Heparin Benedict R. Lucchesi, M. D., Ph. D

Heparin

• Benedict R. Lucchesi, M.D., Ph.D.

• Department of Pharmacology

• University of Michigan Medical School

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.

Interaction of Heparin-ATIII-Clotting Factors

• Heparin needs to interact with both ATIII and Thrombin (IIa)

• To enhance its effect on Factor Xa, heparin needs only to interact with ATIII

• LMWH can only increase the action of ATIII on Factor Xa and not on thrombin (IIa).

Heparin-Thrombin-Fibrin Complex

• Ternary heparin/thrombin/fibrin complex.

• Thrombin binds to fibrin via exosite 1.

• Heparin bridges thrombin to fibrin by binding simultaneously to both fibrin and exosite 2 on thrombin.

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: Factors II, IX, X, XI, XII and XIII
• Binds to lysine sites on AT III, leads to conformational change at the arginine reactive center

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

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.

Heparin Pharmacokinetics

• 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

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.

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

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

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

Heparin-Induced Thrombocytopenia

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

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.

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.

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

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

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.

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

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.

Heparin - Reversal - CABG

• Heparinase I (Neutralase™) In Clinical Development

• °Specific heparin degrading enzyme
• °Produced by gram negative soil bacterium, Flavobacterium heparinum
• °Cleaves heparin through a lyase reaction at alpha glycosidic bond linkages between N-sulfated-O-glucosamine and L-iduronic acid residues.
• °Each heparinase I molecule cleaves about 70 heparin bond linkages per second at 30° C.
• °Eleven heparinase I sensitive cleavage sites per heparin molecule including on located directly within the ATIII-binding pentasaccharide.
• °Reverses aPTT - ACT within seconds - Dose ~ 5-30 µg/kg
• °t1/2 ~ 6-7 min

Heparin - Clinical Uses

• 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

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

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).

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.