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ANTI-COAGULANTS AND

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)

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 (Amicar)
Competitive inhibitor of plasminogen activation
tranexamic acid -- aminocaproic acid analog; similar
activity
Clinical Uses:
Therapy for bleeding following fibrolytic treatment
Adjunctive therapy in hemophilia
Prophylaxis: re-bleeding from intracranial aneurysms
Adverse Effects:
Intravascular thrombosis secondary to plasminogen
activator inhibition

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

{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 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- same sources; amount specified in milligrams
Dalteparin and danaproid- amounts specified in anti-factor
Xa units
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
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-induceddiscontinue heparin
Contraindications:

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:
Drug discontinuation
Use specific antagonist, e.g. protamine sulfate (note:
excess protamine also has an anticoagulant effect)

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:

Cutaneous necrosis related to reduced protein C


activity
Rare: reduced protein C activity breast, fatty
tissues, intestine, extremity infarction
Drug-Drug Interactions: oral anticoagulants
Pharmacokinetic effects include:
Enzyme induction
Enzyme induction
Reduced plasma protein binding
Pharmacodynamic effects include:
Synergistic interactions with Warfarin
1 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 anticoagulation (promote bleeding risk)
Most dangerous: pharmacokinetic interactions with:
pyrazolones phenylbutazone & sulfinpyrazone-effects: an added hypoprothrombinemia, Platelet
function inhibition, Promotion: peptic ulcer disease
Metronidazole, fluconazole, trimethoprimsulfamethoxazole: Stereo-selective in addition of Swarfarin metabolism
Amiodarone, disulfram, cimetadine:
1 Inhibit metabolism of Warfarin (both enantiomorphs)
Aspirin, hepatic disease, hypothyroidism -- enhance
Warfarin effects {pharmacodynamic}
1 Aspirin: effects on platelets
2 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
Lyse thrombi by catalyzing plasmin (serine protease)
formation from plasminogen (the zymogen precursor)
Lytic state induced following IV administration
Note: both target thrombo-emboli 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 (pro-activator)
Enzymatic 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) promotes plasmin formation inside
the thrombus yse 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)
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:

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
Inhibition 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 non-steroidal
anti-inflammatory drugs
Clinical Use --antithrombotic effects
Possible primary prophylaxis of myocardial infarction
FDA approval for this indication
Adverse Effects:
Increased gastrointestinal bleeding
Increased frequency of peptic ulcer disease.
Dietary: antithrombotic effects
Un-saturated fatty acid eicosapentaenoic acid -- generates
prostaglandin I3 and thromboxane A3, anti-aggregation
agents
Ticlopidine:
Inhibits ADP platelet pathway: reduces platelet aggregation
No effect on prostaglandin metabolism
Clinical Use- Efficacy in prevention:
Completed strokes
Unstable angina
Transient ischemic attacks
Adverse Effect:
Gastrointestinal disturbance: frequency = 20%
Hemorrhage: frequency = 5%
Leukopenia (serious): frequency: = 1%

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
1 Adjunctive treatment in high-risk angioplasty and
atherectomy
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
1 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
1 Intermittent administration (effective prophylaxis) -subcutaneous
Oral Anticoagulants:
1 Generally limited use due to bleeding risk/laboratory prothrombin
time monitoring
2 Effective prophylaxis for patients with:

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

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:
1 Evaluate for protein C or protein S deficiency
2 Antithrombin III concentrate: maybe helpful in deficient
patients
3 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
1 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:
1 Beta-blockers
2 Calcium channel blockers
3 Fibrolytic agents