PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021
HEMOSTASIS
o Refers to the finely regulated dynamic process of
maintaining fluidity of the blood, repairing vascular
injury, and limiting blood loss while avoiding vessel
occlusion (thrombosis) and inadequate perfusion of vital
organs.
COMMON CAUSES OF DYSREGULATED HEMOSTASIS:
o Hereditary
o Acquired
o Secondary effects of infection or cancer
o Atrial fibrillation
COMMON CAUSES OF DYSREGULATED HEMOSTASIS
o Atrial fibrillation is associated with stasis of blood in the
atria, formation of clots, and increased risk of occlusive
stroke.
o Because of the high prevalence of chronic atrial
fibrillation, especially in the older population, use of
anticoagulants is common.
o Guidelines for the use of oral anticoagulants (CHA2DS2-
VASC score) are based on various risk factors
(congestive heart failure, hypertension, age, diabetes,
history of stroke, vascular disease, and sex).
MECHANISMS OF BLOOD COAGULATION
o The vascular endothelial cell layer lining blood vessels
has an anticoagulant phenotype and circulating blood
platelets and clotting factors do not normally adhere to
it to an appreciable extent.
o Injury exposes reactive subendothelial matrix proteins
such as collagen and von Willebrand factor, which results
in platelet adherence and activation, and secretion and
synthesis of vasoconstrictors and platelet-recruiting and
activating molecules.
o Thus, thromboxane A2 (TXA2) is synthesized from
arachidonic acid within platelets and is a platelet
activator and potent vasoconstrictor.
o Products secreted from platelet granules include
adenosine diphosphate (ADP), a powerful inducer of
platelet aggregation.
o and serotonin (5-HT), which stimulates aggregation and
vasoconstriction.
o Activation of platelets results in a conformational
change in the αIIbβIII integrin (IIb/IIIa) receptor,
enabling it to bind fibrinogen, which cross-links adjacent
platelets, resulting in aggregation and formation of a
platelet plug.
o Simultaneously, the coagulation system cascade is
activated, resulting in thrombin generation and a fibrin
clot, which stabilizes the platelet plug.
Transcribed by parkjaneyoung
Year 2 | Semester 1
Note:
 Thrombus formation at the site of the damaged vascular wall
(EC, endothelial cell) and the role of platelets and clotting
factors.
 Platelet membrane receptors include the glycoprotein (GP) Ia
receptor, binding to collagen (C); GP Ib receptor, binding von
Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen
and other macromolecules. Antiplatelet prostacyclin (PGI2) is
released from the endothelium.
 Aggregating substances released from the degranulating
platelet include adenosine diphosphate (ADP), thromboxane A2
(TXA2), and serotonin (5-HT). Production of factor Xa by intrinsic
and extrinsic pathways.
 Knowledge of the hemostatic mechanism is important for
diagnosis of bleeding disorders.
o The platelet is central to normal hemostasis and
thromboembolic disease.
o Platelet-rich thrombi (white thrombi) form in the high flow
rate and high shear force environment of arteries.
o Occlusive arterial thrombi cause serious disease by
producing downstream ischemia of extremities or vital
organs, and they can result in limb amputation or organ
failure.
o Venous clots tend to be more fibrinrich, contain large
numbers of trapped red blood cells, and are recognized
pathologically as (red thrombi).
o Deep venous thrombi (DVT) can cause severe swelling
and pain of the affected extremity, but the most feared
consequence is pulmonary embolism (PE).
BLOOD COAGULATION CASCADE
o Blood coagulates due to the transformation of soluble
fibrinogen into insoluble fibrin by the enzyme thrombin.
o Thrombin has a central role in hemostasis and has many
functions.
o Thrombin also activates many upstream clotting factors,
leading to more thrombin generation, and activates
factor XIII, a transaminase that cross-links the fibrin
polymer and stabilizes the clot.
Page 1 of 6
 PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021 Year 2 | Semester 1

Initiation of Clotting: The Tissue Factor-VIIa Complex

Note:
 FIGURE 34–2 A model of blood coagulation. With tissue
factor (TF), factor VII forms an activated complex (VIIa-TF)
that catalyzes the activation of factor IX to factor IXa.
 Activated factor XIa also catalyzes this reaction.
 Tissue factor pathway inhibitor inhibits the catalytic action of
the VIIa-TF complex.
 The cascade proceeds as shown, resulting ultimately in the
conversion of fibrinogen to fibrin, an essential component of
a functional clot
 The two major anticoagulant drugs, heparin and warfarin,
have very different actions. Heparin, acting in the blood, o The main initiator of blood coagulation in vivo is the
directly activates anticlotting factors, specifically tissue factor (TF)–factor VIIa pathway.
antithrombin, which inactivates the factors enclosed in
rectangles. o Antithrombin (AT) is an endogenous anticoagulant
 Warfarin, acting in the liver, inhibits the synthesis of the and a member of the serine protease inhibitor
factors enclosed in circles. Proteins C and S exert (serpin) family; it inactivates the serine proteases IIa,
anticlotting effects by inactivating activated factors Va and IXa, Xa, XIa, and XIIa.
VIIIa.
o The endogenous anticoagulants protein C and
protein S attenuate the blood clotting cascade by
proteolysis of the two cofactors Va and VIIIa.
FIBRINOLYSIS
o Fibrinolysis refers to the process of fibrin digestion by

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 PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021
the fibrin specific protease, plasmin.
o Plasmin is the active fibrinolytic enzyme.
o The fibrinolytic system is similar to the coagulation
system in that the precursor form of the serine
protease plasmin circulates in an inactive form as
plasminogen.
o In response to injury, endothelial cells synthesize and
release tissue plasminogen activator (t-PA), which
converts plasminogen to plasmin.
o If the coagulation and fibrinolytic systems are
pathologically activated, the hemostatic system
may careen out of control, leading to generalized
intravascular clotting and bleeding. This process is
called disseminated intravascular coagulation (DIC).
The treatment of DIC is to control the underlying
disease process; if this is not possible, DIC is often fatal
 Schematic representation of the fibrinolytic system.
Plasmin is the active fibrinolytic enzyme. Several
clinically useful activators are shown on the left in
bold. Anistreplase is a combination of streptokinase
and the proactivator plasminogen.
 Aminocaproic acid (right) inhibits the activation of
plasminogen to plasmin and is useful in some
bleeding disorders. t-PA, tissue plasminogen
activator.
 Streptokinase, r-TPA these are life saving medicines.. I
a case of CVD infarct and ACS, STEMI..
o Increased fibrinolysis is effective therapy for thrombotic
disease.
o Tissue plasminogen activator (t-PA), urokinase, and
streptokinase all activate the fibrinolytic system.
o Aminocaproic acid is a clinically useful inhibitor of
fibrinolysis.
o Heparin and the oral anticoagulant drugs do not affect
the fibrinolytic mechanism.
Transcribed by parkjaneyoung
Year 2 | Semester 1
BASIC PHARMACOLOGY OF THE ANTICOAGULANT DRUGS
 INDIRECT THROMBIN INHIBITORS
 WARFARIN & OTHER COUMARIN ANTICOAGULANTS
 ORAL DIRECT FACTOR Xa INHIBITORS
 DIRECT THROMBIN INHIBITORS
INDIRECT THROMBIN INHIBITORS
o Unfractionated heparin (UFH), also known as high
molecular-weight (HMW) heparin
o Low molecular- weight (LMW) heparin
o And the synthetic Penta saccharide Fondaparinux bind
to antithrombin and enhance it inactivation of factor Xa.
o Heparin is a heterogeneous mixture of sulfated
mucopolysaccharides.
o It binds to endothelial cell surfaces and a variety of
plasma proteins.
o Its biologic activity is dependent upon the endogenous
anticoagulant antithrombin.
o Antithrombin inhibits clotting factor proteases, especially
thrombin (IIa), IXa, and Xa, by forming equimolar stable
complexes with them.
o High-molecular-weight fractions of heparin with high
affinity for antithrombin markedly inhibit blood
coagulation by inhibiting all three factors, especially
thrombin and factor Xa.
o Unfractionated heparin has a molecular weight range of
5000–30,000 Da
o In contrast, the shorter-chain, low-molecularweight
fractions of heparin inhibit activated factor X.
(enoxaparin, dalteparin, and tinzaparin). increased
bioavailability
- from the subcutaneous site of injection, and less frequent
o Close monitoring of the activated partial thromboplastin
time (aPTT or PTT) is necessary in patients receiving UFH.
o (LMWH) For enoxaparin, peak therapeutic levels should
be 0.5–1 unit/mL for twice-daily dosing, determined 4
hours after administration,
Toxicity
− The major adverse effect of heparin is bleeding.
− Elderly women and patients with renal failure are
more prone to hemorrhage.
Heparin-Induced Thrombocytopenia
− occurs in 1–4% of individuals treated with UFH.
Contraindications
− hypersensitivity to the drug, active bleeding,
hemophilia, significant thrombocytopenia, purpura,
severe hypertension, intracranial hemorrhage,
infective endocarditis, active tuberculosis, ulcerative
Page 3 of 6
 PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021 Year 2 | Semester 1

lesions of the gastrointestinal tract, threatened warfarin.

abortion, visceral carcinoma, or advanced hepatic − The resulting inhibition of coagulation is dependent
or renal disease. on their degradation half-lives in the circulation.
These halflives are 6, 24, 40, and 60 hours for factors
− safe in pregnant.
VII, IX, X, and II, respectively.

Administration & Dosage

For this reason in patients with active hypercoagulable
− A plasma concentration of heparin of 0.2–0.4
states, such as acute DVT or PE, UFH or LMW heparin is always
unit/mL (by protamine titration) or 0.3–0.7 unit/mL
used to achieve immediate anticoagulation until adequate
(anti-Xa units) is considered to be the therapeutic
warfarin-induced depletion of the procoagulant clotting
range for treatment of venous thromboembolic
factors is achieved.
disease.
− PTT of 1.5–2.5 times. The duration of this overlapping therapy is generally 5–7
days.
− Continuous intravenous administration of heparin is
accomplished via an infusion pump. After an initial
Toxicity
bolus injection of 80–100 units/kg, a continuous
− Warfarin crosses the placenta readily and can cause
infusion of about 15–22 units/kg per hour is required
a hemorrhagic disorder in the fetus.
to maintain the anti-Xa activity in the range of 0.3–
0.7 units/mL. Low-dose prophylaxis is achieved with
Administration & Dosage
subcutaneous administration of heparin, 5000 units
− Treatment with warfarin should be initiated with
every 8–12 hours.
standard doses of 5–10 mg.
− Because of the danger of hematoma formation at − The initial adjustment of the prothrombin time takes
the injection site, heparin must never be about 1 week.
administered intramuscularly. − The therapeutic range for oral anticoagulant
therapy is defined in terms of an international
− Prophylactic enoxaparin is given subcutaneously in
normalized ratio (INR).
a dosage of 30 mg twice daily or 40 mg once daily.
− The recommended INR for prophylaxis and
− Full-dose enoxaparin therapy is 1 mg/kg treatment of thrombotic disease is 2–3.
subcutaneously every 12 hours. − Patients with some types of artificial heart valves (eg,
tilting disk) or other medical conditions increasing
− Fondaparinux has a long half-life of 15 hours, thrombotic risk have a recommended range of 2.5–
allowing for once-daily dosing by subcutaneous 3.5.
administration.
− Fondaparinux is effective in the prevention and
treatment of venous thromboembolism
Reversal of Heparin Action
− Protamine sulfate
− For every 100 units of heparin remaining in the
patient, 1 mg of protamine sulfate is given
intravenously;

WARFARIN & OTHER COUMARIN ANTICOAGULANTS

Chemistry & Pharmacokinetics
− Has 100% oral bioavailability.
− long half-life in plasma (36 hours)
Mechanism of Action
− Coumarin anticoagulants block the γ-carboxylation
of several glutamate residues in prothrombin and
factors VII, IX, and X as well as the endogenous
anticoagulant proteins C and S.
− The protein carboxylation reaction is coupled to the
oxidation of vitamin K.
− The vitamin must then be reduced to reactivate it.
− Warfarin prevents reductive metabolism of the Reversal of Warfarin Action
inactive vitamin K epoxide back to its active − Parenteral vitamin K1 (phytonadione), fresh-frozen
hydroquinone form plasma, prothrombin complex concentrates, and
− There is an 8- to 12-hour delay in the action of recombinant factor VIIa (rFVIIa).

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 PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021
ORAL DIRECT FACTOR Xa INHIBITORS
o Oral Xa inhibitors, including rivaroxaban, apixaban,
and edoxaban represent a new class of oral
anticoagulant drugs that require no monitoring.
Pharmacology
− inhibit factor Xa, in the final common pathway of
clotting.
− Rivaroxaban has high oral bioavailability when taken
with food.
− Following an oral dose, the peak plasma level is
achieved within 2–4 hours;
− Apixaban has an oral bioavailability of 50% and
prolonged absorption, resulting in a half-life of 12
hours with repeat dosing.
− Edoxaban is a once-daily Xa inhibitor with a 62% oral
bioavailability.
− Peak drug concentrations occur 1–2 hours after
dosage and are not affected by food. The drug half-
life is 10–14 hours.
Administration & Dosage
− approved for prevention of embolic stroke in
patients with atrial fibrillation without valvular heart
disease, prevention of venous thromboembolism
following hip or knee surgery, and treatment of
venous thromboembolic disease (VTE).
Assessment of and Reversal of Anti-Xa Drug Effect
− Andexanet alfa
DIRECT THROMBIN INHIBITORS
PARENTERAL DIRECT THROMBIN INHIBITORS
− Lepirudin, Bivalirudin, Argatroban
ORAL DIRECT THROMBIN INHIBITOR
− Dabigatran etexilate mesylate is the only oral direct
thrombin.
− inhibitor approved by the FDA. Dabigatran is
approved for reduction in risk of stroke and systemic
embolism with nonvalvular atrial fibrillation,
treatment of VTE.
DABIGATRAN
− oral bioavailability is 3–7%.
− The half-life of the drug is 12–17 hours.
− For prevention of stroke and systemic embolism in
nonvalvular atrial fibrillation, the dosage is 150 mg
twice daily for patients with creatinine clearance
greater than 30 mL/min.
− For decreased creatinine clearance of 15–30
mL/min, the dosage is 75 mg twice daily.
− No monitoring is required.
Assessment of and Reversal
− Idarucizumab
Transcribed by parkjaneyoung
Year 2 | Semester 1
BASIC PHARMACOLOGY OF THE FIBRINOLYTIC DRUGS
− Fibrinolytic drugs rapidly lyse thrombi by catalyzing
the formation of the serine protease plasmin from its
precursor zymogen, plasminogen.
− Streptokinase (Acute M.I)
− Urokinase
− Tissue plasminogen activators (t-Pas)
− Recombinant human t-PA is manufactured as
alteplase. (CVD Infarct)
− Tenecteplase
 indicated in cases of pulmonary embolism with
hemodynamic instability, severe deep venous thrombosis
such as the superior vena caval syndrome, and
ascending thrombophlebitis of the iliofemoral vein with
severe lower extremity edema, acute myocardial
infarction.
▪ ASPIRIN
▪ THIENOPYRIDINES: TICLOPIDINE, CLOPIDOGREL, &
PRASUGREL
▪ BLOCKADE OF PLATELET GLYCOPROTEIN IIb/IIIa
RECEPTORS
▪ ADDITIONAL ANTIPLATELET-DIRECTED DRUGS
BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS
− Platelet function is regulated by three categories of
substances.
1. The first group consists of agents generated outside the
platelet that interact with platelet membrane receptors,
eg, catecholamines, collagen, thrombin, and
prostacyclin.
2. The second category contains agents generated within
the platelet that interact with membrane receptors, eg,
ADP, prostaglandin D2, prostaglandin E2, and serotonin.
3. A third group comprises agents generated within the
platelet that act within the platelet, eg, prostaglandin
endoperoxides and thromboxane A2, the cyclic
nucleotides cAMP and cGMP, and calcium ion.
ASPIRIN
− The prostaglandin thromboxane A2 is an
arachidonate product that causes platelets to
change shape, release their granules, and
aggregate.
− Drugs that antagonize this pathway interfere with
platelet aggregation in vitro and prolong the
bleeding time in vivo.
− Utility of aspirin in the secondary prevention of
vascular events among patients with a history of
vascular events.
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 PHARMACOLOGY
Drugs used in coagulation disorders
JOHN HOMMER DY, MD 10/22/2021 Year 2 | Semester 1

THIENOPYRIDINES: TICLOPIDINE, CLOPIDOGREL, & PRASUGREL weekly dosing in many cases.

− reduce platelet aggregation by inhibiting the ADP
pathway of platelets. These drugs irreversibly block
the ADP P2Y12 receptor on platelets.
Ticlopidine is approved for prevention of stroke in patients
witha history of a transient ischemic attack (TIA) or
thrombotic stroke, and in combination with aspirin for
prevention of coronary stent thrombosis.
Clopidogrel is approved for patients with unstable angina or
non-ST-elevation acute myocardial infarction (NSTEMI) in
combination with aspirin; for patients with ST-elevation
myocardial infarction (STEMI); or recent myocardial
infarction, stroke, or established peripheral arterial disease.
Prasugrel, similar to clopidogrel, is approved for patients with
acute coronary syndromes.
Ticagrelor is a newer type of ADP inhibitor (cyclopentyl
triazolopyrimidine) and is also approved for oral use in
combination with aspirin in patients with acute coronary
syndromes.
Cangrelor is a parenteral P2Y12 inhibitor approved for IV use
in coronary interventions in patients without previous ADP
P2Y12 inhibitor therapy.
BLOCKADE OF PLATELET GLYCOPROTEIN IIb/IIIa RECEPTORS
− are used in patients with acute coronary syndromes.
 Abciximab
 Eptifibatide
 Tirofiban
− Dipyridamole is a vasodilator that also inhibits
platelet function by inhibiting adenosine uptake and
cGMP phosphodiesterase activity.
− Cilostazol is a phosphodiesterase inhibitor that
promotes vasodilation and inhibition of platelet
aggregation.
− Cilostazol is used primarily to treat intermittent
claudication.
− Idelvion is a factor IX-albumin conjugate with half-life
of 100 hours (native factor IX has a half-life of 16
hours) and is FDA-approved for prophylaxis or
treatment of bleeding in hemophilia B patients.
− Vonicog alfa is a recombinant von Willebrand factor
product approved for treatment and control of
bleeding in adults with von Willebrand disease.
PLASMA FRACTIONS
Sources & Preparations
− Deficiencies in plasma coagulation factors can
cause bleeding
− Spontaneous bleeding occurs when factor activity is
less than 5–10% of normal.
− Factor VIII deficiency (classic hemophilia, or
hemophilia A) and factor IX deficiency (Christmas
disease, or hemophilia B) account for most of the
heritable coagulation defects.
− Desmopressin acetate increases the factor VIII
activity of patients with mild hemophilia A or von
Willebrand disease.
− Cryoprecipitate may also be used for patients with
factor VIII deficiency and von Willebrand disease if
desmopressin is not indicated and a
pathogeninactivated, recombinant, or plasma
derived product is not available.
− Aminocaproic acid (EACA), which is chemically
similar to the amino acid lysine, is a synthetic inhibitor
of fibrinolysis. It competitively inhibits plasminogen
activation.
− Tranexamic acid is an analog of aminocaproic acid
and has the same properties.

DRUGS USED IN BLEEDING DISORDERS

VITAMIN K
− Vitamin K confers biologic activity upon prothrombin
and factors VII, IX, and X by participating in their
post ribosomal modification.
− Vitamin K is a fat-soluble substance found primarily in
leafy green vegetables.
− Treatment in Warfarin toxicity.
− Onset of effect is delayed for 6 hours but the effect is
complete by 24 hours.
− Eloctate is a factor VIII-Fc domain conjugate that
prolongs the factor VIII half-life and allows twice-

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