HEPARIN INDUCED THROMBOCYTOPENIA: HIT HAPPENS

1
HEPARIN INDUCED THROMBOCYTOPENIA HIT HAPPENS

• Jerrold H. Levy, MD
• Professor of Anesthesiology
• Deputy Chair, Research
• Emory University School of Medicine
• Cardiothoracic Anesthesiology and Critical Care
• Emory Healthcare
• Atlanta, Georgia

2
Hemostasis
Endothelial cell
Subendothelial matrix
Hemostatic plug
WBC
Fibrin
RBC
Platelets
3
COMPONENTS OF HEMOSTASIS

• Vasculature
• Coagulation proteins
• Platelets

4
Stimulation of Platelets
Thrombin

ADP
ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adrenaline
Adhesion
5
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

6
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

7
Heparin-induced Thrombocytopenia

• Clinical Presentation Following heparin
• Thrombocytopenia observed 5 14 days later or
  may occur sooner with previous heparin exposure
• Platelet count lt100,000/µL or
• Platelet count 50 of baseline (pre-heparin
  value)

3050 of patients with HIT will have a
thrombotic complication within 30 days Warkentin
TE Am J Med. 1996101502507
8
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

9
Pathophysiology of HIT and Thrombosis
10
Laboratory Testing for HIT

• Test Advantages Disadvantages
• SRA Sensitivity gt85 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
11
Frequency of Clinical Sequelae in HIT
Sequelae Incidence Thrombosis 3050
Amputation 20 (arterial thrombosis) Death 30
12
Sites of Thrombotic Complications in HIT
Warkentin TE Am J Med 1996101502507

• 3050 of untreated patients with
  thrombocytopenia progress to thrombosis

41 Incidence Ratio Venous to Arterial
Arterial Aortic/Ileofemoral Thrombosis Acute
Thrombotic Stroke Myocardial Infarction
Intraventricular Thrombosis Thrombosis
in upper limb, mesenteric, renal and spinal
arteries
Venous Deep Vein Thrombosis Pulmonary
Embolism Cerebral Dural Sinus Thrombosis Adrenal
Hemorrhagic Infarction
13
HIT Has Occurred with All Types of Heparin
Risk Factor Highest Risk Moderate
Risk Route/Dose IV use SC use High dose Low
dose Type UFH LMWH Source Bovine heparin Porcine
heparin Patient type Surgical Medical CABG
Orthopedic
14
Clinical Diagnosis of HIT

• Platelet count drop occurs during or after
  heparin therapy

Platelet count drops to lt50 of baseline
Platelet count lt100,000/?L
or
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
15
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

16
IV ANTITHROMBINS

• Antithrombin
• Hirudin r-lepirudin, Refludan
• Bivalirudin (Angiomax)
• Argatroban
• Other agents
• Levy JH Novel intravenous antithrombins. Am
  Heart J 20011411043

17
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

18
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

19
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.

20
Bivalirudin 20 amino acid peptide
Gly-Pro-Arg-Pro (active site binding region)
C-terminal dodecapeptide(exosite 1-binding
region)
(Gly)4
21
Specific, reversible binding
22
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)

23
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

24
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

25
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

26
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

27
Relationship at Steady-State Between Argatroban
Dose, Plasma Argatroban Concentration, and aPTT
Plasma Argatroban (µg/mL)
100
75
50
Mean aPTT (secs)
25
0
Infusion dose (µg/kg/min)
28
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

29
Recommended Dosing Guidelinesfor Argatroban
HIT Patients
HIT Patients with Renal Impairment
HIT Patients with Hepatic Impairment
Initiate at 2 µg/kg/min Titrate until
steady-state aPTT is 1.53.0 times baseline value

• Initiate at 0.5 µg/kg/min
• Titrate until steady-state aPTT is 1.53.0 times
  baseline value

No dosage adjustment required
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
30
Safety Results for Argatroban
Argatroban Historical Control Studies 1 2
(n568) (n193) 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
31
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

32
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

33
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)

34
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

35
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 gt4.0, stop Argatroban infusion
If INR is ?4.0, continue concomitant therapy
Repeat INR 4-6 hours later
If INR is below the therapeutic range for
warfarin alone, resume Argatroban therapy
If INR is within therapeutic range on warfarin
alone, continue warfarin monotherapy
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 gt2
?g/kg/min, temporarily reduce to a dose of 2
?g/kg/min 4-6 hours prior to measuring the INR.  
36
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

37
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 126311S337S).
• Pentasaccharide (Fondaparinux) a highly
  selective, indirect inhibitor of activated factor
  X, is the first of a new class of synthetic
  antithrombotic agents

38
FondaparinuxTargeted mechanism of action
Extrinsic pathway
Intrinsic pathway
3
1
2
Xa
Xa
ATIII
ATIII
ATIII
Fondaparinux
IIa
II
Fibrinogen
Fibrin clot
Olson ST, et al. J Biol Chem. 1992
26712528-12538.
39
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

40
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

41
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

42
HeparinInducedThrombocytopenia.com