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Hemostasis
Subendothelial matrix
WBC
Hemostatic plug
Platelets
Fibrin
Endothelial cell
RBC
COMPONENTS OF
HEMOSTASIS
•Vasculature
•Coagulation proteins
•Platelets
Stimulation of Platelets
PAR-1 (Thrombin receptor)
Thrombin
PAR-4
ADP
Aggregation
Aggregation
GpIIb/IIIa
GpIIb/IIIa
GpIIb/IIIa
Adrenaline
Platelet
Adhesion
vWF
Endothelium
Exposed Collagen
HEPARIN
• Polyanion: (-) charge
• From cow lung/pig intestine
• Mixture of 3K to 30K MWt
• Binds ATIII/inhibits thrombin
• Inhibits Xa, esp LMWH
• Reversible with protamine
• Causes HIT
Heparin-induced Thrombocytopenia (HIT)
Definition: HIT is a serious immunemediated syndrome where heparin
administration is associated with:
–Thrombocytopenia
–The generation of heparin-dependent
antibodies (typically IgG)
–A high risk for thrombosis causing
significant morbidity and mortality
Heparin-induced Thrombocytopenia
Clinical Presentation: Following
heparin:
–Thrombocytopenia observed 5 – 14
days later; or may occur sooner with
previous heparin exposure
• Platelet count <100,000/µL or
• Platelet count 50% of baseline (preheparin value)
30%–50% of patients with HIT will have a thrombotic
complication within 30 days Warkentin TE Am J Med. 1996;101:502–507
HIT: Pathophysiology
• Presence of IgG antibodies that recognize
PF4/heparin complexes on platelet surfaces
and vascular walls
• Binding of IgG to PF4/heparin complexes
on platelets
• Antibody activates platelets via the Fc
receptor
• Activated platelets release microparticles
with prothrombotic activity
Pathophysiology of HIT and
Thrombosis
Laboratory Testing for HIT
Test
Advantages
Disadvantages
SRA
Sensitivity >85% Technically demanding, radioisotopes;
Low predictive value
HIPA Rapid, available Variable sensitivity (30% – 80%);
Technique-dependent
ELISA High sensitivity
High cost, low specificity,
10% false-negative tests
There is no Gold Standard in diagnostic testing; HIT requires a
clinical diagnosis
Frequency of Clinical
Sequelae in HIT
Sequelae
Incidence
Thrombosis 30%–50%
Amputation 20% (arterial thrombosis)
Death
30%
Sites of Thrombotic Complications
in HIT: Warkentin TE Am J Med 1996;101:502–507
• 30%–50% of untreated patients with
thrombocytopenia progress to thrombosis
4:1 Incidence Ratio Venous to Arterial
Venous
Arterial
Deep Vein Thrombosis
Pulmonary Embolism
Cerebral Dural
Sinus Thrombosis
Adrenal Hemorrhagic
Infarction
Aortic/Ileofemoral Thrombosis
Acute Thrombotic Stroke
Myocardial Infarction
Intraventricular Thrombosis
Thrombosis in upper limb,
mesenteric, renal and spinal
arteries
HIT Has Occurred with
All Types of Heparin
Risk Factor
Highest Risk
Moderate Risk
Route/Dose
IV use
High dose
SC use
Low dose
Type
UFH
LMWH
Source
Bovine heparin
Porcine heparin
Patient type
Surgical
CABG
Orthopedic
Medical
Clinical Diagnosis of HIT
Platelet count drop occurs during or after heparin therapy
Platelet count drops to
<50% of baseline
or
Platelet count
<100,000/L
No other cause of thrombocytopenia identified
Clinical diagnosis of HIT
Discontinue all types of heparin
Assess the risk of thrombosis
If indicated, initiate alternative anticoagulant therapy
THROMBOCYTOPENIA AND
HIT: KEY POINTS
• 50% decrease in platelets is significant
• Appears day 5-8 of treatment, but
earlier suggestes pre-existing heparin
antibodies (three months).
• Consider other causes: sepsis, DIC,
autoimmune, and other medications.
• MOA: PF4/heparin epitope
IV ANTITHROMBINS
• Antithrombin
• Hirudin: r-lepirudin,
Refludan™
• Bivalirudin (Angiomax)
• Argatroban
• Other agents
Levy JH: Novel intravenous antithrombins. Am Heart J 2001;141:1043
RECOMBINANT HIRUDIN
(LEPIRUDIN, REFLUDAN)
• 65 amino acid peptide with potential
antigenicity
• Direct, IRREVERSIBLE thrombin inhibitor,
most potent.
• Rapid onset IV bolus; efficacy in HIT; short
half life (PK) but accumulates in renal
failure, NOT reversible, and can cause
anaphylaxis.
• Approved in US 1998
ARGATROBAN
• Direct thrombin inhibitor
• Rapid anticoagulation following IV bolus;
efficacy in HIT suggested; short half-life;
does not accumulate in renal failure
• Accumulates in hepatic failure; effect on INR
complicates monitoring during overlap with
warfarin; no antidote
• FDA approved 2002
Bivalirudin
•20-amino acid peptide with an active sitedirected peptide, D-Phe-Pro-Arg-Pro, linked
via a tetraglycine spacer to a dodecapeptide
analogue of the carboxy-terminal of hirudin.
•Binds directly/reversibly to both the active
catalytic site and anion-binding exosite 1 of
both circulating and clot-bound thrombin.
• Thrombin slowly cleaves the bivalirudin Arg3-Pro4 bond, resulting in recovery of
thrombin active site function.
Bivalirudin: 20 amino acid peptide
Gly-Pro-Arg-Pro
(active site binding region)
(Gly)4
C-terminal dodecapeptide
(exosite 1-binding region)
Specific, reversible binding
2
Thrombin
Gly-Pro-Arg-Pro
(active-site-binding
portion)
(Gly)4
C-terminal dodecapeptide
(Exosite 1-binding portion)
2
Thrombin
1
1
Bivalirudin
Argatroban Indications and Usage
Argatroban is a synthetic direct thrombin
inhibitor indicated as an anticoagulant
for prophylaxis or treatment of
thrombosis in patients with heparininduced thrombocytopenia (HIT)
Mechanism of Action for Argatroban
• Directly inhibits all procoagulant and
prothrombotic actions of thrombin
• Reversibly binds to the thrombin
catalytic site
• Active against both free and clotbound thrombin
Argatroban Is Distinct from Indirect
Thrombin Inhibitors (UFH, LMWH, and Heparinoids)
• Argatroban
– Does not interact with or induce heparindependent antibodies
– Does not require a cofactor for thrombin
inhibitory activity
– Active against both free and clot-bound
thrombin
Pharmacokinetics of Argatroban
Infusion in Healthy Volunteers
• Rapid Onset of Action
– Anticoagulant effects are produced
immediately upon infusion
– Steady-state levels are reached within 1 – 3
hours
– Steady-state levels are maintained until
dosage is adjusted or infusion is
discontinued
Pharmacokinetics of Argatroban
Infusion in Healthy Volunteers
• Short Half-Life
–T1/2 = 39 – 51 minutes
–Upon discontinuation of therapy,
anticoagulant parameters return to
baseline within 2 – 4 hours
Relationship at Steady-State Between
Argatroban Dose, Plasma Argatroban
Concentration, and aPTT
Mean aPTT (±secs)
Plasma Argatroban (µg/mL)
0
0.4
0.8
1.2
1.6
2.0
0
2
4
6
8
10
100
75
50
25
0
Infusion dose (µg/kg/min)
Special Populations
• In healthy subjects, the pharmacokinetics
and pharmacodynamics of Argatroban
were NOT affected by renal impairment,
age, or gender
• Dosage adjustment is NOT necessary in
renally impaired patients
• Hepatic impairment decreases Argatroban
clearance; therefore, the dosage must be
reduced for hepatically impaired patients
Recommended Dosing Guidelines
for Argatroban
HIT Patients
HIT Patients with
Renal Impairment
Initiate at
0.5 µg/kg/min†
Initiate at
2 µg/kg/min
No dosage
adjustment required
Titrate until
steady-state aPTT
is 1.5–3.0 times
baseline value*
*
HIT Patients with
Hepatic Impairment
Titrate until
steady-state aPTT
is 1.5–3.0 times
baseline value*
Not to exceed a dose of 10 µg/kg/min or aPTT of 100 seconds
† Due to approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic
function
Safety Results for Argatroban
Argatroban
Historical Control†
Studies 1 & 2 (n=568)
(n=193)
Major Hemorrhagic Events*
Overall Bleeding
Gastrointestinal
Genitourinary and hematuria
5.3%
2.3%
0.9%
6.7%
1.6%
0.5%
Decrease in Hb/Hct
Multisystem hemorrhage and
DIC
0.7%
0.5%
0%
1%
Limb and BKA
Intracranial hemorrhage
0.5%
0%
NOTE: Patients may have experienced more than one adverse event
0%
0.5%
* Defined as overt with a hemoglobin decrease 2 g/dL, that led to a transfusion of 2 units, or that was
intracranial, retroperitoneal, or into a major prosthetic joint. Other overt bleeding was considered minor
† Typical therapy for patients in the historical control group was heparin discontinuation and/or warfarin therapy
Safety Results for Argatroban
• Intracranial bleeding was not observed
in ANY of the 568 HIT patients treated with
Argatroban
– One patient experienced intracranial bleeding 4
days after discontinuation of Argatroban and
following therapy with urokinase and oral
anticoagulation
Re-exposure and Lack of Antibody
Formation
• Plasma from 12 healthy volunteers treated
with Argatroban over 6 days showed no
evidence of neutralizing antibodies
• Repeated administration of Argatroban to
more than 40 patients was tolerated with
no loss of anticoagulant activity
• No change in the dose was required upon
re-exposure for safe/effective
anticoagulation
Guidelines for Conversion to Oral
Anticoagulant Therapy
• All direct thrombin inhibitors, including
Argatroban, may increase prothrombin
time (PT); this must be taken into
consideration when converting to
warfarin therapy
• Coadministration of Argatroban and
warfarin does produce a combined effect
on the laboratory measurement of the
International Normalized Ratio (INR)
Guidelines for Conversion to Oral
Anticoagulant Therapy
• Concurrent therapy with Argatroban and
warfarin does not exert an additive effect
on the warfarin mechanism of action (e.g.,
factor Xa activity)
• The previously established relationship
between INR and bleeding risk is altered
during combination therapy
–For example, an INR of 4 on cotherapy
may not have the same bleeding risk as
an INR of 4 on warfarin monotherapy
Guidelines for Conversion to Oral
Anticoagulant Therapy
Initiate warfarin therapy using the expected
daily dose of warfarin while maintaining Argatroban infusion.*
A loading dose of warfarin should not be used
Measure INR daily†
If INR is 4.0,
continue concomitant
therapy
If INR is >4.0, stop Argatroban infusion
Repeat INR 4-6 hours later
If INR is within
therapeutic range on
warfarin alone,
continue warfarin
monotherapy
*
If INR is below the
therapeutic range for
warfarin alone,
resume Argatroban
therapy
For Argatroban infusion at 2 µg/kg/min, the INR on monotherapy may be estimated
from the INR on cotherapy. If the dose of Argatroban >2 g/kg/min, temporarily reduce
to a dose of 2 g/kg/min 4-6 hours prior to measuring the INR.
Additional Benefits of Argatroban
• Effective anticoagulation, lowering mortality
from thrombosis and preventing new thrombosis
in patients with HIT
• An acceptable bleeding risk, comparable with control
• No dose modification with renal impairment
• No formation of antibodies to itself
• Does not interact with or induce heparin-dependent
antibodies
SYNTHETIC AGENTS
• Danaparoid (Orgaran): Anti-Xa activity,
studied extensively in HIT. For patients with
strongly suspected (or confirmed) HIT,
whether or not complicated by thrombosis,
has Grade 1B recommendation based on
ACCP Guidelines (CHEST 2004; 126:311S–337S).
• Pentasaccharide (Fondaparinux) a highly
selective, indirect inhibitor of activated factor
X, is the first of a new class of synthetic
antithrombotic agents
Fondaparinux:
Targeted mechanism of action
Intrinsic
pathway
1
2
ATIII
Extrinsic
pathway
3
ATIII
Fondaparinux
ATIII
Xa
Xa
II
Fibrinogen
IIa
Fibrin clot
Olson ST, et al. J Biol Chem. 1992; 267:12528-12538.
THROMBOCYTOPENIA AND
HIT: KEY POINTS
• 50% decrease in platelets is significant
• Appears day 5-8 of treatment, but earlier
suggests pre-existing heparin antibodies
(three months).
• Consider other causes: sepsis, DIC, IABP,
autoimmune, other medications.
• MOA: PF4/heparin epitope
Summary
• HIT is a relatively common, often underrecognized, potentially devastating
complication of heparin therapy
• Diagnosis of HIT is based upon clinical
suspicion
• Treatment of HIT should not rely on
laboratory confirmation
• Untreated patients with HIT are at a high
risk of a thromboembolic complication
Summary
• Management of HIT
–Discontinue all types of heparin
–R/O other potential causes of
thrombocytopenia
–Assess risk of thrombosis
–If indicated, initiate alternative
anticoagulant therapy
HeparinInducedThrombocytopenia.com