HemostasisSubendothelial matrixSubendothelial matrix
PlateletsPlatelets
Hemostatic plugHemostatic plug
FibrinFibrinEndothelial cellEndothelial cell
RBCRBCWBCWBC
COMPONENTS OF HEMOSTASIS
•Vasculature•Coagulation proteins•Platelets
Adhesion
GpIIb/IIIa
Stimulation of Platelets
GpIIb/IIIaGpIIb/IIIa Aggregation
ADP
Adrenaline
ThrombinThrombin
Platelet GpIb
Exposed Collagen
Endothelium
vWF
PAR-1 (Thrombin receptor)
PAR-4
GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation
Adhesion
Aggregation
Adhesion
ADP
Adrenaline
Aprotinin
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 immune-mediated 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
30%–50% of patients with HIT will have a thrombotic complication within 30 days Warkentin TE Am J Med. 1996;101:502–507
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 (pre-
heparin value)
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 HITTest 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
Sequelae IncidenceThrombosis 30%–50%
Amputation 20% (arterial thrombosis)
Death 30%
Frequency of Clinical Sequelae in HIT
• 30%–50% of untreated patients with thrombocytopenia progress to thrombosis
4:1 Incidence Ratio Venous to Arterial
ArterialAortic/Ileofemoral ThrombosisAcute Thrombotic Stroke Myocardial Infarction Intraventricular ThrombosisThrombosis in upper limb, mesenteric, renal and spinal arteries
Venous Deep Vein ThrombosisPulmonary EmbolismCerebral Dural Sinus ThrombosisAdrenal Hemorrhagic Infarction
Sites of Thrombotic Complications in HIT: Warkentin TE Am J Med 1996;101:502–507
Risk Factor Highest Risk Moderate Risk
Route/Dose IV use SC useHigh dose Low dose
Type UFH LMWH
Source Bovine heparin Porcine heparin
Patient type Surgical Medical CABG Orthopedic
HIT Has Occurred with All Types of Heparin
Clinical Diagnosis of HITPlatelet count drop occurs during or after heparin therapy
Platelet count drops to <50% of baseline
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
or
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 agentsLevy 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 site-directed 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 peptideGly-Pro-Arg-Pro (active site binding region)
(Gly)4
C-terminal dodecapeptide(exosite 1-binding region)
Specific, reversible binding
(Gly)4
C-terminal dodecapeptide(Exosite 1-binding portion)
2
1
Thrombin
2
1
Thrombin
Bivalirudin
Gly-Pro-Arg-Pro(active-site-binding portion)
Argatroban Indications and Usage
Argatroban is a synthetic direct thrombin
inhibitor indicated as an anticoagulant
for prophylaxis or treatment of
thrombosis in patients with heparin-
induced 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 clot-bound thrombin
Argatroban Is Distinct from Indirect Thrombin Inhibitors (UFH, LMWH, and Heparinoids)
• Argatroban– Does not interact with or induce heparin-
dependent 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
0
25
50
75
Mea
n a
PT
T (
±sec
s) 100
0 4 862 10
0 0.8 1.61.20.4 2.0
Infusion dose (µg/kg/min)
Plasma Argatroban (µg/mL)
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 Guidelinesfor Argatroban
HIT Patients HIT Patients with Renal Impairment
HIT Patients with Hepatic Impairment
* 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
Initiate at 2 µg/kg/min
Titrate until steady-state aPTT
is 1.5–3.0 times baseline value*
No dosage adjustment required
Initiate at 0.5 µg/kg/min†
Titrate until steady-state aPTT
is 1.5–3.0 times baseline value*
Safety Results for Argatroban Argatroban Historical Control†
Studies 1 & 2 (n=568) (n=193)
Major Hemorrhagic Events*
Overall Bleeding 5.3% 6.7%
Gastrointestinal 2.3% 1.6%
Genitourinary and hematuria 0.9% 0.5%
Decrease in Hb/Hct 0.7% 0%
Multisystem hemorrhage and 0.5% 1%
DIC
Limb and BKA 0.5% 0%
Intracranial hemorrhage 0% 0.5%
NOTE: Patients may have experienced more than one adverse event
* 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
If INR is below the therapeutic range for
warfarin alone, resume Argatroban
therapy
If INR is >4.0, stop Argatroban infusion
Initiate warfarin therapy using the expected daily dose of warfarin while maintaining Argatroban infusion.*
A loading dose of warfarin should not be used
If INR is within therapeutic range on
warfarin alone, continue warfarin
monotherapy
If INR is 4.0, continue concomitant
therapyRepeat INR 4-6 hours later
Measure INR daily†
* 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
Olson ST, et al. J Biol Chem. 1992; 267:12528-12538.
IIaII
Fibrinogen Fibrin clot
Extrinsic pathway
Intrinsicpathway
3
ATIII Xa
1
ATIII ATIII
2
Fondaparinux
Xa
Fondaparinux:Targeted mechanism of action
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 under-
recognized, 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
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