Heparin is commonly administered anticoagulant in emergency. It was discovered in 1912 by a medical student at John Hopkins Institute, while experimenting on thromboplastic drug. It was extracted from the liver.
Heparin occurs naturally in human mast cells in lungs and liver. The concentration is low and physiological anticoagulant effects are not marked.
It is prepared conveniently from two sources (animal sources):
- Bovine lung
- Porcine intestinal mucosa
Organic acid with electronegative charge. It is made of hydrated mixture of sulphated mucopolysaccharide.
Two disaccharide units form polymers and are:
- D-glucosamine-L-iduronic acid
- D-glucosamine-D-glucuronic acid
They form chains of variable lengths; some small, some large, as number of saccharide units are variable.
If smaller in length called low molecular weight heparin (LMWH)
If long polymer of larger length called high molecular weight heparin (HMWH).
It is a heterogenous mixture containing both high molecular weight and low molecular weight heparin. Heparin is normally present in this form.
Normal unfractionated heparin is of 5000-30,000
Low molecular weight heparin is of 1000-10,000
They have differences in pharmacokinetics and mechanism of action.
Mechanism of Action
Normally existing antithrombin binds factors II, IX and X, acting as suicide substrate and inactivates them.
Once antithrombin binds, it is used up along with the factors. This process is slow and is accelerated by administration of heparin. Heparin acts as accelerating catalytic template. Its binding causes conformational change in antithrombin, exposing its active sites. Clotting factors attach. The reaction is accelerated 1000 times (no. of units accelerated/unit time).
For normal binding, only requires structure of pentasaccharide polymer on heparin. When present, then heparin binds.
30% of commercially prepared heparin has these units. Thus 1/3 is biologically active.
For binding thrombin, heparin requires more than 18 monosaccharide units, if length is more than this, only then the heparin binds. If less than this, thrombin cannot bind but factor X still binds, requiring only pentasaccharide units.
By unfractionated heparin, thrombin can be inactivated.
By low molecular weight heparin, thrombin cannot be inactivated. Heparin has action only by inhibiting factor X.
Administration and Monitoring
Heparin is available in different forms.
- Sodium and Calcium salts for in vivo administration
- Lithium salts for in vitro administration (not used in humans because of toxicity)
As heparin contains a heterogenous mixture of different length chains, there is poor relation between concentration and therapeutic effect. In such biological preparations, bioassays are used for standardization instead of molecular weight.
Unit of Heparin
Thus given in biological units
“1 unit of heparin is equal to the amount which prevents 1 ml of citrated sheep plasma from clotting, for 1 hour after additional of 0.2 ml of 1:100 CaCl2. This is called biological standardization.
1 gram standardly contains 120-150 units, which is diluted on administration.
a. Can be I/V infused
b. as bolus form in emergency
c. long term intermittent subcutaneous administration
APTT Activated Partial Thromboplastin Time (Intrinsic and Common)
Therapeutic effects are monitored through APTT, time taken by plasma to clot from which Ca+2 is removed by EDTA then recalcified and added with negatively charged phospholipids and kaolin. Normal APTT time is 26-33 seconds. In patients should be 1.5-2.5 times normal. If more than 3 times, there are large chances of bleeding.
Other tests used include:
- Protamine titration (0.2-0.4 units/ml)
- Antifactor Xa (0.3-0.7 units/ml)
Pharmacologically stable, with weight adjusted dosage. Levels are monitored in certain patients with:
- renal problems
- hepatic problems
Only antifactor Xa monitoring test is performed. (0.5-1 unit/ml for BD use, 1.5 unit/ml for OD use)
|Pharmacokinetic profile||Low bioavailability||High bioavailability|
|Dose||More frequent||Less frequent|
|Affinity||Same for all factors (little higher for AT)||High for Xa|
|Neutralization||Protamine sulfate||Incomplete/not specific|
|HIT||Increased chances||Decresaed chances|
|Expression||In units||In grams|
|Levels||Determined by protamine titrationAlso anti-Xa units||Anti-Xa units|
|Natural||Derived from UFH|
|Administration||I/V or I/M||I/V|
Heparin is a large molecular weight, polar compound which is not absorbed by oral route of administration.
Unfractionated (units) is given I/V, subcutaneously or in bolus form. In people who cannot tolerate warfarin, intermittent subcutaneously given.
LMWH has low molecular weight, subcutaneously administered once or twice daily.
Why heparin cannot be given orally?
i. it is a big molecule
ii. it is mucopolysaccharide
iii. it is negatively charged
b. Half Life
Dose determines the half life.
100 units/kg Half life 1 hour
More than 800 units/kg Half life 5 hours
Thus there is direct relation between dose and half life.
LMWH has longer half life.
c. Heparin does not cross BBB or placenta. It is safe in pregnancy. Unfractionated heparin is well established for pregnancy. LMWH is less established.
Reticuloendothelial system degrades heparin. Heparinase is present in liver which converts polymers into small chains, which are excreted in urine.
Unfractionated heparin has low bioavailability 20-30%, subcutaneously
Low molecular weight heparin has 70-90% bioavailability, given once or twice daily.
On repeated administration
- Anti-platelet –in very high doses inhibits platelet aggregation so affects bleeding time
- Lipemia clearing –in large doses release of lipoprotein lipase occurs from endothelial lining and tissues, which acts on lipids (TGs), converting them into free fatty acid and glycerol. Heparin has more effects on post prandial lipemia.
1. Treatment & prevention of thromboembolism
Thrombolytic in cases of thrombus, but once formed, extension also occurs. To prevent this extension, anticoagulants are given.
I/V bolus, 5000 units of which are given I/V.
2. Concurrent oral t/m
3. Short / long-term t/m
Heparin is also given in short term treatment but if others cannot be given, it is used subcutaneously for long term.
– Unstable angina / acute MI
– Pulmonary embolism
– Coronary angioplasty / stent
– Vascular surgery
– Selected DIC cases
– Rheumatic valvular disease / Prosthetic valves
– Atrial fibrillation
– Peripheral arterial occlusion
– Extracorporeal circulation
– PICC line (peripherally induced cerebral cancer)
– Hip replacement surgery -prophylactically
1. Bleeding (most common hemeaturia)
Bleeding occurs in 1-5% of the patients on administration of heparin
It can be avoided by proper patient selection. In high risk individuals it is contraindicated.
Even if administered, careful monitoring with repeated APTT and other assays should be done.
In cases of mild bleeding, only discontinuation of heparin is required, the effects subside immediately.
In cases of intense bleeding, protamine sulphate is used, which is antagonist.
a. Chemistry – basic polypeptide, having positive charge.
b. Mechanism of Action
It complexes with the negatively charged heparin, and thus neutralizes it.
c. Administration – 1mg – 100 U of heparin
d. Neutralization of LMWH is incomplete, and does not have effect on the synthetic derivative of protamine sulphate, Fondaparinux.
i. Overdosage of heparin
ii. When heparin is used in surgical operations, after operation to reverse the effects.
2. Heparin induced thrombocytopenia (HIT)
a. Incidence – 1-4% of people.
Incidence is less with low molecular weight heparin.
iii. Pediatric / pregnant
In certain patients, immune response occurs and heparin binds platelet factor IV, a complex is formed. Antibodies are formed against this complex; platelet aggregation takes place, leading to formation of thrombi and decrease in platelet count (thrombocytopenia).
d. Monitoring & diagnosis
– Platelet count after 5-7 days of administration, if new thrombus forms, thrombocytopenia occurs
– Heparin-dependent platelet activation assay
– Antibody assay
Incidence is low with LMWH, we go for this if patient is a known case of HIT or if cross-immunity occurs, direct thrombin inhibitors are used or Fondaparinux
–leading to fever, rashes, urticaria, anaphylaxis
4. Transient elevation of LFTs
On prolonged usage, leads to:
6. Osteoporosis –due to demineralization
7. Aldosterone synthesis inhibition – leading to hyperkalemia
8. Mineralocorticoid deficiency
9. Lipid clearance –releases LPL increasing clearance of post prandial lipidemia
Some patients develop heparin resistance, 3 phenomena are involved:
- Deficiency of antithrombin or change in antithrombin
- Elevated levels of plasma proteins, other than antithrombin, to which heparin binds
- Increased clearance of heparin by body
1. Bleeding tendency, Hemophilia, thrombocytopenia
2. Platelet abnormality or clotting factor defects, Purpura
3. Hypersensitivity to heparin
4. Recent surgery or lumbar puncture or regional anesthetic block
5. Bleeding peptic ulcer
6. Threatened abortion
8. Severe hypertension
9. Intracranial hemorrhage
10. Infective endocarditis
11. Active T.B
12. Ulcerative lesions of GIT
13. Visceral carcinoma
14. Advanced renal/hepatic disease
Differences – Heparin Warfarin
|Chemistry||Sulfated mucopolysaccharideN-acetyl glucosamine and L-iduronic acid and D-glucuronic acid||Coumarin derivative|
|Mechanism of action||Acts through antithrombin III||Acts by inhibition of Epoxide reductase|
|Neutralization with protamine||Yes||No|
|Incidence of adverse effects||More||Less|
|Source||Natural||SyntheticSpoiled meat clover|
|Antidote||Protamine sulphate||Vit. K (phytonadione)FFP|
|Duration of Action||2-4 hours||1-7 days|
|Activity||In vivo and in vitro||In vivo only|
|Metabolite||Heparinase||Oxidation and Reduction|
|Monitoring||APTTAnti Xa units||PTINR|
|Enzyme Induction||No||Enzyme inducer|
|ROA||I/V or S/C, not oral||Oral|
|Onset||Immediate||Delayed up to 1-2 days|
|Lipolytic effect||Present||Not present|
|Uses||Induction therapy||Maintenance therapy|
|Drug Interactions||Not significant||Significant|