Heparin is a highly sulfated glycosaminoglycan (GAG) that is found in the mast cells of most mammals. The endogenous GAGs are highly acidic and actively charged. Heparin is the most sulfated, and acidic GAGs enable it to bind to different component such as coagulating and fibrinolysing proteins, many growth factors, and immune response proteins such as cytokines and chemokines [
A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar from inception to March 2012 using the following Mesh keywords: (1) heparin, (2) UFH, (3) anticoagulants, (4) dalteparin, (5) enoxaparin, (6) nadroparin, (7) tinzaparin, (8) heparinoids, (9) inflammation, (10) inflammatory process, (11) anti-inflammation, (12) inflammation mediators, (13) inflammatory bowel disease, and (14) anti-inflammatory agents. All keywords from 1 to 8 were separately combined with each keyword from 9 to 14 in all databases. Articles were initially scanned based on titles and abstracts by two reviewers (Sarah Mousavi and Mandana Moradi) and related articles were retrieved in full and assessed for eligibility by two reviewers (Sarah Mousavi and Mandana Moradi). The reference list of each eligible study was checked to identify additional studies.
All Randomized Clinical Trials (RCTs) and studies with quasi-experimental design which evaluated efficacy, using inflammatory biomarkers levels, and safety (significant hemorrhage or thrombocytopenia) of anti-inflammatory effects of heparin and heparin-related derivatives (LMWH or other heparinoids) with an English abstract regardless of rout of administration (intravenous, subcutaneous, topical, or inhaler), age, gender, race, and ethnic origin of participants were included.
The following were excluded: studies based on animal models; preclinical and biological studies, letters, and editorials; report published as meeting abstract only; where insufficient data were reported to allow inclusion.
Data from each eligible study were extracted individually and compared by two authors (Sarah Mousavi and Mandana Moradi) using standard form that included study design, setting, sample size, duration and follow up, dosing regimen, intervention type, and outcomes. Disagreements were resolved through discussion; if necessary they consulted a third person. A narrative synthesis was conducted.
Quality assessment of clinical trials included in the analysis were performed utilizing the Jadad score, a previously validated instrument that assesses trials based on appropriate randomization, blinding, and description of study withdrawals or dropouts [
The Consolidated Standards of Reporting Trials (CONSORT) checklist was also used for randomized trials as it is strongly endorsed by prominent journals and leading editorial organizations [
To summarize and extract data, the database was designed by Microsoft office Access 2007 (Microsoft Corporation, Redmond, WA). A narrative synthesis was conducted and data were extracted into tables and summarized.
Following Initial screening of mentioned databases total of 553 citations (275 duplicates) were extracted but only 70 of them were potentially eligible for investigation of our objectives (according to our proposed inclusion criteria) based on titles and abstracts. The full text screening excluded other 13 citations and the remaining 57 papers were considered relevant for data extraction and following analysis. The flow chart of studies’ selection processes is as shown in Figure
Flow diagram of literature search process.
Sample sizes ranged from 8 to 555 patients in 57 studies that met the criteria to be included. Research designs mostly were randomized controlled trial (
Tables
Summary and findings of common studied diseases.
Clinical setting | Heparin preparation | Mode of administration | Comparator | Number of patients | Clinical outcome | Laboratory outcome | Study design |
---|---|---|---|---|---|---|---|
Exercise-induced Asthma [ |
UFH | Inhaler | Cromolyn sodium or placebo | 12 | Significantly reduction of exercise-induced asthma | Heparin had no effect on histamine-induced bronchoconstriction | Single-blind, randomized, crossover clinical trial |
|
|||||||
Asthma [ |
UFH | Inhaler | Placebo | 8 | Significant reduction of late asthmatic response after allergen administration ( |
— | Randomized, double-blind, crossover clinical trial |
|
|||||||
Atopic asthma [ |
Heparin (IVX-0142) | Nebulizer | Placebo | 19 | No significant decrease in early ( |
— | Randomized single-blind, placebo-controlled, crossover trial |
|
|||||||
Asthma [ |
LMWH | Nebulizer | — | 24 | Effective as an add-on therapy to standard treatment | Reduction in eosinophil ( |
Quasi-experimental (pretest-posttest design) |
|
|||||||
Allergic asthma [ |
UFH | Inhaler | Placebo | 25 | Heparin inhalation significantly reduced bronchial hyperreactivity ( |
— | Randomized, double-blind, placebo-controlled, crossover trial |
|
|||||||
Asthma [ |
UFH | Inhaler | — | 12 | Transient (time-dependent) inhibitory role in allergic reactions | Increased the methacholine PC20 value ( |
Randomized, double-blind, placebo-controlled, crossover trial |
|
|||||||
Asthma (children) [ |
UFH | Inhaler | Placebo | 14 | Single dose of heparin significantly ( |
Provocation test used leukotriene D4 | Randomized, double-blind, placebo-controlled, crossover trial |
|
|||||||
Asthma [ |
UFH | Inhaler | Placebo | 23 | Significant reduction of bronchial hyperreactivity to histamine and leukotriene | — | Randomized, double-blind, placebo controlled, crossover trial |
|
|||||||
IBD [ |
UFH | IV/SC | Hydrocortisone + prednisolone | 20 (12 in control group) | Clinical activity index, stool frequency, and endoscopic and histopathological grading were similar in both treatment groups | CRP and |
Open label randomized, crossover clinical trial |
|
|||||||
IBD [ |
UFH | SC | — | 17 | Histology improved significantly in ulcerative colitis patients (UFH is effective in ulcerative colitis but not Crohn disease) | CRP ( |
Quasi-experimental (pretest-posttest design) |
|
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IBD [ |
UFH | IV | Methyl prednisolone | 25 (13 in control group) | No effect of heparin, also increased bleeding | No change in CRP | Randomized, double-blind, parallel-group trial |
|
|||||||
IBD [ |
Enoxaparin + standard treatment | SC | Aminosalicylate + corticosteroid | 34 (18 in control group) | Significant improvement in disease severity in both groups ( |
No difference ESR, CRP and fibrinogen and coagulation | Randomized controlled trial |
|
|||||||
IBD [ |
Nadroparin | SC | — | 25 | Endoscopic and histological sign of inflammation significantly improved | — | Quasi-experimental (Non-randomized clinical trial) |
|
|||||||
Cataract surgery [ |
UFH | Intraocular lens (IOL) | Polymethylmethacrylate | 524 | — | Heparin surface modification reduced the cellular deposit compared to control group | Randomized, double-blind, parallel group clinical trial |
|
|||||||
Cataract surgery [ |
UFH | Intraocular lens (IOL) | Polymethylmethacrylate | 58 (31 in control group) | Postoperative inflammation decreased significantly in heparin group ( |
Giant cell and cell deposit decreased significantly ( |
Randomized, double-blind, clinical trial |
|
|||||||
Cataract surgery (pediatric) [ |
UFH | Irrigation | Balanced salt solution | 33 (19 in control group) | Heparin irrigation reduced number of postoperative inflammatory related complication | Anterior chamber reaction including fibrin formation was lower in heparin group | Randomized prospective double-blind trial |
|
|||||||
Cataract surgery (pediatrics) [ |
Enoxaparin | Irrigation | No treatment | 40 (20 in each group) | Increase of flare and cell deposit after surgery (1 and 3 months) ( |
Increase in large cell deposits | Randomized, double-blind, controlled trial |
|
|||||||
Cataract surgery [ |
UFH | Irrigation | Regular irrigation solution | 72 | Significant reduction of inflammation in the early (days 1–3) postoperative period ( |
— | Randomized controlled trial |
|
|||||||
Cardiopulmonary bypass (pediatric) [ |
Heparin-coated circuit ( |
— | Non-heparin-coated circuit ( |
21 | Decrease of systemic inflammatory response with the use of heparin-bonded oxygenators | Significantly decreased levels of IL-6, IL-8, terminal complement complex, neutrophils, and elastase in heparin coated circuit | Randomized controlled trial |
|
|||||||
Cardiopulmonary bypass [ |
Heparin-coated circuit ± aprotinin | — | Uncoated circuit ± aprotinin | 200 (4 groups) | Aprotinin and heparin had no effect on cytokine release | TNF- |
Randomized, double-blind, clinical trial |
|
|||||||
Cardiopulmonary bypass [ |
UFH | — | Uncoated circuit | 51 (26 in each group) | Decreased pulmonary vascular resistance index and pulmonary shunt fraction, and increased PaO2/FIO2 ratio | Lower levels of phospholipase A2 and complement activation ( |
Randomized, double-blind, clinical trial |
|
|||||||
Cardiopulmonary bypass [ |
Heparin-coated circuit | — | Non-heparin-coated circuit | 16 (9 in control group) | — | No significant difference between groups regarding: granulocyte elastase IL-6, IL-8 | Quasi-experimental (pretest-posttest design) |
|
|||||||
Cardiopulmonary bypass [ |
Heparin concentration-based system | — | Activated clotting time-based management | 200 (100 in control group) | No effect on postoperative blood loss | Significant reduction of neutrophil activation and fibrinolysis and thrombin generation ( |
Randomized controlled trial |
|
|||||||
Cardiopulmonary bypass (pediatric) [ |
Heparin-coated circuit | — | Non-heparin-coated circuit | 19 (10 in control group) | Improvement of the biocompatibility of CPB during heart surgery | Levels of complement factor C3a ( |
Randomized controlled trial |
|
|||||||
Cardiopulmonary bypass (pediatric) [ |
Heparin-coated circuit | — | Non-heparin-coated circuit | 34 (12 in control group) | No differences in duration of intubation, intensive care unit or hospital stay, or postoperative blood loss | IL-6, IL-8, and TNF- |
Randomized controlled trial |
|
|||||||
Cardiopulmonary bypass [ |
Heparin-coated circuit (heparin + aprotinin) | — | Non-heparin-coated circuit (heparin + aprotinin) | 30 (15 in each group) | No significant differences between the two groups in terms of bleeding and transfusional requirements, the time spent on a ventilator, or in duration of stay in the intensive care unit (ICU) | Levels of IL-6, CRP, and neutrophil count did not change by heparin-coated circuit. Monocyte count increased in heparin-coated circuit | Randomized controlled trial |
|
|||||||
Coronary artery bypass grafting (CABG) [ |
Heparin-coated circuit | — | Non-heparin-coated circuit | 18 (9 in each group) | — | Reduction of levels of IL-8 and TNF- |
Randomized controlled trial |
CRP: C-Reactive Protein, CPB: Cardio Pulmonary Bypass, ECP: Eosinophil Cationic Protein, ESR: Erythrocyte Sedimentation, ICU: Intensive Care Unit, IL: interleukin, IV: intravenous, SC: subcutaneous, SGAW: Specific Airway Conductance, TNF: Tumor Necrosis Factor, and UFH: unfractionated heparin.
Summary and findings of other studied diseases.
Clinical setting | Heparin preparation | Mode of administration | Comparator | Number of patients | Clinical outcome | Laboratory outcome | Study design |
---|---|---|---|---|---|---|---|
Pancreatitis after ERCP [ |
UFH | SC | Saline solution | 105 (54 in control group) | Rate of postoperative pancreatitis was not significant between both groups | — | Randomized placebo-controlled clinical trial |
|
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Acute coronary syndrome (ACS) [ |
UFH | SC | Enoxaparin | 201 | — | No significant difference between CD4 ligand and PAI-1 in both groups | Open label, randomized, clinical trial |
|
|||||||
Skin or pulmonary allergy [ |
UFH | IV/nebulizer | Normal saline/placebo | 25 | Significant inhibition of mast cell-mediated allergic inflammation ( |
— | Double-blind, placebo-controlled, crossover clinical trial |
|
|||||||
COPD [ |
UFH | IV | — | 37 (18 in control group) | Significant improvement in bronchospasm and bronchial secretions (58% response rate) | — | Randomized placebo-controlled clinical trial |
|
|||||||
COPD [ |
Nadroparin | SC | Conventional treatment | 66 (33 in each group) | Decrease of duration of mechanical ventilation and length of hospital and ICU stay ( |
Significant decrease in levels of CRP, IL-6, and fibrinogen | Randomized controlled trial |
|
|||||||
Ischemic stroke [ |
UFH | IV | Aspirin | 167 (97 in control group) | Early onset initiation of heparin might improve recovery after stroke | Rise of sVCAM-1 at 48 h was significantly lower in patients treated with UFH ( |
Quasi-experimental (controlled observational study) |
|
|||||||
Ligneous conjunctivitis [ |
UFH | Topical | Alpha chymotrypsin or steroid | 17 (12 in control group) | Intensive and early use of topical heparin may improve therapy results in disease | — | Quasi-experimental (nonrandomized Clinical trial) |
|
|||||||
Endotoxemia (induced by lipopolysaccharide in healthy subjects) [ |
UFH | IV | LMWH or placebo | 30 (10 in each group) | — | No effect on TNF- |
Randomized, double-blinded, placebo-controlled parallel group trial |
|
|||||||
Mechanical ventilation [ |
UFH | Nebulizer | Normal saline (placebo) | 50 (25 in each group) | Fewer days on mechanical ventilation, better Pao2/Fio2 ratio | — | Double-blind, randomized, placebo-controlled trial |
|
|||||||
Percutaneous coronary intervention [ |
Bivalirudin | IV | UFH + eptifibatide | 63 (29 in control group) | — | Increase in IL-6 and CRP after 1 day. Decrease in CRP in bivalirudin group after 30 days ( |
Randomized controlled trial |
|
|||||||
Cystic fibrosis (adults) [ |
UFH | Inhaler | — | 12 (6 in control group) | Spirometry parameters did not change | IL-6 reduced after treatment | Quasi-experimental (pretest-posttest design) |
|
|||||||
Cystic fibrosis (adults) [ |
UFH | Inhaler | Placebo | 14 | No effect on FEV1 | No effect on sputum inflammatory markers | Randomized, double-blind, placebo-controlled crossover trial |
|
|||||||
Hemodialysis patients [ |
UFH | IV/SC | LMWH and no drug | 33 | LMWH decreased oxidative stress and inflammation whereas heparin increased them | CRP, TNF- |
Quasi-experimental (pretest-posttest design) |
|
|||||||
Stable angina [ |
Heparin + Aspirin ( |
— | Argatroban + Aspirin ( |
No difference in inflammatory response after angioplasty | Fibrinogen decreased significantly in argatroban group. No difference in von Willberand factor between both groups. PAI-1 increased in argatroban group | Randomized controlled trial | |
|
|||||||
Phacoemulsification [ |
Heparin | Coated lenses | Polymethylmethacrylate lenses | 367 | Heparin coated lenses reduced significantly inflammation early postoperation ( |
— | Randomized, double-blind, multicenter, parallel group trial |
|
|||||||
Allergic rhinitis [ |
UFH | Intranasal | — | 10 | — | Reduction of eosinophil cationic protein in the nasal wash | Quasi-experimental (pretest-posttest design) |
|
|||||||
Phacomorphic glaucoma [ |
Dalteparin | Irrigation | Balanced salt solution | 46 (23 in each group) | Significant decrease of postoperative inflammation in dalteparin group | — | Randomized, double-blind, clinical trial |
|
|||||||
Burn [ |
Dalteparin | SC | No treatment | 24 | — | Decrease of nitric oxide synthetase activity significantly | Quasi-experimental (nonrandomized clinical trial) |
|
|||||||
Unstable coronary artery disease [ |
Enoxaparin ( |
SC | UFH ( |
68 | Von Willberand factor may have prognostic value, but other biological variables did not predict outcome | CRP, fibrinogen, Von Willberand factor increased over first 2 days despite medical treatment. Enoxaparin (13%) and dalteparin (19%) reduced release of Von Willberand factor | Open label, randomized, clinical trial |
|
|||||||
ST-Elevated Myocardial Infarction (STEMI) [ |
Enoxaparin | SC | UFH | 34 (17 in each group) | Both heparin and enoxaparin show anti-inflammatory effects in STEMI patients | Serum Amyloid A ( |
Open label, randomized, clinical trial |
|
|||||||
Coronary artery disease [ |
Dalteparin | SC | Placebo | 555 (285 in control group) | Dalteparin reduced coagulation and so Myocardial Infarction but has not inflammatory activity | No effects on IL-6, C-reactive protein and fibrinogen | Randomized, double-blind, parallel-group, multicentre trial |
|
|||||||
Stable coronary artery disease [ |
Enoxaparin | SC | Sodium chloride | 62 (31 in each group) | By mobilizing vessel bound MPO, enoxaparin improves endothelial function | Significant increase of MPO levels | Randomized, double-blind, placebo-controlled trial |
|
|||||||
Acute coronary syndrome and PCI [ |
Tirofiban (high dose) + enoxaparin | Tirofiban (high dose) + UFH | 60 (30 in each group) | The combination of tirofiban (high dose) + enoxaparin reduced inflammation after PCI | Von willberand, CRP, D-dimer, and prothrombin fragment were significantly lower in enoxaparin group than UFH | Open label randomized controlled trial | |
|
|||||||
Superficial venous thrombophlebitis [ |
Dalteparin | SC | Ibuprofen | 72 (37 in dalteparin group) | Significant reduction of pain form baseline to day 14 of follow-up. No difference on thrombosis progression after 3 months | — | Randomized, double-blind, controlled trial |
|
|||||||
Superficial venous thrombosis [ |
Nadroparin | SC | Naproxen | 117 (39 in control group) | Nadroparin reduced symptom and signs of thrombosed superficial vein better than naproxen ( |
— | Randomized, open label clinical trial |
|
|||||||
Superficial venous thrombosis [ |
Nadroparin | SC | Nadroparin + acemetacin | 50 | Significant symptom improvement in both groups ( |
— | Randomized controlled trial |
|
|||||||
Peritoneal dialysis patients [ |
Tinzaparin | Intraperitoneal | Isotonic saline | 21 | Reduction of local and systemic inflammation in peritoneal dialysis patients | Reduced levels of CRP ( |
Randomized, double-blind, placebo-controlled crossover trial |
COPD: Chronic Obstructive Pulmonary Disease, CRP: C-Reactive Protein, CPB: Cardio Pulmonary Bypass, ECP: Eosinophil Cationic Protein, ERCP: Endoscopic Retrograde Cholangiopancreatography, ESR: Erythrocyte Sedimentation, ICU: Intensive Care Unit, IL: interleukin, IV: intravenous, LMWH: low molecular weight heparin, MDA: malondialdehyde, PAI: Plasminogen Activator Inhibitor, SC: subcutaneous, sVCAM: Soluble Vascular Cell Adhesion Molecule, TNF: Tumor Necrosis Factor, and UFH: unfractionated heparin.
Table
Summary of numbers and percentages of adequately reported items in each trial according to CONSORT checklist and Jadad score.
Trials | Jadad score | Adequately reported items ( |
Percentage (%) |
---|---|---|---|
Abdollahi et al. [ |
4 | 29/74 | 39.2% |
Ahmed et al. [ |
3 | 20/74 | 27% |
Ang et al. [ |
2 | 24/74 | 32.4% |
Ashraf et al. [ |
2 | 22/74 | 29.7% |
Becker et al. [ |
3 | 28/74 | 37.8% |
de Vroege et al. [ |
3 | 26/74 | 35.1% |
Defraigne et al. [ |
4 | 28/74 | 37.8% |
Derhaschnig et al. [ |
3 | 32/74 | 43.2% |
Dixon et al. [ |
4 | 50/74 | 67.5% |
Duong et al. [ |
3 | 30/74 | 40.5% |
Gu et al. [ |
2 | 16/74 | 21.6% |
Jerzynska et al. [ |
3 | 20/74 | 27% |
Keating et al. [ |
2 | 21/74 | 28.4% |
Koster et al. [ |
2 | 26/74 | 35.1% |
Montalescot et al. [ |
3 | 35/74 | 47.3% |
Nasiripour et al. [ |
2 | 34/74 | 46% |
Oldgren et al. [ |
3 | 27/74 | 36.5% |
Olsson et al. [ |
2 | 25/74 | 33.8% |
van Ophoven et al. [ |
2 | 27/74 | 36.5% |
Ozawa et al. [ |
2 | 27/74 | 36.5% |
Özkurt et al. [ |
3 | 18/74 | 24.3% |
Paparella et al. [ |
2 | 22/74 | 29.7% |
Polosa et al. [ |
3 | 23/74 | 31.1% |
Rathbun et al. [ |
5 | 44/74 | 59.5% |
Rudolph et al. [ |
3 | 31/74 | 41.2% |
Serisier et al. [ |
5 | 45/74 | 60.8% |
Stelmach et al. [ |
3 | 31/74 | 41.2% |
Suzuki et al. [ |
2 | 23/74 | 31% |
Vancheri et al. [ |
4 | 22/74 | 29.7% |
Vasavada et al. [ |
5 | 52/74 | 70.2% |
Walters et al. [ |
3 | 32/74 | 43.2% |
Zezos et al. [ |
3 | 37/74 | 50% |
We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related derivatives.
Asthma is a chronic inflammatory disorder of airways characterized by bronchial hyperresponsiveness resulting in episodic bronchospasm. Several studies in 1960s described subjective improvement of symptoms in asthmatic patients using intravenous heparin for the first time [
Heparin inhalation reduced bronchial hyperreactivity in a single-blind randomized crossover trial (
Our results showed that inhaled enoxaparin was used just in a pre-post study of 24 asthmatic patients, measuring inflammatory biomarkers, and showed a reduction in eosinophil (
Performed studies did not show any adverse events or harms with heparin or related compounds except increase in the plasma partial thromboplastin time reported by Ahmed et al. [
All in one, considering the results of these studies, we can conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along with other treatments in asthma.
Contact and interaction of blood with foreign surfaces during cardiopulmonary bypass (CPB) cause systemic inflammatory response syndrome (SIRS) through activation of several humoral cascades including cytokines such as IL-6, IL-8, and Tumor Necrosis Factor-
Defraigne et al. [
Paparella et al. [
The side effects of heparin-coated circuits were not reported. In these studies, just a number of included studies reported a decrease in platelet levels in both groups (coated and noncoated circuit). No major events including hemorrhage were reported.
Hypercoagulable state may be an important contributing factor in the pathogenesis of IBD, especially ulcerative colitis (UC) [
Zezos et al. [
Generally the studies show conflicting results. The heparin and LMWHs showed efficacy in regard of disease activity and also well tolerated but inflammatory markers did not change significantly. Therefore the improvement in disease activity might be the result of heparin’s anticoagulant effects.
Inflammation has a key role in the pathogenesis of coronary artery plaque destabilization and rupture leading to acute coronary syndromes (ACS) [
We found 8 studies about heparin and LMWHs in CADs evaluating anti-inflammatory effects as their endpoints. Oldgren et al. [
The ARMADA study [
In summary considering heparins as the main stay treatment of ACS, its effects are more pronounced as anticoagulating than as an anti-inflammatory agent in this pathological condition.
Postoperative inflammation is observed in cataract surgery especially in children. Newer techniques as lensectomy and phacoemulsification cause less complication but still pose potential risks [
Vasavada et al. [
Potential mechanisms of anti-inflammatory effects of heparin have been discussed completely in a review by Young [
As we discussed heparins potential effects as anti-inflammatory agents, supported by several clinical trials in various setting. Heparin and its related derivatives have been shown to benefit patients with asthma and patients undergoing cardiopulmonary bypass and cataract surgery. In other inflammatory diseases, such as IBD (ulcerative colitis), the studies are heterogeneous and incongruent. Most studies did not report any unwanted event with heparins when they used them as anti-inflammatory agents whether through systemic or through local (as inhaler or irrigation or heparin-coated circuit) administration. However, because the majority of these trials did not pose optimal quality scores, we cannot draw a definite conclusion on the efficacy of heparin and its derivatives as anti-inflammatory agents.
The present review included studies which measured inflammatory markers as their endpoints and in most of them these markers were decreased though not significantly. To come to a definite conclusion further double-blind, randomized, placebo-controlled clinical trials with a larger sample size are needed. However, because the inflammation, atherogenesis, thrombogenesis, and cell proliferation are associated with each other, the pleiotropic effects of heparin and related compounds may have greater therapeutic effect than compounds that are directed against a single target.
The authors declare that there is no conflict of interests regarding the publication of this paper.