BACKGROUND

The pharmacokinetics of subcutaneous heparin administration in the obese patient are unpredictable. Peak levels are slowly reached and the effects are not rapidly reversible. Low-dose, continuous, intravenous heparin is easily reversed, is more efficacious and is cost-effective.

METHODS

From November 2000 until July 2005, 822 consecutive patients were administered continuous intravenous unfractionated heparin at 400 U/hr (9,600 U/day) starting in the preoperative holding area and maintained until discharge. All clinically significant events were documented.

RESULTS

634 laparoscopic gastric bypass, 10 revisions and 188 Lap-Band procedures were performed. The mean age was 43+/-11 years (15-74) and mean BMI was 45.2+/-7.1 (30-86). There was only one (0.12%) clinically evident thromboembolic event in the entire cohort (after a gastric bypass). Anti-Xa levels and prothrombin time were followed in a group of 40 patients and were found to be normal in all. Bleeding that required transfusion occurred in 1.3% of patients. In 41 patients (5%), heparin therapy was terminated or temporarily held due to need for extensive adhesiolysis or acute drop in hematocrit, with-or-without other evidence of postoperative bleeding. Average estimated blood loss during surgery was 36 cc (5-500 cc). One patient was inadvertently administered excessive doses of heparin due to a pump error without significant sequelae.

CONCLUSIONS

Continuous low-dose intravenous heparin therapy is associated with an extremely low incidence of thromboembolic events and a low risk for perioperative hemorrhage. Intravenous heparin also has the benefits of being inexpensive and rapidly reversible.

Antithrombin III (ATIII) is used during extracorporeal membrane oxygenation (ECMO) based on physiologic rationale and studies during cardiopulmonary bypass. In February 2008, our institution began using ATIII as replacement for low ATIII activity (<70%) in patients supported with ECMO. We hypothesized that ATIII supplementation would reduce heparin infusion rates, increase unfractionated heparin anti-Xa levels, and prolong ECMO circuit life. Data from 40 consecutive patients (45 deployments) requiring ECMO support for >72 hours with venoarterial ECMO from January 1, 2007, through December 31, 2008, were collected. Antithrombin III concentrate was administered for ATIII activity <70% at the discretion of the attending physician. The primary outcome was whether the heparin infusion rate was reduced by 10% or more as a result of ATIII administration. No difference in heparin infusion rate (p = 0.245) as a result of ATIII administration was observed. Anti-Xa levels were lower before ATIII administration (p< 0.001) and were increased after ATIII administration (p < 0.001). There was an increased frequency of circuit failure in ATIII treatment group compared with nontreatment group (p = 0.018). Neither heparin responsiveness nor circuit life was enhanced by daily ATIII supplementation for activity <70%. Future studies are warranted to evaluate the effectiveness of antithrombin replacement.

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the extrinsic coagulation system. TFPI is increased several-fold in postheparin plasma and thereby thought to contribute significantly to the antithrombotic action of heparin. The present study was conducted to investigate how repeated (n = 8) and continuous (n = 6) administration of heparin affect plasma TFPI and the inhibition of tissue factor (TF)-induced coagulation ex vivo in humans. Free TFPI antigen (TFPI Ag) increased from 19.2 +/- 4.0 ng/ml to 204.7 +/- 31.7 ng/ml after intravenous injection of 5000 IU of unfractionated heparin. Five repeated injections of 5000 IU of heparin at 4 h intervals caused a progressive decrease (-45 +/- 8%, p < 0.0001 for time effect) in heparin-releasable TFPI and a progressive shortening of the clotting time as determined in a dilute prothrombin time assay (dPT) (-8.7 +/- 6.1 s, p < 0.0001). The basal concentration of TFPI Ag in plasma collected immediately before each heparin injection was decreased by 29 +/- 15% (p < 0.0001), whereas the dPT was decreased by 6.9 +/- 3.5 s (p < 0.0001). During a 24 h continuous infusion of heparin TFPI Ag decreased from 161.5 +/- 26.0 ng/ml to 35.6 +/- 4.7 ng/ml (-77.3 +/- 5.1%) (p < 0.0001). The contribution of TFPI to the inhibition of TF-induced coagulation during heparin infusion was estimated to decrease from 60 +/- 15% to 20 +/- 10% (p < 0.0001). The present data indicate partial depletion of intravascular pools of TFPI by repeated and continuous heparin administration and thereby attenuation of its contribution to the antithrombotic action of heparin.

Heparin plus aspirin significantly improves the live birth rate of women with primary antiphospholipid syndrome. Osteopenia is a major concern of long-term heparin therapy. We studied prospectively the bone mineral density (BMD) changes during pregnancy and the puerperium in 123 women with primary antiphospholipid syndrome treated with low-dose aspirin and subcutaneous low-dose heparin (46 women took unfractionated heparin and 77 took low-molecular-weight heparin). Lumbar spine, neck of femur and forearm BMD were measured, using dual energy X-ray absorptiometry, at 12 weeks gestation, immediately postpartum and 12 weeks postpartum. The mean heparin duration was 27 weeks (range 22-29). During pregnancy, BMD decreased by 3.7% (P < 0.001) at the lumbar spine and by 0.9% (P < 0.05) at the neck of femur with no significant change at the forearm. Lactation was associated with a significant decrease in the lumbar spine and neck of femur BMD. There was no significant difference in BMD changes between the two heparin preparations. No woman suffered a symptomatic fracture. Long-term heparin treatment during pregnancy is associated with a small but significant decrease in BMD at the lumbar spine and neck of femur. This decrease is similar to that previously reported to occur in untreated pregnancies.

We investigated the effect of heparin on urinary albumin excretion in patients with insulin-dependent diabetes mellitus. 39 patients with persistent urinary albumin excretion of 30-300 mg/24 h were randomly treated for 3 months with subcutaneous injections twice daily of isotonic saline, 5000 IU unfractionated heparin, or 2000 anti-Xa IU low-molecular-weight heparin. Unfractionated and low-molecular-weight heparin induced a significant reduction in urinary albumin excretion (p = 0.04 and p = 0.004). The mechanism and clinical relevance is unknown but deserve further attention.

A randomised, prospective, double-blind trial was performed, to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) Bemiparin and standard unfractionated heparin (UFH), for the prophylaxis of postoperative venous thromboembolism. 300 patients scheduled to undergo elective hip arthroplasty were included. The principal outcome measures were the incidence of thromboembolic events and bleeding complications. 149 patients received 3,500 anti-Xa IU of bemiparin plus a placebo injection daily and 149 patients received 5,000 IU of UFH twice a day. The two groups were similar with respect to factors likely to affect the risk of developing post-operative venous thromboembolism (VTE) and risk of bleeding events. During the post-operative period, 34 patients developed VTE complications; 9 (7.2%) in the bemiparin group and 25 (18.7%) in the UFH group. VTE in the two groups was statistically significant (OR of 2.96; 95% CI 1.32-6.62 and p = 0.01). There were no significant differences in the frequency of bleeding complications: major bleeding requiring discontinuation of prophylaxis, (OR 1.21; 95% CI 0.36-4.05; p = 1.00), the measured median operative blood loss (p = 0.77) or the median postoperative drain loss (p = 0.97), and the number of patients who developed wound haematoma (OR 0.87; 95% CI 0.31-2.46; p = 1.00). A comparison of coagulation parameters on the preoperative day with post-operative day 2 +/- 1, day 6 +/- 1 and day of discharge showed a significantly higher AT concentration, anti-factor Xa activity and TFPI levels in the bemiparin group when compared with UFH. This study demonstrates that bemiparin, in a single daily subcutaneous dose of 3,500 anti-Xa IU in high risk patients undergoing hip arthroplasty is more effective than UFH administered twice daily at a dose of 5,000 IU in the prevention of postoperative VTE. Both agents are equally safe.

BACKGROUND

Low-molecular-weight heparins (LMWHs) possess several potential pharmacological advantages over unfractionated heparin as an antithrombotic agent.

OBJECTIVE

To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI).

METHODS

We searched MEDLINE for articles from 1990 to 2002 using the index terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences.

METHODS

We selected for review randomized trials comparing LMWHs against either unfractionated heparin or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis.

METHODS

Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting.

RESULTS

The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non-ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction.

CONCLUSIONS

The LMWHs could potentially replace unfractionated heparin as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended.

TNKase is a genetically engineered variant of the alteplase molecule. Three different mutations result in an increase of the plasma half-life, of the resistance to plasminogen-activator inhibitor 1 and of the thrombolytic potency against platelet-rich thrombi. Among available agents in clinical practice, TNKase is the most fibrin-specific molecule and can be delivered as a single bolus intravenous injection. Several large-scale clinical trials have enrolled more than 27,000 patients with acute myocardial infarction, making the use of this drug truly evidence-based. TNKase is equivalent to front-loaded alteplase in terms of mortality and is the only bolus thrombolytic drug for which this equivalence has been formally demonstrated. TNKase appears more potent than alteplase when symptoms duration lasts more than 4 hours. Also, TNKase significantly reduces the rate of major bleeds and the need for blood transfusions. The efficacy of TNKase may be further improved by enoxaparin substitution for unfractionated heparin, provided that enoxaparin dose adjustment is made for patients more than 75 years old. Hitherto, the small available randomized studies and international clinical registries suggest that pre-hospital TNKase is as effective as primary angioplasty, thus laying the foundations for a new fibrinolytic, TNKase-based strategy as the backbone of reperfusion in acute myocardial infarction.

A simple, selective and accurate capillary electrophoresis (CE) method has been developed for the rapid separation and identification of various low molecular weight heparins (LMWHs) and unfractionated heparin. Separation and operational parameters were investigated using dalteparin sodium as the test LMWH. The developed method used a 70 cm fused silica capillary (50 microm i.d.) with a detection window 8.5 cm from the distal end. Phosphate electrolyte (pH 3.5; 50 mM), an applied voltage of -30 k V, UV detection at 230 nm and sample injection at 20 mbar for 5s were used. The method performance was assessed in terms of linearity, selectivity, intra- and inter-day precision and accuracy. The method was successfully applied to the European Pharmacopeia LMWH standard, dalteparin sodium, enoxaparin sodium and heparin sodium with a significant reduction in the run time and increased resolution compared with previously reported CE methods. Different CE separation profiles were obtained for various LMWHs and unfractionated heparin showing significant structural diversity. The current methodology was sensitive enough to reveal minor constituent differences between two different batches of enoxaparin sodium. This CE method also clearly showed chemical changes that occurred to LMWHs under different stress conditions. The sensitivity, selectivity and simplicity of the developed method allow its application in research or manufacturing for the identification, stability analysis, characterization and monitoring of batch-to-batch consistency of different low molecular weight and unfractionated heparins.

Heparin-induced thrombocytopenia is a rare and serious reaction to unfractionated heparin and low-molecular-weight heparins in children. Quick recognition, discontinuation of heparin, and subsequent treatment with an alternative anticoagulant are essential steps to prevent serious complications such as thrombus and limb amputation. The purpose of this review is to describe the clinical features of heparin-induced thrombocytopenia in children and to summarize the data available for its management. This paper summarizes data and relates the use of direct thrombin inhibitors with clinical outcomes. A literature search was conducted with Ovid, using the key terms argatroban, bivalirudin, hirulog, danaparoid, lepirudin, direct thrombin inhibitor, heparin-induced thrombocytopenia, thrombosis, warfarin, and fondaparinux. Articles were excluded if they were classified as editorials, review articles, or conference abstracts or if they involved patients 18 years of age or older or described disease states not related to thrombosis. Nineteen articles containing 33 case reports were identified and evaluated for this review. Of the 33 cases, 14, 10, 4, and 2 cases described the use of lepirudin, danaparoid, argatroban, and bivalirudin, respectively. Two cases did not report the type of anticoagulant used, and 1 case used aspirin. The most commonly reported complication was bleeding.

Acute kidney injury requiring renal replacement therapy occurs in up to 10% of all intensive care unit patients. Those who are hemodynamically unstable are often treated with continuous renal replacement therapy requiring continuous anticoagulation of the extracorporeal circuit. This is usually achieved by infusion of unfractionated heparin, which subsequently increases the risk of bleeding. To avoid systemic anticoagulation for continuous renal replacement therapy, regional anticoagulation with citrate has been introduced. We studied safety and efficacy of regional citrate anticoagulation for continuous venovenous hemodialysis in surgical patients requiring high dialysis doses. This was an observational prospective study in a 40-bed surgical intensive care unit at a university hospital. During a 12-month study period, all consecutive critically ill patients with high risk of bleeding requiring continuous renal replacement therapy continuous renal replacement therapy were treated with citrate anticoagulation for continuous venovenous hemodialysis. Prescribed dialysis dose was 45 mL/kg per h with a 10% increase for expected downtime. We studied filter lifetime, delivered dialysis dose, control of acid-base status, bleeding episodes, and adverse effects, that is, citrate intolerance. The total number of filters analyzed in 75 patients was 100. Mean (± standard deviation) filter running time was 78 ± 25 h. Fifty-one circuits had to be renewed because of extended filter running time (96 ± 18 h), 33 discontinued for reasons not related to renal replacement therapy (62 ± 19 h), and 13 due to filter clotting (58 ± 18 h). The mean dialysis dose during the first 72 h was 49 ± 14 mL/kg per h. Overall, acid-base status after 72 h was well controlled in 62% of patients, metabolic alkalosis (pH>> 7.45) occurred in 29%, and metabolic acidosis (pH < 7.35) in 9%. In one patient, treatment was stopped because of citrate accumulation. Citrate intoxication or overt bleeding episodes were not observed. Regional citrate anticoagulation for continuous venovenous hemodialysis is a safe and effective method to deliver a high dialysis dose in critically ill patients with a high risk of bleeding. Filter patency was excellent, acid-base status was well controlled, and clinically relevant adverse effects were not observed. Therefore, citrate anticoagulated continuous venovenous hemodialysis is a useful treatment option for patients with acute kidney injury requiring high dialysis doses and at risk of bleeding.

OBJECTIVE

Pregnancy in women with prosthetic heart valves remains a risk factor for both mother and fetus, but unselected and unbiased outcome and complication data remain scarce. We analyzed nationwide outcome data from 1977 to 2007 for all pregnancies in women with prosthetic valves.

METHODS

Cardiac, obstetric, and neonatal data were obtained from obligatory databases and compared with general female population data. Questionnaires were used to corroborate important information. Outcome data were analyzed according to type of anticoagulation used. The data were compared between the two first and the last decades of the study period. In the last decade, patients were compared to an age-adjusted selected population of healthy, pregnant women.

RESULTS

Of 356 women between 15 and 40 years of age, 79 women had 155 pregnancies after valve replacement. Two women died during pregnancy, one from heart failure and one from post-partum bleeding. There were four thrombo-embolic episodes in the early study period in women with mitral prosthesis on unfractionated heparin. Important cardiac complications were otherwise almost absent. There were significantly more early miscarriages and terminations in patients compared with controls (last decade 34%, vs 20% (p=0.0036) and 26% vs 13% (p=0.000019)). Post-partum bleeding was more common in the patient group (p=0.0021). Two late fetal losses (one from intracerebral bleeding) were seen. The remaining pregnancies resulted in 60 live births. Cesarean section was the predominant method of delivery in patients as opposed to controls (55% vs 16%, p=0.000000000097). Premature births were more frequent in patients (49% vs 5.5%, p=0.00000000039) as were congenital malformations (14% vs 5.7%, p=0.044). Two of the six malformations were warfarin embryopathy (8% of all first-trimester warfarin exposures), both seen in high-risk patients on high warfarin dosing. Small for gestational age did not differ significantly from the general population (9.3% vs 6.0%, p=0.39).

CONCLUSIONS

Data acquired over 30 years confirm that women with prosthetic heart valves, especially aortic prostheses for congenital lesions, generally tolerate pregnancy well, although cardiac mortality, mortality related to anticoagulation and thrombo-embolic risks are raised. Our data provide further documentation on the significance and importance of the risks associated with predominantly warfarin-based treatment regimens, which still remains optional for a number of patients. Finally, the data also serve as a comparison for recently published series based on low-molecular-weight heparin (LMWH) regimens.

Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999.

To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism).

For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries.

Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE.

Two review authors independently selected trials for inclusion, assessed for quality and extracted data.

Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence).

This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.

BACKGROUND

Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane, particularly new vessel formation and fibrosis. In addition to anticoagulant effects, heparin displays anti-inflammatory and angiostatic properties. Therefore, the effects of administration of heparins on function and morphology of the peritoneal membrane were studied in a rat PD model.

METHODS

Rats received 10 mL conventional PD fluid (PDF) daily, with or without the addition of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in the PDF (1 mg/10 mL intraperitoneally) via a mini access port. Untreated rats served as controls. After 5 weeks, a 90-minute functional peritoneal transport test was performed and tissues and peritoneal leukocytes were taken.

RESULTS

PD treatment induced loss of ultrafiltration (p<0.01), a twofold increase in glucose absorption (p<0.03), increased urea transport (p<0.02), and loss of sodium sieving (p<0.03), which were also found in the PDF+heparin groups. Increased peritoneal cell influx and hyaluronan production (p<0.02) as well as an exchange of mast cells and eosinophils for neutrophils after PD treatment were observed in PD rats; addition of heparin did not affect those changes. Mesothelial regeneration, submesothelial blood vessel and matrix formation, and accumulation of tissue macrophages were seen in PD animals. Spindle-shaped vimentin-positive and cytokeratin-negative cells indicated either partial injury and denudation of mesothelial cells or epithelial-to-mesenchymal transition. Neither UFH nor LMWH affected any of these morphological changes.

CONCLUSIONS

Within 5 weeks, PD treatment induces a chronic inflammatory condition in the peritoneum, evidenced by high transport, leukocyte recruitment, tissue remodeling, and induction of spindle-shaped cells in the mesothelium. Addition of LMWH or UFH to the PDF did not prevent these adverse PDF-induced peritoneal changes.

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome in which one or more clinical events, usually thrombocytopenia or thrombosis, are temporally related to heparin administration and caused by HIT antibodies. Rapid and accurate diagnosis is essential given the high incidence of thrombosis at around the time of initial disease recognition. Discontinuation of heparin and initiation of alternative anticoagulants reduces HIT-associated morbidity and mortality. The clinical consequences of HIT in hemodialysis patients remain unclear, with several studies reporting no clinical sequelae and others describing complications such as thrombocytopenia or clotting of the extracorporeal circuit. Frequent clotting of the extracorporeal circuit has also been reported in HIT-antibody-positive patients on continuous veno-venous hemofiltration. Several recent findings are of particular interest to nephrologists. An acute systemic reaction has been described as a presentation of HIT in hemodialysis patients shortly after administration of an unfractionated heparin bolus. This syndrome is important to recognize as it might mimic a dialyzer reaction. More recently, the presence of a positive HIT-antibody test or increasing titers of HIT antibody were associated with increased mortality in hemodialysis patients, raising the question of whether these antibodies have a role in the increased cardiovascular mortality seen in these patients. HIT-antibody production is often transient and small numbers of hemodialysis patients with undetectable antibody levels have been rechallenged with heparin without adverse clinical consequences.

Heparin derivative-based therapy has evolved from unfractionated heparin (UFH) to low-molecular-weight heparins (LMWHs) and now fondaparinux, a synthetic pentasaccharide. Contrary to UFH or LMWHs, fondaparinux is not neutralized by protamine sulfate, and no antidote is available to counteract bleeding disorders associated with overdosing. To make the use of fondaparinux safer, we developed an antithrombin (AT) variant as a potent antidote to heparin derivatives. This variant (AT-N135Q-Pro394) combines 2 mutations: substitution of Asn135 by a Gln to remove a glycosylation site and increase affinity for heparins, and the insertion of a Pro between Arg393 and Ser394 to abolish its anticoagulant activity. As expected, AT-N135Q-Pro394 anticoagulant activity was almost abolished, and it exhibited a 3-fold increase in fondaparinux affinity. AT-N135Q-Pro394 was shown to reverse fondaparinux overdosing in vitro in a dose-dependent manner through a competitive process with plasma AT for fondaparinux binding. This antidote effect was also observed in vivo: administration of AT-N135Q-Pro394 in 2.5-fold molar excess versus plasma AT neutralized 86% of the anti-Xa activity within 5 minutes in mice treated with fondaparinux. These results clearly demonstrate that AT-N135Q-Pro394 can reverse the anticoagulant activity of fondaparinux and thus could be used as an antidote for this drug.

BACKGROUND

Real-world evidence of the effectiveness of pharmacological thromboprophylaxis for venous thromboembolism (VTE) is limited. Our objective was to assess the effectiveness and safety of thromboprophylactic regimens in Japanese patients undergoing joint replacement in a real-world setting.

METHODS

Overall, 1,294 patients (1,073 females and 221 males) who underwent total knee arthroplasty (TKA) and 868 patients (740 females and 128 males) who underwent total hip arthroplasty (THA) in 34 Japanese national hospital organization (NHO) hospitals were enrolled. The primary efficacy outcome was the incidence of deep vein thrombosis (DVT) detected by mandatory bilateral ultrasonography up to post-operative day (POD) 10 and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding (major or minor) and death from any cause up to POD28.

RESULTS

Patients undergoing TKA (n = 1,294) received fondaparinux (n = 360), enoxaparin (n = 223), unfractionated heparin (n = 72), anti-platelet agents (n = 45), or no medication (n = 594). Patients undergoing THA (n = 868) received fondaparinux (n = 261), enoxaparin (n = 148), unfractionated heparin (n = 32), anti-platelet agents (n = 44), or no medication (n = 383). The incidence rates of sonographically diagnosed DVTs up to POD10 were 24.3% in patients undergoing TKA and 12.6% in patients undergoing THA, and the incidence rates of major bleeding up to POD28 were 1.2% and 2.3%, respectively. Neither fatal bleeding nor fatal pulmonary embolism occurred. Significant risk factors for postoperative VTE identified by multivariate analysis included gender (female) in both TKA and THA groups and use of a foot pump in the TKA group. Only prophylaxis with fondaparinux reduced the occurrence of VTE significantly in both groups. Propensity score matching analysis (fondaparinux versus enoxaparin) showed that the incidence of DVT was lower (relative risk 0.70, 95% confidence interval (CI) 0.58 to 0.85, P = 0.002 in TKA and relative risk 0.73, 95% CI 0.53 to 0.99, P = 0.134 in THA) but that the incidence of major bleeding was higher in the fondaparinux than in the enoxaparin group (3.4% versus 0.5%, P = 0.062 in TKA and 4.9% versus 0%, P = 0.022 in THA).

CONCLUSIONS

These findings indicate that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of DVT but increases bleeding tendency in patients undergoing TKA and THA.

BACKGROUND

University Hospital Medical Information Network Clinical Trials Registry: UMIN000001366. Registered 11 September 2008.

The effect of low molecular weight heparin (LMWH) on serum lipid profile in hemodialysis remains controversial and its effect on bone metabolism has not been studied. A crossover study was conducted in 40 patients on stable hemodialysis using unfractionated heparin (UFH) for more than 24 months. These patients were then treated with a LMWH (nadroparin-Ca) for 8 months during hemodialysis and subsequently switched back to UFH for 12 months. Serum lipid profile, biochemical markers for bone metabolism, and bone densitometry (BMD) were monitored at four-month intervals while all medications remained unchanged. Cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B (Apo B) were raised in 35%, 29%, 12%, 24% and 24% of patients respectively. High-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A-1) were reduced in 47% and 9% of patients. Bone-specific alkaline phosphatase (BALP) and intact osteocalcin (OSC), both reflecting osteoblastic activity, were raised in 65% and 94% of patients. Tartrate-resistant acid phosphatase (TRACP) reflecting osteoclastic activity and parathyroid hormone (PTH) were elevated in 35% and 88% of patients. Following LMWH treatment, TC, Tg, Lp(a) and Apo B were reduced by 7%, 30%, 21% and 10% respectively (p<0.05 or <0.01) while Apo A-1 were raised by 7% (p<0.01). Simultaneously, TRACP was reduced by 13% (p<0.05). These biochemical changes were detected soon after 4 months of LMWH administration. Although BMD values in our patients were lower than those of age-matched normal subjects, significant changes were not observed with LMWH treatment. After switching back to UFH for hemodialysis, these biochemical indices reverted to previous values during UFH treatment with a significant higher level in TC and Apo B while serum Apo A-1 remained elevated. Our study suggests LMWH may partially alleviate hyperlipidemia and, perhaps, osteoporosis associated with UFH administration in patients on maintenance hemodialysis.

Exposure of normal guinea pigs to an aerosol of PAF induced a selective increase in the percentage of eosinophils in bronchoalveolar lavage (BAL) fluid 24 h after challenge. Challenge of actively sensitised guinea pigs with an aerosol of ovalbumin also induced a selective increase in the percentage of eosinophils recovered in BAL fluid 24 h post challenge. Pretreatment of actively sensitised guinea pigs or normal guinea pigs with unfractionated heparin significantly reduced such eosinophil infiltration induced by allergen or PAF challenge respectively, although higher amounts of heparin were required to inhibit antigen induced eosinophil infiltration. Similar effects were also observed following treatment with the low molecular weight heparin-like material ORG 10172 but not the anionic molecule polyglutamic acid or high molecular weight dextrans. These results suggest that proteoglycans may possess anti-allergic activity that is not necessarily related to either such molecules being anionic in nature nor to anti-coagulant activity.

Heparins, either unfractionated or low-molecular-weight (UFH and LMWHs), and vitamin K antagonists (VKAs) are currently the anticoagulants of choice for the prevention of post-operative venous thromboembolism (VTE) and for the treatment of acute venous and arterial thromboembolism. While VKAs are widely used in the US, LMWHs are the standard of care in the EU. Although efficacious, these agents are associated with a number of drawbacks, such as the risk of heparin-induced thrombocytopenia, the need for frequent coagulation monitoring in the case of UFH and VKAs, and the parenteral mode of administration in the case of heparins, which can lead to problems associated with patient compliance. There is a need for new anticoagulants that overcome these limitations. Direct, small-molecule inhibitors of coagulation proteins targeting a single enzyme in the coagulation cascade - particularly thrombin or Factor Xa - have been developed in recent years. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. Here we will review data that suggest that the antithrombin-independent mechanism of action of these agents, particularly that of direct Factor Xa inhibitors, leads to increased efficacy with similar safety profiles compared with the antithrombin-dependent heparins. Although the end of the heparins era is not to be expected, the new anticoagulants presented in this review potentially represent the future of anticoagulation.

Heparin-induced thrombocytopenia (HIT) is an immunoglobulin-mediated adverse drug reaction associated with a high risk of thrombotic complications. The pathogenic antibody, usually immunoglobulin (Ig) G (HIT-IgG), recognises a multimolecular complex of heparin and platelet factor 4, resulting in platelet activation via platelet Fc receptors. In addition to in vivo platelet activation, it is now recognised that there is a concomitant activation of coagulation, as shown by marked elevations in thrombin-antithrombin complex levels. It is possible that this increased thrombin generation predisposes HIT patients to a newly recognised complication: warfarin-induced venous limb gangrene. This syndrome is characterised clinically by necrosis complicating deep venous thrombosis in the absence of large-vessel arterial occlusion, and appears to result from acquired protein C deficiency during warfarin therapy for deep vein thrombosis and HIT. The recommended treatment for HIT is an agent that reduces thrombin generation, either indirectly via factor Xa inhibition [e.g. danaparoid sodium (a mixture of anticoagulant glycosaminoglycans)] or directly using a specific thrombin inhibitor (e.g. recombinant hirudin; argatroban). HIT is potentially preventable: there is a lower frequency of HIT, associated thrombosis and HIT-IgG seroconversion in patients treated with low-molecular-weight heparins, compared with unfractionated heparin.

In many countries, low molecular weight heparins (LMWHs) have replaced unfractionated heparin (UH) for prevention and treatment of venous thromboembolism. The present paper reviews the possible advantages of LMWHs over UH. In spite of their lower molecular weight distribution, LMWHs are functionally more heterogeneous than UH. Their anti-Xa/anti-IIa ratio varies significantly, and the injection of the same dose generates different anti-Xa activities and activated partial thromboplastin time (APTT) prolongations. Their pharmacodynamic properties account for their more convenient use in comparison with UH; however, there is a risk of accumulation in case of renal insufficiency. Even if they are less anticoagulant on the basis of the APTT prolongation, they are not less prohemorrhagic than UH. LMWHs are probably less immunogenic and probably induce less osteoporosis. Several meta-analyses published between 1992 and 1999 indicate that LMWHs are as efficient as UH in preventing postoperative deep vein thrombosis (DVT) in general surgery and more efficient than UH in preventing DVT in orthopedic surgery and treating established DVT.

Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents.

Venous thromboembolism (VTE) is an important cause of preventable morbidity and mortality in medically ill patients. Randomized controlled trials indicate that pharmacologic prophylaxis reduces deep venous thrombosis (relative risk [RR] = 0.46; 95% confidence interval [CI], 0.36-0.59) and pulmonary embolism (RR = 0.49; 95% CI, 0.33-0.72) with a nonsignificant trend toward more bleeding (RR = 1.36; 95% CI, 0.80-2.33]. Low-molecular-weight heparin (LMWH) and unfractionated heparin are equally efficacious in preventing deep venous thrombosis (RR = 0.85; 95% CI, 0.69-1.06) and pulmonary embolism (RR = 1.05; 95% CI, 0.47-2.38), but LMWH is associated with significantly less major bleeding (RR = 0.45; 95% CI, 0.23-0.85). LMWH is favored for VTE prophylaxis in critically ill patients. New VTE and bleeding risk stratification tools offer the potential to improve the risk-benefit ratio for VTE prophylaxis in medically ill patients. Intermittent pneumatic compression devices should be used for VTE prophylaxis in patients with contraindications to pharmacologic prophylaxis. Graduated compression stockings should be used with caution. VTE prevention in medically ill patients using extended-duration VTE prophylaxis and new oral anticoagulants warrant further investigation. VTE prophylaxis prescription and administration rates are suboptimal and warrant multidisciplinary performance improvement strategies.