In Vitro Evaluation of Dextran Sulfate Cellulose Beads for Whole Blood Infusion Low‐Density Lipoprotein‐Hemoperfusion

Abstract: We describe results from a feasibility study of a newly developed low‐density lipoprotein (LDL) adsorbent designed for use in whole‐blood infusion LDL‐hemoperfusion. The adsorbent has almost the same chemical structure as the Liposorber adsorbent (dextran sulfate cellulose beads) but has a larger particle size. In whole‐blood perfusion tests, the adsorbent adsorbed atherogenic LDL cholesterol directly from whole blood but left concentrations of high‐density lipoprotein cholesterol largely unchanged. In whole‐blood perfusion tests using fresh human donor blood or bovine blood anticoagulated with acid citrate dextrose solution or sodium citrate, the adsorbent showed minimal side effects in terms of blood cell activation, complement activation, and blood cell loss, suggesting that it has excellent blood compatibility. In addition, the adsorbent showed mechanical stability and absence of hemolysis. In conclusion, the new adsorbent showed the appropriate characteristics for an LDL adsorbent column for use in whole‐blood infusion LDL‐hemoperfusion.     

DALI Low‐Density Lipoprotein Apheresis in Homozygous and Heterozygous Familial Hypercholesterolemic Patients Using Low‐Dose Citrate Anticoagulation

Abstract: The purpose of this study was to clarify the efficacy and safety of direct adsorption of lipoprotein low‐density lipoprotein apheresis (DALI LDL apheresis) in patients with severe homozygous and heterozygous familial hypercholesterolemia who showed minor adverse effects during treatment with the usual DALI configuration (AC 1:20) through the use of a new system with low‐dose citrate anticoagulation (AC 1:40) developed in order to minimize citrate‐related adverse effects. Serum total cholesterol and LDL‐cholesterol (LDL‐C) showed a decrease of 57% to 61%, and 62 % to 67%, respectively, in the 2 patients. Serum lipoprotein (a) (Lp[a]) was higher in the homozygous patient (Patient 1: MD) and within the normal range in the heterozygous patient (Patient 2: ES). In the former, Lp(a) was reduced by 52%. Serum high‐density lipoprotein cholesterol (HDL‐C) showed a statistically insignificant acute reduction: 15% to 19%. The observed reduction is mainly related to the well‐known effect of hemodilution. The cardiovascular risk (total cholesterol/HDL‐C) was reduced in both patients (46% to 54%) as expected. Serum triglycerides were reduced by 33% to 49%. The mean blood volume processed per session was 7,600 ml. Fifteen treatments for each patient have successfully been completed without the appearance of any clinically significant subjective and objective symptoms related to treatment with the new system.     

Choosing the optimal method of blood pressure measurement for limited‐resource rural communities in the “Community Health Assessment Program—Philippines”

The Community Health Assessment Program—Philippines (CHAP‐P) is an international collaboration of investigators whose aim is to adapt a previously proven Canadian community‐based cardiovascular awareness and prevention intervention to the Philippines and other low‐middle–income countries. Choosing a method of blood pressure measurement for the research program presents a challenge. There is increasing consensus globally that blood pressure measurement with automated devices is preferred. Recommendations from low‐middle–income countries, including the Philippines, are less supportive of automated blood pressure devices. The value placed on factors including device accuracy, durability, cost, energy source, and complexity differ with local context. Our goal was to support the progress of local policy concerning blood pressure measurement while testing a comprehensive approach to community‐based screening for cardiovascular risk. The authors describe the challenges in making a choice of blood pressure device and the approach to determine optimal method of measurement for our research program.     

Long‐Term Effects of Low‐Dose Spironolactone on Chronic Dialysis Patients: A Randomized Placebo‐Controlled Study

The purpose of this 2‐year multicentric, randomized, placebo‐controlled study was to evaluate the long‐term effects and adverse effects of spironolactone on chronic dialysis patients. A total of 253 non–heart failure dialysis patients with end‐stage renal disease were randomly assigned to 2‐year treatment with spironolactone (25 mg once daily, n=125) or a matching placebo (n=128) as add‐on therapy. The primary outcome was a composite of death from cardiocerebrovascular (CCV) events, aborted cardiac arrest, and sudden cardiac death, and the secondary outcome was death from all causes. Other CCV‐related indexes such as left ventricular mass index, left ventricular ejection fraction, heart rate variability, vascular endothelial function, and blood pressure–lowering effect were analyzed for patients who completed the whole 2‐year follow‐up study. Sociodemographic, clinical, and relevant laboratory data were also collected. During the 2‐year follow‐up, the primary outcome occurred less frequently in the spironolactone group vs the control group (7.2% vs 18.0%; adjusted hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.26–0.78). Death from CCV events occurred in 4.0% of patients in the spironolactone group and in 11.7% of patients in the control group. Neither aborted cardiac arrest nor sudden cardiac death was significantly reduced by spironolactone treatment. The secondary outcome occurred less frequently in the spironolactone group vs the control group (9.6% vs 19.5%; adjusted HR, 0.52; 95% CI, 0.29–0.94). Other CCV‐related indexes except for heart rate variability were significantly improved. This study demonstrates that use of low‐dose spironolactone in non–heart failure dialysis patients can effectively reduce the risks of both CCV morbidity and mortality with few side effects. Moreover, the beneficial effect was mediated through improving the endothelial function or reducing left ventricular size independent of blood pressure changes, rather than mediation through changes in salt or potassium handling in the kidney.     

Blood pressure measurement device selection in low‐resource settings: Challenges,compromises, and routes to progress

High blood pressure (BP) is the single leading preventable cardiovascular disease (CVD) risk factor across the world. In order to decrease the global burden of CVD, broad hypertension screening programs that facilitate early hypertension diagnosis and treatment are essential. Accurate BP devices are a key element of hypertension control programs. With the overwhelming number of devices available now on the market, most of which have not been tested for accuracy, it can be challenging to select the optimal BP measurement device for clinical settings. This review details essential factors to consider when selecting a good‐quality BP device, particularly for use in low‐resource settings. Barriers to the procurement and use of good‐quality devices are reviewed and practical solutions proposed.     

State of Percutaneous Transluminal Coronary Artery Angioplasty and Effectiveness of Low‐Density Lipoprotein Apheresis

Abstract: We have recognized percutaneous transluminal coronary artery angioplasty (PTCA) as an important procedure for achieving myocardial revascularization. PTCA has been performed for stable and unstable angina, acute myocardial infarction, and silent myocardial ischemia. Among many new devices, the coronary stent is the most important advancement in PTCA. Frequent stent use is due to the introduction of antiplatelet therapy to prevent stent thrombosis. One serious problem is that PTCA, even with stent use, often causes chronic restenosis. This problem has not been solved, however, despite various strategies. Aggressive lipid‐lowering therapy is one of the most important therapies for coronary heart disease. The findings in aggressive lipid‐lowering therapy show us its importance. We report that low‐density lipoprotein (LDL) apheresis, when performed immediately before and after PTCA, can prevent restenosis of coronary artery lesions. Lipid‐lowering therapy should be applied more aggressively with medicine and/or with LDL apheresis for patients who have undergone PTCA.     

Masked Hypertension in Low‐Income South African Adults

While South Africa has one of the highest hypertension rates globally, there are few data on masked hypertension (MHT) and white‐coat hypertension (WCHT). This study measured the frequency of MHT and WCHT in low‐income (<$500 US per month) South African adults, evaluating cardiovascular risk by arterial stiffness. Participants (n=101, 50% male; mean age 39.4±9.7 years) were recruited from a large North‐West Province employer. Clinic and 24‐hour blood pressure (BP) and pulse wave analysis were recorded. Clinic BP identified 18% of patients as hypertensive, while 24‐hour BP showed that 63% of patients were hypertensive. The frequency of MHT was high (33 of 81, 41%) with only one case of WCHT. In comparison to those with normal clinic and 24‐hour BP, augmentation index and pulse wave velocity were significantly higher in those with hypertensive 24‐hour BP irrespective of clinic BP, indicating that, in this group, masked and sustained hypertension carry a similar elevated cardiovascular risk.     

Acute Ethanol Effects on Brain Activation in Low‐ and High‐Level Responders to Alcohol

Background: A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk of alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption. Methods: A total of 30 matched high‐ and low‐LR pairs (N = 60 healthy young adults) were recruited from the University of California, San Diego, and administered a structured diagnostic interview and laboratory alcohol challenge followed by two functional magnetic resonance imaging (fMRI) sessions under placebo and alcohol conditions, in randomized order. Task performance and blood oxygen level‐dependent response contrast to high relative to low working memory load in an event‐related visual working memory (VWM) task were examined across 120 fMRI sessions. Results: Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p < 0.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity. Conclusions: Alcohol had differential effects on brain activation for low‐ and high‐LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR and identify brain regions that may be associated with the low LR response.     

Low‐Volume Tidal Peritoneal Dialysis Is a Preferable Mode in Patients Initiating Urgent‐Start Automated Peritoneal Dialysis: A Randomized,Open‐Label,Prospective Control Study

The aim of this study is to evaluate the safety of low‐volume tidal peritoneal dialysis (TPD) and intermittent peritoneal dialysis (IPD) in ESRD patients initiating automated peritoneal dialysis (APD) after an acute catheter insertion. Clinical outcomes of patients who received either TPD or IPD using an APD system were compared in a randomized, open‐label, prospective control study in a single‐center setting. From May 2011 to May 2013, 49 patients were enrolled and 27 patients received low‐volume TPD treatment, whereas 22 patients underwent low‐volume IPD right after Tenckhoff catheter insertion. The incidence of complications during the 14‐day APD treatment were observed. After APD treatment, all the patients were transferred to continuous ambulatory peritoneal dialysis and followed up for 2 years. The IPD group demonstrated a significantly higher incidence of catheter‐related complications (omental wrapping 27.3% vs. 0% and suction pain 18.2% vs. 0%) than the TPD group after adjusting for age, gender, baseline diabetes, systolic blood pressure , BMI, and the experience of the operators. However, the short duration of APD treatment with either IPD or TPD mode did not affect the long‐time technical survival. In patients immediately after catheter insertion, low‐volume TPD mode demonstrated a lower incidence of catheter‐related complications compared to IPD. Although our results provided evidence that TPD is a preferable APD mode for this specific population, definitive conclusions about TPD benefit cannot be made, owing to early termination of the trial.     

Low‐molecular‐weight heparin biosimilars: potential implications for clinical practice

A working group of clinicians and scientists was formed to review the clinical considerations for use of low‐molecular‐weight heparin (LMWH) biosimilars. LMWH are biological molecules of significant complexity; the full complexity of chemical structure is still to be elucidated. LMWH biosimilars are products that are biologically similar to their reference product and rely on clinical data from a reference product to establish safety and efficacy. The complex nature of LMWH molecules means that it is uncertain whether a LMWH biosimilar is chemically identical to its reference product; this introduces the possibility of differences in activity and immunogenicity. The challenge for regulators and clinicians is to evaluate the level of evidence required to demonstrate that a LMWH is sufficiently similar to the reference product. The consensus opinion of the working group is that prior to clinical use a LMWH biosimilar should have proven efficacy and safety, similar to the reference product with prospective studies, which should be confirmed with a proactive post‐marketing pharmacovigilance programme.     

Recommendations for blood pressure measuring devices for office/clinic use in low resource settings

This paper, which summarizes the conclusions of a WHO Expert meeting, is aimed at proposing indications to develop technical specifications for an accurate and affordable blood pressure measuring device for office/clinic use in low resource settings. Blood pressure measuring devices to be used in low resource settings should be accurate, affordable, and easily available worldwide. Given the serious inherent inaccuracy of the auscultatory technique, validated and affordable electronic devices, that have the option to select manual readings, seem to be a suitable solution for low resource settings. The agreement on the technical specifications for automated blood pressure measuring devices for office/clinic use in low resource settings included the following features: high accuracy, adoption of electronic transducers and solar batteries for power supply, standard rates of cuff inflation and deflation, adequate cuff size, digital display powered by solar batteries, facilities for adequate calibration, environmental requirements, no need of memory function, resistance to shock and temperature changes, and low cost. Availability of a device with these features should be accompanied by adequate training of health care personnel, who should guarantee implementation of the procedures recommended in recent European and American Guidelines for accurate blood pressure measurement.     

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

Endothelial activation and dysfunction induced by oxidized modified low‐density lipoprotein (ox‐LDL) is one of the key steps in the initiation of atherosclerosis. Recent studies have shown that a new lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) mediates the recognition and internalization of ox‐LDL. LOX‐1 is the main receptor for ox‐LDL and may play an important role in the pathogenesis of hypertension, diabetes, and, especially, of atherosclerosis. The potential role of LOX‐1 in the pathogenesis of atherosclerosis includes: endocytosis of ox‐LDL, expression co‐location with atherosclerosis enhanced by atherosclerosis‐related risk factors, elevated LOX‐1 protein in cardiovascular disease, effects related to atherosclerosis and eliminated by antiatherosclerotic drugs. Identification and regulation of LOX‐1 and understanding its signal transduction pathways might improve our insight toward the pathogenesis of atherosclerosis and provide a selective treatment approach. LOX‐1 might be a potential and promising target for the development of novel antiatherosclerotic drugs. However, due to limited knowledge about LOX‐1, there are still many questions to be answered.     

Outpatient diabetes clinical decision support: current status and future directions

Outpatient clinical decision support systems have had an inconsistent impact on key aspects of diabetes care. A principal barrier to success has been low use rates in many settings. Here, we identify key aspects of clinical decision support system design, content and implementation that are related to sustained high use rates and positive impacts on glucose, blood pressure and lipid management. Current diabetes clinical decision support systems may be improved by prioritizing care recommendations, improving communication of treatment‐relevant information to patients, using such systems for care coordination and case management and integrating patient‐reported information and data from remote devices into clinical decision algorithms and interfaces.     

Vaping cannabis (marijuana): parallel concerns to e‐cigs?

The proliferation of vaporization (‘vaping’) as a method for administering cannabis raises many of the same public health issues being debated and investigated in relation to e‐cigarettes (e‐cigs). Good epidemiological data on the prevalence of vaping cannabis are not yet available, but with current trends towards societal approval of medicinal and recreational use of cannabis, the pros and cons of vaping cannabis warrant study. As with e‐cigs, vaping cannabis portends putative health benefits by reducing harm from ingesting toxic smoke. Indeed, vaping is perceived and being sold as a safer way to use cannabis, despite the lack of data on the health effects of chronic vaping. Other perceived benefits include better taste, more efficient and intense effects and greater discretion which allows for use in more places. Unfortunately, these aspects of vaping could prompt an increased likelihood of trying cannabis, earlier age of onset, more positive initial experiences, and more frequent use, thereby increasing the probability of problematic use or addiction. Sales and marketing of vaping devices with no regulatory guidelines, especially related to advertising or product development targeting youth, parallels concerns under debate related to e‐cigs and youth. Thus, the quandary of whether or not to promote vaping as a safer method of cannabis administration for those wishing to use cannabis, and how to regulate vaping and vaping devices, necessitates substantial investigation and discussion. Addressing these issues in concert with efforts directed towards e‐cigs may save time and energy and result in a more comprehensive and effective public health policy on vaping.     

Techniques for self-measurement of blood pressure: limitations and needs for future research

Self blood pressure measurement (SBPM) improves the overall management of hypertension provided it is implemented with methodologic care. This concerns especially the accuracy and technical requirements of blood pressure (BP) measuring devices that should be validated according to internationally accepted protocols. The use of memory-equipped automatic home monitors is strongly recommended because they reduce observer bias, avoid patients' misreporting, and allow fully automatic analysis by software. For current use, simple software should be worked out that allow for analysis of readings in an objective manner. Miscuffing is also a frequent source of measurement error in obese arms when oscillometric devices are used. Modern automatic devices can overcome this problem because of special software algorithms that can provide accurate measurements over a wide range of arm circumferences when coupled with a single cuff of standard dimensions. Tronco-conical-shaped cuffs are a key component of this instrumentation because they better fit on large conical arms frequently present in obese individuals. Semi-rigid cuffs should be increasingly used because they ensure that the proper amount of tension is applied without the intervention of the user. Continuous technology improvement of instrumentation for SBPM can be achieved through close cooperation between manufacturers and validation centers.     

Low‐Dose Heparin for Elective Percutaneous Coronary Intervention

Objectives

We evaluated the safety and efficacy of low‐dose heparin (40 IU/kg) for elective percutaneous coronary intervention (PCI).

Background

Current guidelines recommend a 70–100 IU/kg bolus of heparin for elective PCI, but this dose may be associated with increased bleeding risk. Low‐dose heparin may have an advantage in this regard, but has not been well studied.

Methods

From January 2008 to October 2012, 300 patients underwent elective transfemoral PCI and were treated with an initial bolus of 40 IU/kg of heparin at the UCLA Medical Center. Dual antiplatelet therapy with clopidogrel and aspirin was administered prior to or just after diagnostic coronary angiography. The primary end‐point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding within 30 days after PCI.

Results

The mean activating clotting time was 233 ± 28 seconds. The primary end‐point occurred in 2.3%. The cardiac death rate was 0.3% but was not related to the PCI. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). The major bleeding rate was 0.3%. No stent thrombosis occurred.

Conclusion

Using a lower dose of heparin with dual antiplatelet therapy is safe and is associated with a low bleeding risk after transfemoral PCI while providing suppression of ischemic events. This may also represent a cost savings compared with other antithrombotic strategies. A randomized clinical trial comparing low‐dose heparin with bivalirudin in patients is required to determine the optimal anticoagulation strategy. (J Interven Cardiol 2014;27:58–62)

     

EXAMINATION OF RESPIRATORY AND CIRCULATORY DYNAMICS DURING EXAMINATION USING A THIN GASTROINTESTINAL ENDOSCOPE IN ADVANCED‐AGE SUBJECTS

Background: Endoscopic examination influences cardiovascular hemodynamics. Upper gastrointestinal examinations are currently performed with a thin endoscope. In the present study, respiratory and circulatory dynamics and autonomic nervous activity using a thin endoscope (XP260) or a standard endoscope (XQ240) were investigated. Methods: The subjects were 25 healthy adults aged less than 60 years (middle‐aged group) and 15 healthy adults aged 60 years or older (advanced‐age group). Percutaneous oxygen saturation, tonometric blood pressure, heart rate, and autonomic nervous activity were evaluated before the examination. After the endoscopic procedure, a questionnaire survey regarding examination‐related stress was conducted. Results: In the questionnaire survey, the proportion of subjects who answered ‘very stress free’ in the thin endoscope group was significantly higher than that in the standard endoscope group. The low frequency power of blood pressure variability (LF_BP), an indicator of sympathetic nervous activity, was significantly lower during the thin endoscopic procedure than during the standard endoscopic procedure. Moreover, the ratio of low frequency power to high frequency power of heart rate variability (LF_RR/HF_RR), an indicator of sympathetic nervous activity, was significantly lower during thin endoscopic procedure than during the standard endoscopic procedure. The maximum rates of change in the LF_BP and HF_RR powers in the advanced‐age group using thin and standard endoscopic procedures were significantly lower than in the middle‐aged group. Conclusions: The findings, although not in cross‐over study, suggest that a thin endoscope has a less marked influence on circulatory kinetics. Gastrointestinal endoscopic examinations using a thin endoscope might reduce complications related to endoscopic screening examinations in advanced‐age subjects.     

Efficacy and safety of renal denervation for the management of arterial hypertension: A systematic review and meta‐analysis of randomized,sham‐controlled,catheter‐based trials

Despite the availability of a numerous antihypertensive agents, hypertension treatment and control rates remain low in many countries. The role of the sympathetic nervous system has long been recognized, but recent sham control renal denervation studies demonstrated conflicting results. In this reviewe paper, the authors performed a systematic review and meta‐analysis to examine outcomes of sham‐controlled studies utilizing new technologies and procedures. Six published randomized, sham‐controlled studies were included in this meta‐analysis. Of those, three trials used the first‐generation radiofrequency renal denervation device and technique and the other three used second‐generation devices and techniques. In total, 981 patients with hypertension were randomized in all 6 trials to undergo renal denervation (n = 585) or sham procedure (n = 396). Overall, renal denervation resulted in a decrease of 24‐hours systolic ambulatory blood pressure (ABP) by 3.62 mm Hg (95% CI: −5.28‐−1.96; I² = 0%), compared to sham procedure (GRADE: low). Renal denervation also reduced daytime systolic ABP by 5.51 mm Hg (95% CI: −7.79‐−3.23; I² = 0%), compared to sham procedure but not nighttime systolic ABP. Office systolic blood pressure was reduced by 5.47 mm Hg (95% CI −8.10‐−2.84; I² = 0%), compared to sham control. Further analysis demonstrated that second‐generation devices were effective in reducing blood pressure, whereas the first‐generation devices were not. These results indicate that effective renal denervation can result in significant and clinically meaningful blood pressure reduction. The second‐generation devices provide better renal nerve ablation.     

Proteomic Analysis of Proteins Eliminated by Low‐Density Lipoprotein Apheresis

Low‐density lipoprotein apheresis (LDL‐A) treatment has been shown to decrease serum LDL cholesterol levels and prevent cardiovascular events in homozygous patients with familial hypercholesterolemia. Recently, LDL‐A treatment has been suggested to have beneficial effects beyond the removal of LDL particles. In this study, to clarify the preventive effects of LDL‐A treatment on atherosclerosis, the waste fluid from the adsorption columns was analyzed. The waste fluid of LDL adsorption columns was analyzed by two‐dimensional electrophoresis followed by mass spectrometry. Serum concentrations of the newly identified proteins before and after LDL‐A treatment were measured by enzyme‐linked immunosorbent assay. We identified 48 kinds of proteins in the waste fluid of LDL adsorption columns, including coagulation factors, thrombogenic factors, complement factors, inflammatory factors and adhesion molecules. In addition to the proteins that were reported to be removed by LDL‐A treatment, we newly identified several proteins that have some significant roles in the development of atherosclerosis, including vitronectin and apolipoprotein C‐III (Apo C‐III). The serum levels of vitronectin and Apo C‐III decreased by 82.4% and 54.8%, respectively, after a single LDL‐A treatment. While Apo C‐III was removed with very low‐density lipoprotein (VLDL) and LDL, vitronectin was removed without association with lipoproteins. The removal of proteins observed in the waste fluid has a certain impact on their serum levels, and this may be related to the efficacy of LDL‐A treatment. Proteomic analysis of the waste fluid of LDL adsorption columns may provide a rational means of assessing the effects of LDL‐A treatment.     

Low‐Molecular‐Weight Heparins in Thrombosis and Cancer: Emerging Links

Heparin as well as low‐molecular‐weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti‐Xa and anti‐IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix‐degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH‐releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix‐degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non‐anticoagulant LMWH derivatives was shown to be reversed by anti‐TFPI. Thus, modulation of tissue factor/Vila noncoagulant activities by LMWH‐releasable TFPI and the inhibitory effects on matrix‐degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis‐associated disorders, including human tumor growth and metastasis.