Chapter 39: Drugs that Influence Coagulation

Drugs and Blood Coagulation

• Introduction

  • Abnormal states of hemostasis

    •  Bleeding (impaired hemostasis)

    •  Thrombus formation (stimulated hemostasis)

Blood Coagulation: Mechanisms

• Thrombogenesis: Sequence and Characteristics

  • Normal:

    • Normal vascular endothelial cells:

      • not thrombogenic (platelet/clotting factors do not adhere)

  •  Injury. ® thrombogenesis

    1. Immediate response: vasospasm

    2. Platelet adherence to damaged epithelium (binds to collagen) referred to as platelet adhesion. (collagen-platelet membrane glycoprotein Ia receptor interaction)

    3. Platelets binding to each other: platelet aggregation

    4. Platelets form a gelatinous mass (losing individual membranes): viscous metamorphosis. ® platelet plug (temporary cessation of bleeding)

    5. Platelet plug -- reinforcement by fibrin

    6. Fibrin reinforcement:

       •  damaged vessel . ® exposed collagen + platelet content released

         • Platelet degranulation releases aggregating substances:

           •  ADP

           •  TXA₂

           •  5-HT

       •  local thrombin production:

         • platelet ADP release (ADP inducer of platelet aggregation)

         • prostaglandin synthesis (derived from platelet membrane arachidonic acid)

           • Thrombogenesis/vasoconstriction: thromboxane A₂ , TXA₂)

           • Thrombogenesis inhibitor: prostacyclin

  •  White Thrombus:

    • where: high-pressure arteries

    • circulating platelet adherence to regions of abnormal epithelium

    • aggregated-platelet thrombus ® reduced flow

    • red thrombus forms around white thrombus nidus

  •  Red Thrombus:

    • forms either secondary to white thrombus or de novo -- low pressure veins

    • Thrombus forms a fibrin network longer tail entraps red cells)

      •  Fibrin tail may detach forming emboli which may travel to pulmonary arteries

  • Summary: platelets

    • Platelet nidus: most significant for arterial thrombus

      •  Concerns: arterial thrombi . ® local vessel occlusion/ischemia

    • Fibrin tail (red thrombus):most significant for venous thrombus

      •  Concerns: venous thrombi . ® embolization at distant sites

•   Blood Coagulation-- soluble fibrinogen ® insoluble fiber

  • Overview:blood coagulation

    • Cascade process:

      • clotting factors zymogen ® limited proteolysis® active protease ® activates next clotting factor® solid fibrin clot

  • Sequence:

    • fibrinogen (factor I; soluble fiber precursor) substrate for thrombin (enzyme, factor IIa)® fibrin clot

      •  thrombin formed from activation of its zymogen, prothrombin (factor II)

      •  prothrombin (factor II): bound by a calcium to platelet phospholipid (PL); activated factor X (Xa) + activated factor Va converts prothrombin (factor II) ® circulating thrombin

    • Possible initiation step:

      • tissue factor (TF) + factor VII

    • Regulation factors:

      •  tissue factor pathway inhibitor (TFPI)

      •  endogenous anticoagulants: protein C, protein S: down-regulation of blood clotting amplification by proteolysis factors Va, VIIIa and IXa.

    • Drug influences:

      •  oral anticoagulants: inhibits clotting factor synthesis

      •  e.g.: heparin inhibits activity of certain activated factors.

Blood Coagulation Cascade: Proposed Model

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Clotting Factors: Drug Target Sites

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Coagulation and Fibrinolysis: Regulation

• Regional blood coagulation must be discreet in order to:

  • not impair blood flow excessively

  • avoid disseminated clotting

• Systems regulating coagulation:

  • Fibrin inhibition

  • Fibrinolysis

• Inactivation of coagulation proteins (away from injury site)

  • Plasma Protease Inhibitors:

    • a₁-antiprotease

    • a₂-macroglobulin

    • a₂-antiplasmin

    • antithrombin III

  • -----Failure of plasma protease inhibitor system: ----- Disseminated Intravascular Coagulation (DIC)-- may occur following:

    • obstetrical emergencies (abruptio placentae; bacterial sepsisreprint

    • major tissue injury

    • cell lysis: neoplastic disease

• Fibrinolysis:

  • Major process: conversion plasminogen (inactive) ® plasmin (proteolytic enzyme, active)

  • plasminogen activators: released from damaged cells

  • Plasmin:

    • limits thrombosis extension (by proteolytic fibrin digestion)

  • Drug interventions: fibrinolytic system:

    • Activators of fibrinolysis:

      • tissue plasminogen activator (t-PA)

      • urokinase (Abbokinase)

      • streptokinase (Streptase, Kabikinase)

    • Inhibitors of fibrinolysis:

      • aminocaproic acid (Amicar)

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Anticoagulant Drugs: Pharmacology

Heparin

• Composition:

  • sulfated mucopolysaccharides (heterogenous)

• Mechanism of Action:

  1. Binds to endothelial cell surface membrane.

  2. Heparin activity dependent on: plasma protease inhibitor antithrombin III

     • Antithrombin III -- inhibitor of clotting factors proteases (forming 1:1 stable complexes)

     • Complex forming reactions normally slow -- accelerated by three orders of magnitude (1000 times) by heparin

     • acceleration mechanism: heparin binding ® induces a change in antithrombin III inhibitor form resulting in ® increased complex formation activity

     • Following antithrombin-protease complex formation, heparin is released; available for binding to other antithrombin molecules

       •   {a heparin high-molecular-weight (HMW) fraction has higher affinity for antithrombin compared to other fractions}

       •   {a heparin low-molecular-weight (LMW) fraction has a lower affinity for antithrombin but inhibits factor Xa (activated)}

         • a low-molecular-weight fraction (LMW), enoxaparin (Lovenox) is FDA approved for primary prevention of deep venous thrombosis following hip replacement surgery.

         • Dalteparin and danaproid have been also approved for prevention of the venous thrombosis following hip replacement surgery

• Heparin (HMW): standardized by bioassay (units)

  • obtained from:

    • porcine intestinal mucosa

    • bovine lung

  • Enoxaparin (Lovenox) -- same sources; amount specified in milligrams

  • Dalteparin (Fragmin)& danaproid (Orgaran)-- amounts specified in anti-factor Xa units

• Toxicity:heparin

  • major adverse/toxic effect: bleeding

    • Risk managed by attention to:

      1. patient selection

      2. dosage control

      3. monitoring of partial thromboplastin time (PTT)

    •  Factors predisposing to hemorrhage:

      • elderly

      • renal failure patients

  •  Long-term heparin use-- increased incidence of:

    • osteoporosis

    • spontaneous fractures

  •  Transient thrombocytopenia: frequency = 25%

  • Severe thrombocytopenia: frequency = 5%

  •  Paradoxical thromboembolism ® heparin-induced platelet aggregation

  •  Patients on heparin:

    • thrombocytopenia that causes bleeding: probably due to heparin

    • new thrombus: may be due to heparin

    • if thromboembolic disease may be heparin-induced:® discontinue heparin

• Contraindications:heparin

  •   Heparin hypersensitivity

  •   Hematologic disease:

    • hemophilia, thrombocytopenia, purpura,

  •   Cardiovascular:

    • severe hypertension, intracranial hemorrhage, infective endocarditis

  •   Active tuberculosis

  •   Gastrointestinal tract

    • ulcerative lesions

    • visceral carcinoma

  •   Advanced hepatic/renal dysfunction

  •   Threatened abortion

  •   Related to medical procedures:

    • after brain, spinal cord, or eye surgery

    • lumbar puncture/regional anesthesia blocks

•  Reversal of Heparin Effects:

  1. drug discontinuation

  2. Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)

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Warfarin & Coumarin

Coumarin

Warfarin

• Chemistry/Pharmacokinetics:Warfarin & Coumarin

  • Coumarin: produces plasma prothrombin deficiency

  • active agent --: bishydroxycoumarin (synthesis -- dicumarol)

  • Uses:

    • rodenticide

    • humans: antithrombotic agent

  • Oral anticoagulants:

    • Warfarin -- agent in use

    •  high bioavailability; most bound to plasma albumin (99%)

    • racemate-- equal amounts of two enantiomorphs

      • levorotatory-S-warfarin: four times more potent than dextrorotatory- R-warfarin

• Mechanism of Action:coumarin anticoagulants

  • Blockade of g-carboxylation of glutamate residues in:

    •    prothrombin

    •   factors: VII, IX, X

    •   endogenous anticoagulant protein C

  •  g-carboxylation results in biologically inactive molecules

  • Carboxylation reaction is coupled with oxidative deactivation of vitamin K

    • anticoagulant prevents reductive metabolism of inactive vitamin K epoxide regenerating active hydroquinone.

  • Anticoagulant effect dependent on two considerations

    1. partially inhibited synthesis of the four vitamin K-dependent clotting factors and

    2. naltered degradation rates of these factors.

  • Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis

•  Toxicity:coumarin anticoagulants

  •  Warfarin: crosses the placenta ® hemorrhagic fetal disorder

    •   Fetal abnormal bone formation (Warfarin effects on fetal proteins with g-carboxylglutamate residues).

    •   Never administer Warfarin during pregnancy

  •  Other Adverse Effects:coumarin anticoagulants

    • Cutaneous necrosis related to reduced protein C activity

    • Rare: reduced protein C activity ® breast, fatty tissues, intestine, extremity infarction

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• Drug-Drug Interactions:oral anticoagulants

  • Pharmacokinetic effects include:

    •   enzyme induction

    •   enzyme induction

    •   reduced plasma protein binding

  • Pharmacodynamic effects include:

    •   synergistic interactions with Warfarin

      • impaired hemostasis, diminish clotting factor synthesis (e.g. hepatic disease)

    •   competitive antagonism (vitamin K)

    •   abnormal physiologic vitamin K control loop (hereditary oral anticoagulant resistance)

  •  Most serious interaction:-- interactions that increase anti-coagulation (promote bleeding risk)

    •  most dangerous: pharmacokinetic interactions with:

      • pyrazolones phenylbutazone & sulfinpyrazone-- effects: a

        1. added hypoprothrombinemia

        2. platelet function inhibition

        3. promotion: peptic ulcer disease

    • Metronidazole, fluconazole, trimethoprim-sulfamethoxazole:

      • stereoselective in addition of S-warfarin metabolism

    • Amiodarone, disulfram, cimetadine:

      • inhibit metabolism of Warfarin (both enantiomorphs)

    • Aspirin, hepatic disease, hypothyroidism -- enhance Warfarin effects {pharmacodynamic}

      • Aspirin:effects on platelets

      • hepatic disease/hypothyroidism: increasing clotting factors turnover rates

    • Third-generation cephalosporins --

      • kill intestinal bacteria that produce vitamin K

      • directly inhibit vitamin K epoxide reductase

  •  Decrease of anticoagulant action:

    • Barbiturates & rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin.

    • Cholestyramine: promotes intestinal Warfarin binding

  •  Pharmacodynamic-mediated reduction of anticoagulant effects:

    • vitamin K -- {increased clotting factors synthesis}

    • diuretics -- chlorthalidone, spironolactone {affect clotting factor concentration}

    • genetics -- {molecular mutations of vitamin K reactivation cycle components}

    • hypothyroidism -- {reduced clotting factors turnover rate}

•   Reversal of Warfarin anticoagulant effects:

  • discontinue drug administration

  • administer vitamin K₁ (phytonadione) & fresh-frozen plasma or factor IX concentrates {Konyne-80 and Proplex which contained prothrombin complex}

  • Objective of intervention: establishing normal clotting factor activity

    • serious bleeding: large amounts of vitamin K₁ (intravenous administration), factor IX concentrates, and possibly whole blood transfusion

• Other related agents:(seldom used due to unfavorable toxicity/pharmacologic properties)

  • dicumarol -- incompletely absorbed; GI symptoms

  • Phenprocoumon:extended half-life; adverse renal/hepatic effects.

Fibrolytic Drugs

• Overview:fibrolytic drugs

  • Lyse thrombi by catalyzing plasmin (serine protease) formation from plasminogen (the zymogen precursor)

  • Lytic state induced following IV administration

  • Note: both target thromboemboli and hemostatic thrombi are dissolved

• Pharmacology:streptokinase, alteplase, tissue plasminogen activator, reteplase, urokinase

  • Streptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci)

    • combines with plasminogen (proactivator)

    • Enzymic complex catalyzes: plasminogen ® active plasmin

  • Urokinase (Abbokinase):(human enzyme; renal)

    • Catalyzes: plasminogen ® active plasmin

    • Note: Plasmin cannot be directly used because of endogenous inhibitors;

      • endogenous antiplasmins do not affect urokinase or streptokinase-proactivator complex

      •  Urokinase (and streptokinase-proactivator complex) promote plasmin formation inside the thrombus ® lyse thrombus from within.

  • Anistreplase (APSAC, Eminase) (anisoylated plasminogen streptokinase activator complex; APSAC)

    • purified human plasminogen - bacterial acylated streptokinase complex {upon administration deacylation activatesstreptokinase-proactivator complex}

    • rapid IV injection

    • enhanced clot selectivity -- more plasminogen activity clot-associated than associated with free blood plasminogen

    • more thrombolytic activity

  • Tissue Plasminogen Activators (t-PA)

    • Plasminogen activator

    • preferential activation of fibrin-bound plasminogen

    • Human t-PA: recombinant DNA technology

    • Alteplase: unmodified human t-PA

    • Reteplase: modified human t-PA

• Clinical Uses: Fibrolytic Drugs---

  • Multiple pulmonary emboli (not requiring surgery)

  • Central deep venous thrombosis

    •  superior vena caval syndrome

    •  ascending thrombophlebitis (iliofemoral vein)

  •  Intra-arterial use -- peripheral vascular disease

  • Acute Myocardial Infarction:

    • careful patient selection (early intervention)

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Antithrombotic -- Antiplatelet Drugs

• Overview: antithrombotic agents

  • Regulation of platelet function -- Three types of substances:

    1. Substances developed outside the platelet but interacts with platelet membrane receptors:

       •   catecholamines

       •   collagen

       •   thrombin

       •   prostacyclin

    2. Agents generated internal to the platelet and interact with membrane receptors:

       •   ADP

       •   prostaglandin D₂

       •   prostaglandin E₂

       •   serotonin

    3. Agents generated internal to the platelet and interact within the platelet:

       • prostaglandin endoperoxidases

       • thromboxane A₂

       •   cAMP

       •   cGMP

       •   Ca²⁺

  • Pharmacological Targets:antithrombotic agents

    • Inhibition of prostaglandin metabolism: aspirin

    • inhibition of ADP-induced platelet aggregation: ticlopidine

    • blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab(ReoPro)& integrelin

• Aspirin:

  • Mechanism of Action:aspirin

    • Prostaglandin thromboxane A2 (arachidonate product) causes:

      • platelet aggregation

      • platelet shape changing

      • platelet degranulation

    • nhibition of this process inhibits platelet aggregation, prolonging in vivo bleeding time

    • Aspirin inhibits thromboxane A₂ synthesis by:

      • irreversible acetylation of cyclooxygenase

      • new cyclooxygenase cannot be synthesize during the 10-day lifespan of the platelet

      • Other cyclooxygenase inhibitors are reversible and therefore have shorter duration of action, e.g. other salicylates & other nonsteroidal anti-inflammatory drugs

  • Clinical Use --antithrombotic effects

    • Possible primary prophylaxis of myocardial infarction

    • FDA approval for this indication

  •  Adverse Effects:aspirin

    • increased gastrointestinal bleeding

    • increased frequency of peptic ulcer disease.

• Dietary:antithrombotic effects

  • unsaturated fatty acid eicosapentaenoic acid -- generates prostaglandin I₃ and thromboxane A₃, anti-aggregation agents

Aspirin

• Ticlopidine:

  • Inhibits ADP platelet pathway: reduces platelet aggregation

  • no effect on prostaglandin metabolism

  • Clinical Use-Ticlopidine: Efficacy in prevention:

    •   completed strokes

    •   unstable angina

    •   transient ischemic attacks

  •  Adverse Effect:ticlopidine

    •   gastrointestinal disturbance: frequency = 20%

    • hemorrhage: frequency = 5%

    •  leukopenia (serious): frequency: = 1%

      • requires blood testing during first three months of ticlopidine treatment

• Blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab, integrelin

  • Abciximab:(ReoPro)

    • mouse/human chimeric monoclonal antibody blocking IIb/IIIa receptors

    • Clinical Use:abciximab

      • adjunctive treatment in high-risk angioplasty and atherectomy

Ticlopidine

Pharmacological Management of Thrombosis

• Venous Thrombosis

  • Most common genetic risk factor: activated protein C resistance

    • frequency: 20% of patients diagnosed with their first deep venous thrombosis

    • Relative risk: 8X-- heterozygotes; 80X in homozygotes

  • Acquired Disease:

    • increased thromboembolism risk: associated with arrhythmia

      • long-term proven efficacy of oral anticoagulants in management of chronic atrial fibrillation

    • increased thromboembolism risk: associated with prolonged bed rest (deep venous thrombosis/embolism)

  • Antithrombotic Management:

    • Prevention: Goal -- reduce incident/mortality rate from pulmonary embolism

    • Heparin -- prevention of venous thrombosis

      • intermittent administration (effective prophylaxis) -- subcutaneous

    • Oral Anticoagulants:

      • generally limited use due to bleeding risk/laboratory prothrombin time monitoring

      • effective prophylaxis for patients with:

        • atrial fibrillation

        • prosthetic heart valves

    • Early postoperative ambulation-- reducing venous stasis

      • also effective: external pneumatic leg compression

    • Enoxaparin  (Lovenox)-- approved for prophylaxis only in hip replacement patients.

  • Venous Thrombosis -- established

    • heparin & warfarin -- maximal dosages; similar treatment for pulmonary embolism

    • small thrombi -- calf veins -- often managed without anticoagulants

    • In patients with recurring thrombi and a positive family history:

      •  evaluate for protein C or protein S deficiency

      •  Antithrombin III concentrate: maybe helpful in deficient patients

      •  Heparin resistance (associate with antithrombin III deficiency) -- overcome with concentrate

    •  Note:since warfarin crosses the placental barrier, venous thromboembolic disease in pregnant women: subcutaneous heparin with mandatory monitoring of anticoagulant effect.

• Arterial Thrombosis:

  • Platelet-inhibiting agents:

    • Examples

      •  aspirin

      •  ticlopidine (Ticlid)

  • Clinical Uses:platelet-inhibiting agents

    • management of unstable angina, transient ischemic attacks, strokes, acute myocardial infarction

    • in myocardial infarction and angina, platelets inhibiting drugs used in combination with:

      •  beta-blockers

      •  calcium channel blockers

      •  fibrolytic agents

 Drugs Used in Bleeding Disorders

• Vitamin K

  • required for biological activity of:

    • prothrombin

    • factors VII, IX, X

  • fat-soluble, available from diet & synthesized by human intestinal bacteria

  • Two natural forms:

    •  vitamin K₁

      • phytonadione, from food

    •  vitamin K₂

      • menaquinone, found in human tissue, bacterial synthesis

  • Vitamins K₁ and K₂-- require bile salts for absorption from intestinal tract

  • Clinical Issues:vitamin K

    • Vitamin K₁:

      • given to all newborns; preventative of hemorrhagic due to  vitamin K deficiency (common in premature infants)

      • Deficiency:

        • hospitalized patients (ICU) due to:

          • poor diet

          • parenteral nutrition

          • recent surgery

          • multiple antibiotic treatment

          • uremia

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Plasma Fractions-- Bleeding due to factor deficiencies

• Overview:factors

  • Coagulation defects: primarily --

    • factor VIII deficiency --classic hemophilia (hemophilia A)

    • factor IX deficiency -- Christmas disease, hemophilia B)

    • concentrated plasma fractions: available to manage hemophilia A & B

  • Factor VIII:-- 2 preparations

    • cryoprecipitate-- plasma protein fraction; derived from whole blood

      •  hemophilia (factor VIII)

      •  von Willebrand's disease

      •  source of fibrinogen (occasionally)

      •  must match Rh status, i.e. RH-negative women should receive only RH-negative cryoprecipitate

    • lyophilized factor VIII concentrates:

      • derived from plasma pools (cryoprecipitate from individual donors, probably safer)

      • Reduced danger of viral disease (hepatitis B, hepatitis C, HIV) transmission by:

        • pasteurization

        • ultraviolet radiation

    • Desmopressin acetate (arginine vasopressin)

      • increases factor VIII activity in patients with mild hemophilia or von Willebrand's disease.

      • Clinically used before minor surgery (e.g.,dental)

  • Factor IX:

    • Freeze-dried plasma concentrates containing:

      • prothrombin, factor IX, factor X, factor VII

      • coagulation factors may be activated in manufacturing (heparin may be added to inhibit these factors)

  • Fibrinogen:

    • Forms: plasma, factor VIII cryoprecipitate, lyophilized factor VIII concentrates.

Fibrolytic Inhibitors:aminocaproic acid

• Aminocaproic acid (Amicar)

  • competitive inhibitor of plasminogen activation

  • tranexamic acid -- aminocaproic acid analog; similar activity

  • Clinical Uses:aminocaproic acid

    • therapy for bleeding following fibrolytic treatment

    • adjunctive therapy in hemophilia

    • prophylaxis: re-bleeding from intracranial aneurysms

  •  Adverse Effects:aminocaproic acid

    • intravascular thrombosis secondary to plasminogen activator inhibition

    • hypotension

    • myopathy

    • gastrointestinal disturbances

Aminocaproic Acid

Serine Protease Inhibitors: Aprotinin

• Aprotinin:
  • serine protease inhibitor
  • inhibits plasmin-streptokinase complex in patients receiving this thrombolytic treatment
  • Significant reduction in bleeding in certain surgeries:
    • currently approved for patients undergoing coronary artery bypass grafting in which there is a high-risk for excessive blood loss