Standard unfractionated heparin is a mixture of mucopolysaccharide chains of various length that may vary from 5000 to 30,000 daltons. Heparin is only effective as an anticoagulant in the presence of a plasma protein termed antithrombin III, with which it forms a complex. High- and low-affinity heparin are 2 types that readily bind or do not bind, respectively, to antithrombin III. The pharmacokinetics of unfractionated heparin are compatible with a model based on the combination of a saturable and a linear mechanism. The primary indication for intravenous infusion of conventional heparin is to prevent extension of an established arterial, venous or intracardiac thrombus. The average requirement is 400 U/kg/24h. Subcutaneous administration of 5000U of concentrated unfractionated heparin, administered every 8 or 12 hours, is effective and safe in the prevention of postoperative venous thrombosis and pulmonary embolism in patients at medium thrombotic risk. Adequate prophylaxis is also obtained in patients at high thrombotic risk if 5000U of heparin combined with 0.5mg dihydroergotamine is given subcutaneously 3 times daily, or by monitoring the 3 subcutaneous doses of heparin in order to maintain an adjusted activated partial thromboplastin time (APTT) of around 50 to 70 seconds. Low molecular weight heparins have been produced by a variety of techniques and their molecular weights range from 3000 to 9000 daltons. These preparations have a ratio of anti-factor Xa activity to anti-factor IIa activity of about 4, while the ratio for unfractionated heparin is 1. After intravenous administration of low molecular weight heparin, the half-life of the anti-factor Xa activity is considerably longer than for unfractionated heparin, while the anti-factor IIa half-lives are similar. In contrast to unfractionated heparin, low molecular weight heparin is completely absorbed after subcutaneous administration and its biological half-life is almost twice as long. In spite of certain differences with regard to the ratio between factor Xa and IIa inhibition, the various low molecular weight preparations show a rather similar absorption pattern. The bioavailability of all low molecular weight heparin fractions is substantially higher than that of unfractionated heparin, which renders their use more simple. Low molecular weight heparins less readily enhance platelet aggregation although there is no evidence that low molecular weight heparins are less antigenic or that they do not interact with platelet IgGFc receptor. A lower bleeding incidence for equivalent antithrombotic efficacy of fractionated heparins when compared to unfractionated heparins has yet to be established in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND

There is no randomized controlled trial (RCT) evaluating the efficacy and safety of low molecular weight heparin (LMWH) compared to unfractionated heparin (UFH) in cerebral venous sinus thrombosis (CVST). In this RCT, we have evaluated the efficacy and safety of LMWH versus UFH in CVST.

METHODS

Consecutive patients with CVST diagnosed on the basis of MR venography (MRV) who was free of bleeding diathesis, malignancy, hepatic or renal failure were prospectively enrolled. History, clinical findings and risk factors were evaluated. MRI and MRV findings were recorded. The patients were randomized to LMWH and UFH groups for 14 days followed by oral anticoagulant. The hospital mortality and 3 months outcome as assessed by Barthel index (BI) score were noted.

RESULTS

32 patients received UFH and 34 received LMWH. The baseline demographic, clinical and radiological parameters were similar in both the groups. Six patients died and all were in UFH group (P = 0.01). At 3 months, insignificantly higher number of patients recovered completely in LMWH compared to UFH group (30 vs. 20). There was no serious side effect needing withdrawal of drugs except one was withdrawn from UFH because of heparin-induced thrombosis.

CONCLUSIONS

Low molecular weight heparin resulted in significantly lower hospital mortality in CVST compared to UFH.

BACKGROUND

Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation.

RESULTS

In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F(1+2) (P<0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; P<0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F(1+2) and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (P<0.01). Concomitantly, factor VIIa levels dropped by >50% at 50 minutes after initiation of either heparin infusion (P<0.01).

CONCLUSIONS

This experimental model proved the anticoagulatory potency of UFH and LMWH in the initial phase of experimental LPS-induced coagulation. Successful inhibition of thrombin generation also translates into blunted activation of coagulation factors upstream and downstream of thrombin.

The actual incidence of neurological dysfunction resulting from haemorrhagic complications associated with neuraxial block is unknown. Although the incidence cited in the literature is estimated to be <1 in 150,000 epidural and <1 in 220,000 spinal anaesthetics, recent surveys suggest that the frequency is increasing and may be as high as 1 in 3000 in some patient populations. Overall, the risk of clinically significant bleeding increases with age, associated abnormalities of the spinal cord or vertebral column, the presence of an underlying coagulopathy, difficulty during needle placement, and an indwelling neuraxial catheter during sustained anticoagulation (particularly with standard unfractionated heparin or low molecular weight heparin). The decision to perform spinal or epidural anaesthesia/analgesia and the timing of catheter removal in a patient receiving antithrombotic therapy is made on an individual basis, weighing the small, although definite risk of spinal haematoma with the benefits of regional anaesthesia for a specific patient. Coagulation status should be optimized at the time of spinal or epidural needle/catheter placement, and the level of anticoagulation must be carefully monitored during the period of neuraxial catheterization. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation, as this appears to significantly increase the risk of spinal haematoma. Vigilance in monitoring is critical to allow early evaluation of neurological dysfunction and prompt intervention. An understanding of the complexity of this issue is essential to patient management.

BACKGROUND

The use of heparin for the treatment of ulcerative colitis has been evaluated in several open and controlled trials, with varying outcomes.

OBJECTIVE

To evaluate the efficacy and safety of heparin as supplemental therapy compared with conventional therapy in patients with ulcerative colitis.

METHODS

All randomized trials comparing heparin supplementation to conventional therapy were included from electronic databases. Statistical analysis was performed with review manager 4.2.8 (The Cochrane Collaboration, Oxford, UK). Sub-analysis and sensitivity analysis were also performed.

RESULTS

Eight randomized-controlled trials, investigating a total of 454 participants, met the inclusion criteria. The odds ratio (OR) for the efficacy of heparin supplementation vs. conventional therapy was 0.78 (95% CI = 0.50-1.21). Few serious adverse events were observed. The OR for the efficacy of unfractionated heparin and low-molecular-weight heparin vs. conventional therapy was 0.26 (95% CI = 0.07-0.93) and 0.92 (95% CI = 0.57-1.47), respectively. The OR for the efficacy of heparin vs. conventional therapy with placebo was 0.87 (95% CI = 0.53-1.44).

CONCLUSIONS

Our meta-analysis suggests that administration of heparin in patients with ulcerative colitis is safe, but no additive benefit over conventional therapy is indicated.

Human mesenchymal stem cells (hMSCs) offer significant therapeutic potential in the field of regenerative medicine and high-resolution magnetic resonance imaging (MRI) is useful modality to visualize in vivo kinetics of transplanted stem cells. For successful MR imaging, there is a great need for effective contrast agents for stem cell labeling with high uptake yield and low toxicity. Here, we present superparamagnetic iron oxide (SPIO) nanoparticles coated with unfractionated heparin (UFH-SPIO) as a new negative contrast agent for in vivo MR imaging of hMSCs. The uptake of UFH-SPIO by hMSCs was effective without the aid of transfection agents, which was dependent on the concentration and exposure time. The uptake efficiency of UFH-SPIO was greater than that of DEX-SPIO (SPIO coated with dextran) by approximately 3 folds when treated for 1 h. TEM and Prussian blue staining confirmed that UFH-SPIO nanoparticles were internalized into the cytosol of hMSCs which existed during in vitro subculture for 28 days. Low temperature endocytosis inhibition assay demonstrated that the incorporation of UFH-SPIO into hMSCs was likely to be mediated by endocytosis. When the phantom of UFH-SPIO-labeled hMSCs was visualized with 3-T T(2)-weighted MRI, the hypointensity signals of UFH-SPIO-labeled hMSCs were linearly correlated with the concentration of the nanoparticles. The cellular labeling using UFH-SPIO did not reduce the viability, proliferation or differentiation potential to osteogenic and adipogenic lineages of hMSCs. When the UFH-SPIO-labeled hMSCs were transplanted into the left renal subcapsular membranes of nude mice, they were successfully visualized and detected by T(2) and T(2)(∗)-weighted MRI for a month. Collectively, these results suggest that UFH-SPIO nanoparticles are promising as a new MRI contrast agent for in vivo long-term tracking of hMSCs.

OBJECTIVE

The aim of the present study was to analyze the risk factors associated with complications of endoscopic sphincterotomy (ES).

METHODS

In all consecutive endoscopic sphincterotomies carried out between September 1994 and December 1996, the possible risk factors (12 patient-related factors and 12 procedure-related ones), as well as the concomitant medical treatment, indications, techniques, and success of endoscopic sphincterotomy were evaluated prospectively. Risk factors were analyzed on an exploratory basis using univariate methods. "Potential risk factors" (univariate, P<0.1) underwent multivariate analysis to determine independent "risk factors" (multivariate, P<0.05). In addition, the complication rate was calculated according to the number of potential risk factors present.

RESULTS

A total of 438 patients who underwent ES were analyzed. Complications occurred in 7.5% (n = 33; acute pancreatitis 4.3%, hemorrhage 2.3 %, cholangitis 0.9%, technical 0.2%). Statistical analysis of the complications identified three independent risk factors (coagulopathy, patient age (< or =60 years, pancreas divisum), and one protective factor (pancreatic duct obstruction). The frequency of acute pancreatitis was increased by two independent risk factors (pancreas divisum, ES frequency <40 procedures/year) and was reduced if low-dose anticoagulation (unfractionated heparin or low molecular weight heparin) was administered (0.9%, one of 115 vs. 5.8%, 18 of 313; P<0.05). The effect of anticoagulation was not confounded by the presence or absence of other potential risk factors for acute pancreatitis. Neither the risk nor the severity of hemorrhage were increased by low-dose anticoagulation. Due to the low number of events, only potential risk factors for hemorrhage were identified (coagulopathy, intensive-care treatment). The overall complication rate and the incidence of pancreatitis and hemorrhage increased significantly depending on the number of simultaneous potential risk factors present (P<0.0001).

CONCLUSIONS

Patients at risk for complications after endoscopic sphincterotomy can be identified by risk factor analysis. These data suggest the hypothesis that low-dose anticoagulation prior to endoscopic sphincterotomy reduces the risk of acute pancreatitis after sphincterotomy.

BACKGROUND

Venous thromboembolism (VTE) is an important complication of neurosurgery. Current guidelines recommend pharmacologic prophylaxis in this setting with either unfractionated heparin or low-molecular-weight heparin (LMWH). We conducted a systematic review asking, "Among patients undergoing neurosurgical procedures, how safe and effective is the prophylactic use of heparin and mechanical devices?"

METHODS

We searched the medical literature to identify prospective trials reporting on VTE prevention (either mechanical or pharmacologic). The rates of VTE and bleeding were our primary end points and were pooled using a random-effects model.

RESULTS

We identified 30 studies reporting on 7,779 patients. There were 18 randomized controlled trials and 12 cohort studies. The results of pooled relative risks (RRs) showed LMWH and intermittent compression devices (ICDs) to be effective in reducing the rate of deep vein thrombosis (LMWH: RR, 0.60; 95% confidence interval [CI], 0.44 to 0.81; ICD: RR, 0.41; 95% CI, 0.21 to 0.78). Similar results were seen when pooled rates from all 30 trials were analyzed. In head-to-head trials, there was no statistical difference in the rate of intracranial hemorrhage (ICH) between therapy with LMWH and nonpharmacologic methods (RR, 1.97; 95% CI, 0.64 to 6.09). The pooled rates of ICH and minor bleeding were generally higher with heparin therapy than with non-heparin-based prophylactic modalities.

CONCLUSIONS

In a mixed neurosurgical population, LMWH and ICDs are both effective in the prevention of VTE. Sensitivity analyses have suggested that isolated high-risk groups, such as those with patients undergoing craniotomy for neoplasm, may benefit from a combination of prophylactic methods, suggesting the need for a more individualized approach to these patients.

Heparin-induced thrombocytopenia (HIT) with thrombosis is a serious complication of heparin use. HIT sera can generate platelet-derived microparticles, which are produced in a heparin-dependent manner and are hypothesized to be important initial pathological participants because they promote vascular occlusion. To date, microparticles have been studied using flow cytometric techniques. However, it is uncertain whether the small-sized material seen in flow cytometric studies represents true platelet microparticles shed from activated platelets or whether they are platelets that have contracted after releasing their internal components. This report describes a morphological investigation of platelet-derived microparticles in HIT using, among other techniques, confocal, scanning electron, and transmission electron microscopy. Following incubation with HIT sera, the existence of small membrane-bound vesicles in the milieu of activated platelets was demonstrated. A population of microparticles, expressing platelet-specific glycoproteins, was separated from platelets by centrifugation over a sucrose layer. These microparticles had identical flow cytometric profiles, size heterogeneity, and GPIb(alpha) and GPIIb/IIIa staining intensity as the microparticle population in unfractionated samples. When microparticles were generated in situ and fixed onto grids, they were demonstrated to be distinct membrane-bound vesicles that originated near the platelet body and terminal ends of pseudopods on activated platelets. These microparticles appeared to be generated by localized swelling, budding, and release. Collectively, these morphological studies document the existence of true microparticles in platelets activated by HIT sera. The microparticles may play an important role in the pathogenesis of HIT.

BACKGROUND

More frequent haemodialysis can improve both survival and quality of life of patients with chronic kidney disease. However, there is little capacity in the UK to allow patients to have more frequent haemodialysis treatments in hospital and satellite haemodialysis units. New means of delivering haemodialysis are therefore required. Our aim was to assess the safety and efficiency of a wearable haemodialysis device.

METHODS

Eight patients with end-stage kidney failure (five men, three women, mean age 51.7 [SD 13.8] years) who were established on regular haemodialysis were fitted with a wearable haemodialysis device for 4-8 h. Patients were given unfractionated heparin for anticoagulation, as they would be for standard haemodialysis.

RESULTS

There were no important cardiovascular changes and no adverse changes in serum electrolytes or acid-base balance. There was no evidence of clinically significant haemolysis in any patient. Mean blood flow was 58.6 (SD 11.7) mL/min, with a dialysate flow of 47.1 (7.8) mL/min. The mean plasma urea clearance rate was 22.7 (5.2) mL/min and the mean plasma creatinine clearance rate was 20.7 (4.8) mL/min. Clotting of the vascular access occurred in two patients when the dose of heparin was decreased and the partial thromboplastin time returned towards the normal reference range in both of these patients. The fistula needle became dislodged in one patient, but safety mechanisms prevented blood loss, the needle was replaced, and treatment continued.

CONCLUSIONS

This wearable haemodialysis device shows promising safety and efficacy results, although further studies will be necessary to confirm these results.

BACKGROUND

Venous thromboembolism (VTE) complicates ∼1.2 of every 1000 deliveries. Despite these low absolute risks, pregnancy-associated VTE is a leading cause of maternal morbidity and mortality.

OBJECTIVE

These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and others in decisions about the prevention and management of pregnancy-associated VTE.

METHODS

ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.

RESULTS

The panel agreed on 31 recommendations related to the treatment of VTE and superficial vein thrombosis, diagnosis of VTE, and thrombosis prophylaxis.

CONCLUSIONS

There was a strong recommendation for low-molecular-weight heparin (LWMH) over unfractionated heparin for acute VTE. Most recommendations were conditional, including those for either twice-per-day or once-per-day LMWH dosing for the treatment of acute VTE and initial outpatient therapy over hospital admission with low-risk acute VTE, as well as against routine anti-factor Xa (FXa) monitoring to guide dosing with LMWH for VTE treatment. There was a strong recommendation (low certainty in evidence) for antepartum anticoagulant prophylaxis with a history of unprovoked or hormonally associated VTE and a conditional recommendation against antepartum anticoagulant prophylaxis with prior VTE associated with a resolved nonhormonal provoking risk factor.

OBJECTIVE

To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU.

METHODS

Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial.

METHODS

Sixty-seven medical-surgical ICUs in six countries.

METHODS

Three thousand seven hundred forty-six medical-surgical critically ill patients.

METHODS

All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses.

RESULTS

Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004).

CONCLUSIONS

Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response.

In a double-blind, randomized, cross-over study the neutralizing action of protamine towards unfractionated heparin (UFH, 150 U/kg i.v.) and a low molecular weight heparin (LMWH, Fragmin, 100 anti-Xa U/kg i.v.) was investigated in 15 healthy subjects in vitro by measuring activated partial thromboplastin time (APTT), thrombin time (TT) and anti factor Xa activity (anti-Xa) in venous blood and in vivo by determination of prothrombin fragment 1.2 (f1.2) and thrombin-antithrombin III complexes (TAT) in venous blood and in shed blood. UFH and LMWH caused a prolongation of APTT and TT, an increase in anti-Xa and significantly inhibited f1.2 and TAT formation in shed blood, whereas only a minimal effect on TAT and f1.2 formation in venous blood was noted. Administration of 1 mg protamine/100 U UFH resulted in a near complete reversal of APTT, TT and anti-Xa, whereas lower doses (0.25 and 0.5 mg) were less effective. The effects of UFH on f1.2 and TAT generation in shed blood were partially (60-70%) neutralized only by the high dose (1.0 mg). Application of 1 mg protamine/100 anti-Xa U LMWH caused a near complete reversal of both APTT and TT but had only a weak effect on anti-Xa. In shed blood, the effect of LMWH on TAT and f1.2 formation was reversed by protamine only by 14% and 23% respectively. Our data do not support the concept that to reduce the incidence of protamine's potential clinical side effects, the administration of a lower dose of protamine than 1 mg protamine/100 U UFH is justified.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain.

OBJECTIVE

To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux.

METHODS

Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010.

METHODS

Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT).

METHODS

Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30.

RESULTS

The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15).

CONCLUSIONS

Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications.

BACKGROUND

clinicaltrials.gov Identifier: NCT00790907.

Patients with COVID-19 have a coagulopathy and high thrombotic risk. In a cohort of 69 intensive care unit (ICU) patients we investigated for evidence of heparin resistance in those that have received therapeutic anticoagulation. 15 of the patients have received therapeutic anticoagulation with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), of which full information was available on 14 patients. Heparin resistance to UFH was documented in 8/10 (80%) patients and sub-optimal peak anti-Xa following therapeutic LMWH in 5/5 (100%) patients where this was measured (some patients received both anticoagulants sequentially). Spiking plasma from 12 COVID-19 ICU patient samples demonstrated decreased in-vitro recovery of anti-Xa compared to normal pooled plasma. In conclusion, we have found evidence of heparin resistance in critically unwell COVID-19 patients. Further studies investigating this are required to determine the optimal thromboprophylaxis in COVID-19 and management of thrombotic episodes.

Keywords: COVID-19; Heparin; Intensive care; Thrombosis.

Unfractionated heparin (UFH) is a widely used anticoagulant that has long been known to potentiate platelet responses to subthreshold doses of platelet agonists. UFH has been reported to bind and induce modest conformational changes in the major platelet integrin, αIIbβ3, and induce minor changes in platelet morphology. The mechanism by which UFH elicits these platelet-activating effects, however, is not well understood. We found that both human and murine platelets exposed to UFH, either in solution or immobilized onto artificial surfaces, underwent biochemical and morphologic changes indicative of a potentiated state, including phosphorylation of key cytosolic signaling molecules and cytoskeletal changes leading to cell spreading. Low molecular weight heparin and the synthetic pentasaccharide, fondaparinux, had similar platelet-potentiating effects. Human or mouse platelets lacking functional integrin αIIbβ3 complexes and human platelets pretreated with the fibrinogen receptor antagonists eptifibatide or abciximab failed to become potentiated by heparin, demonstrating that heparin promotes platelet responsiveness via its ability to initiate αIIbβ3-mediated outside-in signaling. Taken together, these data provide novel insights into the mechanism by which platelets become activated after exposure to heparin and heparin-coated surfaces, and suggest that currently used glycoprotein IIb-IIIa inhibitors may be effective inhibitors of nonimmune forms of heparin-induced platelet activation.

BACKGROUND

An exploratory analysis of a prospective study of risk factors for acute pancreatitis after ERCP combined with endoscopic sphincterotomy showed that the frequency of acute pancreatitis was lower in patients who received heparin compared with patients not treated with heparin. The study was continued to further analyze the effect of heparin on the frequency of acute pancreatitis.

METHODS

Potential risk factors for acute pancreatitis and outcomes were evaluated prospectively for all ERCP procedures with endoscopic sphincterotomy performed between September 1994 and December 1998. The results were analyzed by univariate and multivariate methods to determine risk factors for complications. Heparin was administered to 32.9% of the patients (heparin group [HEP group], n = 268) for various clinical reasons (low-molecular-weight heparin, n = 208, unfractionated heparin n = 60). A group of 547 patients who did not receive heparin served as control patients (CON group).

RESULTS

Eight hundred fifteen patients underwent ERCP with endoscopic sphincterotomy; acute pancreatitis occurred in 6.4% (n = 52). The frequency of acute pancreatitis was significantly lower in the HEP group versus the CON group in the final multivariate model, which included significant risk factors for acute pancreatitis (HEP group: 3.4%, 9/268 vs. CON group: 7.9%, 43/547; p = 0.005). HEP did not increase the risk of hemorrhage (HEP group: 1.1%, 3/268, 2 severe, none fatal vs. CON group: 2.0%, 11/547, 3 severe, 2 fatal). HEP (p = 0.005; OR 0.3: 95% CI [0.16, 0.73]) and the number of risk factors present (p = 0.0001; OR 2.5: 95% CI [1.80, 3.50]) influenced the frequency of acute pancreatitis independently.

CONCLUSIONS

Heparin was significantly associated with an extremely low frequency of post-ERCP pancreatitis without increasing the risk of hemorrhage after endoscopic sphincterotomy. Because this effect could not be attributed to other known or suspected confounders, our conclusion was that heparin administration before ERCP reduces the risk of pancreatitis.

Numerous acquired hemostatic abnormalities have been identified in renal insufficiency. Hemodialysis procedures add to these disturbances as they repetitively imply turbulent blood flow, high shear stress, and contact of blood to artificial surfaces. This nonphysiological environment leads to activation of platelets, leukocytes, and the coagulation cascade, resulting in fouling of the membrane and ultimately in clotting of fibers and the whole hemodialyzer. Anticoagulation in hemodialysis is targeted to prevent this activation of coagulation during the procedure. Most agents inhibit the plasmatic coagulation cascade. Still commonly used is unfractionated heparin, followed by low-molecular-weight heparin preparations with distinct advantages. Immune-mediated heparin-induced thrombocytopenia constitutes a potentially life-threatening complication of heparin therapy requiring immediate switch to nonheparin alternative anticoagulants. Danaparoid, lepirudin, and argatroban are currently being used for alternative anticoagulation, all of which possess both advantages and limitations. In the past, empirical strategies reducing or avoiding heparin were applied for patients at bleeding risk, whereas nowadays regional citrate anticoagulation is increasingly used to prevent bleeding by allowing procedures without any systemic anticoagulation. Avoidance of clotting within the whole hemodialyzer circuit is not granted. Specific knowledge of the mechanisms of coagulation, the targets of the anticoagulants in use, and their respective characteristics constitutes the basis for individualized anticoagulation aimed at achieving full patency of the circuit throughout the procedure. Patency of the circuit is an important prerequisite for optimal hemodialysis quality.

OBJECTIVE

Dabigatran is approved for prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). The safety and effectiveness of periprocedural dabigatran in ablation for AF are unknown.

METHODS

We performed a meta-analysis of all studies comparing periprocedural dabigatran with warfarin for anticoagulation in AF ablation. Studies of >100 patients with post-procedure follow-up were included. Outcomes were compared by calculating maximum likelihood estimates with confidence intervals. The co-primary endpoints were neurological events and major bleeding.

RESULTS

Ten cohort studies were included, including a total of 1,501 patients receiving dabigatran and 2,356 receiving warfarin. The mean age was 59-64 years and inclusion of women varied (10-33 %). Intra-procedural unfractionated heparin and irrigated ablation catheters were used routinely. Adverse events were low overall; however, the dabigatran group demonstrated a numerical excess of neurological events (10/1,501 [0.7 %] versus 4/2,356 [0.2 %]), but equivalent major bleeding outcomes (24/1,501 [1.6 %] versus 40/2,356 [1.7 %]). In the meta-analysis, there was a nonsignificant trend towards higher rates of the composite primary endpoints (any neurological event or major bleeding) in the dabigatran group. Dabigatran demonstrated a significantly higher rate of neurological events (estimated absolute risk difference 0.0047, 95 % confidence interval 0.0007 to 0.0099).

CONCLUSIONS

Compared with warfarin, dabigatran may be associated with a higher frequency of periprocedural neurological events following radiofrequency ablation of AF. Randomized clinical trials are needed to definitively assess the safety and efficacy of novel oral anticoagulant use for periprocedural anticoagulation for ablation of AF.

OBJECTIVE

The aim of this study was to evaluate anticoagulant use patterns and bleeding risk in a contemporary population of patients with acute coronary syndrome.

BACKGROUND

Current practice guidelines support the use of unfractionated heparin, low molecular weight heparin, bivalirudin, or fondaparinux in non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Little is known about how these agents are selected in clinical practice.

METHODS

Between January 2007 and June 2009, data were captured for 72,699 patients with NSTEMI and 48,943 patients with STEMI at 360 U.S. hospitals for the NCDR ACTION Registry-GWTG (National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). Patients were categorized based on anticoagulant strategy selected during hospitalization and their CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of ACC/AHA [American College of Cardiology/American Heart Association] Guidelines) bleeding risk category.

RESULTS

At least 1 anticoagulant was administered to 66,279 patients (91.2%) with NSTEMI and 46,149 patients (94.3%) with STEMI. Among STEMI patients, unfractionated heparin was most commonly used (66%), followed by bivalirudin (14%) and low molecular weight heparin (8%). In NSTEMI patients, unfractionated heparin was also the most commonly used anticoagulant (42%), followed by low molecular weight heparin (27%) and then bivalirudin (13%). There were significant differences in anticoagulant use by age, risk factors, concomitant medications, and invasive care. There was a 5-fold difference in the rate of bleeding between patients in the lowest and highest CRUSADE bleeding risk groups, which was consistently observed in most anticoagulant groups.

CONCLUSIONS

There is a wide variability in the use of anticoagulant regimens with significant differences according to baseline characteristics and concomitant therapies. Major bleeding is common, though a great degree of the variability in the rate of bleeding is largely based on differences in baseline characteristics, comorbidities, and invasive treatment strategies, rather than specific anticoagulant regimens.

BACKGROUND

Many agents are available to treat acute coronary syndromes (ACS), yet limited information is available about their use from a multinational perspective. The objective of this report was to describe patterns of use of antithrombotic and antiplatelet therapies in patients with the spectrum of ACS through the use of data from the Global Registry of Acute Coronary Events (GRACE).

METHODS

Data from 12,665 patients with ACS were analyzed. Baseline characteristics, clinical presentation, and medication use were compared. Regional differences in the administration of antiplatelet and antithrombotic therapies were analyzed. Multivariable logistic regression was implemented to determine independent variables indicating the use of various hospital therapies.

RESULTS

Overall, unfractionated heparin was used in 57% of patients and low-molecular-weight heparin in 47% (P <.0001). More than 90% of patients received aspirin, but approximately 13% were not discharged on aspirin. Overall, 30% of patients received thienopyridines (with percutaneous coronary intervention [PCI] in 79%). Of those who did not receive aspirin, 31% received thienopyridines. Intravenous glycoprotein inhibitors were given to 17% of patients. Among those treated with PCI, only 47% received glycoprotein inhibitors, and 21% of those given glycoprotein inhibitors did not undergo PCI. Significant geographic variation was apparent in the use of unfractionated heparin, low-molecular-weight heparin, thienopyridines, and glycoprotein inhibitors.

CONCLUSIONS

Despite the availability of guidelines, striking geographic and practice variations are apparent in the use of antithrombotic and antiplatelet therapies. There remains significant room for improvement in the use of these therapies in patients with ACS, which should lead to improvement in care and outcomes.

BACKGROUND

Despite widespread heparin use in clinical practice, the associated development of thrombocytopenia is an underrecognized and undertreated complication.

METHODS

We analyzed data from consecutive hospitalized patients treated with heparin (unfractionated or low molecular weight) for 4 days or longer to determine the incidence, predictors, prognostic significance, and management of "thrombocytopenia," defined as a platelet count less than 150 x 10(9)/L, reduction in platelet count of 50% or more from the admission level, or both.

RESULTS

We enrolled 2420 patients (median age, 65.2 years; 43.8% women) in 48 US hospitals. Thrombocytopenia occurred in 881 patients (36.4%; 95% confidence interval [CI], 34.5%-38.3%). Of those who developed thrombocytopenia, 5.1% died, compared with 1.6% of those without thrombocytopenia (odds ratio [OR], 3.4; 95% CI, 2.1-5.6; P< .001). Thrombocytopenia was also associated with greater risk of myocardial infarction (OR, 2.1; 95% CI, 1.5-2.8; P< .001) and congestive heart failure (OR, 1.3; 95% CI, 1.1-1.6; P= .01). After adjustment for important covariates, thrombocytopenia remained an independent predictor of thrombotic and hemorrhagic events. A relative reduction in platelet count of more than 70% was the strongest independent predictor of death (OR, 13.4; 95% CI, 6.5-27.6; P< .001), followed by a relative reduction in platelet count of 50% to 70%, worse Killip class, occurrence of thromboembolic complications, older age, and longer duration of heparin therapy.

CONCLUSIONS

Thrombocytopenia occurs frequently after prolonged heparin therapy and is strongly associated with worse short-term clinical outcome. The relative reduction in platelet count is a powerful independent predictor of all-cause mortality in hospitalized patients.

In a prospective, randomized multicentre trial the efficacy and safety of the low molecular weight heparin (LMWH) fraction Fraxiparin and unfractionated calcium heparin (Calciparin) were compared for the prevention of postoperative deep vein thrombosis. Of 1909 patients included in the trial 1896 underwent abdominal surgery and received either one daily subcutaneous injection of 7500 anti-Xa units Fraxiparin or 5000 units calcium heparin three times a day subcutaneously. Elastic compression stockings were worn by both groups of patients in the postoperative period. Before randomization the patients were stratified in two subgroups with or without malignant disease. To assess the rate of deep vein thrombosis (DVT), 125I-labelled fibrinogen leg scanning was performed daily for 7 postoperative days. Positive results were confirmed by phlebography whenever possible. Venous thrombosis occurred in 27 of 960 patients (2.8 per cent) given Fraxiparin and in 42 of 936 patients (4.5 per cent) given calcium heparin (P = 0.034). The rates of proximal vein thrombosis were 0.4 per cent (4 patients) and 1.4 per cent (13 patients) respectively (P less than 0.05). Pulmonary embolism occurred in 2 of 960 patients (0.2 per cent) treated with Fraxiparin and in 5 of 936 patients (0.5 per cent) treated with calcium heparin. The two treatments were equally well tolerated. Intra- and postoperative blood loss, the number of wound haematomas as well as frequency and volume of transfusions were similar in both groups. The present trial demonstrates that a single daily subcutaneous injection of Fraxiparin is more effective than the established low dose subcutaneous heparin prophylaxis with 5000 units three times per day in preventing postoperative DVT after abdominal surgery in patients wearing compression stockings.