Heparin Induced Thrombocytopenia

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Heparin Induced Thrombocytopenia

• KenwynJames
• 13th May 2008

2
Case History

• 68 year old male
• PC
• AF (ventricular rate approx 150bpm)
• Cardiogenic shock
• O/E
• Hypotensive
• Pulmonary oedema
• Metabolic acidosis, lactate 10mmol/l

3
Management

• Successful electrical cardioversion
• Rapid reversion to AF
• Medical management
• IV heparin
• Digoxin
• Amiodarone

4
Investigations

• Echo severe AS, ejection fraction 15
• Coronary angiography no surgically correctable
  coronary artery lesion
• Mild renal impairment
• Platelets 202 x 109/l

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Progress

• Referred for aortic valve replacement
• Day 7 platelet count 30 x 109/l
• HIT screen sent - antibody positive

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Progress

• IV heparin stopped
• Danaperoid started for anticoagulation
• Aortic valve surgically replaced
• Returned home in sinus rhythm

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Thrombocytopenia

• Occurs in up to 60 of critically ill patients
• Multifactorial
• Sepsis
• Hemodilution
• Drug induced
• Liver disease/hypersplenism
• Plt consumption/destruction
• DIC
• Massive transfusion
• Immune (ITP, TTP)
• Intravascular devices

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History

• 1958 Weismann and Tobin described 10 patients
  with paradoxical thrombi during heparin therapy
• Pale salmon colour, platelet rich on microscopy
• No mention of thrombocytopenia
• 1973 Rhodes et al described thrombocytopenia as
  component of syndrome
• Pathogenic role of heparin confirmed by
  recurrence of thrombocytopenia on reexposure to
  heparin

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History

• Immune component postulated based on ability of
  plasma from affected patients to induce platelet
  aggregation in presence of heparin
• 1992 Amiral et al demonstrated that Platelet
  factor 4 bound to HIT antibody

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Heparin Associated Thrombcytopenia

• Occurs in up to 30 patients receiving heparin
• Mild thrombocytopenia (100-150 x109/l)
• Onset less than 4 days after starting therapy
• Recovers within 1-3 days
• No thrombotic complications

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Heparin Induced Thrombocytopenia

• Anticoagulant induced prothrombotic disorder
  caused by platelet activating heparin dependent
  IgG antibodies
• Occurs in 1 of patients receiving heparin for
  more than 5 days

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Pathophysiology

• IgG antibodies to PF4/Heparin complex
• Platelet factor 4 is a heparin binding tetrameric
  protein found in platelet ? granules
• Binding to heparin causes conformational change
  promoting immune response

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Pathogenesis of Immune-Mediated HIT
Caiola E, Cleve Clin J Med 2000
67621-624 Bartholomew JR et al 2005
72(S1)S32-S36
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Prothrombotic effect

• Thrombin generation
• Platelet activation produces membrane derived
  microparticles ? enhance coagulation reactions
  and thrombin generation
• Immune complexes bind to endothelial cells and
  monocytes promoting expression of tissue factor
  and activation of coagulation cascade

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Prothrombotic effect

• Platelet activation causes further PF4 release
• PF4 binds heparin neutralising anticoagulant
  effect

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Cascade of events leading to formation of HIT
antibodies and prothrombotic components
www.thrombosite.com
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Frequency

• Dependent on dose and duration of therapy
• Dependent on diagnostic criteria used
• SurgicalgtMedicalgtObstetric
• Orthopaedicgtcardiac surgery
• Bovine lunggtPorcine IntestinalgtLMWH
• FemalegtMale

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Iceberg Model
Multiple thrombosis (white clot
syndrome) 0.01-0.1
Isolated thrombosis 30-80 of below groups
Asymptomatic thrombocytopenia 30-50 of below
group
HIT - IgG seroconversion 0-10
Warkentin TE, et al. 199475-127
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Iceberg model
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Clinical Features

• Thrombocytopenia
• Thrombosis
• Heparin induced skin lesions
• Acute systemic reaction

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Thrombocytopenia

• Platelet count starts to fall 5-10 days following
  initiation of heparin
• Mild to moderate thrombocytopenia
• Mean platelet nadir 50-60 x 109/l
• 10-15 pts platelet count not droplt150 x 109/l
• Relative fall gt50 more indicative

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Distribution of Platelet Count in HIT
Median nadir59 ? 109/L
40
30
Number of patients with HIT
20
10
0
3
5
10
30
100
1000
20
50
15
70
200
300
500
Platelet count nadir ? 109/L
Warkentin. Semin Hematol. 199835(suppl 5)9-16.
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Thrombosis

• thromboembolic complications
• occurs in at least 30 to 40 of HIT cases
• mortality estimated at 30
• increased length of hospital stay

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Thrombosis

• Venous
• DVT
• Coumarin induced venous limb gangrene or
  classic skin necrosis
• PE
• Cerebral vein thrombosis
• Adrenal haemorrhagic infarction

• Arterial
• Lower limb artery thrombosis (amputation 20
  risk)
• CVA (transient global amnesia)
• MI (3-5)
• Miscellaneous

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Skin Lesions

• 10-20 patients with HIT antibodies develop
  lesions at site of injection
• erythematous plaques
• skin necrosis
• Appear at least 5 days after initiation of
  heparin treatment
• Majority do not develop thrombocytopenia

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Necrotic lesion in HIT patient receiving LMWH
injections
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Skin Necrosis at UFH injection Sites
(Prophylactic dose)

• Warkentin TE. Br J Haematol. 199692494497.

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Acute Systemic Reactions

• Onset 5-30 minutes post heparin IV
• Clinical Features
• Chills, rigors, fevers
• Tachycardia and hypertension
• Tachypnoea and dyspnoea
• Chest pain
• Nausea and vomiting
• Diarrhoea
• Transient global amnesia
• Death

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Diagnosis

• Clinical features
• Thrombocytopenia
• Timing
• Thrombosis
• Other explanations
• Laboratory tests
• Serological tests
• Activation assays

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4Ts
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Laboratory Tests

• ELISA
• Relatively quick to perform
• Sensitivity gt 95
• Antibodies transient
• Low specificity
• 3-20 pts have antibodies following heparin in
  preceding days to weeks
• 40-60 pts have antibodies following open heart
  surgery

• Activation assays
• Detect antibodies on basis of ability to activate
  platelets in presence of heparin
• High sensitivity and specificity
• Serotonin Release Assay
• Magnitude of positive result diagnostically useful

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Treatment

• Do
• Stop all heparin
• Start alternative, non heparin anticoagulant
• Treatment of HIT with cessation of heparin alone
  results in 50 thrombosis in next 30 days
• Do not
• Tranfuse platelets
• Start warfarin until substantial platelet count
  recovery
• Diagnostic tests

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Could not start DTI due to recurrent GI bleed
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1 week later
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1 week later, L foot
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Treatment

• Warfarin associated with acute worsening of
  thrombosis, venous limb gangrene and skin
  necrosis
• Associated with
• disproportionately high INR
• Very low levels protein C

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Alternative anticoagulants

• Decrease thrombin generation
• Danaparoid
• Direct thrombin inhibitors
• Lepirudin
• Argatroban

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Danaparoid

• a low-molecular-weight heparinoid
• mixture of anticoagulant glycosaminoglycans
  (heparin sulfate, dermatan sulfate, and
  chondroitin sulfate) with predominant anti-factor
  Xa activity
• rapid anticoagulant effect with IV bolus
• long half-life (25 hours) for anti-Xa activity
• in vitro cross-reactivity with the HIT antibody
  (10 to 40 ) does not predict development of
  thrombocytopenia or thrombosis
• Not interfere with INR measurements

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Lepirudin

• A direct thrombin inhibitor
• recombinant form of the leech anticoagulant
  hirudin, the most potent direct thrombin
  inhibitors yet identified
• Rapid anticoagulant effect with IV bolus
• Relatively short half-life (1.3 hours)
• Relatively contraindicated in renal failure
• Anticoagulant effect readily monitored with aPTT
  (target range 1.5-3.0 times normal)
• Associated with antibody production and
  anaphylaxis

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Lepirudin

• German trial of 200 patients with HIT
• 75 to 81 effectively anticoagulated
• significant reduction in composite endpoints
  (death, limb amputation, new thrombotic
  complications) compared with historical control
  7 day 10 vs 23
  35 day 25 vs 52
• Blood 199688(suppl)281a

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Lepirudin

• Lepirudin for Parental Anticoagulation in
  Patient with Heparin-induced Thrombocytopenia
• a prospective, historically controlled trial
• by five weeks after laboratory diagnosis of HIT,
  the incidence of death, limb amputation, or new
  thromboembolic events was 52.1 in the historical
  controls and 30.9 in the Lepirudin-treated group
• Circulation 1999100587-93

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Argatroban

• a small synthetic non-polypeptide molecule
• has the same theoretical advantages of lepirudin
• short half-life (lt 1hr)
• lack of cross-reactivity for HIT antibodies
• potent antithrombin activity
• Monitored via aPTT and activated clotting time
• metabolized predominantly by the liver, may
  require dose adjustment
• excreted normally even in severe renal failure

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Transition to warfarin therapy

• Delay until therapeutic anticoagulation achieved
  with alternative agent
• Delay until resolution of thrombocytopenia (plt
  count gt100, prefrably 150x109/l)
• Do not discontinue DTI until 5 days of warfarin
  and INRgt2 for 2 consecutive days
• DTIs (argatrobangtlepirudin) increase INR

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Warfarin Anticoagulation

• Intravenous Vitamin K to reverse anticogulation
• Minimise risk of warfarin induced microvascular
  thrombosis
• Optimise DTI therapy (prolongation of aPTT by
  warfarin may cause under dosing of DTI)

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Reduce risk of developing HIT

• porcine heparin (vs. bovine heparin)
• LMWH (vs. unfractionated heparin)
• oral anticoagulation should be started as early
  as possible to reduce the duration of heparin
  exposure
• intravenous adapters should not be flushed with
  heparin
• monitor serial platelet counts for developing
  thrombocytopenia