Heparin, also known as unfractionated heparin (UFH), is medication
which is used as an anticoagulant (blood thinner). Specifically it
is used to treat and prevent deep vein thrombosis, pulmonary embolism,
and arterial thromboembolism. It is also used in the treatment of
heart attacks and unstable angina. It is given by injection into a
vein. Other uses include inside test tubes and kidney dialysis
Common side effects include bleeding, pain at the injection site, and
low blood platelets. Serious side effects include heparin induced
thrombocytopenia. Greater care is needed in those with poor kidney
Heparin appears to be relatively safe for use during
pregnancy and breastfeeding.
Heparin is a naturally occurring
The discovery of heparin was announced in 1916. It is on the World
Health Organization's List of Essential Medicines, the most effective
and safe medicines needed in a health system. The wholesale cost in
the developing world, when used for prevention, is about 9.63 to 37.95
USD per month. In the United States it costs about 25 to 50 USD per
month. A fractionated version of heparin, known as low molecular
weight heparin, is also available.
1 Medical use
2 Adverse effects
2.2 Antidote to heparin
3 Physiological function
3.1 Evolutionary conservation
4.1 Mechanism of action
4.3 Natural degradation or clearance
5.1.1 Three-dimensional structure
5.2 Depolymerisation techniques
5.3 Detection in body fluids
7 Other functions
8 Society and culture
8.1 Contamination recalls
8.1.1 2008 recall due to adulteration in drug from China
8.2 Use in homicide
8.3 Overdose issues
10 Further reading
11 External links
A vial of heparin sodium for injection
Heparin is a naturally occurring anticoagulant produced by basophils
and mast cells. In therapeutic doses, it 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 formed.
Heparin is generally used for anticoagulation
for the following conditions:
Acute coronary syndrome, e.g., NSTEMI
Deep-vein thrombosis and pulmonary embolism
Cardiopulmonary bypass for heart surgery
ECMO circuit for extracorporeal life support
Indwelling central or peripheral venous catheters
Heparin and its low-molecular-weight derivatives (e.g., enoxaparin,
dalteparin, tinzaparin) are effective in preventing deep vein
thromboses and pulmonary emboli in people at risk, but no
evidence indicates any one is more effective than the other in
A serious side-effect of heparin is heparin-induced thrombocytopenia
(HIT), caused by an immunological reaction that makes platelets a
target of immunological response, resulting in the degradation of
platelets, which causes thrombocytopenia. This condition is usually
reversed on discontinuation, and in general can be avoided with the
use of synthetic heparins. Also, a benign form of thrombocytopenia is
associated with early heparin use, which resolves without stopping
Two non-hemorrhagic side-effects of heparin treatment are known. 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. More rarely, the side-effects alopecia and osteoporosis can
occur with chronic use.
As with many drugs, overdoses of heparin can be fatal. In September
2006, heparin received worldwide publicity when three prematurely born
infants died after they were mistakenly given overdoses of heparin at
an Indianapolis hospital.
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Heparin is contraindicated in those with risk of bleeding (especially
in people with uncontrolled blood pressure, liver disease, and
stroke), severe liver disease, or severe hypertension.
Antidote to heparin
Protamine sulfate has been given to counteract the anticoagulant
effect of heparin (1 mg per 100 units of heparin that had been
given over the past four hours). It may be used in those who
overdose on heparin or to reverse heparin's effect when it is no
Heparin's normal role in the body is unclear.
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
defense at such sites against invading bacteria and other foreign
materials. In addition, it is observed across a number of widely
different species, including some invertebrates that do not have a
similar blood coagulation system. It is a highly sulfated
glycosaminoglycan. It has the highest negative charge density of any
known biological molecule.
In addition to the bovine and porcine tissue from which
pharmaceutical-grade heparin is commonly extracted, it has also been
extracted and characterised from:
Fresh water mussel
Zebra fish 
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
In nature, heparin is a polymer of varying chain size. Unfractionated
heparin (UFH) as a pharmaceutical is heparin that has not been
fractionated to sequester the fraction of molecules with low molecular
weight. In contrast, low-molecular-weight heparin (LMWH) has undergone
fractionation for the purpose of making its pharmacodynamics more
predictable. Often either UFH or LMWH can be used; in some situations
one or the other is preferable.
Mechanism of action
Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a
conformational change that results in its activation through an
increase in the flexibility of its reactive site loop. The
activated AT then inactivates thrombin, factor Xa and other proteases.
The rate of inactivation of these proteases by AT can increase by up
to 1000-fold due to the binding of heparin.
Heparin binds to
antithrombin via a specific pentasaccharide sulfation sequence
contained within the heparin polymer:
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. 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, with the
ternary complex requiring at least 18 saccharide units for efficient
formation. In contrast, antifactor Xa activity requires only the
This size difference has led to the development of
low-molecular-weight heparins (LMWHs) and, more recently, to
fondaparinux as pharmaceutical anticoagulants. LMWHs and fondaparinux
target antifactor Xa activity rather than antithrombin activity, with
the aim of facilitating a more subtle regulation of coagulation and an
improved therapeutic index. The chemical structure of fondaparinux is
shown above. 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
With LMWH and fondaparinux, the risk of osteoporosis and
heparin-induced thrombocytopenia (HIT) is reduced. Monitoring of the
activated partial thromboplastin time is also not required and 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 having
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%.
The effects of heparin are measured in the lab by the partial
thromboplastin time (aPTT), one of the measures of the time it takes
the blood plasma to clot. Partial thromboplastin time should not be
confused with prothrombin time, or PT, which measures blood clotting
time through a different pathway of the coagulation cascade.
Heparin is given parenterally because it is not absorbed from the gut,
due to its high negative charge and large size. 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 about
one hour, heparin must be given frequently or as a continuous
infusion. Unfractionated heparin has a half-life of about one to two
hours after infusion, whereas LMWH has a half-life of four to five
hours. The use of 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 an oral anticoagulant e.g. warfarin
American College of Chest Physicians publishes clinical guidelines
on heparin dosing.
Natural degradation or clearance
Unfractionated heparin has a half-life of about one to two hours after
infusion, whereas low-molecular-weight heparin's half-life is
about four times longer. Lower doses of heparin have a much shorter
half-life than larger ones.
Heparin binding to macrophage cells is
internalized and depolymerized by the macrophages. It also rapidly
binds to endothelial cells, which precludes the binding to
antithrombin that results in anticoagulant action. For higher doses of
heparin, endothelial cell binding will be saturated, such that
clearance of heparin from the bloodstream by the kidneys will be a
Ball-and-stick model of heparin
Native heparin is a polymer with a molecular weight ranging from 3 to
30 kDa, although the average molecular weight of most commercial
heparin preparations is in the range of 12 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. 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.
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 is usually administered in this form as an
GlcA = β-D-glucuronic acid, IdoA = α-L-iduronic acid, IdoA(2S) =
2-O-sulfo-α-L-iduronic acid, GlcNAc =
2-deoxy-2-acetamido-α-D-glucopyranosyl, GlcNS =
2-deoxy-2-sulfamido-α-D-glucopyranosyl, GlcNS(6S) =
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
The three-dimensional structure of heparin is complicated because
iduronic acid may be present in either of two low-energy conformations
when internally positioned within an oligosaccharide. The
conformational equilibrium is influenced by sulfation state of
adjacent glucosamine sugars. Nevertheless, the solution structure
of a heparin dodecasaccharide composed solely of six
GlcNS(6S)-IdoA(2S) repeat units has been determined using a
combination of NMR spectroscopy and molecular modeling techniques.
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, no evidence suggests that
changes between these conformations occur in a concerted fashion.
These models correspond to the protein data bank code 1HPN.
Two different structures of heparin
In the image above:
A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer
B = van der Waals radius space filling model of A
C = 1HPN (all IdoA(2S) residues in 1C4 conformation) Jmol viewer
D = van der Waals radius space filling model of C
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
Either chemical or enzymatic depolymerisation 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). This bacterium is capable of using
either heparin or HS as its sole carbon and nitrogen source. To do so,
it produces a range of enzymes such as lyases, glucuronidases,
sulfoesterases, and sulfamidases. The lyases have mainly been used
in heparin/HS studies. The bacterium produces three lyases,
heparinases I (EC 126.96.36.199), II (no EC number assigned) and III (EC
188.8.131.52) and each has distinct substrate specificities as detailed
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. The C4-C5 unsaturated uronate is termed ΔUA
or UA. It is a sensitive UV chromophore (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 depolymerise 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
IdoA(2S)-aMan: The anhydromannose can be reduced to an anhydromannitol
At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs
between GlcNS-GlcA and GlcNS-IdoA, albeit 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 not being susceptible to
nitrous acid cleavage.
Detection in body fluids
Current clinical laboratory assays for heparin rely on an indirect
measurement of the effect of the drug, rather than on a direct measure
of its chemical presence. These include activated partial
thromboplastin time (APTT) and antifactor Xa activity. The specimen of
choice is usually fresh, nonhemolyzed plasma from blood that has been
anticoagulated with citrate, fluoride, or oxalate.
Heparin was discovered by
Jay McLean and
William Henry Howell
William Henry Howell in 1916,
although it did not enter clinical trials until 1935. It was
originally isolated from canine liver cells, hence its name (hepar or
"ήπαρ" is Greek for "liver"; hepar + -in).
McLean was a second-year medical student at Johns Hopkins University,
and was working under the guidance of Howell investigating
pro-coagulant preparations, when he isolated a fat-soluble phosphatide
anticoagulant in canine liver tissue. In 1918, Howell coined the
term 'heparin' for this type of fat-soluble anticoagulant. In the
early 1920s, Howell isolated a water-soluble polysaccharide
anticoagulant, which he also termed 'heparin', although it was
different from the previously discovered phosphatide
preparations. McLean's work as a surgeon probably changed the
focus of the Howell group to look for anticoagulants, which eventually
led to the polysaccharide discovery.
In the 1930s, several researchers were investigating heparin. Erik
Karolinska Institutet published his research on the
structure of heparin in 1935, which made it possible for the
Vitrum AB to launch the first heparin product for
intravenous use in 1936. Between 1933 and 1936, Connaught Medical
Research Laboratories, then a part of the University of Toronto,
perfected a technique for producing safe, nontoxic heparin that could
be administered to patients, in a saline 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 as a
blood anticoagulant. Prior to 1933, heparin was available in small
amounts, was extremely expensive and toxic, and, as a consequence, of
no medical value.
Test tubes, Vacutainers, and capillary tubes that use the lithium salt
of heparin (lithium heparin) as an anticoagulant are usually marked
with green stickers and green tops.
Heparin has the advantage over
EDTA of not affecting levels of most ions. However, the levels of
ionized calcium may be decreased if the concentration of heparin in
the blood specimen is too high.
Heparin can interfere with some
immunoassays, however. As lithium heparin is usually used, a person's
lithium levels cannot be obtained from these tubes; for this purpose,
royal-blue-topped (and dark green-topped) vacutainers containing
sodium heparin are used.
Heparin-coated blood oxygenators are available for use in heart-lung
machines. Among other things, these specialized oxygenators are
thought to improve overall biocompatibility and host homeostasis by
providing characteristics similar to those of native endothelium.
The DNA binding sites on
RNA polymerase can be occupied by heparin,
preventing the polymerase from binding to promoter DNA. This property
is exploited in a range of molecular biological assays.
Common diagnostic procedures require
PCR amplification of a patient's
DNA, which is easily extracted from white blood cells treated with
heparin. This poses a potential problem, since heparin may be
extracted along with the DNA, and it has been found to interfere with
PCR reaction at levels as low as 0.002 U in a 50 μL reaction
Heparin has been used as a chromatography resin, acting as both an
affinity ligand and an ion exchanger. Heparin’s specific
affinity for VSV-G, a viral envelope glycoprotein often used to
pseudotype retroviral and lentiviral vectors for gene therapy, allows
it to be used for downstream purification of viral vectors.
Society and culture
Considering the animal source of pharmaceutical heparin, the numbers
of potential impurities are relatively large compared with a wholly
synthetic therapeutic agent. The range of possible biological
contaminants includes viruses, bacterial endotoxins, transmissible
spongiform encephalopathy (TSE) agents, lipids, proteins, and DNA.
During the preparation of pharmaceutical-grade heparin from animal
tissues, impurities such as solvents, heavy metals, and extraneous
cations can be introduced. However, the methods employed to minimize
the occurrence and to identify and/or eliminate these contaminants are
well established and listed in guidelines and pharmacopoeias. The
major challenge in the analysis of heparin impurities is the detection
and identification of structurally related impurities. The most
prevalent impurity in heparin is dermatan sulfate (DS), also known as
chondroitin sulfate B. The building-block of DS is a disaccharide
composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid
residue, connected via 1,4 linkages to form the polymer. DS is
composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four
possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S, or GalNAc4S6S)
building-blocks. The presence of iduronic acid in DS distinguishes it
from chrondroitin sulfate A and C and likens it to heparin and HS. DS
has a lower negative charge density overall compared to heparin. A
common natural contaminant, DS is present at levels of 1–7% in
heparin API, but has no proven biological activity that influences the
anticoagulation effect of heparin.
In December 2007, the US Food and
Drug Administration (FDA) recalled a
shipment of heparin because of bacterial growth (Serratia marcescens)
in several unopened syringes of this product. S. marcescens can lead
to life-threatening injuries and/or death.
2008 recall due to adulteration in drug from China
Main article: 2008 Chinese heparin adulteration
In March 2008, major recalls of heparin were announced by the FDA due
to contamination of the raw heparin stock imported from China.
According to the FDA, the adulterated heparin killed 81 people in the
United States. The adulterant was identified as an "over-sulphated"
derivative of chondroitin sulfate, a popular shellfish-derived
supplement often used for arthritis, which was intended to substitute
for actual heparin in potency tests.
According to the New York Times: 'Problems with heparin reported to
the agency include difficulty breathing, nausea, vomiting, excessive
sweating and rapidly falling blood pressure that in some cases led to
Use in homicide
In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately
administered large doses to patients, killing 7, and attempting to
kill 10 others.
In 2007, a nurse at
Cedars-Sinai Medical Center
Cedars-Sinai Medical Center mistakenly gave the
12-day-old twins of actor
Dennis Quaid a dose of heparin that was
1,000 times the recommended dose for infants. The overdose
allegedly arose because the labeling and design of the adult and
infant versions of the product were similar. The Quaid family
subsequently sued the manufacturer, Baxter Healthcare Corp.,
and settled with the hospital for $750,000. Prior to the Quaid
accident, six newborn babies at Methodist Hospital in Indianapolis,
Indiana, were given an overdose. Three of the babies died after the
In July 2008, another set of twins born at Christus Spohn Hospital
South, 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 was unrelated to the product's
packaging or labeling. As of July 2008[update], the exact
cause of the twins' death was under investigation.
In March 2010, a two-year-old transplant patient from Texas was given
a lethal dose of heparin at the University of Nebraska Medical Center.
The exact circumstances surrounding her death are still under
Pharmaceutical-grade heparin is derived from mucosal tissues of
slaughtered meat animals such as porcine (pig) intestines or bovine
(cattle) lungs. Advances to produce heparin synthetically have
been made in 2003 and 2008. In 2011, a chemoenzymatic process of
synthesizing low molecular weight heparins from simple disaccharides
As detailed in the table below, the potential is great for the
development of heparin-like structures as drugs to treat a wide range
of diseases, in addition to their current use as
Disease states sensitive to heparin
Heparin's effect in experimental models
Acquired immunodeficiency syndrome
Reduces the ability of human immunodeficiency virus types 1 and 2 to
adsorb to cultured T4 cells.
Adult respiratory distress syndrome
Reduces cell activation and accumulation in airways, neutralizes
mediators and cytotoxic cell products, and improves lung function in
Controlled clinical trials
Effective in animal models
Effects as for adult respiratory distress syndrome, although no
specific nasal model has been tested
Controlled clinical trial
Inhibits cell accumulation, collagen destruction and angiogenesis
As for adult respiratory distress syndrome, however, it has also been
shown to improve lung function in experimental models
Controlled clinical trials
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
Controlled clinical trials
Effective in a human experimental model of interstitial cystitis
Related molecule now used clinically
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.
Effect of new drug compared to heparin
Nonanticoagulant, nonimmunogenic, orally active
Plant derived, little anticoagulant activity, anti-inflammatory,
Anti-inflammatory, antiadhesive, antimetastatic
Potent inhibitor of heparanase activity
Antimetastatic, antiangiogenic, anti-inflammatory
Selectively chemically O-desulphated heparin
Lacks anticoagulant activity
Anti-inflammatory, antiallergic, antiadhesive
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History of heparin
Antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs)
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Low molecular weight heparin
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‡Withdrawn from market
§Never to phase III
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heparins or heparinoids for topical use
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