparalleled in medicine, causing, in an alarming number of patients, both thrombotic and hemorrhagic events. Fundamentally, the primary objective of anticoagulant therapy during CPB is to prevent thrombin generation and its attendant prothrombotic, proinflammatory, and vascular effects. Though anticoagulation with unfractionated heparin has been the standard of care for more than a half-century for patients undergoing cardiac surgery, inherent limitations, and an unfavorable safety profile will increasingly stimulate the investigation and development of more safe and effective therapies.

BACKGROUND

Peripheral arterial disease (PAD) is frequently treated by either an infrainguinal autologous (using the patient's own veins) or synthetic graft bypass. The rate of occlusion of the graft after one year is between 12% and 60%. To prevent occlusion, patients are treated with an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. This is an update of a Cochrane review first published in 2003.

OBJECTIVE

To evaluate whether antithrombotic treatment improves graft patency, limb salvage and survival in patients with chronic PAD undergoing infrainguinal bypass surgery.

METHODS

The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3).

METHODS

Randomised, controlled trials; two review authors independently assessed the methodological quality of each trial using a standardised checklist.

METHODS

Data collected included patient details, inclusion and exclusion criteria, type of graft, antithrombotic therapy, outcomes, and side effects.

RESULTS

A total of 14 trials were included in this review; 4970 patient results were analysed. Four trials evaluating vitamin K antagonists (VKA) versus no VKA suggested that oral anticoagulation may favour autologous venous, but not artificial, graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin (ASA) or aspirin and dipyridamole provided evidence to support a positive effect of VKA on the patency of venous but not artificial grafts. Three trials comparing low molecular weight heparin (LMWH) to unfractionated heparin (UFH) failed to demonstrate a significant difference on patency. One trial comparing LMWH with placebo found no significant improvement in graft patency over the first postoperative year in a population receiving aspirin. One trial showed an advantage for LMWH versus aspirin and dipyridamol at one year for patients undergoing limb salvage procedures. Perioperative administration of ancrod showed no greater benefit when compared to unfractionated heparin. Dextran 70 showed similar graft patency rates to LMWH but a significantly higher proportion of patients developed heart failure with dextran.

CONCLUSIONS

Patients undergoing infrainguinal venous graft are more likely to benefit from treatment with VKA than platelet inhibitors. Patients receiving an artificial graft benefit from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers are needed in the future to compare antithrombotic therapies with either placebo or antiplatelet therapies.

Patients with advanced chronic kidney disease (CKD), including those treated with dialysis, are at high risk for the development of cardiovascular disease (CVD). CVD accounts for 45-50% of deaths among dialysis patients. Therapy of acute and chronic coronary heart disease (CHD) that is effective in the general population is frequently less effective in patients with advanced CKD. Drug therapy in such patients may require dose modification in some cases. Oral anti-platelet drugs are less effective in those with advanced CKD than in persons with normal or near normal renal function. The intravenous antiplatelet drugs eptifibatide and tirofiban both require dose reductions in patients with advanced CKD. Enoxaparin requires dose reduction in early stage CKD and is contraindicated in hemodialysis patients. Unfractionated heparin and warfarin maybe used without dose adjustment in CKD patients. Atenolol, acetbutolol and nadolol may require dose adjustments in CKD. Metoprolol and carvedilol do not. Calcium channel blockers and nitrates do not require dose adjustment, whereas ranolazine does. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers may safely be used in CKD patients with close observation for hyperkalemia. The safety of spironolactone in such patients is questionable. Statins are less effective in reducing cardiovascular complication in CKD patients and their initiation is not recommended in dialysis patients. Coronary artery bypass grafting is associated with higher shortterm mortality, but better long-term morbidity and mortality than percutaneous coronary interventions in patients with advanced CKD with non-ST segment ACS and chronic CHD.

As a result of advanced technology, dramatic developments in the area of new anticoagulant and antithrombotic drugs appear to have made a profound impact on the use of LMWHs. Furthermore, because porcine mucosal heparin is used for the preparation of these agents, it is likely that alternative drugs with comparable pharmacologic and clinical efficacy are sought. Antithrombin drugs such as argatroban and hirudin are already approved for alternative management of heparin-compromised patients. Their efficacy in other indications is less superior. The development of specific anti-Xa drugs is slow. Although these agents may inhibit factor Xa and thrombin generation, none of them are capable of mimicking the polytherapeutic effects of LMWHs and thus can only be given in drug combinations. Synthetic and recombinant protein-derived anti-tissue factor agents have also been developed. These drugs only inhibit the tissue factor-mediated process and are limited in their therapeutic spectrum. Plasma-derived and recombinant serine protease inhibitors (serpins) are also available for the management of thrombotic and inflammatory disorders, but these agents cannot be given subcutaneously. Furthermore, because they are proteins, antibodies to these agents are generated. Nucleic acid derivatives (natural and synthetic aptomers) are developed for intravenous administration, but they are relatively weak antithrombotic agents. Dermatans, heparans, and chondroitin sulfates represent nonheparin GAGs, and, in mono-compositional and polycompositional form, these drugs are mainly used for the intravenous management of DVT prophylaxis. They can be given to patients who are heparin compromised. Synthetic heparinomimetics include heparin consensus-binding oligosaccharides and synthetic oligosaccharides with non-serpin affinity. In addition, binding oligosaccharides are conjugated with antithrombin agents to mimic the anti-Xa/anti-IIa activities of heparin. Biotechnology using bacterial and yeast cultures, aqua cultures for marine products, and plant carbohydrates have been the focus of developing heparin analogues. Development of these agents is in the early phase; however, it is likely that this approach may provide a reasonable alternative to LMWHs. Despite these developments, it is unlikely that any of these drugs will have a profound impact on the use of LMWHs in the near future. Unfractionated heparin and LMWHs collectively represent an important group of polypharmacologic drugs without which the management of thrombosis and vascular disorders would not be possible. The continual development of LMWHs in expanded indications did not comprise the use of unfractionated heparin in surgical and interventional cardiovascular indications. Ever since their introduction in the 1980s, the use of LMWHs has continually increased. This is primarily because of expanded indications and growing awareness among the clinicians. It is likely that once an antidote is developed and additional information is available on the mechanism of action of LMWHs, these drugs may gradualty be used for surgery patients. Despite these developments, it is likely that unfractionated heparin will continue to be used for specific indications. Drug combinations with heparins may necessitate dose adjustments, but it is unclear whether unilateral reduction of heparins will be optimal. The coming years will provide useful clinical and applied data on the improved use of unfractionated heparin. LMWHs, and pentasaccharide in the management of thrombotic and cardiovascular disorders. In addition, use of these drugs will be extended to many conditions, including cancer, inflammation, sepsis, and autoimmune diseases. Polytherapeutic approaches emphasizing LMWHs as primary and secondary drugs will also have an impact on the management of thrombotic and nonthrombotic disorders. Ultra-LMWHs and synthetic heparinomimetics, such as fondaparinux, that exhibit a narrow pharmacologic spectrum will only be useful in specific indications and in combination with other drugs.

OBJECTIVE

Heparins, including unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), are glycosaminoglycans that are largely used as anti-thrombotic drugs. While the mechanisms of their anticoagulant actions in blood have been extensively studied, their effects on the hemostatic properties of the endothelium are still under investigation. The aim of this study was to compare the antithrombotic effects of a LMWH, i.e. dalteparin, with UFH on both microvascular (human microvascular endothelial cells [HMEC-1]) and macrovascular (human umbilical vein endothelial cells [HUVEC]) endothelial cells.

METHODS

Endothelial cells were incubated with dalteparin or UFH and exposed to an inflammatory stimulus (i.e. lipopolysaccharide [LPS]). The following parameters were evaluated: tissue factor (TF procoagulant activity, antigen and mRNA), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM).

RESULTS

In HMEC-1 and HUVEC, both heparins inhibited LPS-induced endothelial cell TF expression. However, in HMEC-1, dalteparin was significantly more effective than UFH. Both heparins increased TFPI antigen release in HMEC-1 and HUVEC. Dalteparin also reversed LPS-induced reduction of TM in HMEC-1, while UFH did not.

CONCLUSIONS

These data show that both dalteparin and UFH suppress inflammatory-mediated TF expression and increase the anticoagulant properties of macro- and micro-vascular endothelial cells. However, dalteparin has significantly greater effects than UFH in the microvascular endothelium, a site that plays a central role in many processes involved in inflammation and thrombosis.

Intracoronary thrombus is associated with increased risk of in-laboratory vessel closure, recurrent myocardial infarction (MI), urgent vessel revascularization, and death. There is a lack of consensus on what represents the ideal treatment for patients with thrombotic complications during percutaneous coronary intervention (PCI), but the development of newer thrombolytic agents with increased fibrin specificity and longer half-life provides a potentially useful treatment option. In this study, the safety and efficacy of intracoronary tenecteplase (TNK) was evaluated in 34 patients (22 with acute ST elevation MI, 4 with rescue PCI, 6 with non-ST elevation MI, and 2 during elective PCI) who developed no-reflow, distal embolization, or visible intracoronary thrombus during PCI. The mean age was 57 years, 76% were Caucasian, and there were 14 women and 20 men. Cardiogenic shock was present in seven (21%) patients at baseline. All patients were being treated with aspirin and either unfractionated heparin (33 patients) or bivalrudin. Glycoprotein IIb/IIIa inhibitors were used in 76% of patients. Intracoronary TNK was used at a mean dose of 10.2 +/- 5.2 mg (median, 10 mg; range, 5-25 mg). There was one TIMI major bleeding event and three TIMI minor bleeding events. The mean hematocrit measured the morning following PCI was 35.5% +/- 4.9% in patients receiving TNK and 36.5% +/- 4.4% in a randomly selected sample of 150 consecutive patients undergoing PCI (P = 0.25). In conjunction with mechanical intervention, TNK was successful at dissolving angiographic thrombus and/or improving flow in 91% of patients. In conclusion, intracoronary TNK is safe and well tolerated in patients who develop thrombotic complications during complex PCI.

BACKGROUND

The broad utilization of revascularization and antithrombotic therapy in patients with acute coronary syndrome (ACS) is associated with a substantial risk of bleeding primarily related to arterial punctures, which can lead to worse outcome.

OBJECTIVE

To define the characteristics and outcome of patients who develop upper gastrointestinal bleeding (UGIB) in the setting of ACS.

METHODS

We identified all patients admitted to the coronary care unit between 10/96 and 11/07 with ACS who developed UGIB. For each case 3 control cases were matched. Multiple baseline characteristics, as well as antithrombotic agents, revascularization strategy and endoscopy reports were assessed. Mortality at 30-day was the primary endpoint of the analysis.

RESULTS

Of 7240 ACS patients, 64 (0.9%) developed UGIB. There were no significant differences between groups in the prevalence of diabetes and other risk factors, revascularization strategy, or the use of proton pump inhibitors. Patients with UGIB suffered more from renal impairment and left ventricular dysfunction and were more frequently treated with thienopyridines (89% vs. 68%, p=0.002) and glycoprotein IIb/IIIa inhibitors (39% vs. 24%, p=0.03). The combination of unfractionated heparin (UFH) with glycoprotein IIb/IIIa inhibitors was strongly associated with UGIB (OR: 2.87, 95% CI 1.66-4.97). Patients who developed UGIB had a substantially higher 30-day mortality rate (33% vs. 5%, p<0.001).

CONCLUSIONS

UGIB in patients with ACS is associated with a markedly increased mortality. Previous peptic disease and the use of combined anti-platelet therapy, especially in conjunction with heparin, are strong risk factors for this serious complication.

OBJECTIVE

This study investigated the potential benefits of combination therapy using antithrombin (AT) with danaparoid sodium (DA) compared with the use of AT with unfractionated heparin (UFH) in the treatment of sepsis.

METHODS

Rats infused with lipopolysaccharide were treated with either DA alone, AT alone, AT plus DA, AT plus UFH, or human serum albumin as controls. AT (125 U/kg) was injected into the AT group immediately after lipopolysaccharide infusion. The AT/DA and AT/UFH groups received the same dose of AT in conjunction with either DA (400 U/kg) or UFH (400 U/kg). The status of the mesenteric microcirculation was examined by intra-vital microscopy and the laboratory indices of coagulation, inflammation, and organ dysfunction were measured.

RESULTS

The coagulation markers were improved following the administration of DA or UFH. The decreases in the WBC counts were significantly suppressed in the AT/DA group. The elevation of IL-6 decreased in the AT, DA, and AT/DA groups (all p<0.01) but not in the AT/UFH group. The prostaglandin I2 levels were significantly elevated only in the AT/DA group (p<0.05). The WBC adhesion was significantly suppressed in the DA, AT/UFH, and AT/DA groups (p<0.05), and the RBC velocity was best maintained in the AT/DA group with no associated increase in capillary hemorrhage. The elevation of ALT and BUN significantly improved only in the AT/DA group. ONCLUSION: Organ dysfunction can thus be alleviated by even moderate doses of AT replacement when co-administered with DA.

BACKGROUND

Low molecular weight heparins (LMWHs) are currently used as a standard for anti-thrombotic therapy. Skin necrosis caused by LMWH is a rare and probably under-reported complication. The aim of our systematic review is to analyse the present literature for cases of LMWH-induced skin necrosis, emphasising the pathogenesis, clinical pattern, and management of this rare side effect.

METHODS

We performed a Medline literature search (PubMed database) and manual cross-referencing to identify all articles related to LMWH-induced skin necrosis. Data were analysed for type of LMWH used, time until skin necrosis occurred, localisation, size, laboratory findings, switch anticoagulant, complications, and outcome. Additionally, the case of a patient from our hospital is presented.

RESULTS

We included a total of 20 articles (21 cases) reporting on LMWH-induced skin necrosis. Skin necrosis occurred locally and distant from the injection site. Heparin-induced antibodies were frequently observed (positive 9/11 articles, negative 2/11). However, severe thrombocytopenia (platelet count <100,000 cells/ml) occurred in only four cases, while platelet count remained normal in 50% of the cases. After patients had been switched to other anti-thrombotic drugs, the clinical course was usually benign; however, reconstructive surgery was necessary in two cases.

CONCLUSIONS

LMWH-induced skin necrosis may occur as part of the heparin-induced thrombocytopenia (HIT) syndrome, but other pathomechanisms, including allergic reactions and local trauma, may also be involved. When HIT is excluded, unfractionated heparin is a safe switch anticoagulant. Otherwise, non-heparin preparations such as hirudin or fondaparinux should be preferred.

BACKGROUND

Heparin can significantly reduce pregnancy complications in women with certain thrombophilias, such as antiphospholipid syndrome. Recent reports suggest that heparin may act by mechanisms other than anticoagulation. However, the effect of heparin on trophoblast biology in the absence of thrombophilia has not been extensively investigated. Therefore, this study aimed to evaluate trophoblast invasion, using an established cell line and primary extravillous trophoblasts (EVTs), following exposure to heparin and fractionated heparin.

METHODS

An EVT cell line (SGHPL-4) was used to study invasion in the presence of hepatocyte growth factor (HGF) and varying concentrations of fractionated and unfractionated heparin. These experiments were repeated using first trimester primary EVTs.

RESULTS

Both forms of heparin significantly reduced HGF-induced invasion in the SGHPL-4 cell line. This suppression of invasion appeared to be dose-dependent for fractionated heparin. In primary EVT cells, fractionated heparin also demonstrated significant suppression of invasion.

CONCLUSIONS

Heparin has the potential to reduce trophoblast invasion in cell lines and first trimester EVT cells. This article highlights the need for further evaluation of these medications in vitro and in vivo, especially when used in the absence of thrombophilic disorders.

BACKGROUND

Patients with unstable angina are usually treated with unfractionated heparin and aspirin, but very little is known about the prevalence of heparin-induced antibodies and their relation to thrombotic complications some time after the acute phase of unstable angina. The aim of the present study was to establish the prevalence of heparin-induced thrombocytopenia and the prevalence of heparin-dependent platelet-reactive antibodies in patients treated with unfractionated heparin and the occurrence of thrombosis in a 1 year follow-up.

METHODS

Patient population included 124 consecutive patients with unstable angina treated with unfractionated heparin for almost 5 days. The prevalence of heparin-dependent platelet-reactive antibodies using an ELISA assay was measured before the beginning of heparin therapy and after 7 and 40 days. The platelet count was measured at the same time and the presence of thrombotic occurrences was checked. Clinical follow-up lasted 1 year.

RESULTS

At baseline no one patient was positive for heparin-induced antibodies. On day 6, 38 patients (30%) produced a positive heparin-induced antibody result and 30 patients (24%) had an intermediate result. The majority of patients (74%) who developed antibodies became positive after 6 days of heparin therapy. The combined incidence of death, myocardial infarction, recurrent angina, urgent revascularization and stroke was 66% in patients with antibodies and 44% in patients without antibodies during a 1 year follow-up. The incidence of combined primary end points was statistically higher in patients positive for antibodies. The log-rank test was statistically significant (chi2 = 4.39, p < 0.01).

CONCLUSIONS

No one patient developed a clinical evidence of thrombocytopenia. Nevertheless thrombotic events during follow-up were more common in patients who developed heparin-induced antibodies. These patients need a more accurate evaluation and surveillance after hospital discharge.

Prophylaxis of thromboembolism with low molecular mass (LMM) heparin may offer several advantages over conventional heparin during pregnancy. Heparin-related side effects as osteoporosis, local allergy, thrombocytopenia and increase in liver enzymes may occur less frequently with LMM heparin. However, LMM heparins of different origins have to be considered as individual pharmaceutical compounds. This is of special clinical importance regarding a possible placental passage. We performed a randomized controlled study comparing the anti-factor Xa activities in plasma samples of 60 pregnant women undergoing delivery at term and in the umbilical cord vein of the newborn after subcutaneous administration of 5,000 IU unfractionated (UF) heparin or 1,500 activated partial thromboplastin time units LMM heparin or placebo. Injections were performed about 2 h prior to the delivery. Maternal and fetal blood samples were taken at the same time to assay heparin activity by the heptest coagulation assay and the S2222 chromogenic substrate method. LMM heparin was detected in all maternal plasma samples whereas UF heparin was measurable only in about one third of them. UF heparin as well as LMM heparin were not detectable in samples taken from the umbilical cord vein. The data demonstrate that neither UF nor the LMM heparin used in this study cross the placenta in relevant inhibitory activity towards factor Xa. This finding is in accordance with the previous experiences regarding the safe administration of other LMM heparins for prophylaxis of thromboembolism during pregnancy.

OBJECTIVE

Our objective was to analyze the impact of arterial access site, sheath size, timing of sheath removal, and use of access site closure devices on high-risk patients with acute coronary syndromes (ACS).

BACKGROUND

In the SYNERGY trial, 9,978 patients with ACS were randomly assigned to receive enoxaparin or unfractionated heparin.

METHODS

This analysis includes 9,404 patients for whom sheath access information was obtained for the first PCI procedure or diagnostic catheterization. Comparisons of baseline, angiographic, and procedural characteristics were carried out according to access site and sheath size.

RESULTS

Overall, 9,404 (94%) patients underwent angiography at a median of 21 hr (25th and 75th percentiles: 5, 42) and 4,687 (50%) underwent PCI at a median of 23 hr (6,49) of enrollment. The access site was femoral for 94.9% of cases, radial for 4.4%, and brachial for 0.7%. Radial access was associated with fewer transfusions than femoral access (0.9% vs. 4.8%, P=0.007). For femoral access, the rates of noncoronary artery bypass grafting (CABG)-related TIMI major bleeding by sheath size was 1.5% for 4 or 5 French (Fr), 1.6% for 6 Fr, 3.3% for 7 Fr, and 3.8% for>>or=8 Fr (P<0.0001). After adjustment for baseline characteristics, femoral access site, larger sheath size, and delayed sheath removal were independent predictors of need for transfusion.

CONCLUSIONS

Smaller sheaths, radial access, and timely sheath removal may mitigate the bleeding risk associated with potent antithrombotic/platelet therapy and early catheterization.

BACKGROUND

Venous thromboembolism (VTE) is a frequent and potentially costly complication of major orthopedic surgery.

OBJECTIVE

To estimate the economic consequences of VTE following major orthopedic surgery.

METHODS

Using a large healthcare claims database, we identified all patients who underwent total hip replacement, major knee surgery, or hip fracture repair from January 1993 to December 1998. Patients with clinical VTE (cases) were identified based on a diagnosis of deep vein thrombosis or pulmonary embolism within 90 days of surgery (index admission) and>> or =1 prescription for warfarin or unfractionated heparin within 30 days of the date of initial VTE diagnosis. Each case was matched (using age and procedure type) to 2 randomly selected patients who did not have any claims for clinical VTE (matched controls). Utilization and billed charges were then examined over a 90-day period following admission. Cases were stratified based on whether VTE was first noted during the index admission or thereafter.

RESULTS

A total of 11 960 patients were identified who underwent total hip replacement, major knee surgery, or hip fracture repair (n = 3171, 3955, 4834, respectively). Over a 90-day period, 259 patients (2.2%) developed clinical VTE. Most cases (61.8%) occurred after hospital discharge. For patients with in-hospital VTE, mean length of stay for the index admission was 4.5 days longer than that of matched controls (11.1 vs 6.6); by day 90, there was a 5.4-day difference in total hospital days. Mean billed charges for the index admission were 17,552 higher US dollars (52,037 US dollars vs 34,485 US dollars); the difference rose to 18,834 US dollars by day 90 (54,480 US dollars vs 35,646 US dollars). For patients who developed clinical VTE following hospital discharge, there was a 3.4-day difference in total hospital days at day 90 (10.2 vs 6.8) as a result of readmissions for VTE; mean total billed charges at day 90 were 5765 US dollars higher (41,411 US dollars vs 35,646 US dollars).

CONCLUSIONS

Among patients who have undergone major orthopedic surgery, the economic consequences of VTE are substantial, regardless of the setting in which it occurs.

OBJECTIVE

An immune-based aetiology is one of the several accepted causes for recurrent foetal loss (RFL). However, most of the immunological theories have not fulfilled the criteria for causality. This is a review of the various immunological causes of RFL and the outcome of different treatment protocols.

METHODS

Both auto- and alloimmune maternal immunological abnormalities have been proposed to account for foetal loss. Among the autoimmune factors, anti-phospholipid antibodies (APAs) have been demonstrated to be the strongest risk factors for foetal loss, the prevalence of which is as high as 40% in women with RFL. Other autoimmune antibodies implicated in RFL are anti-nuclear antibodies (ANAs), anti-thyroid antibodies and anti-endothelial cell antibodies. The alloimmune factors implicated in pregnancy loss of unknown aetiology include abnormal natural killer (NK) cell activity, alteration in T helper 1 (Th1) and T helper 2 (Th2) ratios, presence of alloimmune antibodies like anti-paternal cytotoxic antibodies, anti-idiotypic antibodies, mixed lymphocyte reaction blocking antibodies and abnormal expression of HLA-G molecules. Management of patients with RFL is mainly based on immunomodulatory (prednisolone, intravenous immunoglobulins, plasma exchange, paternal lymphocyte therapy), anti-aggregation (aspirin) or anti-coagulation (unfractionated or low molecular weight heparin) agents.

RESULTS

Low-molecular-weight heparin with low-dose aspirin has been found to be the most effective treatment for women with APAs and RFL. Differences in dosage, timing of treatment, inclusion criteria, outcome assessment parameters etc. are some of the factors which have resulted in discrepancies in various reports.

CONCLUSIONS

Identification of the immunological mechanisms involved in pregnancy loss and the action of different therapeutic reagents is important so that effective therapies can be designed and investigated.

Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)(n) tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [K(d)], approximately 50 nM), similar potencies in neutralizing anti-Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)(3)VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti-Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.

Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular-weight heparins 10 years ago advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy with even greater efficacy and safety.

Heparan sulphate and dermatan sulphate have both antithrombotic and anticoagulant properties. These are, however, significantly weaker than those of a comparable amount of standard pig mucosal heparin. Antithrombotic and anticoagulant effects of glycosaminoglycans depend on their ability to catalyse the inhibition of thrombin and/or to inhibit the activation of prothrombin. Since heparan sulphate and dermatan sulphate are less sulphated than unfractionated heparin, we investigated whether the decreased sulphation contributes to the lower antithrombotic and anticoagulant activities compared with standard heparin. To do this, we compared the anticoagulant activities of heparan sulphate and dermatan sulphate with those of their derivatives resulphated in vitro. The ratio of sulphate to carboxylate in these resulphated heparan sulphate and dermatan sulphate derivatives was approximately twice that of the parent compounds and similar to that of standard heparin. Anticoagulant effects were assessed by determining (a) the catalytic effects of each glycosaminoglycan on the inhibition of thrombin added to plasma, and (b) the ability of each glycosaminoglycan to inhibit the activation of 125I-prothrombin in plasma. The least sulphated glycosaminoglycans were least able to catalyse the inhibition of thrombin added to plasma and to inhibit the activation of prothrombin. Furthermore, increasing the degree of sulphation improved the catalytic effects of glycosaminoglycans on the inhibition of thrombin by heparin cofactor II in plasma. The degree of sulphation therefore appears to be an important functional property that contributes significantly to the anticoagulant effects of the two glycosaminoglycans.

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short-term anticoagulation could be much improved. The heparins delivered the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focus on inhibitors of thrombin or FXa. Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three direct thrombin inhibitors (DTI) (lepirudin, argatroban, and bivalirudin) are clinically used for limited indications, whereas there is still no direct FXa inhibitor available. The DTI ximelagatran represented the first oral anticoagulant since the introduction of VKA, but was withdrawn due to safety concerns. Among numerous drug candidates in the clinical development, two orally active anticoagulants dabigatran etexilate, a DTI, and rivaroxaban, the direct FXa inhibitor, are in the most advanced stage of development and may allow a paradigm change in anticoagulation in the foreseeable future. This review describes the pharmacological profile of all these anticoagulants.

The increased risk of thrombosis-related morbidity and mortality in patients with cancer remains, even in the face of anticoagulant therapy. Moreover, recurrent venous thromboembolism (VTE) complicates the management of cancer and adversely affects quality of life and survival. Until recently, initial therapy with unfractionated heparin or low-molecular-weight heparin (LMWH) followed by long-term therapy with an oral anticoagulant was the standard of care for the secondary prevention of acute thromboembolism in most patients. However, according to the results of the CLOT trial (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients With Cancer), extended LMWH therapy with dalteparin represents an alternative to standard oral anticoagulation. In terms of efficacy, the incidence of recurrent VTE in patients receiving dalteparin was half that of those receiving warfarin (27 of 336 patients vs 53 of 336 patients, respectively), for a 52% relative risk reduction. The incidence of major bleeding in this trial was not significantly different in the two arms. Although this LMWH regimen is supported by the latest practice guidelines of the American College of Chest Physicians, the question of whether long-term treatment with LMWH in cancer patients actually affects survival apart from the benefits of thromboprophylaxis remains to be answered.

As the number of anticoagulant drugs increases and new ones are brought to market, the utility of the routine screening coagulation tests of today--namely the prothrombin time and activated partial thromboplastin time--will be significantly reduced in many clinical situations. Although the new anticoagulants are designed to require less frequent monitoring, it is imperative that the proper test is selected in situations where monitoring is needed. In addition, tests that are designed for the new generation of drugs may be informative in certain situations for monitoring the anticoagulants that have been in use for many years. Here, we present the chromogenic antifactor Xa assay and demonstrate its utility and its limitations in monitoring three anticoagulant drugs (unfractionated heparin, low molecular weight heparin, and fondaparinux) as well as one emerging anticoagulant, rivaroxaban.