An acidic glycosaminoglycan found especially in lung and liver tissue and having the ability to prevent the clotting of blood, used in the treatment of thrombosis.
[Late Latin hēpar, liver (from Greek) + –IN.]
Dictionary:
hep·a·rin (hĕp'ər-ĭn) ![]() |
An acidic glycosaminoglycan found especially in lung and liver tissue and having the ability to prevent the clotting of blood, used in the treatment of thrombosis.
[Late Latin hēpar, liver (from Greek) + –IN.]
| 5min Related Video: heparin |
| Oncology Encyclopedia: Heparin |
Key Terms: Angiogenesis, Anticoagulant, Blood clot, Coagulation, Embolism, Endothelial cells, Parenteral, Procoagulants, Thromboembolism.
Definition
Heparin is a drug that helps prevent blood clots from forming and belongs to the family of drugs called anticoagulants (blood thinners), although it does not actually thin the blood. It is sold in the United States under the brand names of Calciparine, Liquaemin, Calciparine, Hepalean, and Heparin Leo, and Calcilean in Canada.
Purpose
Heparin is used to decrease the clotting ability of the blood and to help prevent harmful clots from forming in the blood vessels. Heparin will not dissolve blood clots that have already formed, but it may prevent the clots from becoming larger and causing more serious problems. Heparin possesses several antithrombotic mechanisms. It is often used as a treatment for certain blood vessel, heart, and lung conditions and is also used to prevent blood clotting during open-heart surgery, bypass surgery, and dialysis. Heparin is used in low doses to prevent the formation of blood clots in certain patients, especially those who must have certain types of surgery or who must remain in bed for a long time. It is also used for the long-term treatment of thromboembolic disease, a common side effect of cancer.
One of the most common hematological complications is disordered coagulation. Approximately 15% of all cancer patients are affected by thromboembolic disease, which is the second leading cause of death for cancer patients. However, thromboembolic disease may represent only one of many complications in end-stage patients. Thromboembolic disease includes superficial and deep venous thrombosis, pulmonary emboli, thrombosis of venous access devices, arterial thrombosis, and embolism. The cancer itself or cancer treatments may induce coagulation. For example, chemotherapy can increase the risk of thromboembolic disease. An increased risk for arterial thrombosis has been observed with chemotherapy treatment.
Cancer and its treatment can affect all three causes of thromboembolic disease, including the alteration of blood flow, damage to endothelial cells (the cells in blood vessels), and enhancing procoagulants (causing the blood to clot). Cancer can affect blood flow by mechanically affecting blood vessels close to a tumor. In addition, tumors cause angiogenesis, which may create complexes of blood vessels that have a disordered appearance and flow (varying in magnitude and direction). Chemotherapy or tumors may directly damage endothelial cells. Procoagulants may be secreted into the blood stream by cancer cells or can be increased on the surface of cancer cells.
Antithrombotic treatment, in the form of the low-molecular-weight heparin reviparin, has been shown for the first time to safely improve the outcomes of patients with an acute myocardial infarction. The new findings show that reviparin "clearly improves the outcomes of patients who undergo thrombolysis with streptokinase or urokinase, and it also appears to be a useful adjunct for patients treated with primary percutaneous coronary intervention [PCI]," said Dr. Anderson, associate chief of the division of cardiology at LDS Hospital in Salt Lake City. The study has some limitations.
Description
Heparin is the most common anticoagulant used and the generic name product may be available in the U.S. and Canada.
Mechanisms of Action:
Heparin increases the release of specific proteins, like tissue plasminogen activator and tissue factor pathway inhibitor (TFPI), into the blood in order to inhibit blood coagulation. It can also increase the activity of these proteins. Heparin augments the activity of antithrombin III, a natural compound that inhibits activated clotting factors from contributing to more coagulation. Furthermore, heparin has been found to inhibit substances that may contribute to angiogenesis, including vascular endothelial growth factor, tissue factor, and plateletactivating factor.
Whether anticoagulants like heparin may also improve cancer survival rates independent of their effect on thromboembolism has been investigated. In fact, experimental and clinical data have demonstrated that heparin is an effective compound in preventing metastases. Many investigators have shown that heparin inhibits tumor metastasis in experimental animals; a few clinical trials also suggest a positive effect in humans with cancer.
Recommended Dosage
Heparin is available only with a doctor's prescription, in parenteral and injection (United States and Canada) dosage forms. A doctor will need to prescribe a specific dose for an individual's based on the type of heparin, as well as the patient's medical condition and body weight.
Dosing Schedule
Heparin should be taken under the doctor's direction and at the same time every day. If a dose is missed, take it as soon as possible. However, if a dose is missed until the following day, patients should not double-dose, but just take the usual daily dose. Double-dosing may cause bleeding.
Precautions
Some medications should not be combined. Over-the-counter medicines, vitamins, and herbal products may cause interactions when combined with heparin, so the patient should check with the doctor monitoring the heparin medication before taking any new medication, even when prescribed by another doctor.
Patients who are pregnant, breastfeeding, have given birth recently, or using an IUD for birth control should consult their doctors. The doctor should also be notified if radiation treatments, surgery, or a fall or other injury has recently occurred.
The presence of other medical problems may affect the use of heparin. Patients should be sure to tell their doctors about any other medical problems, in particular:
Side Effects
The doctor should be contacted immediately if any of these side effects are present:
Interactions
Using any of the following medicines together with heparin may increase the risk of bleeding. Again, candidates for heparin should alert their physicians if they are taking any of these medications:
—Crystal Heather Kaczkowski, MSc.
| Sci-Tech Encyclopedia: Heparin |
A highly sulfated mucopolysaccharide with blood anticoagulant activity, isolated from mammalian (chiefly beef) tissues. Heparin was first found in abundance in the liver, hence the name, but it is present in substantial amounts in the spleen, muscle, and lung as well. In the blood of most mammals, heparin is an antagonist to thrombin, prothrombin, and thromboplastin. It lessens the tendency of platelets to agglutinate. It is used in the treatment of venous thrombosis, embolism, myocardial infarction, and certain types of cerebral thrombosis. See also Polysaccharide.
| World of the Body: heparin |
This, the body's natural anticoagulant, is a muco-polysaccharide of variable molecular weight (12 000-25 000) containing sulphate groups. Heparin is produced in the liver and stored there and in other cells, such as mast cells. The levels in circulating blood are very low in normal conditions. It is able to prevent blood coagulation by acting at three separate points on the ‘cascade’ of chemical events in the plasma that causes blood clotting. First it prevents the interaction of thrombin with fibrinogen, so that the conversion of the latter to fibrin, the basic structural element of a clot, is prevented. Second, it prevents the conversion of prothrombin to thrombin and causes the destruction of Factor Xa, an early factor in the cascade. Given intravenously or subcutaneously heparin can be used to treat deep vein thrombosis and acute arterial thrombosis.
— Alan W. Cuthbert
See also blood; blood clotting.
| Drug Info: Heparin |
Brand names: HemochronHep-Lock®Hep-Lock® U/PHeparinHepFlush®-10Momoject®Monoject®
Chemical formula:

Heparin Sodium Solution for injection
What is this medicine?
HEPARIN (HEP a rin) is an anticoagulant. It is used to treat or prevent clots in the veins, arteries, lungs, or heart. It stops clots from forming or getting bigger. This medicine prevents clotting during open-heart surgery, dialysis, or in patients who are confined to bed.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
•bleeding disorders, such as hemophilia or low blood platelets
•bowel disease or diverticulitis
•endocarditis
•high blood pressure
•liver disease
•recent surgery or delivery of a baby
•stomach ulcers
•an unusual or allergic reaction to heparin, benzyl alcohol, sulfites, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding
How should I use this medicine?
This medicine is given by injection or infusion into a vein. It can also be given by injection of small amounts under the skin. It is usually given by a health care professional in a hospital or clinic setting.
If you get this medicine at home, you will be taught how to prepare and give this medicine. Use exactly as directed. Take your medicine at regular intervals. Do not take it more often than directed.
It is important that you put your used needles and syringes in a special sharps container. Do not put them in a trash can. If you do not have a sharps container, call your pharmacist or healthcare provider to get one.
Talk to your pediatrician regarding the use of this medicine in children. While this medicine may be prescribed for children for selected conditions, precautions do apply.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.What may interact with this medicine?
Do not take this medicine with any of the following medications:
•aspirin and aspirin-like drugs
•mifepristone
•medicines that treat or prevent blood clots like warfarin, enoxaparin, and dalteparin
•protamine
This medicine may also interact with the following medications:
•dextran
•digoxin
•hydroxychloroquine
•medicines for treating colds or allergies
•nicotine
•NSAIDs, medicines for pain and inflammation, like ibuprofen or naproxen
•phenylbutazone
•tetracycline antibiotics
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
What should I watch for while using this medicine?
While you are taking this medicine, carry an identification card with your name, the name and dose of medicine(s) being used, and the name and phone number of your doctor or health care professional or person to contact in an emergency.
Notify your doctor or health care professional at once if you have cold, blue hands or feet, or any unusual bleeding. Monitor your skin closely for easy bruising or red spots, which can indicate bleeding.
If you are going to have surgery or dental work, tell your doctor or health care professional that you have received this medicine. Be careful brushing and flossing your teeth or using a toothpick while receiving this medicine because you may bleed more easily.
Avoid sports and activities that might cause injury while you are using this medicine. Severe falls or injuries can cause unseen bleeding. Be careful when using sharp tools or knives. Consider using an electric razor.
What side effects may I notice from receiving this medicine?
Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•any sign of bleeding like bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine, bleeding gums, nosebleeds
•back pain
•bleeding in the eye
•breathing problems
•burning or itching on the bottoms of the feet
•cold, blue, or painful hands and feet
•coughing up blood
•feeling faint or lightheaded, falls
•fever, chills
•heavy menstrual bleeding
•nausea, vomiting
•stomach pain
•unusually low blood pressure
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•pain at site where injected
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Where should I keep my medicine?
Keep out of the reach of children.
Store unopened vials at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Do not freeze. Do not use if solution is discolored or particulate matter is present. Throw away any unused medicine after the expiration date.
Last updated: 7/1/2002
Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.
| Britannica Concise Encyclopedia: heparin |
For more information on heparin, visit Britannica.com.
| Sports Science and Medicine: heparin |
A complex organic acid found in mast cells (large cells in the connective tissue involved in inflammation response). It inhibits blood coagulation by interfering with the formation and action of thrombin (a blood clotting factor). A heparin drug can be prepared from snake venom. In addition to its anticoagulant properties, it has effects similar to caffeine, increasing free fatty acid levels. These effects may be utilized during aerobic exercise, reducing the rate of muscle glycogen utilization and delaying fatigue.
| Columbia Encyclopedia: heparin |
| Veterinary Dictionary: heparin |
An acid mucopolysaccharide present in many tissues, especially the liver and lungs, and having potent anticoagulant properties. It also has lipotrophic properties, promoting transfer of fat from blood to the fat depots by activation of lipoprotein lipase. Also, a mixture of active principles capable of prolonging blood clotting time, obtained from domestic animals; used in the prophylaxis and treatment of disorders in which there is excessive or undesirable clotting and as a preservative for blood specimens.
| Wikipedia: Heparin |
|
Heparin
|
|
| Systematic (IUPAC) name | |
| see Heparin structure | |
| Identifiers | |
| CAS number | |
| ATC code | B01 C05 S01 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C12H19NO20S3 |
| Mol. mass | 12000–15000 g/mol |
| Pharmacokinetic data | |
| Bioavailability | nil |
| Metabolism | hepatic |
| Half life | 1.5 hrs |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
C |
| Legal status |
? |
| Routes | i.v., s.c. |
Heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule.[1] It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines. Pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung.[2]
Although used principally in medicine for anticoagulation, the true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by endothelial cell-derived heparan sulfate proteoglycans.[3] Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is in a defensive mechanism at sites of tissue injury against invading bacteria and other foreign materials.[4] In addition, it is preserved across a number of widely different species, including some invertebrates that lack a similar blood coagulation system.
Contents |
Native heparin is a polymer with a molecular weight ranging from 3 kDa to 50 kDa, although the average molecular weight of most commercial heparin preparations is in the range of 12 kDa to 15 kDa. Heparin is a member of the glycosaminoglycan family of carbohydrates (which includes the closely-related molecule heparan sulfate) and consists of a variably-sulfated repeating disaccharide unit.[5] The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.[6] Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S,6S)) or a free amine group (GlcNH3+). Under physiological conditions, the ester and amide sulfate groups are deprotonated and attract positively-charged counterions to form a heparin salt. It is in this form that heparin is usually administered as an anticoagulant.
One unit of heparin (the "Howell Unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 mL of cat's blood fluid for 24 hours at 0°C.[7]
The three-dimensional structure of heparin is complicated by the fact that iduronic acid may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium being influenced by sulfation state of adjacent glucosamine sugars.[8] Nevertheless, the solution structure of a heparin dodecasacchride composed solely of six GlcNS(6S)-IdoA(2S) repeat units has been determined using a combination of NMR spectroscopy and molecular modeling techniques.[9] Two models were constructed, one in which all IdoA(2S) were in the 2S0 conformation (A and B below), and one in which they are in the 1C4 conformation (C and D below). However there is no evidence to suggest that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.
In the image above:
In these models, heparin adopts a helical conformation, the rotation of which places clusters of sulfate groups at regular intervals of about 17 angstroms (1.7 nm) on either side of the helical axis.
Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells.[10] Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have not yet formed. Heparin is used for anticoagulation for the following conditions:
Heparin and its derivatives (enoxaparin, dalteparin, tinzaparin) are effective at preventing deep-vein thromboses and pulmonary emboli in patients at risk,[11][12] but there is no evidence that they are effective at preventing death.[13] Current Scottish guidelines recommend aspirin and leg stockings instead.[14]
Heparin binds to the enzyme inhibitor antithrombin (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop.[15] The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin.[16]
AT binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer
GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)
The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly-negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin.[1] The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason heparin's activity against thrombin is size-dependent, the ternary complex requiring at least 18 saccharide units for efficient formation.[17] In contrast anti factor Xa activity only requires the pentasaccharide binding site.
This size difference has led to the development of low-molecular-weight heparins (LMWHs) and more recently to fondaparinux as pharmaceutical anticoagulants. Low-molecular-weight heparins and fondaparinux target anti-factor Xa activity rather than anti-thrombin (IIa) activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. The chemical structure of fondaparinux is shown to the left. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate.
With LMWH and fondaparinux, there is a reduced risk of osteoporosis and heparin-induced thrombocytopenia (HIT). Monitoring of the APTT is also not required and indeed does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa.
Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate, can be used as an anticoagulant in patients that have developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.[18]
The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), (the time it takes the blood plasma to clot).
Details of administration are available in clinical practice guidelines by the American College of Chest Physicians:[19]
Heparin is given parenterally, as it is degraded when taken by mouth. It can be injected intravenously or subcutaneously (under the skin). Intramuscular injections (into muscle) are avoided because of the potential for forming hematomas.
Because of its short biologic half-life of approximately one hour, heparin must be given frequently or as a continuous infusion. However, the use of low-molecular-weight heparin (LMWH) has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until the oral anticoagulant warfarin takes effect.
A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT). HIT is caused by an immunological reaction that makes platelets a target of immunological response, resulting in the degradation of platelets. This is what causes thrombocytopenia. This condition is usually reversed on discontinuation, and can generally be avoided with the use of synthetic heparins. There is also a benign form of thrombocytopenia associated with early heparin use, which resolves without stopping heparin.
There are two nonhemorrhagic side-effects of heparin treatment. The first is elevation of serum aminotransferase levels, which has been reported in as many as 80% of patients receiving heparin. This abnormality is not associated with liver dysfunction, and it disappears after the drug is discontinued. The other complication is hyperkalemia, which occurs in 5 to 10% of patients receiving heparin, and is the result of heparin-induced aldosterone suppression. The hyperkalemia can appear within a few days after the onset of heparin therapy.
Rarer side-effects include alopecia and osteoporosis with chronic use.
As with many drugs, overdoses of heparin can be fatal. In September 2006, heparin received worldwide publicity when 3 prematurely-born infants died after they were mistakenly given overdoses of heparin at an Indianapolis hospital.[20]
In case of overdose, protamine sulfate (1 mg per 100 Units of Heparin that had been given over 4 hours) can be given to counteract the action of heparin.
Heparin is one of the oldest drugs currently still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration of the United States, although it did not enter clinical trials until 1935.[21] It was originally isolated from canine liver cells, hence its name (hepar or "ήπαρ" is Greek for "liver"). Heparin's discovery can be attributed to the research activities of two men, Jay McLean and William Henry Howell.
In 1916, McLean, a second-year medical student at Johns Hopkins University, was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anti-coagulant. It was Howell who coined the term heparin for this type of fat-soluble anticoagulant in 1918. In the early 1920s, Howell isolated a water-soluble polysaccharide anticoagulant, which was also termed heparin, although it was distinct from the phosphatide preparations previously isolated. It is probable that the work of McLean changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery.
Between 1933 and 1936, Connaught Medical Research Laboratories, then a part of the University of Toronto, perfected a technique for producing safe, non-toxic heparin that could be administered to patients in a salt solution. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was a safe, easily-available, and effective blood anticoagulant. Prior to 1933, heparin was available, but in small amounts, and was extremely expensive, toxic, and, as a consequence, of no medical value.[22]
For a full discussion of the events surrounding heparin's discovery see Marcum J. (2000).[23]
Now the leading manufacturer of heparin is SPL a company owned by Oscar Meyer.
As detailed in the table below, there is a great deal of potential for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.[24][25]
| Disease states sensitive to heparin | Heparins effect in experimental models | Clinical status |
| Adult respiratory distress syndrome | Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models | Controlled clinical trials |
| Allergic encephalomyelitis | Effective in animal models | - |
| Allergic rhinitis | Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested | Controlled clinical trial |
| Arthritis | Inhibits cell accumulation, collagen destruction and angiogenesis | Anecdotal report |
| Asthma | As for adult respiratory distress syndrome, however it has also been shown to improve lung function in experimental models | Controlled clinical trials |
| Cancer | Inhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal models | Several anecdotal reports |
| Delayed type hypersensitivity reactions | Effective in animal models | - |
| Inflammatory bowel disease | Inhibits inflammatory cell transport in general. No specific model tested | Controlled clinical trials |
| Interstitial cystitis | Effective in a human experimental model of interstitial cystitis | Related molecule now used clinically |
| Transplant rejection | Prolongs allograft survival in animal models | - |
- indicates no information available
As a result of heparin's effect on such a wide variety of disease states a number of drugs are indeed in development whose molecular structures are identical or similar to those found within parts of the polymeric heparin chain.[24]
| Drug molecule | Effect of new drug compared to heparin | Biological activities |
| Heparin tetrasaccharide | Non-anticoagulant, non-immunogenic, orally active | Anti-allergic |
| Pentosan polysulfate | Plant derived, little anticoagulant activity, Anti-inflammatory, orally active | Anti-inflammatory, anti-adhesive, anti-metastatic |
| Phosphomannopentanose sulfate | Potent inhibitor of heparanase activity | Anti-metastatic, anti-angiogenic, anti-inflammatory |
| Selectively chemically O-desulphated heparin | Lacks anticoagulant activity | Anti-inflammatory, anti-allergic, anti-adhesive |
Either chemical or enzymatic de-polymerisation techniques or a combination of the two underlie the vast majority of analyses carried out on the structure and function of heparin and heparan sulfate (HS).
The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).[26] This bacterium is capable of utilizing either heparin or HS as its sole carbon and nitrogen source. In order to do this it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases and sulfamidases.[27] It is the lyases that have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I (EC 4.2.2.7), II (no EC number assigned) and III (EC 4.2.2.8) and each has distinct substrate specificities as detailed below.[28][29]
| Heparinase enzyme | Substrate specificity |
| Heparinase I | GlcNS(±6S)-IdoA(2S) |
| Heparinase II | GlcNS/Ac(±6S)-IdoA(±2S) GlcNS/Ac(±6S)-GlcA |
| Heparinase III | GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA) |
The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue.[30][31] The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromaphore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed as well as providing a convenient method for detecting the fragments produced by enzyme digestion.
Nitrous acid can be used to chemically de-polymerise heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions nitrous acid effects deaminative cleavage of the chain.[32]
At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, all be it at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit.
At low pH deaminative cleavage results in the release of inorganic SO4, and the conversion of GlcNS into anhydromannose (aMan). Low pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysacchrides such as chondroitin sulfate and dermatan sulfate; chondroitin sulfate and dermatan sulfate being un-susceptible to nitrous acid cleavage.
In addition to the bovine and porcine tissue from which pharmaceutical-grade heparin is commonly extracted, heparin has also been extracted and characterised from the following species:
The biological activity of heparin within species 6–11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1–5. The above list also demonstrates how heparin has been highly evolutionarily conserved with molecules of a similar structure being produced by a broad range of organisms belonging to many different phyla.
In December 2007, the U.S. Food and Drug Administration (FDA) recalled a shipment of heparin because of a growth of Serratia marcescens in several unopened syringes of this product. The bacteria Serratia marcescens can lead to life-threatening injuries and/or death.[50]
In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.[51][52] According to the FDA, the contaminated heparin killed 81 people in the United States. The contaminant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used for arthritis.[53]
In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing 7, and attempting to kill 10 others.[54]
Actor Dennis Quaid's twelve-day-old twins mistakenly were given an adult dosage, which is 1,000 times the recommended dosage for infants, in November 2007.[55] The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were easily confused. The Quaid family subsequently sued the manufacturer, Baxter Healthcare Corp.,[56][57] and settled with the hospital, Cedars-Sinai Medical Center, for $750,000.[58]
In July 2008, another set of twins born at Christus Spohn Hospital South, a hospital located in Corpus Christi, Texas, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and, unlike the Quaid case, was unrelated to the product's packaging or labeling.[59] As of July 2008[update], whether the deaths were due to the overdose is under investigation.[60][61]
Prior to the Quaid accident, 6 newborn babies at Methodist Hospital in Indianapolis, Indiana were given an overdose. Three of the babies died after the mistake. http://www.wthr.com/Global/story.asp?s=5418800
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This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)
| Warfarin | |
| blood | |
| blood clotting |
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