Agenda

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

2. 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

3. Indications • Prevention of VTE • Treatment of VTE • Acute coronary syndrome • Surgery: cardiac bypass

4. 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:

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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.

14. 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

15. 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

16. 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

17. 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)

18. 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

19. 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.