Introduction to Heparin

Heparin is a sulfated polysaccharide used as an anti-coagulation drug, administered to prevent blood clot formation in case of any surgery and various other medical procedures. Heparin is a naturally occurring complex of monosaccharides and polysaccharides in the body. It is mainly produced in the tissue of the lungs and liver. Its molecular weight ranges from 3000 Da to  30000 Da.


Pharmacology of Heparin

Pharmacology refers to the mechanism of action of the drugs. Heparin is an anticoagulant, which means it prevents blood clots when administered into the body. Heparin achieves this by binding with the antithrombin III (AT). AT has heparin receptors, when heparin binds to the receptor, it causes conformational changes in the protein AT. Heparin has a specific pentasaccharide sulfation sequence through which it binds to the receptor. Antithrombin III inactivates prothrombin, inactivated prothrombin can not be converted in thrombin which in turn can not be used to convert fibrinogen into fibrin. Fibrin is the molecule that Comparative Clots the blood with the help of blood clotting factors. For thrombin inactivation, a ternary complex is formed where thrombin binds to another site of heparin, thrombin, antithrombin III, and heparin are the constituents of this ternary complex. Heparin associates with thrombin through electrostatic interaction, it is crucial for the inactivation of thrombin. Heparin also inactivates another protein named factor Xa, it does not require direct association with heparin for its inactivation, rather it is inactivated by the conformational change in AT brought by heparin binding.

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Types of Heparin

There are two types of heparin, low molecular weight heparin (LMWH)  or fractionated heparin, and the second type unfractionated heparin (UFH), these are also known as standard heparin. LMWH is constituting several groups of drugs, for example, enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin. These drugs are rapidly taking the place of the standard heparin. 

Another class of newly synthesized heparin is also in light, these are synthetic heparin called fondaparinux.


Fractionated Heparin or LMWH (Low Molecular Weight Heparin)

It binds and accelerates the activity of AT similar to the standard heparin but it has a preferential, and prolonged effect on factor Xa. LMWH has comparatively less ability to bind with the thrombin and inhibit their production, it also has a reduced binding affinity with plasma proteins and endothelial cells because of its smaller size. This decrease in affinity leads to low binding and thus there is a significant amount of free LMWH present in the body leading to increased bioavailability of about 85-99%. This increased bioavailability leads to a more prominent anticoagulant response, prolonged duration of action as compared to heparin, and lesser inter-patient variability.


Fondaparinux

It binds to antithrombin III, AT has high specificity which results in no or minimal unwanted binding with other plasma proteins. Fondaparinux has a high binding affinity with AT, its binding enhances the AT activity by 300-fold, specifically the anti-factor Xa ( inhibition of factor Xa) activity. It does not have any direct effect on thrombin, also it has high bioavailability after subcutaneous administration. 


Unfractionated Heparin or Standard Heparin

Binds to and potentiates the actions of antithrombin (AT) to inactivate factor Xa and prevent the conversion of prothrombin to thrombin, as well as prevent the conversion of fibrinogen to fibrin. Standard heparin also binds to a variety of plasma proteins which results in decreased bioavailability of the drug after heparin subcutaneous administration. The unwanted binding between plasma protein and heparin also results in an unpredictable dose-response relationship.


Comparative Study of Features of Heparin, LMWH, and Fondaparinux.

Features 

Heparin 

LMWH

Fondaparinux 

Source 

Biological 

Biological 

Synthetic 

Molecular weight

15000 Da

5000 Da

1500 Da

Bioavailability 

30%

90%

100%

Renal excretion 

No 

Yes 

Yes 

Thrombocytopenia 

<5%

<1%

<1%

Antidote effect

Complete 

Partial 

None 


Heparin Use Apart From Anticoagulant

Heparin is well known for its application as an anticoagulant in the healthcare industry, but apart from it is also used like the following-

  1. Inhibitors of adhesion molecules

  2. Inhibitors of cytokines.

  3. Inhibitor of complement activation

  4. Inhibitor of angiogenesis (formation of new blood vessels). 

  5. It also acts as an anti-inflammatory drug.

  6. It also has some potential applications in cancer therapy.


Adverse Effects of Heparin

Common side effects of heparin administration include the following,

  1. Bleeding 

  2. Allergy or hypersensitivity reactions

  3. Irritation on the site of administration

  4. Heparin-induced thrombocytopenia.

  5. Osteoporosis

  6. Skin necrosis

  7. Anaphylaxis. 


Heparin Resistance

Heparin resistance can be described as the condition where a patient is unresponsive or shows a very low response to the heparin administration. Alternatively, it can also be described as the requirement of a high dosage of the drug to achieve therapeutic benefits. Heparin resistance can be of two types: true resistance and pseudo resistance. True resistance is the case where a patient has low activated partial thromboplastin time (APTT) which reflects the low concentration of thromboplastin. Pseudo Resistance is the condition where a patient shows significant anticoagulation despite the low value of activated partial thromboplastin time (APTT).

Reasons For Heparin Resistance

Given below are some of the reasons for heparin resistance

  1. Deficiency of antithrombin

  2. Increased clearance of the heparin molecule, which results in low bioavailability of the drug.

  3. An increase in the concentration in heparin-binding protein, which eventually leads to low bioavailability of heparin.

  4.  High concentration of fibrinogen in the blood.


The Risk Associated With Heparin Resistance

There are various harmful effects of heparin resistance some of which are reduced antithrombin synthesis, which can be genetic or acquired. This reduced synthesis will lead to an increased amount of blood clots during any injury. Another risk is accelerated AT clearance which results in deficiency of AT in the body. The high preoperative concentration of plasma cells, which causes abnormality in the immune response of the body against potential pathogens or injury.

FAQs (Frequently Asked Questions)

1. When is Heparin Medication Administered and What is the Site of Heparin Administration?

Ans- It is an anticoagulant drug, it is administered to prevent the formation of blood clots during surgery or other medical procedure. It is administered subcutaneously.

2. What are the Types of Heparin?

Ans- There are 3 types of heparin, standard heparin, fractioned, and fondaparinux.

3. State the Antagonist of Heparin.

Ans- Protamine is the name of heparin antagonist.