1. Journal Session Dr Wan Zaidah Abdullah

2. Agenda  Heparin resistance  BJA, 2002 vol 88, no 4, 467-469  J A M Anderson and E L Saenko

3. Overview  Heparin was discovered in 1916  Most widely used anticoagulant but not all its actions are fully understood  Eg: pain relief in i.v administration for the treatment of DVT, how HIT developed and what is the relevance of the occurrence of heparin resistance

4. Indications  Prevention of VTE  Treatment of VTE  Acute coronary syndrome  Surgery: cardiac bypass

5. Introduction  Heparin is a negatively charged sulphated glycosaminoglycan composed of alternating uronic and glucoronic acid residues  Commercially prepared are isolated fr porcine int mucosa or bovine lungs. There are heterogenous mixtures of polysacharide chains ranging in molecular weight from 3000 to 30,000.  Mode of action:

6. MOA 1  1. Antithrombin dependent  -Activate AT  Hep-AT complex  inactivate thrombin, fXa and other coagulation factors  The combination of disaccharide units makes- up pentasacharide sequence containing high affinity binding site for AT. This sequence occurs in only about 1/3 rd of heparin chains and is randomly distributed

7. MOA 2  2. AT independent  Direct Inhibition of the intrinsic tenase complex ( PL complex of FVIIIa, FIXa which generates Fxa)  * In plasma milieu, AT-dependent effect predominates  In vivo, variation in response to a fixed dose of heparin occurs bet individuals  Pharmacokinetics limitation of heparin caused by the binding of hep to plasma proteins  Heparin resistance state

8. Significance to know the ‘R’ state  1. Prevent over administration of heparin  hemorrhagic consequences  Particularly during post-op or in the setting of cardiac bypass surgery and to consider alternative therapy  2. In VTE  the phenomenon is of unclear clinical practice

9. Definition of heparin resistance state  1. In the context of VTE:  The need for more than 35,000 u/24 hour to prolong the APTT into the therapeutic range  2. Cardiac bypass procedure:  The definition is based on the ACT with at least one ACT < 400 secs after heparinization and/or the need for exogenous antithrombin administration

10. Questions  1. What causes heparin resistance  2. Which patient groups are susceptible?  Some answers can be gained from the understanding on the limitation of UFH

11. Limitations of heparin  1. Biophysical  Reflects the inability of hep-AT complex to inactivate FXa bound to platelets within the prothrombinase, the PL memb bound fVa – fXa complex,  in addition to the resistance of fibrin bound thrombin to inactivation by heparin

12. Limitation of heparin 2  2. Pharmacokinetic  A. Reflects the binding of hep to plasma proteins including PF4, fib, fVIII and histidine rich glycoprotein  As many heparin- binding poteins are acute phaase proteins/reactants- the phenomenon is often encountered in acutely ill pts, malignancy, peri or post partum periods and drugs ( aprotinin and nitroglycerin – hep clearance)  B. Lowering of the AT levels by heparin  contributes to the resistance state

13. How to monitor the anticoagulant effects of heparin in the lab? … not easy  1. APTT  failed to prolonged  APTT has its own limitations:  Influenced by:  -blood collection  -Sampling tube composition  -Type of anticoagulant  -Time of sampling to avoid PF4 mediated neutralization of heparin  * APTT response to heparin varies

14. APTT response to Heparin  Possibolity of ApTT lies in the target range for heparin therapy whilst the heparin levels is suboptimal occurs in acquired/congenital factor deficiency, LA, warfarin effects.

15. Monitor  2. Anti- Xa monitorring  Less dose of heparin is required compared to when APTT is used as monitorring agent  The development of heparin resistance is therefore an indication for the use of the heparin assay to measure the anticoagulant effect of the drug  Chromogenic anti fXa assays have limitations: assay variation and technique  Bedside anti fXa monitorring test to permit a quicker and more accurate asessment of the true anticoagulant activity of heparin: bypass surgery

16. Monitor  3. ACT  At present ACT, is the most commonly used lab test to control heparin effects on extracorporeal membrane  ACT results also dependent on the instrumentation, vary with the presence of haemodilution and hypothermia

17. Heparin Resistance and CPB  CPB circuit  ECM: activate the coagulation pathway  fXa generation. The inhibition of Fxa in these situations involves the AT dependent mechanisms of heparin.  Imbalance of activation of FX via extrinsic vs intrinsic p/way  In general, hep is given 3mg/kg body wt to prevent extracorporeal clot formation with repeated doses to maintain ACT > 400 sec to maintain level at 3iu/ml

18. Solution to heparin resistance during CPB  Potential solution: Argatroban: a selective, reversible thrombin inhibitor  Hirudin also a direct thrombin inhibitor : prevent clotting within the CPB circuit of pts with HIT  Ecarin clotting time to monitor the antithrombotic effects (PT activation by the snake venom)  Pentasacharide: a selective synthetic fXa inhibitors: once daily subcut dose without monitoring requirement (prevention of venous thrombosis)

19. Conclusion  Heparin still remains the optimal means of anticoagulation in CPB, but improvements are needed in terms of practical bedside monitorring of its anticoagulant effects.  Bedside monitorring permit reasessment of the optimal level of ACT to achieve prior to starting the bypass circuit

20. Significance of heparin resistance  In the context of VTE- heparin R has its clinical relevance?  What is the outcome of pts treated with empirical doses of heparin when APTT cannot be prolonged into the therapeutic range?  The optimal means of monitorring the anticoagulant effects in cardiac surgery? to avoid bleeding post-op and usage of blood products  Oral heparin in future and synthetic indirect and direct fXa inhibitors.

21. Thank you