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Hematology. American Society of... Dec 2017Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last... (Review)
Review
Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last century can also produce the most extreme prothrombotic diathesis is but one of the paradoxes that surround heparin-induced thrombocytopenia. Standard treatment is alternative anticoagulation. Advances continue to be made regarding pathophysiology, prevention, and treatment. Currently, an epidemic of overdiagnosis threatens the well-being of patients, so efforts to educate clinicians on when and how to make this diagnosis are pressing.
Topics: Heparin; History, 20th Century; History, 21st Century; Humans; Thrombocytopenia
PubMed: 29222319
DOI: 10.1182/asheducation-2017.1.667 -
Blood Mar 2012Heparin-induced thrombocytopenia is a prothrombotic adverse drug effect induced by platelet-activating antibodies against multimolecular complexes of platelet factor 4... (Review)
Review
Heparin-induced thrombocytopenia is a prothrombotic adverse drug effect induced by platelet-activating antibodies against multimolecular complexes of platelet factor 4 and heparin. Diagnosis rests on a clinical assessment of disease probability and laboratory testing. Management involves immediate discontinuation of heparin and initiation of an alternative anticoagulant. Because of the frequency of thrombocytopenia among heparinized patients, the limited specificity of widely available immunoassays, the limited availability of more specific functional assays, and clinicians' fears of missing a case of true disease, overtesting, overdiagnosis, and overtreatment have become common. As a result, a substantial number of thrombocytopenic patients are unnecessarily exposed to costly alternative anticoagulants and their attendant risk of bleeding. In this review, we describe not only our approach to the evaluation and management of patients with heparin-induced thrombocytopenia, but also the measures we use to minimize misdiagnosis and unnecessary treatment of patients without the disease. In addition, we propose areas of investigation for improvement of the diagnosis and management of this potentially fatal disorder.
Topics: Antibodies; Anticoagulants; Heparin; Humans; Immunoassay; Platelet Count; Platelet Factor 4; Thrombocytopenia
PubMed: 22246036
DOI: 10.1182/blood-2011-11-376293 -
Natural Product Reports Dec 2014Heparan sulfate is a polysaccharide that plays essential physiological functions in the animal kingdom. Heparin, a highly sulfated form of heparan sulfate, is a widely... (Review)
Review
Heparan sulfate is a polysaccharide that plays essential physiological functions in the animal kingdom. Heparin, a highly sulfated form of heparan sulfate, is a widely prescribed anticoagulant drug worldwide. The heparan sulfate and heparin isolated from natural sources are highly heterogeneous mixtures differing in their polysaccharide chain lengths and sulfation patterns. The access to structurally defined heparan sulfate and heparin is critical to probe the contribution of specific sulfated saccharide structures to the biological functions as well as for the development of the next generation of heparin-based anticoagulant drugs. The synthesis of heparan sulfate and heparin, using a purely chemical approach, has proven extremely difficult, especially for targets larger than octasaccharides having a high degree of site-specific sulfation. A new chemoenzymatic method has emerged as an effective alternative approach. This method uses recombinant heparan sulfate biosynthetic enzymes combined with unnatural uridine diphosphate-monosaccharide donors. Recent examples demonstrate the successful synthesis of ultra-low molecular weight heparin, low-molecular weight heparin and bioengineered heparin with unprecedented efficiency. The new method provides an opportunity to develop improved heparin-based therapeutics.
Topics: Drug Design; Heparin; Heparitin Sulfate; Molecular Structure
PubMed: 25197032
DOI: 10.1039/c4np00076e -
Clinical and Applied... Mar 2017The role of anticoagulants in the prevention of pregnancy complications, including recurrent miscarriage, late fetal loss, and preeclampsia, continues to be an area of... (Review)
Review
The role of anticoagulants in the prevention of pregnancy complications, including recurrent miscarriage, late fetal loss, and preeclampsia, continues to be an area of active research and debate. Although prophylactic anticoagulation with heparin and aspirin is considered the standard of care in some conditions, such as obstetric antiphospholipid antibody syndrome, the optimal management of pregnant women with factor V Leiden mutation, prothrombin G20210A mutation, and other inherited thrombophilias without a history of thrombosis remains unknown. Some studies suggest a benefit of heparins in preventing late-term losses but not earlier miscarriages in the inherited thrombophilias. In the following review, we will discuss the recent literature regarding anticoagulation and pregnancy complications and conclude with our suggested approach to the management of these challenging patients.
Topics: Anticoagulants; Disease Management; Female; Heparin; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombophilia
PubMed: 26566668
DOI: 10.1177/1076029615615972 -
Glycoconjugate Journal Dec 2015Nattokinase (NK) is a serine protease extracted from a traditional Japanese food called natto. Due to its strong fibrinolytic and thrombolytic activity, NK is regarded...
Nattokinase (NK) is a serine protease extracted from a traditional Japanese food called natto. Due to its strong fibrinolytic and thrombolytic activity, NK is regarded as a valuable dietary supplement or nutraceutical for the oral thrombolytic therapy. In addition, NK has been investigated for some other medical applications including treatment of hypertension, Alzheimer's disease, and vitreoretinal disorders. The most widely used clinical anticoagulants are heparin and low molecular weight heparins. The interactions between heparin and proteins modulate diverse patho-physiological processes and heparin modifies the activity of serine proteases. Indeed, heparin plays important roles in almost all of NK's potential therapeutically applications. The current report relies on surface plasmon resonance spectroscopy to examine NK interacting with heparin as well as other glycosaminoglycans (GAGs). These studies showed that NK is a heparin binding protein with an affinity of ~250 nM. Examination with differently sized heparin oligosaccharides indicated that the interaction between NK and heparin is chain-length dependent and the minimum size for heparin binding is a hexasaccharide. Studies using chemically modified heparin showed the 6-O-sulfo as well as the N-sulfo groups but not the 2-O-sulfo groups within heparin, are essential for heparin's interaction with NK. Other GAGs (including HS, DS, and CSE) displayed modest binding affinity to NK. NK also interfered with other heparin-protein interactions, including heparin's interaction with antithrombin and fibroblast growth factors.
Topics: Animals; Cattle; Heparin; Humans; Kinetics; Protein Binding; Subtilisins; Swine
PubMed: 26412225
DOI: 10.1007/s10719-015-9620-8 -
Electrophoresis Jun 2012The adulteration of raw heparin with oversulfated chondroitin sulfate (OSCS) in 2007-2008 produced a global crisis resulting in extensive revisions to the pharmacopeia... (Review)
Review
The adulteration of raw heparin with oversulfated chondroitin sulfate (OSCS) in 2007-2008 produced a global crisis resulting in extensive revisions to the pharmacopeia monographs and prompting the FDA to recommend the development of additional methods for the analysis of heparin purity. As a consequence, a wide variety of innovative analytical approaches have been developed for the quality assurance and purity of unfractionated and low-molecular-weight heparins. This review discusses recent developments in electrophoresis techniques available for the sensitive separation, detection, and partial structural characterization of heparin contaminants. In particular, this review summarizes recent publications on heparin quality and related impurity analysis using electrophoretic separations such as capillary electrophoresis (CE) of intact polysaccharides and hexosamines derived from their acidic hydrolysis, and polyacrylamide gel electrophoresis (PAGE) for the separation of heparin samples without and in the presence of its relatively specific depolymerization process with nitrous acid treatment.
Topics: Chondroitin Sulfates; Drug Contamination; Electrophoresis; Heparin
PubMed: 22736353
DOI: 10.1002/elps.201100479 -
Kidney International Jun 1987Heparin free hemodialysis was compared to systemic heparinization, intermittent saline flushes and constant saline infusions in eight, stable chronic patients dialyzing... (Clinical Trial)
Clinical Trial Comparative Study
Heparin free hemodialysis was compared to systemic heparinization, intermittent saline flushes and constant saline infusions in eight, stable chronic patients dialyzing on hollow-fiber artificial kidneys (HFAK) at blood flows of 250 to 300 ml/min. No significant differences in small molecule clearance, fluid removal or dialyzer clotting were noted. Since this data showed that heparin free hemodialysis without supplemental saline was feasible in a group of stable, chronic dialysis patients, we then prospectively studied twenty-nine patients judged to be at increased risk of hemorrhage from heparinization during 100 heparin-free dialyses. The incidences of severe and moderate dialyzer clotting were 7% and 20%, respectively. Seventeen of 27 treatments in which moderate or severe clotting occurred had identifiable factors thought to predispose to dialyzer clotting such as low blood flows, poor vascular-access function, severe hypotension and intradialytic blood transfusions. Although higher hematocrit values were associated with greater degrees of dialyser clotting, stepwise discriminant analysis employing blood flow, blood pressure, hematocrit and transfusion administration could not develop an accurate predictor or combination of predictors of clotting. No patient experienced de novo or increased bleeding and problems with inadequate dialysis were not observed. Since this method of heparin free dialysis is as safe and effective as previously reported strategies and requires no specialized equipment or procedures, it is a reasonable initial strategy for dialyzing high risk patients.
Topics: Acute Kidney Injury; Blood Coagulation; Dose-Response Relationship, Drug; Female; Heparin; Humans; Kidney Failure, Chronic; Male; Prospective Studies; Renal Dialysis; Risk
PubMed: 3613407
DOI: 10.1038/ki.1987.149 -
International Journal of Molecular... Apr 2022Heparin is a polysaccharide expressed in animal connective tissue-type mast cells. Owing to the special pentasaccharide sequence, heparin specifically binds to...
Heparin is a polysaccharide expressed in animal connective tissue-type mast cells. Owing to the special pentasaccharide sequence, heparin specifically binds to antithrombin (AT) and increases the inhibitory activity of AT towards coagulation enzymes. Heparin isolated from porcine intestinal mucosa has an average molecular weight of 15 kDa, while heparins recovered from rat skin and the peritoneal cavity were 60-100 kDa and can be fragmented by the endo-glucuronidase heparanase in vitro. In this study, we have examined heparin isolated from in vitro matured fetal skin mast cells (FSMC) and peritoneal cavity mast cells (PCMC) collected from wildtype (WT), heparanase knockout (Hpa-KO), and heparanase overexpressing (Hpa-tg) mice. The metabolically S-labeled heparin products from the mast cells of WT, Hpa-KO, and Hpa-tg mice were compared and analyzed for molecular size and AT-binding activity. The results show that PCMC produced heparins with a size similar to heparin from porcine intestinal mast cells, whilst FSMC produced much longer chains. As expected, heparanase overexpression resulted in the generation of smaller fragments in both cell types, while heparins recovered from heparanase knockout cells were slightly longer than heparin from WT cells. Unexpectedly, we found that heparanase expression affected the production of total glycosaminoglycans (GAGs) and the proportion between heparin and other GAGs but essentially had no effect on heparin catabolism.
Topics: Animals; Anticoagulants; Antithrombins; Glucuronidase; Glycosaminoglycans; Heparin; Mast Cells; Mice; Rats; Swine
PubMed: 35563215
DOI: 10.3390/ijms23094821 -
Molecules (Basel, Switzerland) May 2017Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage... (Review)
Review
Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage brain injury. Previous work suggests that heparin, due to the multimodal nature of its actions, reduces the incidence of clinical vasospasm and delayed cerebral ischemia that accompany the disease. This narrative review examines how heparin may mitigate the non-vasospastic pathological aspects of aSAH, particularly those related to neuroinflammation. Following a brief review of early brain injury in aSAH and heparin's general pharmacology, we discuss potential mechanistic roles of heparin therapy in treating post-aSAH inflammatory injury. These roles include reducing ischemia-reperfusion injury, preventing leukocyte extravasation, modulating phagocyte activation, countering oxidative stress, and correcting blood-brain barrier dysfunction. Following a discussion of evidence to support these mechanistic roles, we provide a brief discussion of potential complications of heparin usage in aSAH. Our review suggests that heparin's use in aSAH is not only safe, but effectively addresses a number of pathologies initiated by aSAH.
Topics: Animals; Anticoagulants; Brain Ischemia; Heparin; Humans; Reperfusion Injury; Subarachnoid Hemorrhage
PubMed: 28468328
DOI: 10.3390/molecules22050724 -
BioMed Research International 2015Heparan sulfate (HS) and heparin (Hp) are linear polysaccharide chains composed of repeating (1→4) linked pyrosulfuric acid and 2-amino-2-deoxy glucopyranose... (Review)
Review
Heparan sulfate (HS) and heparin (Hp) are linear polysaccharide chains composed of repeating (1→4) linked pyrosulfuric acid and 2-amino-2-deoxy glucopyranose (glucosamine) residue. Mentioned glycosaminoglycans chains are covalently O-linked to serine residues within the core proteins creating heparan sulfate/heparin proteoglycans (HSPG). The latter ones participate in many physiological and pathological phenomena impacting both the plethora of ligands such as cytokines, growth factors, and adhesion molecules and the variety of the ECM constituents. Moreover, HS/Hp determine the effective wound healing process. Initial growth of HS and Hp amount is pivotal during the early phase of tissue repair; however heparan sulfate and heparin also participate in further stages of tissue regeneration.
Topics: Animals; Heparin; Heparitin Sulfate; Humans; Wound Healing
PubMed: 26236728
DOI: 10.1155/2015/549417