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