drugs used in disorders of coagulation
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Drugs Used in Disorders of Coagulation
By
M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
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Drugs Used in Disorders of Coagulation
Stages of Blood Coagulation Nomenclature Thrombus Formation Prothrombotics & Antithrombotics DIC Anticoagulant Drugs Regulation of Fibrinolysis Fibrinolytic Drugs Fibrinolytic Inhibitors Anti Platelet Drugs Plasma fractions Drug Pictures
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Stages of Blood Coagulation
Vasospasm Platelet adhesion Platelet aggregation Viscous metamorphosis Activation of coagulation factors Fibrin synthesis Summary of coagulation process
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EDTA: Ethylene Diamine Tetraacetic Acid
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Blood plasma after the addition of Tissue Factor. The gel-like structure is strong enough to hold a steel ball.
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Nomenclature Thrombus: Clot Prothrombotic: Promotes clot formation. Antithrombotic: Inhibits clot formation. Coagulation: The process of clot formation. Procoagulant: Promotes clot formation. Anticoagulant: Inhibits clot formation. Fibrinolysis: The process of dissolving the fibrin. Fibrinolytic: Promotes dissolving the fibrin. Fibrinolytic Inhibitor: Inhibits dissolving the fibrin.
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Thrombus Formation
White thrombus: forms in arteries by adherence of platelets
Red thrombus: forms around a white thrombus or in low-pressure
veins Consists of a fibrin network in which red cells are
enmeshed The platelets dominate the arterial thrombus
and the fibrin tail dominates the venous thrombus
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Prothrombotics & Antithrombotics
Platelet ADP: a powerful inducer of platelet aggregation
Platelets Thromboxane A2 (TXA2): induces thrombogenesis and vasoconstriction
Platelets Serotonin (5-HT): stimulating further aggregation and vasoconstriction
Endothelial Prostacyclin (PGI2): inhibits thrombus formation
Endogenous anticoagulants: protein C and S.
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DIC
Introduction Diagnosis Treatment
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DIC Introduction
There are inhibitors that inactivate the coagulation proteins as they escape from the site of vessel injury
They include: α1-antiprotease, α2-macroglobulin,α2-antiplasmin, and antithrombin
If this system is overwhelmed, Disseminated Intravascular Coagulation (DIC) occurs
DIC is seen in: massive tissue injury, abruptio placentae, or bacterial sepsis
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DIC. Note the characteristic skin hemorrhage ranging from small purpuric lesions to larger ecchymoses.
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DIC
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DIC Diagnosis
DIC should prompt a search for the underlying disease if not already apparent.
No single test establishes the diagnosis of DIC. The tests include:
aPTT, PT, thrombin time (TT) Fibrin degradation products (FDP) Platelet and RBC count Blood smear.
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DIC Diagnosis (Cont’d)
Common findings include: The prolongation of PT and/or aPTT Platelet counts 100,000/mm3, or a rapid decline in platelet
numbers The presence of schistocytes (fragmented red cells) Elevated levels of FDP.
The most sensitive test for DIC is the FDP level. Because fibrinogen has a prolonged half-life, plasma
levels diminish acutely only in severe cases of DIC.
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DIC Treatment The control of bleeding requires replacement
therapy.
FFP is indicated (1 unit of FFP increases most coagulation factors by 3% in an adult without DIC).
Brisk hyperfibrinolysis or low levels of fibrinogen requires cryoprecipitate.
Cryoprecipitate is plasma fraction enriched for fibrinogen, FVIII, and vWF.
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DIC Treatment (Cont’d)
The replacement of 10 U of cryoprecipitate for every 2–3 U of FFP is sufficient to correct the hemostasis.
Platelet concentrates 1–2 U/10 kg body weight are sufficient for DIC patients with severe thrombocytopenia.
Clotting factor concentrates are NOT used. Because single factor replacement has limited
efficacy for control of bleeding.
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Anticoagulant Drugs
Parenteral: Heparin Hirudin
Oral: Warfarin
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Heparin Antithrombin inhibits thrombin (II), VIIa, IXa, Xa,
XIa and XIIa (2 7 9 10 11 12) Heparin accelerates the reaction 1000 fold Heparin is not consumed and after reaction binds to
more antithrombin It is extracted from porcine intestine and bovine lung LMW heparins for thromboembolism include:
Enoxaparin Dalteparin
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Heparin Toxicity
The major adverse effect is bleeding Elderly women and patients with renal failure
are more prone to hemorrhage It causes transient thrombocytopenia in 25% of
patients The heparin-induced antibody, causes platelet
aggregation and thromboembolism
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Heparin Contraindications Hypersensitivity to the drug Active bleeding & hemophilics Thrombocytopenia & purpura Severe hypertension, intracranial hemorrhage Infective endocarditis & active tuberculosis Ulcerative lesions of the GI tract Threatened abortion Visceral carcinoma & advanced hepatic or renal disease Recent surgery of the brain, spinal cord or eye Patients undergoing lumbar puncture or regional
anesthesia
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Heparin Administration & Dosage
Heparin should prolong the activated partial thromboplastin time (aPTT) 2–2.5 times
Must never be administered intramuscularly (hematoma at the injection)
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Reversal of Heparin Action
Discontinuance of the drug
Protamine sulfate (heparin antagonist)
Excess protamine must be avoided; it also has an anticoagulant effect
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Hirudin
Hirudin is a thrombin inhibitor from the leech (Hirudo medicinalis) now available as Lepirudin
Its action is independent of antithrombin so inactivates fibrin-bound thrombin in thrombi
Is monitored by the aPTT
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(Hirudo medicinalis)
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Warfarin
Found in spoiled sweet clover silage causing bleeding in cattle
It prevents activation of vitamin K Blocks synthesis of prothrombin (II), VII, IX, and
X as well as the anticoagulant proteins C and S There is an 8 to 12 hour delay in its action Inhibition of coagulation is dependent on the half-
lives of inhibited factors
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Warfarin toxicity
Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus
The drug can also cause abnormal bone formation Warfarin should NEVER be administered during
pregnancy
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Administration & Dosage of Warfarin
The adjustment of the prothrombin time (PT) takes 1 week
The prothrombin time should be 25% of normal If prothrombin time < 20%, the warfarin should be
reduced or omitted The therapeutic range for warfarin is now defined as
International Normalized Ratio (INR) Dosage is adjusted to achieve an INR of 2.5 – 3.5
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Warfarin drug interaction
The most serious are those that increase the risk of bleeding and include: Phenylbutazone, also inhibits platelet function and
may induce peptic ulcer Metronidazole, fluconazole, and trimethoprim-
sulfamethoxazole Aspirin, hepatic disease, and hyperthyroidism The third-generation cephalosporins Heparin
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Warfarin drug interaction Cont,d
Drugs that decrease warfarin effect: Vitamin K Hypothyroidism
Drugs with no effect on warfarin: Benzodiazepines Acetaminophen Opioids Indomethacin Most antibiotics
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Warfarin Reversal of Action Stopping the drug Fresh-frozen plasma (FFP) Vitamin K
Vitamin K1 (Phytonadione) is found in food Vitamin K2 (Menaquinone) is synthesized by intestinal
bacteria Vitamin K3 (Menadione) should NEVER be used. It is
ineffective in warfarin overdosage Onset of effect is delayed for 6 hours Rapid infusion of vitamin K1 can produce dyspnea,
chest and back pain, and DEATH
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Regulation of Fibrinolysis
Fibrinolysis is fulfilled by conversion of plasminogen to plasmin
Injured cells release activators of plasminogen Plasmin limits thrombosis by digestion of fibrin Fibrinolysis is therapeutic for thrombotic disease Heparin and the oral anticoagulant drugs do not
affect the fibrinolytic mechanism
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Fibrinolytic Drugs
Fibrinolytic drugs activate formation of plasmin Usually both protective and target thrombi are
broken The drugs include:
Streptokinase & Urokinase Alteplase & Anistreplase (plasminogen+streptokinase) Tissue plasminogen activator (t-PA)
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Indications of Fibrinolytic Drugs
Multiple pulmonary emboli
Central deep venous thrombosis
Acute myocardial infarction
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Fibrinolytic Inhibitors
Inhibit plasminogen activation and include: Aminocaproic acid Tranexamic acid
Clinical uses: Adjunctive therapy in hemophilia Therapy for bleeding from fibrinolytic drugs
Adverse effect is intravascular thrombosis Should not be used in DIC or bleeding of the kidney
and ureters (potential for excessive clotting)
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Fibrinolytic Inhibitors Cont,d
Aprotinin inhibits fibrinolysis by free plasmin It also inhibits the plasmin-streptokinase
complex in patients who have received it Approved for use in patients undergoing
coronary artery bypass grafting
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Plasma Fractions
Spontaneous bleeding occurs when factor activity is less than 5–10% of normal
Factor VIII deficiency (classic hemophilia) & factor IX deficiency (Christmas disease) are the most common heritable coagulation defects
Cryoprecipitate is used to treat fibrinogen defects in DIC & liver disease
Desmopressin acetate increases the factor VIII activity and is used for minor surgery (tooth extraction)
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SummaryIn English
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Thank youAny question?