Anticoagulants, Fibrinolytics, and Antiplatelets
Mechanism of Action Absorption & Distribution
Aspirin
- Enzymatic inhibition of prostaglandin
synthase enzymes/COX
- Action on platelet COX-1 is permanent,
lasting for the life of the platelet (7-10 days)
Dipyridamole (Persantine, Aggrenox*)
- Interferes with platelet function by
increasing cellular cAMP
- Inhibition cNT PDE, blockade of adenosine
uptake via A2 receptors
- stimulate adenylyl cyclise
- ñ cellular cAMP
Ticlopidine (Ticlid)
- thienopyridine that inhibits P2Y12 receptor
by forming disulfide bridge between thiol on
the drug & free cysteine residue in
extracellularregion of receptor
Clopidogrel (Clopivaz, Plavix)
- Irreversible inhibitor of platelet P2Y12
receptors
Prasugrel (Effient, efient )
- Among newest, thienopyridine class;
prodrug > requires metabolic activation
- Active metabolites bind irreversibly to P2Y12r
Glycoprotein IIb / IIIa Inhibitors – Inhibits platelet aggregation
1. Abciximab (Reopro)
- Fab fragment of humanized
mouse monoclonal Ab directed
against Gp IIb/IIIa receptor
- binds to vitronectin receptor on
platelest, vascular endothelial
cells, and smooth muscle cells
2. Eptifibatide (Integrilin)
- Cyclic peptide inhibitor of Gp
IIb/IIa
- Admistered via IV, blocks platelet
aggregation
Source: Goodman and Gillman 12th ed. Chapter 30
Metabolism & Excretion
- rapidly & completely absorbed from
GI tract (partly from stomoach,
mostly in the upper small intestine)
- Peaks: within 1-4 hours
- Food delays absorption
- - 95-99% protein bound
- -
- Rapidly absorbed
- Highly bioavailable
- Short half-life with long duration of
action
- [prodrug] slow onset action
- More rapid onset of action (vs.
ticlopidine, clopidogrel)
- Rapid and complete absorption
from gut
ANTIPLATELET DRUGS
- hepatic metabolism
- renal excretion
- not recommended for patients - Renal: salt a]&water retention, edema
with advanced hepatic/renal - CNS: headache, vertigo, dizziness
disease
- Converted to active thiol
metabolite by hepatic CYP
- 15% of absorbed > metabolic
activation, remainder
inactivated by esterases
- Plasma t1/2 – 30 mins
- Platelet bound t1/2 - long
(days)
- Plasma t1/2 – 2.5 h
- Platelet bound t1/2 – short
(sec)
- cleared by kidneys
Adverse Effects & Precautions
- GI: abd. pain, nausea, anorexia, gastric
erosion/ulcers, anemia, GI haemorrhage
- Platelets: inhibited plt. activation, propensity for
bruising, inc. risk for haemorrhage
- - vasodilator, with warfarin inhibits embolization from
- Nausea, vomiting, diarrhea,
- Severe neutropenia (most serious)
- Fatal agranulocytosis with thrombocytopenia on first
3 mo. of therapy
- Rare AR: thrombocytopenia, leukopenia
- D-D:
~Proton pump inhibitors (inhibitors of
CYP2C19)ð small reduction on clopidogrel’s
inhib effect on ADP-induced platelet aggregation
~Atorvastatin (competitive inhibition of CYP3A4)
reduce clopidogrel’s inhib effect on ADP-induced
platelet aggregation
- CAUTION: those require urgent surgery (at risk
bleeding, stop at least 5d prior) *prolonged effect
after discontinuation; <60kg; with renal impairment
- AR: fatal, life threatening bleed
- C/I cerebrovascular dse
- Bleeding
- Contraindication similar to those for fibrinolytic
agents
- Thrombocytopenia (2% of pxs) – d/t devt of
neoepitopes induced by bound Ab
Therapeutic Use
- antiplatelet
- pain/ mild analgesic
- fever
- Maximal effective dose: 50-320 mg/day
prosthetic heart valves
- [has LITTLE or NO benefit as anti-thrombotic]
- in combination with aspirin as 2° prevention to stroke
and TIAs [BUT recent study and some trials show no
advantage of the combo]
- Prevents CVA in secondary prevention of stroke
- Reduces cardiac events in pts. with unstable angina
- Maximal inhibition of platelet aggregation not seen until
8-11 days
- Inhibition of platelet aggregation persists for a few days
after stopping
- Replaced by clopidogrel d/t AE
- Reduce rate stroke, MI and death with recent
occurrence
- [ with aspirin] prevent recurrent ischemia with unstable
angina
- Post-angioplasty and coronary stent implantation (at
least 4-6wks)
- Established PAD
- Acute coronary syndrome
- Usual dose: 300 / 600 mg
- Alternative to clopidogrel in those with loss-of-function
CYP2C19 allele
- Acute coronary syndromes for coronary intervention
- 2° prevention stroke, nonfatal MI, death
- Prevention stent thrombosis
- Administered to patient undergoing percutaneous
angioplasty for coronary thromboses
- In conjunction with aspirin and heparin: prevent
restenosis, recurrent MI, and death
- 0.25 mg/kg bolus followed by 0.125 ug/kg/min for 12 hrs
or longer
- bolus of 180 ug/kg followed by 2ug/kg/min for up to 96
hrs
- acute coronary syndrome and for angioplastic coronary
interventions
- generally administered in conjunction w/ heparin and
aspirin
- platelet aggregation restored within 6-12 hours after
stopping infusion
Anticoagulants, Fibrinolytics, and Antiplatelets
3. Tirofiban (Aggrastat)
- Nonpeptide RGD-mimetic
Newer Antiplatelet Agents
1. Cangrelor
- adenosine analog that
- binds reversibly to P2Y12 and
inhibits its activity
2. Ticagrelor
- orally active reversible
- inhibitor of P2Y12
- produces greater and more
predictable inhibition of ADP-
induced platelet aggregation
3. SCH530348
- orally active inhibitor of PAR-1
Heparin (Heparin Sodium ADD-Vantage™
Vial, HEPARTN-Rotex, Hep-Pak, Hep-Lock)
- binds to antithrombin via specific
pentasacch. sequence (3-O-sulfated
glucosamine) à conformational change à
active site more accessible to proteases à
accelerates rate at which antithrombin
inhibits coagulation proteases
- Acts in a catalytic fashion: after binding
antithrombin & promoting formation of
covalent complexes bet. antithrombin &
protease à dissociates from the complex
àcatalyze other antithrombin molecules
Low Molecular Weight Heparin
Enoxaparin (LOVENOX), dalteparin
(FRAGMIN), tinzaparin (INNOHEP, others),
ardeparin (NORMIFLO), nadroparin
(FRAXIPARINE, others), and reviparin
(CLIVARINE)
- MOA: same with Heparin
- have little effects on platelets at high doses
- Heparin resistance rarely occurs
Source: Goodman and Gillman 12th ed. Chapter 30
- source: porcine intestinal mucosa
(rich in mast cells)
- not absorbed through GI à given
parenterally
- can be given by
>continous IV infusion
>intermittent (q 4-6h)
>subcutaneous (q 8-12h)
- t ½:
>100 units/kg à 1 hr
>400 units/kg à 2.5 hr
>800 units/kg à 5 hr
- Does not cross placenta
- Not absorbed through the GI
mucosa > given parenterally
- Absorbed more uniformly after SQ
injection
- t1/2: 4-6 hours
- Plasma t1/2 – 2 h - SE similar to those of eptifibatide
- Platelet bound t1/2 – short
(sec)
- cleared by kidneys
- t1/2 3-6 mins
PARENTERAL ANTICOAGULANTS
- cleared & degraded by Bleeding
reticuloendothelial system - primary untoward effect
- small amount of undegraded - Incidence less in patients treated with LMWH
heparin in urine - Protamine sulphate = antidote for heparin; only
partially reverses the anticoagulant activity of
LMWHs and has no effect on that of fondaparinux.
Heparin-induced thrombocytopenia
- (platelet count <150,000/mL or a 50% decrease from
the pretreatment value) occurs in 0.5% of medical
pts. 5-10 days after initiation of therapy
- Higher in surgical pts. than in medical pts; women
are 2x as prone
Other Toxicities
- Abno. hepatic function tests occur frequently in
patients who are receiving heparin or LMWHs
- Osteoporosis resulting in spontaneous vertebral
fractures can occur, in patients who have received
full therapeutic doses of heparin (>20,000 units/day)
for extended periods; lower with LMWHs or
fondaparinux
- Inhibits synthesis of aldosterone by the adrenal
glands and may cause hyperkalemia
- Cleared almost exclusively in - Same as heparin +
the kidneys - CI in pts. with creatinine clearance <30 mL/min
- Does not cross placenta - Incidence of bleeding is somewhat less in patients
treated with LMWH
- Although incidence may be lower, thrombocytopenia
also occurs with LMWHs and fondaparinux, and
platelet counts should be monitored
- should be discontinued immediately if unexplained
thrombocytopenia or any of the clinical
manifestations mentioned above occur 5 or more
days after beginning therapy, regardless of the dose
or route of administration
- IV initial rate: 0.4 ug/kg/min for 30 mins then continued
at 0.1 mg/kg/min for 12-24 h
- efficacy in non-Q wave MI and unstable angina
- used in conjunction w/ heparin
- IV as bolus followed by an infusion
- when stopped, platelet function recovers within 60 mins
- given BID
- under investigation as an adjunct to aspirin / aspirin +
clopidogrel
- initiate tx of venous thrombosis and pulmonary
embolism
- initial mgmt of patients with unstable angina or acute MI
- coronary balloon angioplasty
- DOC for anticoag in pregnancy
- cardiopulmonary bypass surgery
- DIC
- prevention of post-op DVT
- and pulmo. embolism in pts. w/abdominothoracic
surgery
- therapy monitored by measuring aPTT: if 2-3x the
normal = therapeutic
- Same as heparin +
- Pharmacokinetic properties permit SQ injects once or
twice daily in fixed/weight-adjusted doses w/o
coagulation monitoring > can be used for out-of hospital
mgt.
- Lower risk for heparin-induced thrombocytopenia or
osteoporosis
- Heparin resistance rarely occurs
Anticoagulants, Fibrinolytics, and Antiplatelets
Fondaparinux (Arixtra):
- Synthetic Heparin derivative
- five-saccharide analog that mediates their
interaction with antithrombin
- MOA: same with Heparin
Other Parenteral Agents
Lepirudin (Refludan):
- recombinant derivative of hirudin
(direct thrombin inhibitor in
salivary glands of medicinal leech.
Desirudin (Iprivask):
- recombinant derivative of hirudin;
Lacks sulphate group on Tyr63
Bivalirudin (Angiomax):
- synthetic 20- Amino Acid
polypeptide; Phe-Pro-Arg-
- Pro at catalytic site & tetraglycine
linker
- at exosite I. Thrombin regains
activity by cleaving Arg-Pro.
Argatroban:
- Synthetic compound based on
structure of L-arginine; binds
reversibly to catalytic site of
thrombin
Drotrecogin Alfa (Xigris):
- recombinant form of human
activated protein C; Inhibits
coagulation by proteolytic
inactivation of Factor Va & VIIIa;
also has anti-inflammatory effects
Warfarin
- Synthetic derivative of bishydroxycoumarin
(dicoumarol)
- MOA: Inhibits vitamin K epoxide reductase
(VKOR)
- Lower initial dose-pts with inc. risk of
bleeding (elderly).
- Age correlates with increased sensitivity to
the drug
Source: Goodman and Gillman 12th ed. Chapter 30
- Absorbed more uniformly after
subQ injection
- t ½ : 17 hours
- peak plasma conc in 2hrs
- Binds tightly to catalytic site and
extended substrate recognition site
of thrombin.
- -t ½ : 2 hours after Subcutaneous
injection
- t ½ : 25mins in those with normal
renal function
- Administered via IV
- -Administered via IV; immediate
onset of action
- -t ½ : 40-50mins
- Bioavailability nearly complete
when administered orally,
intravenously, or rectally.
- Food dec. rate of absorption
- Detectable in plasma within 1 hour
of its oral administration
- Peak onset: 2-8 hours.
- Almost completely (99%) bound to
plasma proteins, principally albumin
- Distributes rapidly into a volume
equiv. to the albumin space (0.14
L/kg)
- Conc. in fetal plasma approach the
maternal values
- Warfarin can safely be administered
to nursing mothers(active warfarin
is not found in milk)
- Kidney
- Does not cross placenta
- Excreted by the kidneys
- t ½ : 1.3 hours
- May dev. antibodies against
hirudrin → prolong its t ½ →
paradoxical ↑ aPTT
- Kidney
- Kidney
- Metabolized by hepatic CYPs
- Excreted in bile
ORAL ANTICOAGULANTS
- Warfarin is administered as a Bleeding
racemic mixture of S- and R- -
warfarin.
- S-warfarin is 3-5 fold more
potent and is metabolized
principally by CYP2C9.
- Inactive metabolites excreted
in urine and stool
- Ave. rate of clearance from
plasma: 0.045 mL/min–1.kg–
1.
- t1/2: 25-60 hour), ave. 40
hours
- Duration of action: 2-5 days
- Same as heparin +
- CI: Creatinine clearance <30ml/min, Body weight
<50kg in patients with hip fracture, hip replacement
and knee replacement surgery
- Caution in patients renal failure: may accumulate and
cause bleeding
- Daily monitoring of aPTT
- No antidote
- Caution in patients with decreased renal function
- Daily monitoring of aPTT and Serum Creatinine
- Reduce dosage in patients with moderate or severe
renal impairment.
- Reduce dosage if with hepatic insufficiency
- Adjust dose to maintain aPTT of 1.5-3x the baseline
- Major Adverse Effect: BLEEDING
Major toxicity of warfarin
- Risk of bleeding inc. with intensity and duration of
anticoagulant therapy, the use of other
medications that interfere with hemostasis, and
the presence of a potential anatomical source of
bleeding.
Birth Defects and abortion
- 1st trimester: syndrome char. by nasal hypoplasia
and stippled epiphyseal calcifications that resemble
chondrodysplasia punctata
- 2nd and third trimester: CNS abnormalities
- Fetal or neonatal hemorrhage and intrauterine death
(even when maternal PT values are in the
therapeutic range)
Skin necrosis(rare)
- Appear 3-10 days after treatment is initiated; typically
are on the extremities(adipose tissue, penis, and
female breast also may be involved)
- Same as heparin +
- Initial therapy of DVT & pulmonary embolism
- Less likely to trigger HIT.
- Once daily at fixed dose without coagulation monitoring
- Heparin resistance rarely occurs
- Administered via IV at a dose adjusted to maintain the
aPTT at 1.5-2.5x the median of the lab normal range of
aPTT
- Treatment of Heparin-induced thrombocytopenia
- Prophylaxis of DVT in patients undergoing elective hip
replacement surgery.
- 15mg q12H SubQ injection
- Heparin-induced thrombocytopenia (HIT)
- Alternative to heparin in px undergoing coronary
angioplasty; cardiopulmonary bypass surgery
- Alternative for Lepirudin in patients with or at risk for
HIT.
- Prolongs aPTT and PT
- 96 hours continuous infusion ↓ mortality in adults at risk
for death from severe sepsis if given within 48hrs of
onset of organ dysfunction
Prevention of:
- Progression or recurrence of acute DVT or pulmonary
embolism ff. an initial course of heparin.
- Venous thromboembolism in pts undergoing
orthopedic or gynecological surgery
- *heparin, LMWH, or fondaparinux-cont. for at least 5
days after warfarin Rx is begun & the INR is in the
therapeutic range on 2 consecutive days. (overlap
allows for adequate depletion of the vitamin K-
dependent coagulation factors with long t1/2, esp. factor
II)
- Recurrent coronary ischemia in pts with acute MI
- Systemic embolization in pts with prosthetic heart
valves or chronic atrial fibrillation.
Dosing
- PO, IV
- IM-not recommended, risk of hematoma formation.
- Adult: 2-5 mg/day for 2-4 days, followed by 1-10 mg/day
as indicated by international normalized ratio (INR).
Anticoagulants, Fibrinolytics, and Antiplatelets
Other Vit. K Antagonists
Phenprocoumon
(MARCUMAR)
Acenocoumarol
(SINTHROME)
Indandione derivatives
- Anisindione (MIRADON)
- Phenindione (DINDEVAN)
Rodenticides
- Bromadiolone, brodifacoum,
diphenadione, chlorophacinone,
and pindone
- Long-acting agents (prolongation of
the PT may persist for weeks)
New Oral Anticoagulants
1.Dabigatran Etexilate
(Pradaxa, Pradax)
- Prodrug converted to dabigatran
- Reversibly blocks active site of
thrombin
2. Rivaroxaban (Xarelto)
- Oral factor Xa inhibitor
Streptokinase (STREPTASE):
- protein produced by b-hemolytic
streptococci
- has no intrinsic enzymatic activity
- MOA: forms a stable, noncovalent 1:1
complex with plasminogen à free plasmin
Source: Goodman and Gillman 12th ed. Chapter 30
- Longer plasma t ½ (5 days) than
warfarin
- Slower onset of action a longer
duration of action (7-14 days)
- Shorter t ½ (10-24 hrs)
- More rapid effect on PT
- Shorter duration of action (2 days)
- Similar to warfarin in its kinetics of
action
- Long acting agents ( prolongation of
PT may persist for weeks)
- Oral bioavailability: 6 %
- Peak onset: 2 hours
- Plasma t1/2: 12-14 hours
- Bioavailability=80 %
- Peak onset= 3 hours
- t1/2= 7-11 hours
- -
- Prodrug is metabolized to
active form: dabigatran
- Excretion: N/A
- -excretion= 1/3 is excreted
unchanged in urine
- -remainder is metabolized in
the liver and excreted in feces
or urine
THROMBOLYTIC DRUGS
- Widespread thrombosis of the microvasculature and
can spread rapidly, sometimes becoming necrotic
and requiring disfiguring débridement or occ.
amputation
Purple toe syndrome
- Reversible, sometimes painful, blue-tinged
discoloration of the plantar surfaces and sides of the
toes that blanches with pressure and fades with
elevation of the legs
- Develop 3-8 weeks after initiation of therapy
- Cholesterol emboli released from atheromatous
plaques have been implicated as the cause.
- Alopecia, urticaria, dermatitis, fever, nausea,
diarrhea, abdominal cramps, and anorexia.
(infrequent)
- Can precipitate the syndromes of venous limb
gangrene and multicentric skin necrosis in pts
with heparin-induced thrombocytopenia who are not
receiving parenteral anticoagulant
- administered in daily maintenance doses(0.7-6 mg)
- Maintenance dose: 1-8 mg daily
- Serious hypersensitivity reactions, occasionally fatal, - No clear advantage and may have higher frequency
can occur within a few weeks of starting therapy with untoward effects
this drug and its use is no longer recommended
- Agents of accidental or intentional poisoning
(reversal of coagulopathy can require large doses of
vit. K (i.e., >100 mg/day) for weeks or months.
- - Prevention of venous thromboembolism after elective
hip/knee replacement surgery
- Stroke prevention for patients with atrial fibrillation
- - -thromboprophylaxis after hip/knee replacement therapy
- Less selective than t-PA since it activates both - Higher risk of bleeding compared to t-PA
fibrin-bound plasminogen & fluid-phase “free” - Rarely used clinically for fibrinolysis since the advent of
plasminogen à prone to cause bleeding newer agents
Anticoagulants, Fibrinolytics, and Antiplatelets
Tissue Plasminogen Activator t-PA
(ALTEPLASE, ACTILYSE)
- Serine protease, produced by recombinant
DNA technology
- Poor plasminogen activator in the absence
of fibrin
- MOA: binds to fibrin via lysine binding sites
at its amino terminus and activates bound
plasminogen 100x more rapidly than it
activates free plasminogen
- Recombinant mutant variants:
- Reteplase (RETAVASE) & Tenecteplase
(TNKASE)
- increased t ½ allowing convenient bolus
dosing
- relatively resistant to inhibition by plasma
activator inhibitor-1
- Similar to t-PA in efficacy and toxicity
- t ½: 5 to 10 minutes
- Clearance: primarily by - Under physiologic conditions, the specificity of t-PA - More widely used clinically
hepatic metabolism for fibrin limits systemic formation of plasmin and - t-PA is effective in lysing thrombi during treatment of
induction of a systemic lytic state à less risk of acute myocardial infarction
bleeding - (although efficacies of t-PA & streptokinase in tx of MI
are essentially identical)
THROMBOLYTIC TX TOXICITY: - Current recommended “accelerated” regimen for
- Hemorrhage (major toxicity of coronary thrombolysis:
- all thrombolytic agents) - 15-mg IV bolus,
- Intracranial hemorrhage - Followed by 0.75 mg/kg of body weight over 30 minutes
- (most serious problem) (not to exceed 50 mg)
- hemorrhagic stroke (more common when heparin is - Followed by 0.5 mg/kg (up to 35 mg accumulated dose)
used) over the ff. hour
THROMOBOLYTIC TX C/I:
- Surgery w/in 10 days
- Serious GI bleeding w/in 3 months
- Hx of HPN (diastolic >110 mmHg)
- Active bleeding or hemorrhagic d/o
- Previous CVA or active intracranial process
- Aortic dissection
- Acute pericarditis

Absolute and Relative Contraindicaiton to Fibrinolytic Therapy

Absolute Contraindications
- Prior intracranial hemorrhage
- Known structural cerebral vascular lesion
- Known malignant intracranial neoplasm
- Ischemic stroke within 3 months
- Suspected aortic dissection
- Active bleeding or bleeding diathesis (excluding menses)
- Significant closed-head trauma or facial trauma within 3 months

Relative Contraindications
- Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)
- Traumatic or prolonged CPR or major surgery within 3 weeks
- Recent (within 2-4 weeks) internal bleeding
- Noncompressible vascular punctures
- For streptokinase: prior exposure (more than 5 days ago) or prior allergic reaction to streptokinase
- Pregnancy
- Active peptic ulcer
- Current use of warfarin and INR >1.7

Source: Goodman and Gillman 12th ed. Chapter 30