Drugs affecting coagulation

Hemostasis Prevention of blood loss when vessel rupture .

Hemostasis Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and Limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs

HEMOSTASIS 1. VASCULAR PHASE 2. PLATELET PHASE 3. COAGULATION PHASE 4. FIBRINOLYTIC PHASE

Normal Hemostasis Following injury to a blood vessel: Vascular retraction (vasoconstriction) to slow blood loss 2. Adherence of platelets to the vessel wall (endothelium) and then to each other to form a platelet plug 3. Initiation of the coagulation cascade resulting in the formation and deposition of fibrin to form a clot 5

COAGULATION PHASE THROUGH TWO SEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE.

THE CLOTTING MECHANISM INTRINSIC EXTRINSIC Collagen Tissue Thromboplastin XII XI VII IX VIII X V FIBRINOGEN (I) PROTHROMBIN THROMBIN (II) (III) FIBRIN

Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI 2 ) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A 2 (TXA 2 ), and serotonin (5-HT)

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 surface sites (gingiva, skin, heavy menses) with injury.

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.

FIBRINOLYTIC PHASE ANTICLOTTING MECHANISMS ARE ACTIVATED TO ALLOW CLOT DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL. Blood clot are broken down by plasmin which is derived from plasma protein plasminogen.

Drug used to break up thrombi A- antithrombotic drug B- anticoagulant drug C- fibrinolytic drug

Antithrombotic drug (Antiplatelet Drugs)

Antithrombotic drug (Antiplatelet drugs) antithrombotic drug interfere with platelet adhesion and aggregation Aspirin (irreversible effect for life of the platelet ~ 7-10 days) Clopidogrel Ticlopidine Dipyridamole

1- Aspirin

mechanism of action Aspirin block thromboxane A2 synthesis, a potent platelet aggregation The resulting suppression of platelet aggregation last for the life of the platelet (Approximately 7 to 10 days)

uses in the prophylactic of cerebral ischemia to reduce The incidence of recurrent myocardial infraction to decrease mortality in postmyocardial infraction patient.

Aspirin and Bleeding All studies found no significant difference in perioperative or postoperative blood loss between patients taking aspirin and controls Conclusion: Aspirin should not be withdrawn in most cases

If pt is on aspirin, and intraoperative bleeding is feared, a short-acting NSAID can be temporarily substituted.

Adverse effect GIT irritation and bleeding Tinnitus

Clopidogrel Ticlopidine mechanisms of action Inhibits platelet aggregation and platelet - platelet interactions

uses in patients contraindication or unresponsive to aspirin Preventing cerebrovascular and cardiovasculare as well as vascular disease by prevent thrombus formation .

Adverse effects sever bone marrow toxicity including aplastic anemia , agranulocytosis

Dipyridamol (vasodilator ) mechanisms of action Decease platelet adhesion by potentiates action of prostacyclin and inhibits platelet phosphdiestrase

uses Used with aspirin to prevent thrombosis To treat angina pectoris Used with aspirin to prevent thrombosis as vasodilator during myocardial perfusion scan (cardiac stress test )

Anticoagulant drugs

Anticoagulant drugs Differentiated on basis of A- route of administration 1- Parenteral Anticoagulant eg heparin . 2- subcutaneous Anticoagulant eg enoxaparin , dalteparin 3- oral Anticoagulant eg coumarin derivative , including warfarin

Anticoagulant drugs B- Direct or indirect interfere with the normal clotting mechanism of blood and reduce the incidence of thrombembolic disorder Either inhibit of the coagulation factors ( heparin ) (direct interfere ) Or interfere with synthesis of coagulation factors (warfarin ) . (indirect interfere )

Patient receiving anticoagulant therapy include those with history of : 1- myocardial infraction 2 - cerebrovascular thrombosis 3- venous thrombosis 4- pulmonary embolism 5 - before and during dialysis.

HEPARIN Mechanism of action: -Interfere with blood coagulation by inhibit the conversion of prothrombin to thrombin and fibrinogen to fibrin - Heparin accelerate the action of antithrombine III to neutralize thrombin (factor IIa )

Therapeutic uses of heparin: 1- for treatment of deep vein thrombosis 2- pulmonary embolism 3. as a prophylactic to prevent post operative venous embolism in some patient .

Therapeutic uses of heparin: 4. in acute case of myocardial infraction . 5. in dialysis mechanism to prevent thrombosis. 6. it is drug of choice for treating pregnant women with prosthetic heart valves or venous thromboembolism because it dose not cross the placenta.

Pharmacokinetic: Metabolize in liver Excreted in urine Given parentally: IV: Onset immediate; peak minutes; duration 2–6 h SC: Onset 20–60 min; peak 2–4 h; duration 8–12 h T½: 30–180 min

Adverse effect 1.bleeding complication 2. hypersensitivity reaction 3.thrombocytopenia

Contraindications Hypersensitive to heparin . Bleeding disorder Alcoholic person Surgery of brain .

Subcutaneous Anticoagulant eg enoxaparin , dalteparin mechanisms of action antifactor Xa , antifactor IIa activity

Oral Anticoagulants (Indirect acting) Coumarin Derivatives (dicoumarol, warfarin)

Coumarin antagonizes the production of vitamin K Vitamin K is necessary for the synthesis of four of the coagulation factors (VII, IX, X and prothrombin)

Conditions for which Coumarin is prescribed to prevent unwanted blood clotting Prophylaxis/Treatment of: Venous thrombosis Pulmonary embolism Atrial fibrillation Myocardial infarction Mechanical prosthetic heart valves Recurrent systemic embolism

Pharmacologic Properties (warfarin: Coumadin) Taken orally Metabolized in the liver Half-life: 1.5-2.5 days Duration of action: 2-5 days. Excreted in urine and feces Contraindication : pregnancy and bleeding disorder

Drug interaction Potentiation of anticoagulant effect of warfarin 1.aspirin , phenylbutazone cause inhibition of platelet aggregation . 2.acute alcohol intoxication ,cimetidine, chloramphenicol ,disulfiram, metronidazole phenylbutazone cause inhibition of warfarin metabolism

Drug interaction Attenuation of anticoagulant Chronic alcohol ingestion ,barbiturate, grisofulvin cause stimulation of warfarin metabolism

Drug interaction Disease state : vit K deficiency Hepatic disease that impairs synthesis of clotting factors.

Fibrinolytic (Thromblytic)drugs Agent that activate the conversion of plasminogen to plasmin then hydrolyze fibrin and thus dissolve clot .

Streptokinase Mechanism of action Streptokinase acts indirectly by forming an activator complex with plasminogen action occurs both within thrombi and circulating blood , leading to lysis of both normal and pathogenic thrombi . Antidote : aminocaproic or tranexamic acid.

Uses of Streptokinase Acute pulmonary embolism Deep venous thrombosis Myocardial infraction Atrial thrombosis

Adverse effect of Streptokinase Bleeding disorder hypersensitivity

Alteplase and reteplase Has low affinity for free plasminogen but rapidly activate plasminogen bound to fibrin in thrombus or haemostatic plug thus is fibrin selective.

Uses of Alteplase and reteplase Treatment of myocardial infraction Massive pulmonary embolism Dissolve older clot

Hemostatic drugs

Hemostatic drugs A-Vitamin K This fat-soluble vitamin is found in leafy green vegetables Its produced by bacteria that colonize the human intestine and needs bile salt for absorption . Its require in synthesis of prothrombin (factor II) and factorXII , IX, X

Uses Prevention of hemorrhagic disease of the newborn (I.M , S.C) Treatment of dietary Vit K deficiencies and reversal of the effect of warfarin (oral or parentral ) Adverse effect Hemolysis , jaundice , and hyperbilirubinemia occasionally occur in newborn.

B- Plasma fraction Available as factor VIII concentrate and factor IX concentrate , either from pooled human plasma or as recombinant antihemophilic factor . Uses: hemophilias A and B marked by deficiencies of factor VIII and factor IX. Adverse effect : risk of AIDS and hepatitis transmission from concentrated plasma fraction .

C- Fibrinolytic inhibitor (aminocaproic acid ) Uses : systemic or urinary hyperfibrinolysis (as in aplastic anemia, hepatic cirrhosis ) D - Protamine sulfate Mechanism of action Chemical antagonist of heparin Uses : hemorrhagic associated with heparin overdose .

DENTAL PATIENTS LOW RISK MODERATE RISK Normal Laboratory Results Patients with No Hx of Bleeding Disorders Normal Laboratory Results MODERATE RISK Patients on Chronic Oral Anticoagulant Therapy. PT is 1.5 - 2 Times Control Range Patients on Chronic Aspirin Therapy

DENTAL PATIENTS HIGH RISK Patients with Known Bleeding Disorders Patients without Known Bleeding Disorders Who Have Abnormal Laboratory Results

DENTAL MANAGEMENT LOW RISK PATIENTS MODERATE RISK PATIENTS Normal Protocol MODERATE RISK PATIENTS Anticoagulants - Consult Physician Aspirin Therapy - BT, Consult Physician

DENTAL MANAGEMENT HIGH RISK PATIENTS (Factor Replacement) Close Coordination with Physician Hospitalization (Platelet Transfusion) (Factor Replacement) (Vit K Therapy) (Dialysis)

Local Measures to Control Postoperative Bleeding Careful, a traumatic surgical technique Post-operative pressure pack (damp gauze for 30-60 minutes); especially important for flap compression Use of absorbable hemostatic agent in socket (e.g. Gelfoam,Avitene,Surgicel) Careful suturing; primary closure over sockets not essential May use antifibrinolytic agents: tranexamic acid [Cyklokapron Oral] or epsilon amino caproic acid [Amicar] as a mouthwash or to soak pressure gauzes

Antifibrinolytic Mouthrinses Epsilon amino caproic acid (Amicar) Syrup (1.25 gm/5cc) , Use either as mouthwash or as a soak for the pressure gauze Tranexamic acid (Cyklokapron) Used topically as a mouthwash for 2 minutes,

Additional Postoperative Measures For analgesia, consider use of Acetaminophen. Codeine COX 2 inhibitor (rofecoxib) Avoid drugs that increase bleeding For continued bleeding, 25% Amicar soaked gauze pressure pack Consider intranasal desmopressin acetate spray; for 1-2 days; Stimulates the release of factor VIII and vWFactor Vitamin K; 2.5-25 mg iv, im, sc, or oral

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