Drugs Used in Disorders of Coagulation  Patients with defects in the formation of the primary platelet
plug typically bleed from surface sites with injury (defects in
 Hemostasis → 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
Mechanisms of Blood Coagulation
1. VASCULAR INJURY
 the endothelial cell layer rapidly undergoes a series of
changes resulting in a more procoagulant phenotype
 exposes reactive subendothelial matrix proteins such as
collagen and von Willebrand factor
 results in platelet adherence and activation, and
secretion and synthesis of vasoconstrictors and platelet-
recruiting and activating molecules
2. Activation of Platelets
 conformational change in the αIIbβIII integrin (IIb/IIIa)
receptor →→ binds fibrinogen →→ cross-links adjacent
platelets >>> aggregation and formation of a platelet
plug
3. Coagulation System Cascade
 resulting in thrombin generation and a fibrin clot, which
stabilizes the platelet plug
 Thromboxane A2 (TXA 2) - synthesized from arachidonic acid
within platelets and is a platelet activator and potent
vasoconstrictor
 Adenosine diphosphate (ADP) - powerful inducer of platelet
aggregation
 Serotonin (5-HT) - stimulates aggregation and vasoconstriction
primary hemostasis, platelet function defects, von Willebrand
disease)
 Patients with defects in the clotting mechanism (secondary
hemostasis, hemophilia A) tend to bleed into deep tissues often
with no apparent inciting event, and bleeding may recur
unpredictably
 Platelet-rich thrombi (white thrombi) - form in the high flow
rate and high shear force environment of arteries
 Occlusive arterial thrombi - produce downstream ischemia of
extremities or vital organs >>> result in limb amputation or
organ failure
 Red Thrombi (venous clots)
 tend to be more fibrin rich, contain large numbers of
trapped red blood cells
 cause severe swelling and pain of the affected extremity,
but the most feared consequence is pulmonary embolism
 when part or all of the clot breaks off from its location in
the deep venous system and travels as an embolus through
the right side of the heart and into the pulmonary arterial
circulation
 cause acute right heart failure and sudden death
 lung ischemia or infarction will occur distal to the occluded
pulmonary arterial segment
 platelet nidus dominates the arterial thrombus and the
fibrin tail dominates the venous thrombus
Coagulation System Cascade
 coagulates due to the transformation of soluble fibrinogen into
insoluble fibrin by the enzyme thrombin
 a clotting factor zymogen undergoes limited proteolysis and
becomes an active protease
 each protease factor activates the next clotting factor in the
sequence culminating in the formation of thrombin
Thrombin
 proteolytically cleaves small peptides from fibrinogen, allowing
fibrinogen to polymerize and form a fibrin clot
 activates many upstream clotting factors, leading to more
thrombin generation
 activates factor XIII, a transaminase that cross-links the fibrin
polymer and stabilizes the clot
 potent platelet activator and mitogen
 exerts anticoagulant effects by activating the protein C pathway,
which attenuates the clotting response
The Tissue Factor-VIIa Complex
 main initiator of blood coagulation in vivo
 TF - transmembrane protein ubiquitously expressed outside the
vasculature
- not normally expressed in an active form within vessels
 exposure on damaged endothelium or to blood that has
extravasated into tissue binds TF to factor VIIa
 propagation of the clot is by feedback amplification of thrombin
through the intrinsic pathway factors VIII and IX
 patients with deficiency of factor VIII or IX (hemophilia A and
hemophilia B) have a severe bleeding disorder
Antithrombin (AT)
 an endogenous anticoagulant and a member of the serine
protease inhibitor (serpin) family
 inactivates the serine proteases IIa, IXa, Xa, XIa, and XIIa
Protein C and Protein S
 attenuate the blood clotting cascade by proteolysis of the two
cofactors Va and VIIIa
 factors V and VIII have an identical overall domain structure and
considerable homology
 descendants of a trypsin-like common ancestor
 most common defect in the natural anticoagulant system is a
mutation in factor V (factor V Leiden), results in resistance to
inactivation by the protein C, protein S mechanism
Fibrinolysis
 process of fibrin digestion by the fibrin specific protease,
plasmin
 precursor form of the serine protease plasmin circulates in an
inactive form as plasminogen
 endothelial cells synthesize and release tissue plasminogen
activator (t-PA), which converts plasminogen to plasmin
 Plasmin remodels the thrombus and limits its extension by
proteolytic digestion of fibrin
 specialized protein domains (kringles) bind to exposed lysines
on the fibrin clot and impart clot specificity to the fibrinolytic
process
 Negative Regulators of Fibrinolysis
 endothelial cells synthesize and release plasminogen
activator inhibitor (PAI), which inhibits t-PA
 α2 antiplasmin circulates in the blood at high
concentrations and will rapidly inactivate any plasmin that is
not clot-bound
 Disseminated Intravascular Coagulation (DIC)
 hemostatic system may careen out of control, leading to
generalized intravascular clotting and bleeding
 follow massive tissue injury, advanced cancers, obstetric
emergencies such as abruptio placentae or retained
products of conception, or bacterial sepsis
 Tx control the underlying disease process; DIC is often fatal
 Increased fibrinolysis is effective therapy for thrombotic disease
 Tissue plasminogen activator, urokinase, and streptokinase
all activate the fibrinolytic system
 decreased fibrinolysis protects clots from lysis and reduces the
bleeding of hemostatic failure
 Aminocaproic acid is a clinically useful inhibitor of fibrinolysis
Drug Class & its PK & Chemistry PD Uses Toxic Effect D-D Interaction & CI
members
INDIRECT THROMBIN INHIBITORS
Unfractionated  inhibit blood  prevents  bleeding  Px with renal
heparin (UFH) coagulation by pulmonary emboli  loss of hair and failure are more
inhibiting all three in patients with reversible alopecia prone to
factors, especially established venous  osteoporosis and hemorrhage
thrombin and thrombosis spontaneous  use cautiously in
factor Xa fractures px with allergy
 molecular weight  accelerates the  px recently had
range of 5000– clearing of surgery of the
30,000 postprandial brain, spinal cord,
Low molecular-  inhibit activated lipemia or eye
weight heparin factor X but have  mineralocorticoid  px undergoing
(LMWH) less effect on deficiency lumbar puncture
 enoxaparin thrombin than the  Heparin-Induced or regional
 dalteparin HMW Thrombocytopenia anesthetic block
 tinzaparin 
ORAL DIRECT FACTOR XA INHIBITORS
Rivaroxaban  inhibit factor Xa,  excreted in part  prevention of  increase in bleeding  patients with
in the final by the kidneys venous risk without a renal impairment
common pathway thromboembolism significant decrease
of clotting following hip or in ischemic events
 rapid onset of knee surgery
Apixaban action and shorter  venous
half-lives than thromboembolism
warfarin  stroke prevention
(approximately 10 in patients with
hours) atrial fibrillation