FIBRINOLYTICS
Moya McLeod
MD7
March 14, 2015.
Coagulants
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
Plasma Fractions-- Bleeding due to factor deficiencies
Factors:
Coagulation defects: primarily - Factor VIII deficiency --classic hemophilia (hemophilia
A)
Hypotension
Myopathy
Gastrointestinal disturbances
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
Anti-Coagulants
Heparin
Composition:
Sulfated muco-polysaccharides (heterogenous)
Mechanism 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
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
Heparin hypersensitivity
Hematologic disease:
Hemophilia, thrombocytopenia, purpura,
Cardiovascular:
Severe hypertension, intracranial hemorrhage,
infective endocarditis
Active tuberculosis
Gastrointestinal tract
Ulcerative lesions
Visceral carcinoma
Threatened abortion
Warfarin
Chemistry/Pharmacokinetics:
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%)
Race mate- equal amounts of two enantiomorphism
Levorotatory-S-warfarin: four times more
potent than dextrorotatory- R-warfarin
Mechanism of Action:
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
Partially inhibited synthesis of the four vitamin Kdependent clotting factors and
Altered degradation rates of these factors.
Higher initial doses (loading doses) speed onset by
maximally inhibiting synthesis
Toxicity:
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:
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)
Antithrombotic -- Antiplatelet Drugs
Overview: antithrombotic agents
Regulation of platelet function -- Three types of
substances:
Substances developed outside the platelet but
interacts with platelet membrane receptors:
catecholamines
Collagen
Thrombin
Prostacyclin
Agents generated internal to the platelet and interact
with membrane receptors:
ADP
Prostaglandin D2
Prostaglandin E2
Serotonin
Agents generated internal to the platelet and interact
within the platelet:
Prostaglandin endoperoxidases
Thromboxane A2
cAMP
cGMP
Ca2+
Pharmacological Targets:
atrial fibrillation
prosthetic heart valves
Early postoperative ambulation-- reducing venous
stasis
1 Also effective: external pneumatic leg compression
Enoxaparin (Lovenox)-- approved for prophylaxis
only in hip replacement patients.
Venous Thrombosis -- established