Drugs Used in Coagulation Disorder

• Anticoagulant Drugs

• Fibrolytic Drugs

• Antithrombotic / Antiplatelet Drugs

Hemostasis

• Hemostasis is the arrest of blood loss from damaged vessels and is essential for survival.

• The main phenomena are: 1) platelet activation, 2) blood coagulation 3) vascular contraction.

Hemostasis Dysregulation

• Common causes of dysregulated hemostasis include:

1. hereditary or acquired defects in the clotting mechanism.

2.secondary effects of infection or cancer.

MECHANISMS OF BLOOD COAGULATION

• Simultaneously, the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot, which stabilizes the platelet plug .

Hemostasis Defects

1. Primary hemostasis : Patients with defects in the formation of the

primary platelet plug (defects in primary hemostasis, eg, platelet function defects, von Willebrand disease) typically bleed from mucosal sites (gingiva, skin, heavy menses) with injury.

Hemostasis Defects

2. Secondary hemostasis: In contrast, patients with defects in the

clotting mechanism (secondary hemostasis, eg, hemophilia A) tend to bleed into deep tissues (joints, muscle, retroperitoneum), often with no apparent inciting event, and bleeding may recur unpredictably.

Thrombus (Blood Clot) formation

• It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e. clotting factors).

• A thrombus is normal in cases of injury, but pathologic in instances of thrombosis.

Thrombus

• Thrombus has two type:1.Platelet-rich thrombi (white thrombi) that

form in arteries. Occlusive arterial thrombi cause serious

disease by producing downstream ischemia of extremities or vital organs, and can result in limb amputation or organ failure.

Thrombus

2. Venous clots tend to be more fibrin-rich, contain large numbers of trapped red blood cells, and are recognized pathologically as red thrombi.Venous thrombi can cause severe swelling and pain of the affected extremity, but the most feared consequence is pulmonary embolism.

BLOOD COAGULATION CASCADE

• Blood coagulates by the transformation of soluble fibrinogen into insoluble fibrin.

• Several circulating proteins interact in a cascading series of limited proteolytic reactions.

http://en.wikipedia.org/wiki/File:Coagulation_full.svg

Thrombin roles

1. Conversion of fibrinogen to fibrin2. Activation many upstream clotting factors (V,

VIII, XI and protein C), leading to more thrombin generation.

3. Activation factor XIII, a transaminase that cross-links the fibrin polymer and stabilizes the clot.

Thrombin roles

4. Thrombin is a potent platelet activator and mitogen.

5. Thrombin also exerts anticoagulant effects by activating the protein C pathway, which attenuates the clotting response.

endogenous anticoagulant

1. Antithrombin (AT) is an endogenous anticoagulant and a member of the serine protease inhibitor (serpin) family; it inactivates the serine proteases IIa, IXa, Xa, XIa, and XIIa.

2. The endogenous anticoagulants protein C and protein S attenuate the blood clotting cascade by proteolysis of the two cofactors Va and VIIIa.

defect in natural anticoagulant system

• The most common defect in the natural anticoagulant system is a mutation in factor V (factor V Leiden), which results in resistance to inactivation by the protein C, protein S mechanism.

Fibrinolysis

• Fibrinolysis refers to the process of fibrin digestion by the fibrin-specific protease, plasmin. In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA), which converts plasminogen to plasmin. Plasmin remodels the thrombus and limits its extension by proteolytic digestion of fibrin.

regulators of fibrinolysis

• endothelial cells synthesize and release plasminogen activator inhibitor (PAI), which inhibits t-PA; in addition a2 antiplasmin circulates in the blood at high concentrations and under physiologic conditions will rapidly inactivate any plasmin that is not clot-bound.

disseminated intravascular coagulation (DIC)

• If the coagulation and fibrinolytic systems are pathologically activated, the hemostatic system may careen out of control, leading to generalized intravascular clotting and bleeding.

disseminated intravascular coagulation (DIC)

• DIC occur after massive tissue injury, advanced cancers, obstetric emergencies such as abruptio placentae or retained products of conception, or bacterial sepsis. DIC is often fatal.

fibrinolytic system

• Increased fibrinolysis is effective therapy for thrombotic disease.

• Tissue plasminogen activator, urokinase, and streptokinase all activate the fibrinolytic system. Aminocaproic acid is a clinically useful inhibitor of fibrinolysis and is useful in some bleeding disorders.

• Heparin and the oral anticoagulant drugs do not affect the fibrinolytic mechanism.

Anticoagulant Drugs

1. HeparinMechanism of Action: Binds to endothelial cell surface membrane 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.

Heparin Toxicity• major adverse/toxic effect: bleeding• Risk managed by attention to: patient selection dosage control monitoring of partial thromboplastin time (PTT) Factors predisposing to hemorrhage: elderly renal failure patients Long-term heparin use: increased incidence of: osteoporosis spontaneous fractures

Heparin Contraindications

1. Heparin hypersensitivity2. Hematologic disease: hemophilia,

thrombocytopenia, purpura3. Cardiovascular: severe hypertension,

intracranial hemorrhage, infective endocarditis

4. Active tuberculosis

Heparin Contraindications

5. Gastrointestinal tract: ulcerative lesions visceral carcinoma6. Advanced hepatic/renal dysfunction7. Threatened abortion8. Related to medical procedures: a. after brain, spinal cord, or eye surgery b. lumbar puncture/regional anesthesia blocks

Reversal of Heparin Effects

• Drug discontinuation• Use specific antagonist, e.g. protamine sulfate

(note!- excess protamine also has an anticoagulant effect)

Oral anticoagulants: Warfarin

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

• It has equal amounts of two enantiomers. levorotatory-S-warfarin: four times more

potent than dextrorotatory- R-warfarin.

Mechanism of Action

• Coumarin anticoagulants Blockade of g-carboxylation of glutamate residues in:

1. prothrombin 2. factors: VII, IX, X 3. endogenous anticoagulant protein C g-carboxylation results in biologically inactive

molecules. Carboxylation reaction is coupled with oxidative

deactivation of vitamin K.

Coumarin anticoagulants

• Anticoagulant effect dependent on two considerations:

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

2.Altered degradation rates of these factors Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis.

Toxicity of coumarin anticoagulants

• Warfarin: crosses the placenta and resulted in hemorrhagic fetal disorder Fetal abnormal bone formation (Warfarin effects on fetal proteins with g-carboxylglutamate residues).

• Never administer Warfarin during pregnancy.

Other Adverse Effects of coumarin anticoagulants

• Cutaneous necrosis related to reduced protein C activity

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

Drug Interactions of oral anticoagulants

• Drug interactions occur at:1.Pharmacokinetic2.Pharmacodynamic

Reversal of Warfarin anticoagulant effects

1. discontinue drug administration2. administer vitamin K1 (phytonadione) &

fresh-frozen plasma or factor IX concentrates. for establishing of normal clotting factor

activity in serious bleeding: large amounts of vitamin K1 (intravenous

administration), factor IX concentrates, and possibly whole blood transfusion.

Fibrolytic Drugs

1. Fibrolytic drugs Lyse thrombi by catalyzing plasmin (serine protease) formation from plasminogen (the zymogen precursor).

2. Lytic state induced following IV administration.

Note: both target thromboemboli and hemostatic thrombi are dissolved.

Fibrinolysis• Major process: conversion plasminogen (inactive) to

plasmin (proteolytic enzyme, active)• plasminogen activators: released from damaged cells.• Plasmin: limits thrombosis extension (by proteolytic

fibrin digestion)

• Activators of fibrinolysis:1. tissue plasminogen activator (t-PA)2. Urokinase3. Streptokinase

• Inhibitors of fibrinolysis: aminocaproic acid (Amicar)

Fibrinolysis

Fibrolytic Drugs

1. Streptokinase2. Alteplase3. Tissue plasminogen activator4. Reteplase5. Urokinase

Streptokinase

• Streptokinase is a protein (not an enzyme) which is derived from streptococci.

• It combines with plasminogen (proactivator) and make an enzymic complex that catalyzes plasminogen to active plasmin.

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

plasminogen to 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

Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC):

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

• Rapid IV injection enhances clot selectivity: more plasminogen activity clot-associated than

associated with free blood plasminogen resulted to more thrombolytic activity.

Tissue Plasminogen Activators (t-PA)

• Tissue Plasminogen Activators (t-PA) activate preferential fibrin-bound plasminogen.

Human t-PA (recombinant DNA technology):1.Alteplase: unmodified human t-PA2.Reteplase: modified human t-PA

Clinical Uses of Fibrolytic Drugs

1. Multiple pulmonary emboli (not requiring surgery)

2. Central deep venous thrombosis 2a. superior vena caval syndrome 2b. ascending thrombophlebitis (iliofemoral

vein)3. Intra-arterial use: peripheral vascular disease4. Acute Myocardial Infarction: careful patient

selection (early intervention)

Antithrombotic / Antiplatelet Drugs

• Antithrombotic agents are regulated platelet function by three types substances:

1.Substances develop outside the platelet but interact with platelet membrane receptors:

a. Catecholaminesb.Collagenc. Thrombind.Prostacyclin

Antithrombotic / Antiplatelet Drugs

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

a. ADPb. Prostaglandin D2c. Prostaglandin E2d. Serotonin

Antithrombotic / Antiplatelet Drugs

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

a. Prostaglandin endoperoxidasesb. Thromboxane A2c. cAMPd. cGMPe. Ca2+

Pharmacological Targets of Antithrombotic Agents

1. Inhibition of prostaglandin metabolism: aspirin

2. Inhibition of ADP-induced platelet aggregation: Clopidogrel and Ticlopidine

3. Blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: Abciximab & Integrelin

Antithrombotic / Antiplatelet Drugs: Aspirin

• Mechanism of Action: Prostaglandin thromboxane A2 causes:

platelet aggregation, platelet shape changing and platelet degranulation.

Inhibition of this process inhibits platelet aggregation, prolonging in vivo bleeding time.

Antithrombotic / Antiplatelet Drugs: Aspirin

• 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 of Aspirin

• As antithrombotic effects for possible primary prophylaxis of myocardial infarction (FDA approval).

• Adverse Effects:• aspirin increased gastrointestinal bleeding• increased frequency of peptic ulcer disease

Antithrombotic / Antiplatelet Drugs: Ticlopidine

• Inhibits ADP platelet pathway: reduces platelet aggregation.

It has no effect on prostaglandin metabolism.

Clinical Use of Ticlopidine (efficacy in prevention): completed strokes unstable angina transient ischemic attacks

Antithrombotic / Antiplatelet Drugs: Ticlopidine

• Adverse Effect of ticlopidine:• gastrointestinal disturbance(frequency =

20%)• Hemorrhage (frequency = 5%)• leukopenia (serious) (frequency = 1%) that

requires blood testing during first three months of ticlopidine treatment