Heparin

History

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.

Source

It is prepared conveniently from two sources (animal sources):

Bovine lung
Porcine intestinal mucosa

Chemistry

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).

Unfractionated Heparin

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)

Standardization

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)

LMWH

Pharmacologically stable, with weight adjusted dosage. Levels are monitored in certain patients with:

renal problems
hepatic problems
obese
pregnant

Only antifactor Xa monitoring test is performed. (0.5-1 unit/ml for BD use, 1.5 unit/ml for OD use)

	Unfractionated Heparin	LMW Heparin
Weight	High (300-5000)	Low
Pharmacokinetic profile	Low bioavailability	High bioavailability
Dose	More frequent	Less frequent
Affinity	Same for all factors (little higher for AT)	High for Xa
Monitoring	Required	Not required
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
Cost	Cheaper	Costly
Administration	I/V or I/M	I/V

Pharmacokinetics

Heparin is a large molecular weight, polar compound which is not absorbed by oral route of administration.

a. 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.

d. Elimination

Reticuloendothelial system degrades heparin. Heparinase is present in liver which converts polymers into small chains, which are excreted in urine.

e. Bioavailability

Unfractionated heparin has low bioavailability 20-30%, subcutaneously

Low molecular weight heparin has 70-90% bioavailability, given once or twice daily.

Tachyphylaxis

On repeated administration

Pharmacological Actions

Anti-coagulant
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.

Clinical Uses

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

Along with heparin, orally acting warfarin is started straight away, which requires 4-5 days to act, till the time warfarin takes up whole function.

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

– DVT

– Pulmonary embolism

– Coronary angioplasty / stent

– Vascular surgery

– Selected DIC cases

– Rheumatic valvular disease / Prosthetic valves

– Atrial fibrillation

– Peripheral arterial occlusion

– Extracorporeal circulation

– Dialysis

– PICC line (peripherally induced cerebral cancer)

– Hip replacement surgery -prophylactically

Adverse effects

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.

Management

In cases of mild bleeding, only discontinuation of heparin is required, the effects subside immediately.

Protamine sulfate

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.

e. Use

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.

i. LMWH

Incidence is less with low molecular weight heparin.

ii. Bovine

More common

iii. Pediatric / pregnant

Rare

b. Pathophysiology

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).

c. Outcome

Thrombotic 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

e. Management

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

3. Hypersensitivity

–leading to fever, rashes, urticaria, anaphylaxis

4. Transient elevation of LFTs

On prolonged usage, leads to:

5. Alopecia

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

Heparin resistance

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

Contraindications

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

7. HIT

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
Site	Blood	Liver
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
Pregnancy	Yes	No
Drug Interactions	Not significant	Significant