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



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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.



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