1) The document summarizes hemostasis, thrombosis, and their treatment. It describes the vascular endothelium, platelets, coagulation system, and fibrinolytic system which maintain hemostasis and how perturbations can lead to thrombosis. 2) Thrombosis can occur in arteries or veins and is treated using antiplatelet drugs like aspirin, anticoagulants like heparin and warfarin, and thrombolytic drugs. 3) Antiplatelet drugs inhibit platelet activation while anticoagulants inhibit thrombin generation; together they prevent clot formation and growth to treat thrombosis.

1. Braunwald Heart Disease Chapter 95
Hemostasis, Thrombosis, Fibrinolysis,
and Cardiovascular Disease
JEFFREY I. WEITZ

2. Introduction
● Hemostasis preserves vascular integrity by balancing the
physiologic processes that maintain blood fluidity under
normal circumstances and prevent excessive bleeding
after vascular injury
● Perturbation of hemostasis can lead to thrombosis, which
can occur in arteries or veins and causes considerable
morbidity and mortality.

3. TABLE OF CONTENTS
Hemostatic System
Thrombosis
Treatment of Thrombosis
01
02
03

4. Hemostatic
System

5. Vascular Endothelium
● A monolayer of endothelial cells lines the intimal surface of the circulatory
tree and separates blood from the prothrombotic subendothelial
components of the vessel wall
● Healthy vascular endothelium dynamically regulates hemostasis by
inhibiting platelets, suppressing coagulation, and promoting fibrinolysis
Platelet Inhibition
● Endothelial cells synthesize prostacyclin and nitric oxide  potently
vasodilate and inhibit platelet activation and subsequent aggregation by
stimulating adenylate cyclase

6. Anticoagulant Activity
● Endothelial cells express heparan sulfate proteoglycans on their surface 
Binds circulating antithrombin and enhances its activity, binds tissue factor
pathway inhibitor (TFPI), a naturally occurring inhibitor of coagulation.
● Endothelial cells are central to the protein C anticoagulant pathway
because they express thrombomodulin and endothelial cell protein C
receptor (EPCR) on their surfaces.
● Activated protein C serves as an anticoagulant by degrading and
inactivating activated factor V and factor VIII

8. Fibrinolytic Activity
● The vascular endothelium modulates fibrinolysis by synthesizing and
releasing tissue and urokinase plasminogen activators (t- PA and u- PA),
which initiate fibrinolysis by converting plasminogen to plasmin
● Endothelial cells also produce type 1 plasminogen activator inhibitor (PAI-
1)
● Therefore, net fibrinolytic activity depends on the dynamic balance
between the release of plasminogen activators and PAI- 1.

9. Platelets
● Damage to the intimal lining of the vessel exposes the underlying
subendothelial matrix.
● Platelets home to sites of vascular disruption and adhere to the exposed
matrix proteins.
● Adherent platelets undergo activation and not only release substances that
recruit additional platelets to the site of injury, but also promote thrombin
generation and subsequent fibrin formation (Fig. 95.3).
● A potent platelet agonist, thrombin amplifies platelet recruitment and
activation.
● Activated platelets then aggregate to form a plug that seals the leak in the
vasculature.

11. Platelets
Adhesion
● Platelets adhere to exposed collagen and von Willebrand factor (vWF) and form a
monolayer that supports and promotes thrombin generation and subsequent fibrin
formation
Activation
● Adhesion to collagen and vWF initiates signaling pathways that result in platelet
activation. These pathways induce cyclooxygenase- 1 (COX-1)- dependent synthesis
and release of thromboxane A2 and trigger the elease of ADP from storage granules.
● ADP interacts with a family of G protein–coupled receptors on the platelet membrane.
The most important of these is P2Y12, which is the target of the thienopyridines
Aggregation
● Aggregation serves as the final step in formation of the platelet plug by linking platelets
to each other to form clumps. GP IIb/IIIa mediates these platelet- to- platelet linkages.

13. Coagulation
● Results in the generation of thrombin, which converts soluble fibrinogen to fibrin.
● Occurs through the action of discrete enzyme complexes composed of a vitamin K–
dependent enzyme and a nonenzyme cofactor that assemble on anionic phospholipid
membranes in a calcium- dependent fashion
● The three enzyme complexes involved in thrombin generation are extrinsic tenase,
intrinsic tenase, and prothrombinase
Extrinsic tenase
● Forms on exposure of tissue factor–expressing cells to blood
Intrinsic tenase
● Factor IXa binds to factor VIIIa on anionic cell surfaces to form the intrinsic tenase
complex
Prothrombinase
● Prothrombin binds to the prothrombinase complex, where it undergoes conversion to
thrombin in a reaction that releases prothrombin fragment 1.2 (F1.2)

14. Fibrin formation
● Thrombin, the final effector in
coagulation, converts soluble
fibrinogen to insoluble fibrin.
● Thrombin binds to the amino
terminals of the Aα and Bβ chains
of fibrinogen, where it cleaves
specific peptide bonds to release
fibrinopeptide A and fibrinopeptide
B and generates fibrin monomers

16. Contact System

17. Fibrinolytic System
● Fibrinolysis begins when
plasminogen activators convert
plasminogen to plasmin, which
then degrades fibrin into soluble
fragments
●

18. Mechanism of action
t-PA
● t- PA has little enzymatic activity in the absence of fibrin, but its activity
increases by at least three orders of magnitude when fibrin is present
Urokinase
● Synthesized as a single- chain polypeptide, single- chain u- PA (scu- PA)
has minimal enzymatic activity.
● Plasmin readily converts scu- PA into an active two- chain form that can
bind u- PAR on cell surfaces
Thrombin- Activatable Fibrinolysis Inhibitor
● synthesized in the liver and circulates in blood in a latent form, where
thrombin bound to thrombomodulin can activate it.

19. Thrombosis

20. Arterial thrombosis
● Most arterial thrombi occur on top of disrupted atherosclerotic plaques
● Breakdown of the regulatory mechanisms that limit platelet activation and
inhibit coagulation can augment thrombosis at sites of plaque disruption.
● Decreased production of nitric oxide and prostacyclin by diseased
endothelial cells can trigger vasoconstriction and platelet activation.
● Proinflammatory cytokines lower expression of thrombomodulin by
endothelial cells, which promotes thrombin generation, and stimulate
expression of PAI- 1, which inhibits fibrinolysis.

21. Venous thrombosis
● May be caused by genetic or acquired hypercoagulable states or by such
factors as advanced age, obesity, or cancer
● Superimposed triggering factors, such as surgery, smoking, pregnancy, or
hormonal therapy, modify this risk, and thrombosis occurs when the
combination of genetic, acquired, and triggering forces exceeds a critical
threshold
● Some acquired or triggering factors entail a higher risk than do others

23. Hypercoagulable states

24. Treatment of
Thrombosis

25. Antiplatelet
drugs

26. Aspirin
Mechanism of action
● Produces its antithrombotic effect by irreversibly acetylating and inhibiting platelet COX- 1
Indications
● Widely used for secondary prevention in patients with established coronary,
cerebrovascular, or peripheral artery disease.
Dosages
● Usually administered at dosages of 75 to 325 mg once daily, there is no evidence that
higher- dose aspirin is more effective than lower doses, and some meta- analyses suggest
reduced efficacy with higher doses.
Side effects
● The most common side effects are gastrointestinal
● The risk for major bleeding with aspirin is 1% to 3% per year.
Aspirin resistance
● Defined as failure of aspirin to protect patients from ischemic vascular events

27. Thienopyridines
● Include ticlopidine, clopidogrel, and prasugrel, drugs that target P2Y12, the key
ADP receptor on platelet
Mechanism of action
● Selectively inhibit ADP- induced platelet aggregation by irreversibly blocking P2Y12
 require metabolic activation by the hepatic cytochrome P- 450 (CYP) enzyme
system.
Indications
● Clopidogrel is marginally more effective than aspirin, but it is more expensive
● The combination of clopidogrel and aspirin capitalizes on the capacity of each drug
to block complementary pathways of platelet activation
Dosages
● Clopidogrel once daily at a dose of 75 mg.3
● Because its onset of action is delayed for several days, 300- to 600- mg loading
doses of clopidogrel are given when rapid ADP receptor blockade is desired
● After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg.38
Patients older than
● 75 years or weighing less than 60 kg should receive a daily prasugrel dose of 5 mg

28. Ticagrelor
● Ticagrelor differs from the thienopyridines in that it does not require metabolic
activation and it produces reversible inhibition of the ADP receptor
Mechanism of action
● Inhibits P2Y12
Indications
● Produced a greater reduction in the primary efficacy endpoint—a composite of
cardiovascular death, myocardial infarction, and stroke at 1 year—than did
clopidogrel
● Guidelines give preference to ticagrelor over clopidogrel, particularly in higher- risk
patients.
Dosages
● Initiated with an oral loading dose of 180 mg followed by 90 mg twice daily
Cangrelor
● rapidly acting reversible inhibitor of P2Y12 that is administered intravenously.

29. Dypiridamole
Mechanism of Action
● By inhibiting phosphodiesterase, dipyridamole blocks the breakdown of cAMP
Dosage
● Twice daily. Each capsule contains 200 mg of extended- release dipyridamole and
25 mg of aspirin
Side Effects
● Because dipyridamole has vasodilatory effects, caution is necessary in patients with
coronary artery disease. Gastrointestinal complaints, headache, facial flushing,
dizziness, and hypotension can also occur
Indications
● Although dipyridamole/aspirin can replace aspirin for stroke prevention, because of
the vasodilatory effects of dipyridamole and thepaucity of data supporting the
usefulness of this drug in patients with symptomatic coronary artery disease,
dipyridamole/aspirin is contraindicated in such patients; clopidogrel is a better
choice in patients with coronary artery disease

30. Glycoprotein IIb/IIIa Receptor Antagonists
The three agents in this class are abciximab, eptifibatide, and tirofiban.
Mechanism of action
● With platelet activation, however, inside- outside signal transduction pathways
trigger conformational activation of the receptor. Once activated, GPIIb/IIIa binds
fibrinogen and, under high- shear conditions, vWF.
Indications
● Abciximab, eptifibatide, and tirofiban are used occasionally in patients undergoing
PCI, particularly those with acute myocardial infarction, whereas tirofiban and
eptifibatide are used in high- risk patients with unstable angina.
Dosages
● All of the GPIIb/IIIa antagonists are given as an intravenous bolus followed by an
infusion.

31. Vorapaxar
● Inhibits PAR- 1, the major thrombin receptor on human platelets.
● Overall, vorapaxar reduced the risk for cardiovascular death, myocardial infarction,
or stroke by 13% but doubled the risk for intracranial bleeding.
● Based on these data, the drug is now licensed for patients younger than 75 years
with myocardial infarction who have no history of stroke, transient ischemic attack,
or intracranial bleeding and who weigh more than 60 kg

32. Anticoagulants

33. Heparin
Mechanism of Action
● Activating antithrombin (previously known as antithrombin III) and accelerating the
rate at which it inhibits clotting enzymes, particularly thrombin and factor Xa.
● The APTT or anti- factor Xa level is used to monitor heparin.
Dosage:
● For prophylaxis, heparin is usually given in fixed doses of 5000 units
subcutaneously two or three times daily.
Limitations :
● The pharmacokinetic limitation .reflect heparin's propensity to bind in a
pentasaccharide- independent, fashion to cells and plasma proteins
Side effects
● Heparin- induced thrombocytopenia (HIT) is an antibody- mediated process
triggered by antibodies against neoantigens on PF4 that are exposed when heparin
binds to this protei
Parenteral Anticoagulants

36. Low- Molecular- Weight Heparin
● Consisting of smaller fragments of heparin, LMWH is prepared from unfractionated
heparin by controlled enzymatic or chemical depolymerization
Mechanism of Action
● Like heparin, LMWH exerts its anticoagulant activity by activating antithrombin
● In most patients, LMWH does not require monitoring of coagulation
● If monitoring is necessary, the anti–factor Xa level is measured because most
LMWH preparations have little effect on the APTT
● Situations that may require LMWH monitoring include renal insufficiency and
obesity.
Dosage
● For prophylaxis, oncedaily subcutaneous doses of 4000 to 5000 units are often
used, whereas doses of 2500 to 3000 units are given when the drug is administered
twice daily

37. Fondaparinux
● A synthetic analogue of the antithrombin- binding pentasaccharide sequence
Mechanism of Action
● Fondaparinux binds only to antithrombin and is too short to bridge thrombin to
antithrombin
● Consequently, fondaparinux catalyzes inhibition of factor Xa by antithrombin and
does not enhance the rate of thrombin inhibition
Pharmacology
● complete bioavailability after subcutaneous injection.
● contraindicated in patients with creatinine clearance lower than 30 mL/min, and it
should be used with caution in those with a creatinine clearance lower than 50
mL/min
● 2.5 mg once daily for prevention of VTE and acute coronary syndromes
Side Effects
● Although fondaparinux can induce the formation of HIT antibodies, HIT rarely occur
● The major side effect of fondaparinux is bleeding, and it has no antidote

39. Argratroban
● A univalent inhibitor that targets the active site of thrombin
● Metabolized in the liver  must be used with caution in patients with hepatic
insufficiency
● administered by continuous intravenous infusion and has a plasma half- life of
approximately 45 minutes
● APTT is used to monitor its anticoagulant effect, and the dosage is adjusted to
achieve an APTT 1.5 to 3 times the baseline value, but not to exceed 100 seconds
● When given in high doses in the cardiac catheterization laboratory, the
anticoagulant activity of bivalirudin is monitored with the activated clotting time
● With lower doses, its activity can be monitored using the APTT
Bivalirudin
Direct Thrombin Inhibitors

40. Warfarin
● Like other vitamin K antagonists, warfarin interferes with the synthesis of vitamin K–
dependent clotting proteins, which include prothrombin (factor II) and factors VII, IX, and X
● Also impairs synthesis of the vitamin K–dependent anticoagulant proteins C and S
Mechanism of Action
● Warfarin inhibits vitamin K epoxide reductase, blocking the gamma- carboxylation process
 partially gamma- carboxylated clotting proteins with little or no biologic activity
● Warfarin exerts its anticoagulant activity when the newly synthesized clotting factors with
reduced activity gradually replace their fully active counterparts.
Monitoring
● Warfarin therapy is most often monitored with the prothrombin time, a test sensitive to
reductions in the levels of prothrombin, factor VII, and factor X
● For most indications, warfarin is administered at doses that produce a target INR of 2.0 to
3.0
Oral Anticoagulants

41. Warfarin
Side Effects
● Like all anticoagulants, the major side effect of warfarin is bleeding
○ At least half of the bleeding complications with warfarin occur when the INR exceeds
the therapeutic rang
● A rare complication of warfarin, skin necrosis usually occurs 2 to 5 days after initiation of
therapy. Well- demarcated erythematous lesions form on the thighs, buttocks, breasts, or
toes.
● Warfarin crosses the placenta and can cause fetal abnormalities or bleeding
● Patients with a lupus anticoagulant (LA) or those who need urgent or elective surgery
present special challenges
● There is no need to stop warfarin treatment before procedures associated with a low risk
for bleeding
● In contrast, warfarin must be stopped 5 days before elective invasive procedures
associated with a moderate or high risk for bleeding
Oral Anticoagulants

42. Direct oral anticoagulants (DOACs)
● Direct oral anticoagulants that target thrombin or factor Xa
● Rapid onset of action and half- lives that permit once- or twice- daily administration
MECHANISM OF ACTION
● Direct oral anticoagulants are small molecules that bind reversibly to the active site
of their target enzyme

44. Fibrinolytic drugs

45. Fibrinolytic drugs
● Used to degrade thrombi, fibrinolytic drugs are administered systemically or are
delivered via catheters directly into the substance of the thrombus
● These agents acts by converting the proenzyme, plasminogen, to plasmin, the
active enzyme
● Alteplase and its derivatives are fibrin- specific plasminogen activators, whereas
streptokinase, anistreplase, and urokinase are nonspecific agents

46. Streptokinase
● Streptokinase is not an enzyme and does not directly
convert plasminogen to plasmin
● Instead, it forms a 1:1 stoichiometric complex with
plasminogen, thereby inducing a conformational change
in plasminogen that exposes its active site
● No affinity for fibrin, and the streptokinase- plasminogen
complex activates both free and fibrin- bound
plasminogen
● When given systemically to patients with acute
myocardial infarction, streptokinase reduces mortality
rates
● For this indication the drug is usually administered as an
intravenous infusion of 1.5 million units over a period of
30 to 60 minutes

47. Alteplase
● A recombinant form of single- chain t- PA, alteplase has a molecular weight of
68,000.
● Alteplase has a considerably higher affinity for fibrin than for fibrinogen
● Consequently, the catalytic efficiency of plasminogen activation by alteplase is two
to three orders of magnitude higher in the presence of fibrin than in the presence of
fibrinogen
● A trial comparing alteplase with streptokinase for the treatment of patients with
acute myocardial infarction demonstrated significantly lower mortality rates with
alteplase than with streptokinase, although the absolute difference was small
● Patients older than 75 years with anterior myocardial infarction presenting less than
6 hours after the onset of symptoms derived the greatest benefit from alteplase
● Acute myocardial infarction or acute ischemic stroke is treated with an intravenous
infusion of alteplase over a 60- to 90- minute period, total dose of alteplase usually
ranges from 90 to 100 mg

48. Urokinase
● Originally isolated from cultured fetal kidney cells and later synthesized using
recombinant DNA technology
● Unlike streptokinase, urokinase is not immunogenic, and allergic reactions are rare
● Urokinase produces a systemic lytic state because it does not discriminate between
fibrin- bound and circulating plasminogen
● Despite many years of use, systemic urokinase has never been evaluated for
coronary fibrinolysis; instead, urokinase was mostly used for catheter- directed lysis
of thrombi in the deep veins or in peripheral arteries.
● Because of production problems, urokinase is no longer available

49. Tenecteplase
● A genetically engineered variant of t- PA, tenecteplase was designed to have a
longer half- life than t- PA and to be resistant to inactivation by PAI- 1
● Tenecteplase is more fibrin specific than t- PA
● For coronary fibrinolysis, tenecteplase is administered as a single intravenous
bolus.
● The 30- day mortality rate with single- bolus Tenecteplase was like that with
accelerated- dose t- PA

50. Reteplase
● A recombinant t- PA derivative, reteplase is a single- chain variant that lacks the
finger, epidermal growth factor, and first kringle domains
● Reteplase binds fibrin with lower affinity than t- PA does because it lacks the finger
domain
● Plasma halflife longer than that of t- PA.
○ Given as two intravenous boluses separated by 30 minutes
● Clinical trials in patients with acute myocardial infarction showed improved 30- day
survival rates when reteplase was compared with streptokinase, but its
noninferiority compared with alteplase

51. Thank You