Anti-Coagulants

→ Hemostasis: cessation of blood loss after injury; 4 stages: vascular spasm, platelet plug formation (1°), blood coagulation (2°), and dissolution of fibrin clot (3°)
→ 1° hemostasis: injury exposes collagen, vWF and other components which bind to GPVI and GPIb on platelet!platelet activation and adherence to subendothelium!granules containing ADP, Ca2+, ATP, serotonin, vWF, and platelet factor 4 are
secreted
o ADP! platelet aggregation via P2Y1 receptor (Gq!↑Ca2+) and P2Y12 receptor (Gi!↓AC)
o Active platelets is enhanced by thrombin (Gq)
o Aggregation via fibrinogen!binds to GPIIb/IIIa receptor (shift to high affinity receptor once activation occurs) on 2 separate platelets!cross-linking!formation of plug
→ 2° hemostasis: coagulation by transformation of fibrinogen into fibrin via thrombin and coagulation cascade
o Coagulation factors= proenzymes of serine proteases!cleaved to activate intrinsic/extrinsic pathways
o Intrinsic activated via factor XII (Hageman factor) and extrinsic via tissue factor/thromboplastin activating factor VII
o Both pathways come together to create factor X!cleaves prothrombin to thrombin!converts fibrinogen into fibrin
→ Factors II. VII. IX, X, protein C and S!vitamin K-dependent post translational modification! γ-carboxylation of glutamic acid residues ! γ-carboxyglutamyl residues bind Ca2+ (needed for interaction with platelet plasma membranes)!binds to
phospholipids on surface of platelets via γ-glutamyl carboxylase and requires O2, CO2 and the reduced vitamin K cofactor! vitamin K cofactor becomes vitamin K epoxide
o Vit K a regenerated from the epoxide via Vitamin K epoxide reductase
→ PGI2-!↑cAMP!inhibit platelet aggregation and cause vasodilation
→ Antithrombin III inactivates thrombin and Factors IXa, Xa, XIa, and XIIa
→ Protein C is activated by thrombin and need Protein S as a cofactor to degrade Factors Va and VIIIa
→ Tissue factor pathway inhibitor (TFPI) prevents excessive activation of tissue factor mediated activation of factors IX and X
→ Plasminogen from the liver is cleaved to form plasmin via tissue plasminogen activator (t-PA) !degradation of fibrin (fibrinolysis)
→ Predisposition to thrombosis via Virchow’s triad (endothelial injury, abnormal blood flow, and hypercoagubility)
→ Venous thrombus: d/t blood stasis or inappropriate activation of clotting cascade; clots are rich in fibrin, with fewer platelets than in arterial clots
→ Arterial Thrombus: usually d/t atherosclerosis of medium-sized vessels; clots are platelet rich
Drugs Used to Reduce Clotting (arterial thrombi > venous thrombi)
Drug Name Class Description MOA Uses PK Adverse effects /Contraindications
Prophylaxis for transient cerebral
Irreversible acetylation of ischemia
Anuclear platelet= no new
COX!blocks TXA2 synthesis
Aspirin COX inhibitor COX synthesized during 10 ↑ risk of bleeding 5-7 days after drug cessation
!interferes with platelet ↓ incidence of recurrent MI
day lifetime
aggregation and ↑bleeding time
↓ mortality in post-MI pts.
↑ risk of bleeding 5-7 days after drug cessation (no antidote)
Clopidogrel is a prodrug
activated by CYP2C19 (DO Thrombocytopenic purpura
Prevent cerebrovascular, cardiovascular
Clopidogrel Irreversible inhibition of P2Y12! NOT use with
and peripheral vascular disease
↓ platelet aggregation and ↑ omeprazole/CYP2C19 Contraindicated in CYP2C19 poor metabolizers with acute coronary

Platelet ADP Receptor bleeding time inhibitors) syndrome/ pts. undergoing percutaneous coronary
↓ rate of MI, stroke, and death in pts.
Aggregation blockers intervention(PCI)!↑ cardiovascular event rates
with recent MI or stroke d/t peripheral
Inhibitors inhibit CYP450!Interfere w/ ↑ risk of bleeding 5-7 days after drug cessation (no antidote)
artery disease or acute coronary
metabolism of other drugs
syndrome
Ticlopidine 1° hemostasis Thrombocytopenic purpura

↓formation/action Neutropenia
of chemical Prophylactic txt of angina pectoris
↑cAMP! inhibit
signals that
phosphodiesterase or blocks
promote Adjunct to warfarin in prevention of
uptake of adenosine (acts at A2 Little or no beneficial
Dipyridamole aggregation post-op thromboembolism
Phosphodiesterase receptors to activate platelet AC) effect by itself

inhibitor
Adjunct to aspirin! 2° prophylaxis of
Coronary vasodilator
cerebrovascular disease
Promotes vasodilation and
Cilostazole Intermittent claudication
inhibition of platelet aggregation
chimeric mouse-human
Abciximab monoclonal Ab Prevent thrombotic events in pts with
Irreversible antagonist NSTE-ACS Parenteral IIb/IIIa receptor for fibrinogen and vitronectin mainly, but also for
GPIIb/IIIa receptor
Cyclic peptide fibronectin and vWF- patients lacking this receptor have a bleeding
Eptifibatide blockers
Reversible antagonist Adjunct to PCI for prevention of cardiac Abciximab t½=18-24hrs disorder called Glanzmann’s Thrombasthenia
Non-peptide tyrosine analogue ischemic complications
Tirofiban
Reversible antagonist

 Anti-Coagulants Continued
Drugs Used to Reduce Clotting
Drug Name Class Description MOA Uses PK Adverse effects /Contraindications
Heterogeneous 5 carbohydrate residue sequence on heparin is critical Injectable, rapidly acting
mixture of straight for binding to Antithrombin III!conformational
chain, sulfated change!more rapid interaction with proteases Monitor heparin to maintain
Bleeding (reverse with Protamine), ↑liver
Heparin mucopolysaccharides! (thrombin, factor IXa and Xa) Adjunct to warfarin for txt of venous effect within therapeutic range
transaminases, osteoporosis, HSN rxns
Unfractionated thrombosis and pulm embolism until and prevent bleeding!use aPTT

(standard) heparin Fxns as a cofactor for Antithrombin-protease rxn warfarin achieves full effects assay!tests the intrinsic and -
Heparin-induced thrombocytopenia (HIT):
(UFH) without being consumed common pathways
Type I=more common and less severe;
Anticoagulants Initial mgmt. of unstable angina or -Equal efficacy to UFH but higher
Type II=systemic hypercoagulable state in pts
2° Hemostasis inactivation of thrombin: heparin must bind acute MI bioavailability, longer half-life,
txt with UFH for a min of 7 days!thrombosis
simultaneously to thrombin and Antithrombin and less frequent dosing
Low molecular weight and thrombocytopenia d/t platelet
Indirect !ternary complex Prevent thrombosis during coronary requirements
heparins (LMWH) consumption! DVT, pulm embolism, MI or
Enoxaparin thrombin and balloon angioplasty -Weight based dosing of
produced by chemical stroke
Dalteparin factor Xa inactivation of factor Xa: heparin must only bind to LMWH= no need to monitor
or enzymatic
Tinzaparin inhibitors Antithrombin DOC for anticoagulation during heparin levels except in pts with
depolymerization of TXT of HIT: stop drug use and give direct
pregnancy renal insufficiency, obesity, or
UFH thrombin inhibitor or Fondaparinux
LMWH have less of effect on thrombin b/c the cant pregnancy (potency can be
form the ternary complex, while UFH efficiently monitored with anti-factor Xa
inactivates both assays)
-Selective, indirect inhibitor of factor Xa, with
Synthetic Potency monitored with anti-Xa
Fondaparinux negligible Antithrombin activity Prophylaxis and TXT of DVT
pentasaccharide assay
-Contains the 5 carbohydrate sequence
Powerful and specific Excreted by
Actions are independent from Antithrombin III!can
thrombin inhibitor Prevents further thromboembolic kidney Caution in patients with renal
Lepirudin each and inactivate both free and fibrin bound
(recombinant of complication in pts with HIT Monitored by the insufficiency!no antidote exists
thrombin in clots
Hirudin found in leech) aPTT
Synthetic congener of Bivalent inhibitor of thrombin Pts undergoing percutaneous
Bivalirudin Parenteral
Anticoagulants Hirudin Inhibits platelet activation coronary intervention (PCI)

2° Hemostasis -Prophylaxis/TXT of thrombosis in pts Given IV
with HIT Monitored by the
Argatroban Direct Small molecule Thrombin inhibitor -Pts with/at risk for HIT undergoing aPTT
thrombin percutaneous coronary intervention
inhibitors (PCI)
-Oral
Prodrug rapidly -Produces predictable response
Dabigatran -Prevention of thromboembolic
converted to Reversibly blocks the active site of thrombin so monitoring is not necessary No antidote but is dialyzable
Etexilate stroke in pts with non-valvular a-fib
dabigatran -Excreted in urine (not

metabolized by liver)
-Prophylaxis/TXT of DVT and pulm
10a has -Oral
been Apixaban Anticoagulants Direct Factor Xa embolism
Direct Factor Xa inhibitors -Produces predictable response No antidote to reverse anticoagulant effect
banned Rivaroxaban 2° Hemostasis inhibitors
so monitoring is not necessary
Inhibits vitamin K epoxide reductase !cant γ-
carboxylase Factors II, VII, IX, and X (Factor VII is the Prevents progression/recurrence of a Oral
first to go) previously formed clot (acute DVT or Peak effect seen at 72-96hours
-Hemorrhage
pulm embolism) and secondary Duration of single dose= 2-5days
Anticoagulants -Cutaneous necrosis d/t ↓protein C (Associated
Coumarin Inhibit metab: Cimetidine, chloramphenicol, thromboembolic complications Narrow therapeutic index w/
Warfarin 2° Hemostasis with venous thrombosis)
anticoagulant disulfiram, fluconazole, metronidazole, following initial course of heparin many drug interactions!
-Contraindicated in pregnancy (Category
phenylbutazone, sulfinpyrazone, and TMP-SMX monitor every 2-4 weeks using
X)!birth defects/abnormal bone formation
Effect overcome by vitamin K admin. PT(INR)!tests extrinsic an
Stimulate metab: barbiturates, carbamazepine, (takes about 24hr) common pathways
phenytoin, rifampin
Acute MI Catalyzes the degradation of
Protein produced by β- Convert zymogen plasminogen to active protease Acute pulm embolism fibrinogen and factors V and VII
Streptokinase Contraindicated in pts with healing wounds,
Direct hemolytic strep plasmin!digests fibrin Arterial thrombosis by forming complex with
pregnancy, hx of cerebrovascular accidents or
Systemic Occluded access shunts plasminogen
metastatic cancer
Human enzyme from

Urokinase neonatal kidney cells directly converts plasminogen!plasmin Lysis of pulm emboli Found in urine
Thrombolytics
grown in culture
Activate
Mgmt. of acute MI and acute
Alteplase plasmin
t-PA
Recombinant t-PA ischemic stroke (given w/i 4.5 hrs of t1/2= 3-6min
activates only 3° Hemostasis -Hemorrhage
plasminogen stroke)
in a clot and
Tissue plasminogen activators (t-PA)
not systemically
Modified recombinant t1/2= 14-18min
Reteplase “fibrin selective”!rapidly activates plasminogen -Contraindicated in pts with healing wounds,
human t-PA (less fibrin- Mgmt. of acute MI double bolus- 2 boluses 30 min
bound to fibrin in a thrombus or plug pregnancy, hx of cerebrovascular accidents or
specific) apart
metastatic cancer
mutant t-PA (more t1/2= 20-24min
Tenecteplase Mgmt. of acute MI
fibrin-specific) single IV bolus

Anti-Coagulants Continued
Drugs Used to Treat Bleeding
Adverse effects
Drug Name Class Description MOA Uses PK
/Contraindications
Adjunct therapy in hemophilia Oral or IV
Aminocaproic Acid Synthetic inhibitors of Competitively inhibit plasminogen activation
t-PA inhibitors Intravascular thrombosis
Tranexamic Acid fibrinolysis
Therapy for bleeding from fibrinolytic therapy Excreted in urine
Chemical antagonist of heparin: positively charged Interfere in coagulation when
Low molecular weight Reverses the effects of heparin (most active against UFH,
protein interacts with negatively charged given in the absence of
Protamine Sulfate protein partially active against LMWHs and inactive against IV
heparin!stable complex with no anticoagulation heparin!HSN, dyspnea, flushing,
High in arginine Fondaparinux)
activity bradycardia and hypotension
Carboxylates clotting factors
Antidotes Stops bleeding induced by oral anticoagulants (Warfarin) Oral
Vitamin K Response is complete in 24 hours, onset in 6
Hypoprothrombinemia in babies parenteral
Fresh frozen plasma used for immediate hemostasis
Classic hemophilia or hemophilia A!Factor VIII
Plasma Fractions Replace coagulation factors that are deficient in certain genetic disorders
Christmas disease or hemophilia B! Factor IX

Aminocaproic Acid/
- Tranexamic Acid