Heparin

1. Heparin Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University of Michigan Medical School

2. Heparin Chemistry • Low molecular weight fractions of heparin have a high affinity for ACTIVATED FACTOR X (Xa), but have less of an effect on thrombin.

3. I I I I I I I V V OSO-3 COO- CH2OSO3 H2CO R’ O O O O O COO- * O O OH O H OSO-3 O H O O O O - - - H N S O OH O S O H N S O NH R’’ 3 3 3 D-Glucosamine Unit D-Glucuronic Acid D-Glucosamine L-Iduronic Acid D-Glucosamine R’= H or -SO3- R’’= COCH3 or -SO3- Antithrombin-Binding Structure of Heparin * Antithrombin binding region Groups essential for high affinity binding of antithrombin

4. A T I I I T h r o m b i n Lysine Sites 5 13 or more saccharide units Heparin A T I I I F a c t o r X a Lysine Sites <13 5 Low Molecular Weight Heparin Inhibition of thrombin and Factor Xa by the Heparin/AT III complex through a unique pentasaccharide unit. Binding to thrombin requires a minimum of 13 saccharide units. Low molecular weight heparin acts to inhibit Factor Xa and requires that the latter only bind to AT III.

5. Anticoagulant Therapy Heparin • Actions of Heparin • Inactive by itself as an anticoagulant • Requires the presence of a plasma cofactor- ANTITHROMBIN III (AT III) • Heparin potentiates the action of AT III • Heparin-AT III-complex neutralizes the actions of: FactorsII, IX, X, XI, XII and XIII • Binds to lysine sites on AT III, leads to conformational change at the arginine reactive center

6. = sites of Heparin/ATIII Inhibition aPC Protein S aPC Inactivation Va & VIIIa INTRINSIC PATHWAY EXTRINSIC PATHWAY IXa VIIa / Tissue Factor VIIIa TFPI Platelet Aggregation aPC FACTOR Xa Fibrinogen ProthrombinThrombin Va XIIIa PC / Thrombomodulin Fibrin

7. Actions of Heparin • Low concentrations of heparin increase the activity of AT III considerably, especially against Factor Xa and THROMBIN - these are the most sensitive components of the coagulation cascade • Rationale for the clinical use of “mini-dose” heparin • Inhibition of THROMBIN requires that both the AT III complex and the ENZYME bind to heparin • Inhibition of FACTOR Xa requires that heparin only bind to AT III

8. Actions of Heparin (continued) • Binds strongly to AT III - leads to conformational change of AT III • Active site of AT III is exposed • The active AT III inhibits the proteases involved in coagulation - Factors II, IX, X, XI, XII and XIII • Heparin is NOT consumed, but is released from the AT III complex and is available to react to AT III.

9. HeparinPharmacokinetics • Heparin binds to saturable sites on the endothelial cells • It is internalized and depolymerized • It displaces platelet factor 4 from the endothelial cells - a protein that neutralizes heparin

10. Heparin-Anticoagulant action is modified by: Fibrin - • Clot bound fibrin binds thrombin and protects it from inactivation by heparin-AT III. Platelets - • Bind factor Xa and protect it from heparin-AT III complex inhibition and by secreting platelet factor 4 • Not the case with HIRUDIN (AT III independent). • Subendothelial thrombin is protected from heparin-AT III as well.

11. Heparin-Contraindications • Patients who are hypersensitive • Presence of active bleeding or hemophilia • Thrombocytopenia • Purpura • Severe hypertension • Intracranial hemorrhage • Bacterial endocarditis • Active tuberculosis • Ulcerative lesions of GI tract

12. Heparin-Contraindications • Threatened abortion • Visceral carcinoma • During or after surgery on the brain, spinal cord or eye • Patients undergoing lumbar puncture or regional anesthesia block • History of heparin-induced thrombocytopenia

13. Heparin-Adverse Effects Side Effects Dose Related Frequency Major Bleeding Yes 5% Thrombocytopenia Yes 5 - 15% with thrombosis Yes 0.4% Osteoporosis Yes Rare Anaphylaxis No Rare Skin necrosis ? Rare Local urticaria ? Rare Hypoaldosteronism ? Rare

14. Heparin-Induced Thrombocytopenia vs Heparin-Induced Thrombocytopeniaand Thrombosis

15. Heparin-Adverse Effects (continued) Heparin-Induced Thrombocytopenia - TWO FORMS: • Mild reduction in platelet count, 2-15 days after initiation of full-dose heparin therapy • Platelet count usually remains above 100,000/µl. Bleeding risk is minimal

16. Heparin-Adverse Effects (continued) Heparin-Induced Thrombocytopenia-and Thrombosis • Severe reduction in platelet count, 7-14 days after initiation of therapy with full-dose or low-dose heparin • May be associated with thrombotic complications, including arterial thrombosis with platelet-fibrin clots that may cause MI or stroke • Presence of antiplatelet IgG in patients with severe form ? • May be less common with heparin from pork.

17. Heparin - Laboratory Monitoring aPTT / TCT • Therapy is routinely monitored by means of the aPTT (at UofM it is the TCT) • A clotting time of 1.5 to 2.0 times the normal mean aPTT value (50 - 70 seconds) is therapeutic • Initially the aPTT should be measured and the infusion rate adjusted every 4 hours. • Once a steady state is achieved, daily monitoring is sufficient.

18. Resistance to Heparin • Some patients may not show a prolongation of the aPTT unless very high doses of heparin are used • Presence of an increased concentration of FACTOR VIII will give rise to a very short control aPTT - they may not be truly resistant to heparin

19. Heparin-Resistance to Heparin (continued) • Accelerated clearance of heparin may exist - as in the case of massive pulmonary embolism • Inherited AT III deficiency have 40 - 60 % of the normal plasma concentration of AT III. They respond normally to heparin • Acquired AT III deficiency as with hepatic cirrhosis, nephrotic syndrome or disseminated intravascular coagulation; large doses of heparin may not prolong the aPTT

20. Heparin - Managing Over-Anticoagulation • Anticoagulant effect of heparin disappears within hours after discontinuation of the drug. • Mild bleeding due to heparin can be controlled without administration of an antagonist. • Antagonists are used if bleeding is life-threatening.

21. Heparin - Managing of Over-Anticoagulation • Degree of over-anticoagulation • Presence or absence of bleeding • A specific, immediate heparin antagonist • Protamine Sulfate • Use 25 - 50 mg intravenously • Side-effects largely allergic in nature • Management depends on:

22. Heparin:Managing Overanticoagulation (cont’d) • Protamine binds to the acidic (negatively charged) heparin molecule - neutralizes heparin. • Protamine also interacts with platelets, fibrinogen, and other plasma proteins. • Use smallest dose, give by slow IV infusion - do not exceed 50 mg over 10 min. - Causes, flushing, bradycardia, dyspnea, hypotension, anaphylaxis. • Use 1 mg of protamine for every 100 units of heparin remaining in the patient. • Protamine sulfate is a low molecular weight, basic (positively charged) protein.

23. Heparin - Clinical Uses • Effective for the prevention and treatment of: • venous thrombosis and pulmonary embolism • mural thrombosis after acute MI • managing unstable angina • prevention of coronary artery rethrombosis • used to prevent blood clotting in extracorporeal circulation - e.g. surgery, hemodialysis • treat selected cases of disseminated intravas-cular coagulation (DIC) • treat fetal growth retardation in pregnant women

24. Heparin - Recommendations for Clinical Use Pregnancy - heparin is the anticoagulant of choice • does not cross the placenta • no untoward effects in the fetus or newborn • given in therapeutic doses - 15,000 U sc q 12 hrs to women with prosthetic heart valves or venous thromboembolism • doses in excess of 20,000 U per 24 hrs for more than 5 months is questionable -due to risk of OSTEOPOROSIS

25. Low Molecular-Weight Heparins Enoxaparin (Lovenox™) Dalteparin (Fragmin™) • contain a lower proportion of the critical pentasaccharide sequence than the parent compound. • they increase the action of ATIII on factor Xa, but not its action on thrombin.

26. Low Molecular-Weight Heparins • The LMWHs are not inactivated by platelet factor 4, therefore activity extends to factor Xa bound to platelet membranes. • In clinical doses, no affect on platelet reactivity, PT or aPTT. • Currently approved for prevention of deep vein thrombosis: • After hip or knee surgery or abdominal surgery. • Unstable angina (NQWMI).

27. Low Molecular Weight Heparins • Do not require routine monitoring of INR, PT, or aPTT. • One fixed dose administered subcutaneously. • 30 mg every 12 hours. • Must not be administered IM and is not intended for IV administration. • Use with caution in patients with a history of heparin-induced thrombocytopenia. • Reversed by protamine, 1 mg for each mg of LMWH.