Heparin-Induced Thrombocytopenia (HIT)

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Heparin-Induced Thrombocytopenia(HIT)
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Heparin-Induced Thrombocytopenia(HIT)

• HIT
• is an immune-mediated
• adverse effect of heparin that
• paradoxically increases risk of thrombosis

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HIT is a clinico-pathological syndrome
Clinical

• Thrombocytopenia and/or
• Thrombosis

Pathological

• Heparin-dependent, platelet-activating IgG
  antibodies

Warkentin TE, Chong BH, Greinacher A. Thromb
Haemost 1998791-7. Greinacher et al. Blood
20051062921-2922. Greinacher et al. Thromb
Haemost 200594132-135.
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Heparin-induced thrombocytopenia (HIT)
Less frequent clinical manifestations

• Anaphylactoid reaction after i.v. heparin bolus
• Skin lesions at s.c. heparin injection sites
• Overt (decompensated) disseminated intravascular
  coagulation (DIC)

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Approach to diagnose HIT
Yes HIT
Possible
Thrombocytopenia (gt 50 decrease)

Timing 5-14 days after starting heparin

Thrombosis

Unusual thromboembolism skín lesions anaphylaxis

OTher cause not apparent

Strongly Suspected
Confirmed when positive in context of
strong clinical suspicion

Test for HIT antibodies positive (usually
strongly positive)
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Clinical events associated with HIT

• Venous thrombosis (30-70)
• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Adrenal necrosis (adrenal vein thrombosis)
• Cerebral venous (sinus) thrombosis
• Venous limb gangrene (VKA associated)
• Arterial thrombosis (white clots) (15-30)
• Limb artery thrombosis
• Stroke
• Myocardial infarction
• Skin lesions at heparin injection sites (10)
• Skin necrosis
• Erythematous plaques
• Acute reactions after i.v. heparin bolus (10)
• Disseminated intravascular coagulation (DIC) (10)

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Drugs associated with HIT

• Unfractionated heparin
• Prophylactic dose
• Therapeutic dose
• Flushes
• Heparin-coated devices
• Low-molecular-weight heparin
• Prophylactic dose
• Therapeutic dose
• Other highly sulfated polysaccharides
• Pentosan polysulfate
• Hypersulfated chondroitin sulfate
• PI-88 (anti-angiogenic drug)

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HIT a link between immune system and hemostasis
PF4 tetramer
Li et al, Blood 2002 991230
Thrombosis
Warkentin TE, Chong BH, Greinacher A. Heparin
induced thrombocytopenia Towards consensus.
Thromb Haemost 1998,791-7
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Sequence of eventsin the development of HIT
Initiation

• Current or recent exposure to heparin
• Immune response against platelet factor 4
  (PF4)/heparin complexes
• Anti-PF4/heparin IgG antibodies crosslink
  platelet Fc receptors and trigger platelet
  activation
• Positive feedback for platelet activation (e.g.,
  adenosine diphosphate, thromboxane A2)
• Platelet activation results in shedding of
  procoagulant platelet microparticles

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Sequence of events in the development of HIT
Development of a hypercoagulable state

• Platelet microparticles promote thrombin
  generation
• Endothelial cell injury and monocyte activation
  further enhance thrombin generation
• PF4 release neutralizes heparin
• PF4 release leads to formation of additional
  PF4/heparin complexes, exposing more antigens,
  and thus further amplifying platelet activation

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HIT - a vicious cycle of platelet activation and
coagulation
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Factors influencing frequency of HIT
Factor Influence
Type of heparin Bovine UFH gt porcine UFH gt LMWH
Patient population Post-surgery gt medical gt obstetrical
Duration of heparin 5 or more days heparin use gt 1-4 days
Dose of heparin Change from low to full dose can lead abrupt platelet ? in immunized patient
Gender Female gt male
Definition of thrombocytopenia Proportional platelet count fall (e.g. gt50) more sensitive than absolute platelet ?
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Iceberg model of HIT
HIT and associated thrombosis occurs in the
subset of patients with platelet-activating
anti-PF4/H antibodies
Thrombosis
HIT syndrome
Thrombocytopenia
Positive washed platelet activation assay
PositivePF4 antigen assay
Numbers of Patients
Adapted from Warkentin TE. Br J Haematol
2003,121535
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Platelet count nadir distribution in HIT
Adapted from Warkentin TE. Br J Haematol
2003,121535
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Management of HIT diagnosisThree different
clinical presentations
Adapted from Warkentin TE. Br J Haematol 2003,
121 535
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Detection of HIT antibodies

• Platelet activation assays
• Serotonin release assay (SRA uses washed
  platelets)
• Heparin-induced platelet activation (HIPA) assay
  (uses washed platelets)
• Platelet aggregation test (PAT uses
  citrate-anticoagulated platelet-rich plasma)
• Platelet microparticles (flow cytometry)
• Antigen assays
• PF4/heparin-enzyme immunoassay (EIA)
• PF4/polyvinyl sulfonate EIA
• Fluid-phase EIA
• Particle gel immunoassay

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Detection of HIT antibodies
Specificity () Specificity ()
Diagnostic assay Sensitivity () Early platelet ? Late platelet ?
Serotonin release assay (SRA) 90-98 gt95 80-97
Heparin-induced platelet activation assay (HIPA) 90-98 gt95 80-97
Platelet aggregation (PRP) 35-85 90 82
PF4/heparin EIA gt90 gt95 50-93
Combination of platelet activation assay PF4 antigen EIA 100 gt95 80-97
Adapted from 7th. ACCP Conference 2004 Chest
126, 311S
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Detection of HIT antibodies

• High negative predictive value
• Negative test usually rules out HIT
• Moderate positive predictive value
• Stronger test result higher chance of HIT
• Routine antibody testing is NOT recommended
  unless
• Thrombocytopenia or gt50 ? in platelet count
• Thrombosis
• Heparin-induced skin necrosis
• Other sequelae of HIT
• Applies to solid-phase EIAs and washed platelet
  activation assays

7th. ACCP Conference 2004 Chest 126, 311S
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Clinical signs of HIT
1 Reproduced with permission Blackwell
Publishing (Warkentin TE. Br J Haematol 1996 2
Warkentin TE et al. Ann Intern Med 1997
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Clinical signs of HIT
Acute reactions after intravenous heparin bolus

• Fever, chills, flushing
• Respiratory distress
• Hypertension, tachycardia, chest pain
• Transient global amnesia, headache

Venous and/or arterial thrombosis

• Deep vein thrombosis
• Pulmonary embolism
• Limb ischemia and infarction
• Thrombotic stroke and cerebral (sinus) vein
  thrombosis
• Myocardial infarction
• Adrenal necrosis

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Differential diagnosis

• Hemodilution post-surgery
• Severe pulmonary embolism
• Sepsis
• DIC (multiple causes besides HIT)
• Cancer-associated DIC
• Antiphospholipid syndrome
• Thrombolytic therapy
• EDTA-induced pseudothrombocytopenia
• GP IIb/IIIa inhibitor-induced thrombocytopenia
• Drug-induced thrombocytopenia (other than
  heparin)
• Post-transfusion purpura
• Thrombotic thrombocytopenic purpura
• Non-immune heparin-associated thrombocytopenia

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Platelet count monitoring is recommended in
patients at risk of HIT gt 0.1
Platelet count monitoring Platelet count monitoring
Patient population Yes/No Frequency
Risk for HIT common (gt1) Receiving therapeutic dose UFH Yes min. alternate day ? 14 d
Receiving post-op prophylactic dose UFH Yes min. alternate day 4 - 14 d
Starting UFH/LMWH have received UFH in last 100 d or exposure uncertain Yes baseline value-repeat in 1 d
Systemic reaction after UFH bolus Yes immediate compare with pre-bolus value
Risk for HIT infrequent (0.1-1). Medical/Obstetric UFH Post-op LMWH Post-op UFH flush LMWH after UFH Yes every 2 -3 days, 4 - 14 d
Risk HIT lt 0.1. Medical/obstetric patients on LMWH No -
7th. ACCP
Conference 2004 Chest, 126 311S
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Diagnosis - pretest probability the 4 Ts

2 1 0
Thrombocytopenia gt 50 platelet count fall to nadir 20 30-50 platelet count fall to nadir 10-19 lt30 platelet count fall to nadir 10
Timing of fall in platelet count or other sequelae Onset d 5-10 or lt 1 d (if heparin exposure within 30 d) gt d 10, or timing unclear, or lt d 1 with recent heparin 31-100 d Platelet count fall lt d 4 (without recent heparin exposure)
Thrombosis or other sequelae New thrombosis skin necrosis post-heparin bolus acute systemic reaction Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not confirmed None
OTher cause for thrombocytopenia No other cause for platelet count fall is evident Possible other cause is evident Definite other cause is present
Points Score 0, 1 or 2 for each of 4 categories
A
B
C
D
Adapted from Lo et al. J Thromb Haemost 2006, in
press
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Diagnosis - pretest probabilityInterpretation of
4 Ts score

• Score 0-3 very unlikely to be HIT (lt5)
• Score 4 - 5 a minority have HIT (10-30)
• Score 6 8 20 to gt80 have HIT, depending on
  the clinical setting and scorers experience
  these patients usually require an alternative,
  non-heparin anticoagulant in therapeutic doses

Adapted from Lo et al. J Thromb Haemost 2006, in
press
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Management of HIT treatment
When HIT is strongly-suspected

• Stop heparin (UFH/LMWH), even in patients without
  thrombosis
• Initiate alternative non-heparin anticoagulant
  because of high risk of symptomatic thrombosis
• Test for HIT antibodies
• Duplex ultrasonography for lower-limb DVT

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Management of HIT treatment
When HIT is strongly-suspected

• Do not start a vitamin K antagonist (VKA) - if
  started prior to diagnosis it should be reversed
  by vitamin K
• Do not use low-molecular-weight heparin (LMWH)
• Do not give platelet transfusions unless needed
  to manage serious hemorrhage
• Recommendation to give vitamin K applies
  particularly to direct thrombin inhibitors
  (DTIs), because prolongation of the aPTT by
  warfarin can lead to underdosing of DTI therapy
  (in contrast, danaparoid is not monitored by
  aPTT)

• 7th. ACCP Conference 2004 Chest, 126 311S-337S
• Warkentin TE. J Thromb Haemost 2006 in press.

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Management of HIT treatment
When the diagnosis of HIT is confirmed

• Postpone starting overlapping coumarin until the
  platelet count has recovered to at least 100 (and
  preferably) 150 x 109/L
• Therapeutic doses of alternative, non-heparin
  anticoagulants are usually required
• If a sensitive test for HIT is negative, heparin
  therapy may be re-started with regular platelet
  count monitoring

7th. ACCP Conference 2004 Chest, 126, 311S-337S
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Management of HIT treatment
When HIT is clinically possible but platelet
count decrease is more likely caused by other
reasons

• If the patient requires therapeutic dose
  anticoagulation for non-HIT reasons, use
  alternative anticoagulant in therapeutic dose.
• If patient does not require therapeutic dose
  anticoagulation for non-HIT reasons, consider
  prophylactic-dose alternative anticoagulation,
  e.g. danaparoid 750 U b.i.d. or t.i.d. until HIT
  antibody test results are available.

Selleng K and Greinacher A Intensiv up-2-date
20051329-341
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Occurrence of symptomatic thrombosis after
stopping heparin in patients confirmed to have
isolated HIT
14-year retrospective study
Cumulative thrombotic event-rate ()
N 62
52.8
Days after isolated HIT recognized
Adapted from Warkentin TE, Kelton JG. Am J Med.
1996101502507.
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Odds ratios for risk of thrombosis

• Prothrombin anomaly 2.0
• Lupus anticoagulant 5.4
• Factor V Leiden 6.6
• Protein S deficiency 10.9
• Dysfibrinogenaemia 11.3
• Protein C deficiency 14.4
• Antithrombin deficiency 24.1

• HIT 20-40

Warkentin TE. Can J Cardiol 199511(Suppl.
C)29C-34C Warkentin TE. Thromb Res 2003
11073-82
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Management of HIT treatment
Suitable alternative non-heparin antithrombotic
therapies are

• Danaparoid Xa/IIa inhibitor (anti-Xa gtgt
  anti-IIa)
• Direct thrombin inhibitor (DTI)
• Lepirudin
• Argatroban
• Bivalirudin

7th. ACCP Conference 2004 Chest 126 311S-337S
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HIT summary conclusions

1. HIT is a potentially fatal side effect of heparin
   that is more common with UFH than LMWH
2. HIT is a clinico-pathologic syndrome its
   diagnosis is based on compatible clinical
   features and presence of HIT antibodies
3. Antibodies against PF4/heparin are formed
   commonly during heparin treatment HIT occurs in
   the subset of patients with strong
   platelet-activating IgG antibodies

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HIT summary conclusions

• Binding of HIT antibodies to PF4/heparin
  complexes on the platelet surface results in
  platelet activation, thrombocytopenia and
  increased risk of arterial thrombosis
• Platelet, monocyte, and endothelial cell
  activation results in a hypercoagulable state,
  and increased risk of venous thrombosis
• HIT-associated thrombosis occurs in some patients
  1 2 days before platelet counts decrease

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HIT summary conclusions

1. Platelet count monitoring is important to
   diagnose isolated HIT and thus has the potential
   to prevent thrombosis
2. Recognizing a relative decrease of platelet count
   is important since platelets do not always fall
   below 150 x 109/L
3. Platelet count monitoring is recommended in most
   patients receiving UFH and in some patients
   receiving LMWH.

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HIT summary conclusions

1. Heparin should be stopped immediately in all
   situations where HIT is strongly suspected
2. Due to the high risk of thrombosis in patients
   with HIT anticoagulation with a non-heparin
   anticoagulant should be started even in the
   absence of overt thrombosis
3. Danaparoid provides an option for anticoagulation
   in either prophylactic or therapeutic doses

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Heparin-Induced Thrombocytopenia(HIT)