A Study: Heparins in CTVS in detail.pptx

Heparin in Cardiovascular Studies

1. Heparin By Deepanshu Pilwan MSc Cardiac Perfusion 2nd year Presented to Dr Ujjwal Chowdhury

2. What is Heparin? Heparin is an anticoagulant (blood thinner)that prevents the formation of blood clots. Heparin is used to treat and prevent blood clots in the veins, arteries, or lung. Heparin is also used before surgery to reduce the risk of blood clots. the molecule heparin is heterogeneous of un branched polysaccharide chains Alternating monosaccharide units of L-iduronic acid and D-glucosamine one third of the polysaccharide chain contain a specific antithrombin binding Penta saccharide sequence. Heparin was accidentally discovered in 1918 by Jay McLean , a second-year medical student working at the Department of Physiology.

3. Structure of Heparin Heparin belongs to glycosaminoglycan family it is a polysaccharide It is released by mast cells and basophils. Lower sulfur content dangles tantalizing from endothelial cell membrane to attract circulating Antithrombin lll irresistibly and potentiate thrombin inhibition. Molecular weight 3000 to 40000 Da. Mean molecular mass approximately 15000 Da. Heparin is a strongest macromolecular acid.

4. Tissue Source and Commercial Preparation Heparin originally isolated from liver extracts intestinal mucosa and lung tissue represent the most common commercial source Mucosal heparin tends to have a mean molecular weight, more cross linked polysaccharide structure and lower cost than lung Heparin Mucosal heparin from pigs ( porcine mucosal Heparin) Lung Heparin from cattle ( bovine lung Heparin) Both porcine and bovine widely used as Anticoagulation for cpb effective anticoagulation and prevent thrombosis Mucosal heparin can neutralized with 25% to 30 % less protamine than can lung Heparin

5. Forms of Heparin Unfractionated heparin (UF) Low molecular weight heparin (LMW) Unfractionated heparin is relatively safe, easy to use has a fast onset of action and is measurable and reversible. It is also cost effective.

6. Mechanism of Action Heparin induces anticoagulation primarily by potentiating the activity of AT lll ,plasma glycoprotein with molecular weight 58000 Da Heparin attaches to a lysine residue on AT III, altering AT lll configuration and more attractive to thrombin Heparin therefore increases the thrombin inhibitory potency of circulating AT lll by a factor of 1000 or more Converts fibrinogen to fibrin Thrombin activates cofactors Vlll,V and increase the rate of fibrin clots AT lll also inhibits factor lXa,Xa,Vlla,kallikrein and plasmin Unfractioned Heparin inhibits thrombin quickly then inactivates Xa,lXa,Xla,and Xlla Thrombin inhibition involves transient simultaneous Heparin binding to AT lll and thrombin which requires large oligosaccharide chain Factor Xa inhibition involves Heparin binding to AT lll Heparin also binds to cofactor ll a GP of 65000 Da that inactivates thrombin independently of AT lll

7. Pharmacokinetic Heparin IV administration After central venous injection of Heparin bolus the onset of maximal ACT prolongation in the radial artery occurs within 1 min. Heparin action peaks 10 to 20 mins after administration in cardiac surgery patients. Prolongation of ACT by other factors such as hemodilution and hypothermia. The onset of action of Heparin is much faster and maximal ACT prolongation probably occurs in less than 5 minutes. Anticoagulant effect of Heparin occurs 3 to 13 mins after the peak effect. No oral route

8. Intravenous - Immediate onset of action Subcutaneous route - delayed by 1-2hrs Half life 1-5 hrs Anticoagulant of choice in pregnancy

9. Dosing Initial doses usually ranging from 300 to 400 IU/KG Maintenance dose of 50 to 100 units /kg given every 30 mins or infrequently every 2 hours The priming fluid used for the extracorporeal circuit usually contained 10000 to 20000 units of Heparin

10. Distribution Heparin is macromolecular and highly polarized so expect minimal distribution beyond the bloodstream Redistribution of Heparin into the endothelial cells Uptake the extracellular fluid, alveolar macrophages, splenic and hepatic reticulo -endothelial cells and vascular smooth muscles also occurs Some or all of these tissues create a relatively small reservoir for Heparin that probably contribute to the delayed recurrence of Heparin induced anticoagulation after protamine neutralization of the heparin residing in the blood stream

11. Monitoring A clot does not form in the oxygenator circuit with an ACT exceeding 300 seconds ACT below 180 secs should be considered Inadequate, life threating ACT between 180 to 300 secs should be considered highly questionable ACT exceeding 600 secs seem unwise Minimum ACT of 180 secs had been suggested for pts undergoing long term extracorporeal oxygenator for pulmonary support ACT of 480 secs before initiating cpb it represents minimum safe level for cpb anticoagulation Administer 350 to 400 units of Heparin per kg IV Draw an arterial sample for ACT in 2 to 5 mins Manual method described by bull etal 2ml of blood with draw from a venous catheter is placed in a glass tube containing celite Kavolin Powder /K- lyte Powder are also used in ACT The tube is then inverted 30secs before placing it in a heat warmed by a 40 watt bulb

12. The tube is then rocked slowly until the clot is bulb The tube is then rocked slowly until the clot is formed A clot is a bedside test immediately performed Hemochron ACT is one such technique that is a commercially available. It uses 2 ml of blood with celite as an activator. The blood is mixed in a test tube that contains a small magnet. Hypothermia, hemodilution, platelet function abnormalities and low fibrinogen are some of the factors that can prolong ACT ,even in the setting of incomplete heparinization Give additional heparin as needed to achieve an ACT above 400 secs before initiating cpb and to maintain an ACT above 400 secs during normothermic cpb and above 480 secs during hypothermic between 24⁰ to 30⁰ Prime the extracorporeal circuit with app 5 IU of Heparin per ML [ eg : 5000 IU for 1000 ml clear priming solutions] Monitor ACT every 30 mins during cpb or more frequently if the patients proves resistance to heparin induced prolongation of the ACT

13. Elimination/Excretion Very small doses of Heparin produce minimal or no effects, suggesting a rapid initial clearance, possibly the result of the affinity of Heparin for endothelial membranes The doses used for cpb anticoagulation are very large and the biologic elimination half life of heparin is dose dependent Hypothermia delays heparin elimination with Virtually constant heparin conc shown during 40 to 100 mins of cpb at 25⁰ Found a small decrease in rate of ACT decline at 30⁰ Several renal impairment may prolong heparin action Liver disease apparently has little effect on heparin

14. Side Effects Bleeding Deep vein thrombosis Heparin induced hyperkalemia Heparin induced thrombocytopenia Plasma coagulation, the formation of a platelet plug and fibrinolysis constitute three major components of blood clot formation and dissolution. Heparin induced activation of fibrinolysis has been identified in a primate model. Baboon model heparin administration led to activation of fibrinolysis.

15. Alternative to Heparin Low Molecular Weight Heparin : Different components of UF heparin poses differing affinities for platelets and AT- IlI . UF heparin contains polysaccharides chains with molecular weight above 5,400 and has antifactor Xa and antithrombin action in the ratio of 1:1. LMWH are less capable of inhibiting thrombin factor Xa. Moderate inhibition factor Xa prevents thrombus formation without impairing haemostasis . Reduce protein binding may enhance the bioavailability of LMWH.

16. LMWH has longer plasma life compared to UFH 110 to 200 mins. Renal excretion is the principal route of elimination. Mean molecular weight 4,000-6,500Da. LMWH has been used in prevention of deep vein thrombosis during hemodialysis and in the treatment of thrombosis occurring HIT. Risk Factors: Postoperative bleeding 2. Blood loss is significantly more in patients who received LMWH with in 12  hrs  of surgery

17. Danaparoid Danapariod sodium is a synthetic heparinoid compound prepared from a porcine intestinal source and consist of heparin sulfate (84%) dermaltan sulfate (12%) and chondroitin sulfate (4%). It produce the anticoagulant effect primarily via inhibition of factor Xa. The incidence of cross reactivity with HIT antibodies is significantly lower with Danapariod . Elimination dependent on kidney. No reversal agent for this drug. Intermittent bolus doses and continuous infusion. Risk Factors: Inadequate anticoagulation [formation of clot] Severe postope bleeding Large quantities of blood transfusion

18. Defibrinogenating Agents ANCROD Ancrod is derived from Malayan pit viper venom. It lyses fibrinogen there by preventing formation of fibrin polymers. The avg dose used was 1.65 U/Kg. Elimination by reticulo endothelial system may take several days. It has also been used in pts with acute HIT undergoing cardiac surgical procedures. DISADVANTAGES No antidote Lack of monitoring Bleeding and increase need for homologous blood products

19. Direct Thrombin Inhibitors: HIRUDIN: Isolated from the salivary glands of leech and it inhibits thrombin directly without requiring AT Ill. Lepirudin has been used more commonly. It is effective in inhibiting free as well as clot bound thrombin. Elimination primarily by the kidneys and plasma half life may be prolonged as long as 120 hrs ( nrml -80 mins)in the presence of renal failure. MUF may be utilized to enhance the elimination of hirudin during cpb . DISADVANTAGES: No effective reversal agent Excessive bleeding can occur with renal insufficiency Anaphylactic reactions Eliminated by hemofiltre

20. ARGATROBAN Widely used in pts with HIT who requires percutaneous coronary interventions. It is a synthetic direct thrombin inhibitor that binds reversibly to the active site of thrombin molecule. Primarily metabolized by liver. Short half life 39-59 mins which is prolonged in pts with moderate impairment [152 mins]. DISADVANTAGES: Bleeding/clotting No monitoring device BIVALIRUDIN It is a bivalent direct thrombin inhibitor inhibitor that inhibits free as well as clot bound thrombin thus preventing thrombin mediated platelet activation.

21. Half life app 25 to 30 mins. No antidote It primarily undergoes dual elimination via proteolytic cleavage adrenal elimination. Elimination improved by hemofiltration Dosing protocol 1 to 1.5 mg/kg ,50 mg added to the pump

22. Clinical Use Venous thrombosis and pulmonary embolism. Unstable angina or acute myocardial infarction. During and after coronary angioplasty or stent placement. Low dose s/c heparin in Preventing venous thromboembolism.

23. THE END