Heparin was invented accidentally by a 26 year old , Jay McLean, a pre clinical medical student in 1916 .It was one of the greatest discovery in medicine .It helped us prevent blood from clotting.Frozen blood inside human circulatory system constituted one of important mechanisms of human death.This ranged from acute myocardial infarction to cerebral thrombosis .
As we decoded the mechanism of action of heparin , it was clear it bound to the naturally occurring molecule antithrombin 3 and effectively blocks the intrinsic coagulation mechanism and thus behaves as an important anticoagulation agent.
How heparin acts as a thrombolytic agent ?
We know , our hematological system has a powerful natural fibrinolytic mechanisms to protect against unwarranted( pathological ) intravascular coagulation. This is mediated by anti thrombin, protein C , protein S , plasminogen system etc . Natural concentrations of tissue plasminogen activator (Tpa) also help in lysing intravascular clots.
There is a constant , delicate balance between procoagulant , anticoagulant and antifibrinolytic molecules .Intra vascular clots occur when a vascular injury triggers a clot formation and the clinical event occurs.
But, once insulted , the circulating blood does not remain a silent spectator . It is constantly on the look out for a foe to attack the thrombus that is interfering with its natural flow . Antithrombin 3 is one such molecule. Success of lysis depends on the power of natural forces. There are hundreds of episodes of microlysis that take place every day (Which happen without our knowledge ) .In patients with vascular disease these episodes are likely to be further more.
What does Intravenous heparin in high doses do ?
Heparin immediately blocks of powerful procaogualtion activity .One of the important heamatological principle is “Thrombus begets thrombus “. It is a vicious cycle. This is immediately tackled by heparin .The powerful trigger of thrombus induced thrombus propogation is shut off .
This makes a 2 cm sized clot to remain in 2cm . After making sure of this , the blood in the immediate vicinity start percolating the clot. The heparinised blood switches to a pro- fibrinolytic mode as the balance of forces is fully tilted in favor of fibrinolysis or thrombolysis.
Is there clinical evidence to call heparin as thrombolytic agent ?
Yes . Contrary to the popular scientific principle we have only clinical evidence . laboratory evidence is not convincing as heaprin lyses clot only in vivo . Since , evidnece based medicine requires laboratory evidence we hesitate to call this as thrombolytic agent !
It has been a strong clinical observation , many major intracardiac or intravascular clots regress in size
(or totally dissolve ) with intensive heparin regimen .The effect is seen in 48-72 hours.Some times in first 24 hours.
What are the clinical situations where heparin has successfully lysed the clots*?
- Pulmonary embolism
- LV clot
- LA clot
- Cortical venous thrombus
- Deep vein thrombosis
- Coronary thrombosis**
- Portal vien thrombois
- Renal vein thrombois
* Plenty of case reports available for each condition
** Sustained micro thrombolysis is the major mechanism of benefit in NSTEMI
If it is true , heparin dissolves thrombus , why it is not called as thrombolytic agent ?
Why not ? You decide yourself !
How does heparin compares with the great thrombolytic agents* like Strepotiknase, Urokinase,Altepase, Retepalse , Teneckteplase (TNK TPA) ?
Many (Rather most . . .) would consider it , as foolish , to compare heparin with these agents .But the fact of the matter is except for streptokinase there is no comparison studies available. Attempting such a study in humans will be considered unethical. Without a proper scientific data heparin can not be ignored either.
But , some of the control groups in major studies of thrombolysis through some light !
In pulmonary embolism thrombolytic agents and heparin have similar effects on intrapulmonary thrombus
An important point to remember here is , the powerful thrombolyic agents are administered in as short duration (Bolus / 1 hour infusion ) .This is invariably followed by heparin infusion . Why do we do that ? because we know it is important . One may never know , how much of lysis is done by the trhombolytic agent and how much by heparin .
if you analyse the data success rate of thrombolytic agents are infact attributable to the follow up heparin
Thrombolytic agents piggy packs on heparin and claims the credit for thrombolysis *
In thrombolytic therapy , heparin is considered as an adjunct to streptokinsae but in reality streptokinase may an adjunct to heparin
Importance of heparin In Acute MI (HEAP Trial)
It should be realized there is a time window for heparin too . . . early administration can have great benefit
Early heparin prevents formation of core of the clot .The importance of acute administration of aspirin in suspected STEMI is well recognized by paramedics . A bolus of heparin (10000 u) immediately could have great impact on the outcome as well .Paradoxically we talk more about emergency PCI, on transit TPA etc . . . We have seen number of patients referred with STEMI from suburban areas traveling for hours with out any anticoagulants but promptly getting sorbitarate tablets ! Unfortunately prehospital heparin is rarely stressed in literature .
Watch the video : Heparin : The forgotten hero
Final message
- Heparin is an under rated drug as a thrombolytic agent.
- Just because it has no direct action on thrombus it is considered an inferior agent.( One other reason for it to be considered inferior , it is very cheap !)
- Heparin too , has a time window effect in acute MI (Class 3 evidence ie wide clinical experience)
- It’s usage should be early and liberal , especially in out of hospital setting in vascular emergency.
Note of caution : This article is not meant to defame the thrombolytic agents.It only stresses a point that , heparin has also a role , as a thrombolytic agent. *Whenever rapid thrombolysis is required in life threatening situations specific thrombolysis is indicated as per guidelines.
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Dr.S.Venkatesan MD 