Hemostasis and Thrombosis

Hemostasis and
Thrombosis
Core Curriculum Lecture

The Hemostatic Process

• Formation of the platelet plug

• Coagulation cascade

• Fibrinolysis

The remarkable
endothelium

• A monolayer of endothelial cells lines the intimal surface of the
entire circulatory tree
• It is a dynamic organ that controls
• vascular permeability
• the flow of biologically active molecules and nutrients
• cell-cell/cell-matrix interactions
• blood flow and vascular tone
• inflammatory response
• angiogenesis

The remarkable endothelium: a regulator
of hemostasis

It can be prothrombotic
or antithrombotic !

Primary Hemostasis - the A D

formation of the platelet
plug
Platelet
Step 1: Platelet Adhesion
• Triggered by damage to the vessel wall
and exposure to collagen B
• Initial contact mediated by
GP1b/IX/V -- vWF interaction
Step 2: Platelet Activation
• Rapid release of serotonin, ADP, Glycoprotein
IIb/IIIa

thrombin, epinephrine, and thromboxane
A2 C
• These mediators amplify and sustain the
initial platelet plug
• Activation of platelet glycoprotein 2b3a Glycoprotein
IIb/IIIa

- the main receptor for adhesion and
aggregation
Platelet

Step 3: Platelet Aggregation
• Activation of GIIb/IIIa receptor it binds
to ﬁbrinogen and vWF
• This leads to a positive feedback loop
that culminates in the formation of the
platelet plug

Platelets and the development of
atherosclerotic lesions The n e w e ng l a n d j o u r na l of m e dic i n e

• Activated platelets release inﬂammatory Activated
platelet
Time-dependent new protein synthesis

substances into the local environment CD40 ligand
Tissue factor or interleukin-1
pre-mRNA
Splicing
Cleavage
Immediate mRNA

• CD40 - induces endothelial cells to produce
release
Soluble CD40 ligand
Synthesis

reactive oxygen species, adhesion RANTES Platelet
P-selectin
PSGL-1
Thrombin
generation Interleukin-1
receptor
molecules, chemokines, and tissue factor factor 4
Soluble CD40 ligand Tissue factor
RANTES
MMPs

•
Interleukin-6
IL-1 - causes endothelial cells to increase of Monocyte
Recruitment
Soluble CD40 ligand
Interleukin-8
MCP-1
chemokine release and promotes adhesion CD40 Activated

of neutrophils and monocytes endothelium

Resting
endothelium O2-

•
E-selectin VCAM
P selectin - released from platelet granules ICAM H2O2
OH-
which leads to the adhesion of monocytes Monocyte
Resident
to the endothelium macrophage
Degradation of
matrix proteins

• Platelet Factor 4 promotes the Differentiation

differentiation of monocytes into Figure 2. Platelet-Derived Mediators of the Inflammatory Response.
macrophages Activated platelets release inflammatory and mitogenic substances into the microenvironment, primarily altering the chemotactic, adhe-
sive, and proteolytic properties of the endothelium. Preformed platelet mediators, stored in α-granules, can be released immediately af-
ter platelet activation through a process of exocytosis triggered by increased intracellular calcium levels. Activated platelets are also ca-

•
pable of time-dependent synthesis of protein mediators, such L O R F I G U R E and interleukin-1β. CD40 ligand is stored in the cytoplasm
C O as tissue factor

MMPs lead to the degradation of matrix of resting platelets and rapidly presents on the surface after5platelet activation. After cleavage, to generate a soluble, functional frag-
Rev 11/26/07
ment (soluble CD40 ligand), the mediator is released into the extracellular environment, inducing inflammatory responses in the endo-
proteins
Author Patrono
thelium by binding CD40 on endothelial cells. P-selectin is released from platelet granules and binds to the P-selectin glycoprotein li-
Fig # 2
gand 1 (PSGL-1) receptor on monocytes, enhancing the adhesion of the monocytes to vascular-cell adhesion molecule (VCAM) 1 and
Title
the other adhesins expressed on activated endothelial cells and inducing the production of tissue factor by monocytes. Activated plate-
ME
lets also release chemokines that trigger the recruitment of monocytes (e.g., regulated on activation normal T-cell expressed and secret-
DE
ed [RANTES]) or promote the differentiation of monocytes SBL macrophages (e.g., platelet factor 4), as well as matrix-degrading en-
Artist into
zymes such as matrix metalloproteinase (MMP) 2 or 9. Interleukin-1β is a major mediator of platelet-induced activation of endothelial
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
cells, causing enhanced chemokine release and up-regulation of endothelial adhesion molecules to promote the adhesion of neutrophils
Please check carefully
and monocytes to the endothelium. ICAM denotes intracellular adhesion molecule, mRNA messenger RNA, MCP-1 monocyte chemoat-
Issue date
tractant protein 1, and OH− hydroxyl radical.

is a trimeric transmembrane protein in the tumor molecules, chemokines,42 and tissue factor,45 all

The Platelet - friend or foe?
Aspirin1 Mechanisms of Disease
ADP receptor
antagonists1
• Irreversible binds COX-1 A D

(which is found only in the • ADP ampliﬁes the
plt) and COX 2 thereby response to other agonists,
blocking the formation of thereby contributing to the
TXA2 Platelet
growth and staibility of
thrombus
• Anucleate plts are unable
to synthesize new COX2 for B • Ticlopidine and clopidigrel
their remaining 7 to 10 day incompletely and variably
life span inhibit ADP-induced plts
aggregation
• Bleeding time returns to
nil in 1-2 d as new plts are Glycoprotein
IIb/IIIa • Exert a permanent effect
formed on the platelet which lasts
COX-2 Inhibitors2 C
for plt lifetime

• Irreversible binds COX-2, Glycoprotein IIB/
which is found throughout IIIA Antagonist
Glycoprotein
the vascular endothelium. IIb/IIIa

• Three types
• Decrease systemic levels • Monoclonal Ab -
of PGI2, which are crucial in Platelet
Tirofoban (Aggrastat)
plt inhibition • Peptide antagonists -
Epiﬁbatide (Integellin)
•Have no effect on systemic • Nonpeptide antagonists
TXA2 levels Tirofoban (Aggrastat)

• Rofecoxib (VIOXX) found
increase serious CV events • All are IV as oral agents
by a factor of 3.9 have been disappointing

Restraining Thromboxane A2
The Second International Study of Infarct
Survival
ISIS-2, Lancet 1988

• Study Design

• Multicenter, multinational, randomized,
double-blind, placebo-controlled

• Patients: 17,187 patients with suspected MI in previous 24h; patients with
history of stroke or GI hemorrhage/ulcer were excluded

• Follow up and primary endpoint: Median 15 months follow up. Primary
endpoint vascular mortality

• Patients randomized to one of four groups Streptokinase and aspirin
(160 mg/day for 1 month), Streptokinase, Aspirin (160 mg/day for 1
month), Placebo

ASA and SK have similar reductions in
mortality
Vascular mortality over 35 days: individual therapies

1029 1016
Cumulative 1000 (12.0%)
1000
(11.8%)
no. of
vascular 800 791 800 804
deaths (9.2%) (9.4%)

600 600
Placebo Placebo
infusion tablets
400 SK 400 Aspirin
Odds reduction: Odds reduction:
200 25%, SD 4 200 23%, SD 4
2P<0.00001 2P<0.00001
50 50
0 7 14 21 28 35 0 7 14 21 28 35
Days after randomization

The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.

ASA + SK lead to better outcomes

Vascular mortality at 35 days in four treatment arms and combination

Vascular mortality (%) at 35 days Combination therapy compared with
matched combination placebo
600
Aspirin Placebo Cumulative 568 (13.2%)
no. of 500
vascular
deaths 400
Streptokinase 8.0 10.4 * 343 (8.0%)
300

200 Odds reduction:
42%, SD 5
Placebo 10.7 * 13.2 100
2P<0.00001
0
0 7 14 21 28 35
* Significantly higher than combination therapy: Days after randomization
2P<0.0001
Placebo infusion and tablets
SK and aspirin

The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.

The Clopidogrel Trials
CURE TRIAL GERSCHUTZ AND BHATT
CAPRIE (1996) - ASA vs clopidogrel in CURE (2001) - dual antiplatelet ther apy in high-risk patients (2006) - Preventing
Use in UA/ CHARISMA
preventing ischemic events NSTEMI Atherothrombotic Events
be superior to aspirin alone in reducing the risk weeks following Primary endpt (MI, CVA,
percutaneous coronary inter-
A
Clopidogrel stroke, myocardial infarction, or death
of ischemic is beneficial early vention. 10 CV death)
Primary endpt (annual rate from vascular causes. However, there was debate
0.06 Bleeding was not significantly increased
Clopodigrel+ASA 6.8%
in the clopidogrel group. Fewer patients
as to whether P2Y12-receptor blockade provided

Cumulative Incidence of the
of MI, CVA, vascular death) received a GP IIb/IIIa inhibitor in 7.3%
8 ASA alone the clopi-
0.05
Clopodigrel 5.3% uniform benefit. Since CAPRIE, four large clini-

Cumulative hazard rate

Primary Composite
Placebo dogrel group than in the placebo0.22
CI 0.83-1.05; p group

End Point (%)
ASA alone 5.8% cal trials have added to the body of evidence that
0.04 (20.9% vs 26.6%, relative risk 0.70, P = .001).
Placebo
CI 0.3-16.6; p 0.043 supports the use of dual antiplatelet therapy in The benefit of 6 clopidogrel persisted through Clopidogrel
0.03 Clopidogrel the end of the study.
patients with acute coronary syndromes and in Thus, in patients presenting with acute
4
those undergoing percutaneous coronary inter-
0.02 coronary syndromes, pretreatment with clopi-
vention.6-9 CHARISMA represented the logical next
P < .001
dogrel prior to percutaneous coronary inter-
step of evaluation of the potential role of this
0.01 vention followed by long-term therapy is supe-
2
rior to standard treatment.
approach in a broad population of patients with
0.00 0
established vascular disease or multiple cardio-
0 10 20 30 ! INTERPRETATION: WHEN 6 USE 12
0 TO 18 24 30
vascular risk factors. follow-up
Days OR WITHHOLD CLOPIDOGREL
Months
A subgroup analysis suggested that clopido-
. . . and in the long term The at Risk study demonstrated long-term
No. CURE
grel was beneficial with respect to the primary clopidogrel therapy to be 7653
Clopidogrel 7802 superior to7510
placebo 7363 5299 2770
0.14 in high-risk patients presenting with acute 7316
efficacy end point in patients who were classified Placebo 7801 7644 7482 5212 2753
coronary syndromes without ST-segment ele-
0.12symptomatic for the purposes of the trial (i.e.,
as Placebo
vation. This is an impressive result, since the
B
Cumulative hazard rate

who were enrolled because of a documented his- benefit is in addition to that of aspirin.
0.10 20
tory of established vascular disease). However, the The benefit of a reduction in the rate of

Cumulative Incidence of the
Clopidogrel
P value for this association and the P value for
0.08 myocardial infarction is at the cost of an

Secondary Composite
increase in bleeding, however. Placebo
0.06 interaction between enrollment status and
the 15

End Point (%)
The findings support the routine use of Clopidogrel
therapy were only marginally significant, sug-
P < .001 long-term clopidogrel in the management of
0.04 acute coronary syndromes everywhere as well
gesting that this observation should be interpreted 10
0.02 caution, especially since this subgroup anal-
with as the use of clopidogrel on presentation at
centers pursuing a conservative approachendpt (ﬁrst MI, CVA,
Secondary with
ysis was only one of several such analyses per-
0.00 medical therapy. CV death, UA, TIA, revasc)
formed. Furthermore, the risk of moderate or se-
0 3 6 9 12 5
To reduce the morbidity and mortality of
Clopodigrel+ASA 16.7%
vere bleeding in Months of follow-up
symptomatic patients was greater bleeding complications, it would be advisable
to avoid other medications, suchASAnon- as alone 17.9%
with clopidogrel than with placebo, although there CI 0.86-0.995; p 0.04
steroidal anti-inflammatory drugs, that may
0
FIGURE 1. Cumulative hazard rates for cardiovascular fatal
was no significant increase in intracranial or
death, myocardial infarction, and stroke in patients also increase bleeding risk. 6
0 12 18 24 30

presenting with acute as a practical matter, it is unclear
bleeding. Finally, coronary syndromes without The PCI-CURE substudy demonstrates Months
ST-segment elevation in the CURE trial. Theimplemented
how such a classification could be results benefit Risk pretreatment with clopidogrel
No. at with
demonstrate the early (top) and sustained (bottom) prior to percutaneous coronary intervention. 6802
Clopidogrel 7802 7401 7104 4774 2450
clinically, since some patients in the asymptomatic
benefit of clopidogrel. This study, together with the results 7029
Placebo 7801 7371 of other 6705 4640 2374
15,16

Primary Efﬁcacy
The Rise of Prasugrel Endpoint - CV
death, non fatal
MI or CVA
• Prasugrel - a novel thienopyridine - is
prodrug that requires conversion to an
active metabolite
• It has almost complete absorption after
Key Safety
oral ingestion of a loading dose
Endpoint - Major
• Hydrolysis bu intestinal caroxyesterases bleeding not
and oxidation by P-450 covert it to active related to
form CABG
• It has greater antiplatelet effect than
clopidogrel
• Increase risk of bleeding esp. the elderly, the Pr asugrel vs. Clopidogrel in Patients with Acute Coronary Syndromes
underweight, and those with previous CVA
or TIA
Table 3. Thrombolysis in Myocardial Infarction (TIMI) Bleeding End Points in the Overall Cohort at 15 Months.*

• Patients with previous CVA or TIA had Hazard Ratio
higher risk of intracranial hemmorhage
T h e n e w e ng l a n d j o u r na l o f m e dic i n e
End Point
Prasugrel
(N = 6741)
Clopidogrel
(N = 6716)
for Prasugrel
(95% CI) P Value

• It is not recommended for pts >75 yrs. old
Table 2. Major Efficacy End Points in the Overall Cohort at 15 Months.*
Non–CABG-related TIMI major bleeding
no. of patients (%)
146 (2.4) 111 (1.8) 1.32 (1.03–1.68) 0.03
Hazard Ratio (key safety end point)
Prasugrel Clopidogrel for Prasugrel
End Point (N = 6813) (N = 6795) (95% CI) P Value†
Related to instrumentation 45 (0.7) 38 (0.6) 1.18 (0.77–1.82) 0.45
no. of patients (%) Spontaneous 92 (1.6) 61 (1.1) 1.51 (1.09–2.08) 0.01
Death from cardiovascular causes, nonfatal MI, 643 (9.9) 781 (12.1) 0.81 (0.73–0.90) <0.001 Related to trauma 9 (0.2) 12 (0.2) 0.75 (0.32–1.78) 0.51
or nonfatal stroke (primary end point) Figure 1. Cumulative Kaplan–Meier Estimates of the Rates of Key Study End Points during the Follow-up Period.
Life-threatening† 85 (1.4) 56 (0.9) 1.52 (1.08–2.13) 0.01
Death from cardiovascular causes 133 (2.1) 150 (2.4) 0.89 (0.70–1.12) 0.31 Panel A shows data for the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial in-
Nonfatal MI 475 (7.3) 620 (9.5) 0.76 (0.67–0.85) <0.001 farction [MI], instrumentation
Related to or nonfatal stroke) (top) and for the(0.5)safety end point (Thrombolysis in Myocardial Infarction
28 key 18 (0.3) 1.55 (0.86–2.81) 0.14
Nonfatal stroke 61 (1.0) 60 (1.0) 1.02 (0.71–1.45) 0.93 [TIMI] major bleeding not related to coronary-artery bypass grafting) (0.5)
Spontaneous 50 (0.9) 28 (bottom) during (1.12–2.83)
1.78 the full follow-up period.
0.01
Death from any cause 188 (3.0) 197 (3.2) 0.95 (0.78–1.16) 0.64 The hazard ratio for prasugrel, as compared with clopidogrel, for the primary efficacy end point at 30 days was 0.
Related to trauma 7 (0.1) 10 (0.2) 0.70 (0.27–1.84) 0.47
Death from cardiovascular causes, nonfatal MI, 652 (10.0) 798 (12.3) 0.81 (0.73–0.89) <0.001 (95% confidence interval [CI], 0.67 to 0.88; P<0.001) and at 90 days was 0.80 (95% CI, 0.71 to 0.90; P<0.001). Dat
or urgent target-vessel revascularization for Fatal‡
the primary efficacy end point are also shown (0.4) the time of randomization4.19 (1.58–11.11) and0.002
21 from 5 (0.1) to day 3 (Panel B) from
Death from any cause, nonfatal MI, or nonfatal 692 (10.7) 822 (12.7) 0.83 (0.75–0.92) <0.001 3 days to 15 months, with all end points occurring before day 3 censored (Panel C). In(0.87–1.81) number at risk
Nonfatal 64 (1.1) 51 (0.9) 1.25 Panel C, the 0.23
stroke includes all patients who were alive (regardless of whether a nonfatal event had occurred during the first 3 days
Intracranial 19 (0.3) 17 (0.3) 1.12 (0.58–2.15) 0.74
Urgent target-vessel revascularization 156 (2.5) 233 (3.7) 0.66 (0.54–0.81) <0.001 after randomization) and had not withdrawn consent for follow-up. The P values in Panel A for the primary efficac
Death from cardiovascular causes, nonfatal MI, 797 (12.3) 938 (14.6) 0.84 (0.76–0.92) <0.001
Major orpoint were calculated with the use of the 303 (5.0)
end minor TIMI bleeding 231 (3.8) 1.31 (1.11–1.56) 0.002
Gehan–Wilcoxon test; all other P values were calculated with the us
nonfatal stroke, or rehospitalization for of therequiring transfusion§
Bleeding log-rank test. 244 (4.0) 182 (3.0) 1.34 (1.11–1.63) <0.001
ischemia
Stent thrombosis‡ 68 (1.1) 142 (2.4) 0.48 (0.36–0.64) <0.001 CABG-related TIMI major bleeding¶ 24 (13.4) 6 (3.2) 4.73 (1.90–11.82) <0.001

The Glycoprotein IIb/IIIa Story
• GIIb/IIIa inhibitors have been studied since the mid 1990s

• These are generally used in UA/NSTEMI patients

• Meta-analysis (2002) of these trials included

• All randomized trials with ACS without ST elevation that compared GIIb/IIIA to control therapy
and that did not recommend early revascularization

• 18,927 patients in the study group and 13,105 in the control

TBoersma, Eric, Harrington, Robert et al., “Platelet glycoprotein IIB/IIIa
inhibitors in acute coronary syndromes: a meta-analysis of all major
randomized clinical trials,” Lancet, v 359, January 19, 2002 p 189-198

The Coagulation Cascade

Intrinsic Pathway -
unlikely to activate
coagulation, but rather
helps propagate it once Extrinsic Pathway -
it has begun likely initiates
coagulation. Injury leads
to the expression of
tissue factor, which is
present on endothelial
cells, smooth muscle
cells, ﬁbroblasts and
circulating blood cells

Vitamin K Clotting
Factors

4-6 h half life

24 h half life

48 h half life

60 h half life

The problems of warfarin

• Dosing based on 10% rule of weekly
warfarin dose totals
• Warfarin dosing affected
• Dosing and compliance
• Genetics
• Lab testing

On a knife’s edge

Hylek, EM, NEJM 1999

On a knife’s edge

Risk Factors for
Intracranial
Hemorrhage in
Outpatients Taking
Warfarin, Hylek, EM,
Annals of Internal
Medicine, 1994

Pharmacogenetics of Warfarin

Variations in the
CYP2CP and
the Vit K Oxide
Reductase
genotype lead to
variations in
coumadin dosing

Now to Heparin

Antithromin
neutralizes
thrombin, Factors
Xa, IXa,XIa,XIIa

Now to Heparin

Heparin
catalyzes AT
activity on unbound
thrombin
Antithromin
neutralizes
thrombin, Factors
Xa, IXa,XIa,XIIa

Heparin versus its low molecular weight cousin
• Unfractionated heparin
• 2 mechanisms of catalysis
• Makes AT inhibit Factor Xa by two orders of
magnitude
• Binds thrombin in a Thrombin-AT-Heparin
complex
• PTT becomes immeasurably prolonged at heparin
concentrations of more than 1.0 U/ml (which
occurs during cath)
• Activating clotting time is used at high
concentrations
• LMWH
• Exerts is anticoagulant activity by activating AT only
• Shorter heparin chains bind less avidly to
endothelial cells, macrophages, plasma proteins
• Has 90% bioavailability after subq injection
• Fondaparinux
• Synthetic analog of the AT-binding pentasacharide
• Cleared unchanged by the kidneys and cannot be
used if circle<30
• Does not cause HITT

The future is here - oral Factor Xa inhibitors
Apixaban
• Pharmacokinetics
• Has 50% bioavailability
• Reaches plasma concentration in 3 to 4 hrs
• Unclear whether it can be used in pst with hepatic or renal impairment
• Clinical Trial Data
• ADVANCE-1: randomized 3195 patients to either apixaban or enoxaparin
for orthopedic prophylaxis. Study found that the primary endpt (VTE or
death) was similar btw the two groups
• ADVANCE-2: presented this past summer and the primary endpoint (VTE
after knee replacement) Apixaban vs Enoxaparin 15.1 v 24.4 (95%CI
0.51-0.74 p 0.001). Also, there was a non sig trend towards less bleeding in
the apixaban arm
• APPRAISE: phase 2 study looking at placebo vs 4 diff’t doses of apixaban
for 6 months after ACS. Trial had to be terminated due to excess bleeding.
• ARISTOTLE: not published, but plans to study stroke prevention in AF
patients.
Garcia, et al. Blood Jan 2010

in the risk of the composite endpoint of cardiovascular death, myocar-
similar indications in has United States, citing a data, and that doses.22 The decision to administer rivaroxaban twice daily in the phase
website. The agency the requested more safety concern the
The future is here - oral Factor Xa inhibitors
possibility “could lead a bleeding remains open. In each more dial infarction, or stroke. A dose-finding phase 2 study (ATLAS, TIMI
rivaroxabanof approval atto later date events in significantlyof the 3 acute coronary syndrome study emerged from observations in ATLAS
4 “REgulation of Coagulation in Food and Drug Administration 46) demonstrated benefit with respect to the primary (composite
patients” than enoxaparin on the ORthopaedic surgery to prevent that, for this population (many of whom are also taking one or more

possibility of approval
Rivaroxaban
Deep-vein thrombosis and pulmonary embolism” (RECORD)
mg by mouth once daily proved superior to
endpoint) but also showed increased bleeding with higher rivaroxaban
website. The agency has requested more safety data, and the antiplatelet agents), the risk-benefit ratio may be better when the
22
studies, rivaroxaban 10at a later date remains open. In each of the doses. The decision to administer rivaroxaban twice daily in the phase

•
total amount of drug is split into 2 doses rather than adminis-
the comparator inCoagulation in ORthopaedicTaken together, the 3 acute coronary syndrome study emerged from observations in ATLAS
Pharmacokinetics
4 “REgulation of the prevention of VTE.12-15 surgery to prevent
results from these clinical studies suggest that a 10-mg oral dose of
tered for a single tablet. (many of whom are also taking one or more
that, as this population
Deep-vein thrombosis and pulmonary embolism” (RECORD)
•
rivaroxaban can, compared with standard doses of enoxaparin, antiplatelet agents), the risk-benefit ratio may be better when the
studies, rivaroxaban 10 mg by mouth once daily proved superior to appox 3 hrs after oral ingestion
Achieves maximum plasma levels
reduce the risk of VTE after total hip or knee arthroplasty (Table 5). total amount of drug is split into 2 doses rather than adminis-
the comparator in the prevention of VTE.12-15 Taken together, the

•
tered as a single tablet.
results from these clinical studies suggest that is10-mg oral dose of Practical considerations
Overall rates of major hemorrhage were low, but the pooled results
from more than 12 000bioavailability these 4 trials show a
Oral patients included in doses of enoxaparin,
a 80%
rivaroxaban can, compared with standard
trend toward increased major bleeding (0.39% vs 0.21%, P .08) All 3 drugs discussed in this review are eliminated, to some extent,
•
reduce the risk of VTE after total hip or knee arthroplasty (Table 5).
Currently contraindicated in patients w/ CrCl<30
with rivaroxaban. When the trial definition of major bleeding is by the kidneys; thus, whether (or at what dose) patients with
Overall rates of major hemorrhage were low, but the pooled results Practical considerations
combined with surgical site bleeding, the rates for rivaroxaban and moderate to severe renal insufficiency can use these agents may not
•
from more than 12 000 patients included in these 4 trials show a
trend toward increased Trials
Clinical major bleeding (0.39% vs 0.21%, P .08) All 3 drugs discussed in this review are eliminated, to 23,24 extent,
enoxaparin are 1.80% and 1.37%, respectively (P .06; Table 6). be determined for some time. Although each of these agents affects
After a phase 2 trial of rivaroxaban for the treatment of acute conventional clotting assays to some degree (Table 7), some further

•
with rivaroxaban. When the trial definition of major for patients research kidneys; thus, to determine how what dose) patients with
VTE,21 2 phase 3 studies are currently underway: one bleeding is by the will be needed whether (or at clinicians can best assess
Now approved in Canada and Europe, but in May 2009 FDA did not
combined with surgical site bleeding, the rates for rivaroxaban and moderate to severe renal insufficiency can use these agents may not
enoxaparin are 1.80% and 1.37%, respectively (P .06; Table 6).excess bleeding events
approve rivaroxaban because of be determined for some time. Although each of these agents affects
Table 5. Total VTE
After a phase 2 trial of rivaroxaban for the treatment of acute conventional clotting assays to some degree (Table 7),23,24 further

•
RECORD 1 (hip) RECORD 2 (hip) RECORD 3 (knee) RECORD 4 (knee)
VTE,21 2 phase 3 studies are currently underway: one for patients research will be needed to determine how clinicians can best assess
Rivaroxaban
Four clinical trials were completed to study rivaroxaban as prophylaxis
n compared to enoxaparin 864
Table 5. Total VTE
1595 824 965
Endpoint 18 (1.1%) 17 (2.0%) 79 (9.6%) 67 (6.9%)
Enoxaparin RECORD 1 (hip) RECORD 2 (hip) RECORD 3 (knee) RECORD 4 (knee)
n
Rivaroxaban 1558 869 878 959
nEndpoint 58
1595 (3.7%) 864 (9.3%)
81 166 (18.9%)
824 97 (10.1%)
965
EndpointVTE occurrence of: any DVT(1.1%)
Total
18 (symptomatic or asymptomatic), nonfatal PE, or death of any cause in RECORD studies of rivaroxaban after major orthopedic
17 (2.0%) 79 (9.6%) 67 (6.9%)
Enoxaparin All differences favor rivaroxaban, and all reach statistical significance (P .05).
surgery.12-15
n 1558 869 878 959
Endpoint 58 (3.7%) 81 (9.3%) 166 (18.9%) 97 (10.1%)
Table 6. Pooled rates of bleeding from the 4 RECORD trials
Total VTE occurrence of: any DVT (symptomatic or asymptomatic), nonfatal PE, or death of any cause in RECORD studies 1000 patients after major orthopedic
Rivaroxaban, no. per 1000 patients Enoxaparin, no. per of rivaroxaban P
surgery.12-15 All differences favor rivaroxaban, and all reach statistical significance (P .05).
Major bleeding 3.9 2.1 .08
Major bleeding surgical site bleeding 18.0 13.7 .06
Table 6. Pooled rates of bleeding from the 4 RECORD trials
Rivaroxaban, no. 2009). Garcia, et al. Blood Jan 2010
Adapted from the FDA Advisory Committee Briefing Document (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascu-
larandRenalDrugsAdvisoryCommittee/UCM181524.pdf; accessed October 5, per 1000 patients Enoxaparin, no. per 1000 patients P

I got the HIT
• More than 30% of hospitalized patients are exposed
to heparin

• The highest frequency of HIT (about 3 to 5%) has been
reported in postoperative orthopedic patients who
received prophylactic doses of UFH for 10-14 day.

• The incidence of HIT among cardiac surgical patients
receiving postoperative UFH is 1 to 3 percent

• HIT can occur in 0.1 – 0.2% of pts receiving LMWH

• Life or limb thrombosis occurs in about 50% of patients
if left untreated

I got the HIT
Making the Clinical Diagnosis
Timing of Thrombocytopenia
• 5 to 14 days after initiation of
heparin
• Heparin re-exposure can lead
to an earlier onset
• Onset may occur up to 90 days
after exposure
• Degree of drop
•Decrease from baseline 30
to 50 percent

Pretest Probability

High: 6 to 8 points
Intermediate: 4 to 5 points
Low: < 3 points

Making the Diagnosis
• Serotonin release assay platelets and testing whether they bind
• to heparin radiolabeling
Requires
IgG
• Sensitivity and specificity >95%
• Solid phase ELISA
• serum is added
Heparin-PF4 complexes are coated on a microtiter and patient

• varies from 50-93% 91-97%, but positive predicted value
Highly sensitive assay

•positive HITpatients up to 18% of pts on dialysis will have
In dialysis
ELISA
• Unclear of the did not portend development of
significance
•thrombocytopenia or for arterial or venous thromboembolic
Positive result

events, vascular access occlusion, or mortality.

What’s up with Direct
Thrombin Inhibitors?
• Thrombin inhibition can take place by binding three domains -
active site and two exosites

• Exosite1 - acts as a dock for substrates such as ﬁbrin

• Exosite 2 serves as a heparin binding domain

• UFH binds both thrombin-AT, but cannot bind ﬁbrin-bound
thrombin

•
Figure 2. Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin.
This decreases its activity since active thrombin activates further thrombinof activity of thrombin inactivation by antithrombin is relatively low, but after conformational
In the absence heparin, the rate
change induced by heparin, antithrombin irreversibly binds to and inhibits the active site of thrombin. Thus, the antico-
agulant activity of heparin originates from its ability to generate a ternary heparin–thrombin–antithrombin complex. The

•
activity of DTIs is independent of the presence of antithrombin and is related to the direct interaction of these drugs with
Direct Thrombin Inhibitors - block either the active site or exosite 1 or just the active site the thrombin molecule. Although bivalent DTIs simultaneously bind the exosite 1 and the active site, the univalent drugs
in this class interact only with an active site of the enzyme. In the lower panel, the heparin–antithrombin complex cannot
bind fibrin-bound thrombin, whereas given their mechanism of action, DTIs can bind to and inhibit the activity of not

•
only soluble thrombin but also thrombin bound to fibrin, as is the case in a blood clot. An animated version of this figure
Bivalent - hirudin and bivalirudin is available with the full text of the article at www.nejm.org.

• Of note, bivalirudin only provides transient inhibition of thrombin as it aispcleavedckoid yen ac si c s
h a r m a c o by thrombin after it is bound
nd pharma
n ti
m
renal function. Although excessive anticoag-
ulation with hirudin in patients with renal insuffi-
12,15

ciency can be managed with high-volume hemo-

•
The routes of administration, plasma half-lives, and filtration with hirudin-permeable hemodialysis
Univalent - argatroban, melagatroban, and dabigatran main sites of clearance of the various DTIs are list- membranes,15 the available data remain scarce.
ed in Table 1. DTIs with a predominant renal clear- Studies in animals suggest that excessive plasma
ance such as hirudin, melagatran, and dabigatran concentrations of melagatran can be managed by

• Also, DTIs have antiplatelet properties given that thrombin is a potent platelet activator
1030
are likely to accumulate in patients with impaired

n engl j med 353;10
either hemodialysis or the administration of acti-

www.nejm.org september 8, 2005

• Clearance
Downloaded from www.nejm.org by RAJ M. KHANDWALLA MD on March 19, 2010 .
Copyright © 2005 Massachusetts Medical Society. All rights reserved.

• Renal - hirudin, melagatran, dabigatran

• Bivalirudin is partially cleared by kidneys, liver, and proteolysis

• Argatroban is hepatically cleared

Nisei, et al. NEJM, Sept 2005

What’s the evidence show ?
Table 2. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients with Coronary Syndromes (with or without Percutaneous Coronary Intervention)
or Atrial Fibrillation.*

Percentage of
No. of Control Major Efficacy Patients with a Major Serious Bleeding
Study Diagnosis or Treatment Patients DTI Regimen Treatment Outcomes Efficacy Outcome (percentage)
Short-term treatment of
coronary artery disease
Direct Thrombin Inhibitor Acute coronary syndromes 35,970 Hirudin, bivalirudin, ar- Unfractionated Death or myocardial Combined DTIs, 7.4; Combined DTIs, 1.9;
Trialists’ Collaborative with or without percutane- gatroban, efegatran heparin infarction at 30 unfractionated unfractionated
Group23 study ous coronary intervention days heparin, 8.2 heparin, 2.3
HERO-224 Myocardial infarction with ST 17,073 Bivalirudin at 0.25 mg/ Unfractionated Death at 30 days Bivalirudin, 10.8; Bivalirudin, 0.7;
elevation kg intravenously, fol- heparin for unfractionated unfractionated
lowed by 0.5 mg/kg/ 48 hr heparin, 10.9 heparin, 0.5
hr for 12 hr and then
0.25 mg/kg/hr for 36 hr
REPLACE-225 Percutaneous coronary inter- 6,010 Bivalirudin at 0.75 mg/kg Unfractionated Death, myocardial Bivalirudin, 9.2; Bivalirudin, 2.4;
vention intravenous bolus, heparin plus infarction, urgent unfractionated unfractionated
followed by 1.75 mg/ GPIIb/IIIa in- repeat revascular- heparin, 10.0 heparin, 4.1
kg/hr for duration of hibitors for ization, or serious
procedure 12–18 hr bleeding
Long-term treatment of
coronary artery disease
ESTEEM26 Myocardial infarction with or 1,883 Ximelagatran at 24 mg, Placebo twice Death from any cause, Combined ximela- Combined ximela-
without ST elevation 36 mg, 48 mg, or daily for 6 mo nonfatal myocar- gatran, 12.7; gatran, 2;
60 mg twice daily for dial infarction, or placebo, 16.3 placebo, 1
6 mo severe recurrent
ischemia
Atrial fibrillation
SPORTIF III27 Nonvalvular atrial fibrillation 3,407 Ximelagatran at 36 mg Warfarin for a All strokes or systemic Ximelagatran, 2.3; Ximelagatran, 1.7;
twice daily for a mean mean of 17 mo embolism warfarin, 3.3 warfarin, 2.4
of 17 mo
SPORTIF V28 Nonvalvular atrial fibrillation 3,922 Ximelagatran at 36 mg Warfarin for a All strokes or systemic Ximelagatran, 2.6; Ximelagatran, 3.2;
twice daily for a mean mean of 20 mo embolism warfarin, 1.9 warfarin, 4.3
of 20 mo

* DTI denotes direct thrombin inhibitor, HERO-2 Hirulog and Early Reperfusion or Occlusion 2, REPLACE-2 Randomized Evaluation in Percutaneous Coronary Intervention Linking Angi-
omax to Reduced Clinical Events 2, ESTEEM Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage, and SPORTIF Stroke Pre-
vention Using an Oral Thrombin Inhibitor in Atrial Fibrillation.
Nisei, et al. NEJM, Sept 2005

Stent Thrombosis
• Timing

• Acute - occurs 0 24 hrs after implantation

• Subacute - occurs >24 hrs to 30 days

• Late - occurs >30 days to 1 yr

• Very late: occurs > 1 yr.

• Incidence

• Stent thrombosis within the ﬁrst year appears to occur with equal frequency in patients with BMS and DES (as long as these patients
are on dual plt therapy)

• Pathophysiology

• Stent implantation is an inherently thrombogenic procedure. Coating prevents in-stent restenosis

• Sirlolimus - potent antiproliferative, antiinﬂammatory, and immunospuuresive effects that causes the arres of the cell cycle. SIRIUS
trial helped gain FDA approval after showing restenosis rates were dramatically lower (3.2% vs 35.4%, p<0.001) compared to BMS

• Paclitaxel - potent antiproliferative that inhibits the disassembly of microtubules. TAXUS-IV trial led to FDA approval which
showed that slow-release placlitaxel decreased the need for repeat procedure from 4.7% vs 12%, p<0.001

• Risk factors for in-stent thrombosis

• Cinical Variables - DM, Decreased EF, Renal Failure, Bailout stenting

• Anatomic Variables - Small vessel diameter, long lesion (multiple stents), bifurcating stenosis, Large plaque volume, poor perfusion

• Procedural - Residual uncovered dissection, suboptimal post prodecural lumen, inadequate stent expansion, thrombus

Stent Thrombosis

• Acute and subacute

• Majority of cases occur within the ﬁrst 30 days

• Dutch stent thrombosis registry found 437 of 21,009 (2.1%) presented with
thrombosis during mean follow up 31 months

• Acute - 32%

• Subacute - 41%

• Late - 13%

• Very late - 14%

• Both randomized and observational studies have demonstrated that the rate of stent
thrombosis is similar in BMS vs DES

• But BMS tend to thrombose at a higher rate <1 yr and DES > 1 yr
Van Wekum, JW, et al, JACC 2009
Weisz G, JACC 2009

Hemostasis and Thrombosis

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