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Posts Tagged ‘heparin as a thrombolytic agent’

The news that wasn’t . It is January 1 st 2016 .

NBC reports from Karolinska ,Sweden , Heparin  the wonder drug  has been reclassified as a thrombolytic agent and Jay Maclean  who doscovered this drug in 1916  is awarded the Nobel prize in Medicine posthumously on the 100th  anniversary of  discovery  of  the glorius drug ! The entire Hopkins  campus at Baltimore has erupted into a  non stop party tonight !

Hopkins_hospital

The Majestic Hopkins at Baltimore  : This  monumental hospital is home to 18 Nobel Laureates in Medicine and Jay Maclean is the most famous for missing it !

 

And now to the True story

Heparin   the wonder  drug  was discovered by Medical student Jay Maclean in 1916 at the Jhon Hopkins when the rest of the world was   fighting the  world war 1 . It was separated from the cannine liver and the name Heparin was coined by Maclean’s Guide at Hopkins  William Henry Howell . Even though it was invented early  it was available for human use only in 1936  when Swedish company Vitrum AB produced it .Since then   It has a very distinguished career and still going strong after 100 years.

The only regret is Dr Maclean  narrowly missed  the  Noble prize for this great invention .I still believe he should  get it on its 100th   anniversary  in 2016.

A partial  “curriculum vitae”  of Heparin.

Heparin is an  Anti-thrombin 3 agonist .It blocks the pro thrombotic cascade and hence a powerful anticoagulant. Further ,it completely tilts the balance towards fibrinolytic  system.Hence the natural forces take over and  start dissolving the thrombus  in due course.

So Heparin is an indirect thrombolytic agent .No second thoughts on this.

But a century old teaching  goes like this  . . .

Heparin prevents fresh clot formation . . . but it do not have any action on already formed clots “

What do you infer from this statement . Do you agree ?

Role of Heparin in real clinical scenario

Heparin is the key drug in all acute coronary syndromes when the  coronary artery goes for sudden thrombosis . An un estimated one  million prescriptions are done every day world wide for this indication alone.

(*And mind you it does have a  significant  impact  on already formed thrombus as well ! Ref : HEAP Pilot  study  )

Apart from this.

1. Heparin dissolves post MI LV  apical clot over a period of  few  weeks.
2.Heparin is very effective in most cases of sub-massive pulmonary embolism
3.Heparin infusion has opened up many near total coronary occlusion
4.Heparin clears the micro vascular from thrombotic debri in lungs in CTEPH.
5.Heparin dissolves  deep vein thrombosis
6.Heparin almost result in complete cure and clears cortical venous thrombosis

7.Heparin is exceedingly successful in clearing   thrombosis in placental micro-circulation (APLS) which  threatens the  fetus with IUGR.

Al these clinical events are well documented and well appreciated.

Still we feel awkward to call the heparin as thrombolytic agent

Why ?
It is almost a  scientific non- sense .We think a thrombolytic should  show it’s action in vivo in the lab and it should shrink the clot on a petri dish !  What a wrong  mind set ! We have  tell-tale evidence  for heparin’s  magic act of vanishing clots   inside the human vascular tree (However organized  it may be ! ) .

I struggle to understand  , why  our scientific  mind does not want to give credit to a drug  which does a neat job of  dissolving  clots  through its  indirect action . Is it a curious bias  ?  or is it an act of  ignorance  or  just a nomenclature  error  in the  foundations of therapeutic  pharmacology ?

At this point one should  realise  streptokinase  too does not act directly on the clot.It acts indirectly through a TPA-enzyme complex.So can we call it an  non thrombolytic agent ?

Final message

  • Heparin is indeed a thrombolytic agent , through  a chain  of action and reaction  which  it confers to the naturally occurring lytic system.
  • In vivo ,this  indirect  lytic action can be  powerful than some of the direct acting thrombolytic agents .Not only that, it lacks the side effects  vested with direct  lytics.
  • The only issue is  , heparin is a slowly acting indirect thrombolytic it has to be given long-term or on an infusion .
  • It is right time the pharmacologists  and nomenclature authorities  include heparin as indirect thrombolytic drugs.

Read further

Heparin a forgotten Hero

 

Reference

1.High Dose Bolus Heparin as Initial Therapy Before Primary Angioplasty for Acute Myocardial Infarction: Results of the Heparin in Early Patency (HEAP) Pilot Study Freek W.A Verheugt,  Aylee Liem, Felix Zijlstra,J Am Coll Cardiol. 1998;31(2):289-293.

3.Esteves  FP, Braga  JC, Latado  A; Confirmation that heparin is an alternative to promote early reperfusion in acute myocardial infarction. the CHEAPER study [abstract]. Circulation. 94 (Suppl I) 1996:I-553

 

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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  .

heparin3

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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