Low molecular weight heparin

From Wikipedia, the free encyclopedia

In medicine, low-molecular-weight heparin (LMWH) is a class of anticoagulant med
ications.[1] They are used in the prevention and treatment of venous thromboembo
lism (deep vein thrombosis and pulmonary embolism) and in the treatment of myoca
rdial infarction.
Heparin is a naturally occurring polysaccharide that inhibits coagulation, the p
rocess that leads to thrombosis. Natural heparin consists of molecular chains of
varying lengths, or molecular weights. Chains of varying molecular weights, fro
m 5000 to over 40,000 Daltons, make up polydisperse pharmaceutical-grade heparin
.[2] LMWHs, in contrast, consist of only short chains of polysaccharide. LMWHs a
re defined as heparin salts having an average molecular weight of less than 8000
Da and for which at least 60% of all chains have a molecular weight less than 8
000 Da. These are obtained by various methods of fractionation or depolymerisati
on of polymeric heparin.
Heparin derived from natural sources, mainly porcine intestine or bovine lung, c
an be administered therapeutically to prevent thrombosis. However, the effects o
f natural, or unfractionated heparin are more unpredictable than LMWH.[3]
Contents [hide]
1
Anti-factor Xa activity
2
Manufacturing process
2.1
Differences between LMWHs
2.2
Differences from unfractionated heparin
3
Clinical uses
3.1
Venous thromboembolism and cancer
3.2
Antidote
3.3
Contraindications
3.4
Precautions
3.5
Side effects
3.6
Generics
4
References
5
External links
Anti-factor Xa activity[edit]
Coagulation cascade is a normal physiological process which aims at preventing s
ignificant blood loss or hemorrhage following vascular injury. Unfortunately, th
ere are times when a blood clot (thrombus) will form when it is not needed. For
instance, some high risk conditions such as prolonged immobilization, surgery, o
r cancer can increase the risk of developing a blood clot which can potentially
lead to significant consequences.
The coagulation cascade consists of a series of steps in which a protease cleave
s and subsequently activates the next protease in the sequence.[2] Since each pr
otease can activate several molecules of the next protease in the series, this b
iological cascade is amplified. The final result of these reactions is to conver
t fibrinogen, a soluble protein, to insoluble threads of fibrin. Together with p
latelets, the fibrin threads form a stable blood clot.
Antithrombin (AT), a serine protease inhibitor, is the major plasma inhibitor of
coagulation proteases.[4] LMWHs inhibit the coagulation process through binding
to AT via a pentasaccharide sequence (see also heparin: mechanism of action). T
his binding leads to a conformational change of AT which accelerates its inhibit
ion of activated factor X (factor Xa). Once dissociated, the LMWH is free to bin
d to another antithrombin molecule and subsequently inhibit more activated facto
r X. Unlike AT activated by Heparin, AT activated by LMWH cannot inhibit thrombi
n, but can only inhibit clotting factor Xa.
The effects of LMWHs cannot be acceptably measured using the partial thromboplas

tin time (PTT) or activated clotting time (ACT) tests.[5] Rather, LMWH therapy i
s monitored by the anti-factor Xa assay, measuring anti-factor Xa activity. The
methodology of an anti-factor Xa assay is that patient plasma is added to a know
n amount of excess factor Xa and excess antithrombin. If heparin or LMWH is pres
ent in the patient plasma, it will bind to antithrombin and form a complex with
factor Xa, inhibiting it.[6] The amount of residual factor Xa is inversely propo
rtional to the amount of heparin/LMWH in the plasma. The amount of residual fact
or Xa is detected by adding a chromogenic substrate that mimics the natural subs
trate of factor Xa, making residual factor Xa cleave it, releasing a colored com
pound that can be detected by a spectrophotometer.[6] Antithrombin deficiencies
in the patient do not affect the assay, because excess amounts of antithrombin i
s provided in the reaction.[6] Results are given in anticoagulant concentration
in units/mL of antifactor Xa, such that high values indicate high levels of anti
coagulation and low values indicate low levels of anticoagulation.[6]
LMWHs have a potency of greater than 70 units/mg of anti-factor Xa activity and
a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5.[7] (see ta
ble 1)
LMWH
Average molecular weight
Ratio anti-Xa/anti-IIa activity
Bemiparin
3600
8.0
Nadroparin
4300
3.3
Reviparin
4400
4.2
Enoxaparin
4500
3.9
Parnaparin
5000
2.3
Certoparin
5400
2.4
Dalteparin
5000
2.5
Tinzaparin
6500
1.6
Table 1 Molecular weight (MW) data and anticoagulant activities of currently ava
ilable LMWH products. Adapted from Gray E et al. 2008.[8]
Manufacturing process[edit]
Figure 1: The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anh
ydromannitol
Various methods of heparin depolymerisation are used in the manufacture of low-m
olecular-weight heparin.[2] These are listed below:
Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ar
deparin (Normiflo)
Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin
(Sandoparin)
Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the m
anufacture of enoxaparin (Lovenox and Clexane)
Oxidative depolymerisation with Cu2+ and hydrogen peroxide. Used in the manufact
ure of parnaparin (Fluxum)
Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of t
inzaparin (Innohep and Logiparin)
Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (F
ragmin), reviparin (Clivarin), and nadroparin (Fraxiparin)
Deaminative cleavage with nitrous acid results in the formation of an unnatural
anhydromannose residue at the reducing terminal of the oligosaccharides produced
. This can subsequently be converted to anhydromannitol using a suitable reducin
g agent as shown in figure 1.
Figure 2: UA(2S)-GlcNS(6S)
Likewise both chemical and enzymatic beta-elimination result in the formation of
an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as s
hown in figure 2.

In addition, low molecular weight heparins can also be chemoenzymatically synthe

sized from simple disaccharides.[9]
Differences between LMWHs[edit]
Comparisons between LMWHs prepared by similar processes vary. For example, a com
parison of Dalteparin and Nadroparin suggests they are more similar than product
s produced by different processes. However, comparison of enoxaparin and tinzapa
rin shows they are very different from each other with respect to chemical, phys
ical, and biological properties.
As might be expected, products prepared by distinctly different processes are di
ssimilar in physical, chemical, and biological properties.[2][4] Hence a slight
change in the depolymerisation process could result into substantial variation o
f the structure or composition of a given LMWH.
Therefore for every LMWH, a strictly defined depolymerisation procedure is neede
d to guarantee the sameness of the final LMWH product and the predictability of
clinical outcomes. LMWHs, as biological origin products, rely on stringent manuf
acturing procedures to guarantee the absence of biological or chemical contamina
tion. It is therefore critical to adopt stringent manufacturing practices, throu
gh rigorous quality assurance steps, to ensure the highest quality of the produc
ed LMWHs and to guarantee patient safety. These quality assurance steps, to be e
ffective, need to be implemented from the raw material (crude heparin) collectio
n to the final LMWH product.
Due to these identified and potential differences, several organizations, includ
ing the United States Food and Drug Administration, the European Medicines Agenc
y, and the World Health Organization, regard LMWHs as individual products that s
hould not be considered as clinically equivalent, as they differ in many crucial
aspects such as molecular, structural, physiochemical, and biological propertie
s.[10][11][12] According to international guidelines, the choice of an individua
l LMWH should be based on its proven clinical safety and efficacy for each indic
ation.[13]
Differences from unfractionated heparin[edit]
Differences from heparin (i.e. "unfractionated heparin") include:
Average molecular weight: heparin is about 15 kDa and LMWH is about 4.5 kDa.[14]
Less frequent subcutaneous dosing than for heparin for postoperative prophylaxis
of venous thromboembolism.
Once or twice daily subcutaneous injection for treatment of venous thromboemboli
sm and in unstable angina instead of intravenous infusion of high dose heparin.
No need for monitoring of the APTT coagulation parameter as required for high do
se heparin.[15]
Possibly a smaller risk of bleeding.
Smaller risk of osteoporosis in long-term use.
Smaller risk of heparin-induced thrombocytopenia, a potential side effect of hep
arin.
The anticoagulant effects of heparin are typically reversible with protamine sul
fate, while protamine's effect on LMWH is limited.
Has less of an effect on thrombin compared to heparin, but about the same effect
on Factor Xa.
Clinical uses[edit]
Because it can be given subcutaneously and does not require APTT monitoring, LMW
H permits outpatient treatment of conditions such as deep vein thrombosis or pul
monary embolism that previously mandated inpatient hospitalization for unfractio
nated heparin administration.
Because LMWH has more predictable pharmacokinetics and anticoagulant effect, LMW

H is recommended over unfractionated heparin for patients with massive pulmonary

embolism,[16] and for initial treatment of deep vein thrombosis.[17] Prophylact
ic treatment of hospitalized medical patients with LMWH and similar anticoagulan
ts results in a 53% reduction of risk for symptomatic deep vein thrombosis.[18]
More recently these agents have been evaluated as anticoagulants in acute corona
ry syndrome (ACS) managed by percutaneous intervention (PCI).[19][20]
The use of LMWH needs to be monitored closely in patients at extremes of weight
or in-patients with renal dysfunction. An anti-factor Xa activity may be useful
for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasi
ble in patients that have end-stage renal disease. LMWH can also be used to main
tain the patency of cannulae and shunts in dialysis patients.
Venous thromboembolism and cancer[edit]
The CLOT study, published in 2003, showed that, in patients with malignancy and
acute venous thromboembolism, dalteparin was more effective than coumadin in red
ucing the risk of recurrent embolic events.[21] Use of LMWH in cancer patients f
or at least the first 3 to 6 months of long-term treatment is recommended in num
erous guidelines and is now regarded as a standard of care.[22]
Antidote[edit]
In clinical situations in which the antithrombotic effect of LMWHs needs to be n
eutralized, protamine is used to neutralize heparin by binding to it.[20] Studie
s in animals and in vitro studies have demonstrated that protamine neutralizes t
he antithrombin activity of LMWHs, normalizing the aPTT and thrombin time. Howev
er, protamine appears to only partially neutralize the anti-factor Xa activity o
f LMWH. Because the molecular weight of heparin impacts its interaction with pro
tamine, it is likely that the lack of complete neutralization of anti-factor Xa
is due to a reduced protamine binding to the LMWHs moieties in the preparation.
Protamine is a medicine that requires a high level of caution when used.
Contraindications[edit]
The use of LMWHs should be avoided in patients with known allergies to LMWHs, he
parin, sulfites or benzyl alcohol, in patients with active major bleeding, or pa
tients with a history of heparin-induced low blood platelet count (also known as
heparin-induced thrombocytopenia or HIT). High treatment doses are counter indi
cated in acute bleedings such as cerebral or gastrointestinal haemorrhage.
Precautions[edit]
LMWHs should be used with extreme caution in patients undergoing any procedure i
nvolving spinal anaesthesia/puncture, in conditions with increased risk of bleed
ing or in patients with a history of heparin-induced thrombocytopenia.
Side effects[edit]
The most common side-effects include bleeding, which could be severe or even fat
al, allergic reactions, injection site reactions, and increases in liver enzyme
tests, usually without symptoms.[23] The use of heparin and LMWHs can sometimes
be complicated by a decrease in platelet count, a complication known as Heparin
Induced Thrombocytopenia.13 Two forms have been described: a clinically benign,
non-immune and reversible form (Type I) and a rare, more serious immune-mediated
form or Type II. HIT Type II is caused by the formation of auto antibodies that
recognize complexes between heparin and platelet factor 4 (PF4) and is therefor
e associated with a substantial risk of thrombotic complications. The incidence
is difficult to estimate but may reach up to 5% of patients treated with UFH or
about 1% with LMWH.[23]
Generics[edit]
The patents of LMWHs are expiring.[when?] Therefore, generic, or biosimilar, LMW
Hs are being produced by several companies. The first generic was approved by th

e Food and Drug Administration in July 2010. FDA has used 5 analytical and pharm
acological criteria to establish the authenticity of a generic LMWH, without req
uiring clinical studies in patients.[24]
The European Medicines Agency considers LMWHs as biological products in nature c
onsisting of not fully characterised polysaccharide mixtures. Therefore the EMA
requires that the efficacy and safety of a biosimilar LMWH candidate be establis
hed in a clinical trial with patients at high risk for thromboembolism.[citation
needed]
References[edit]
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