Heparin-Induced Thrombocytopenia (HIT)

Heparin-Induced Thrombocytopenia(HIT)

HIT

is an immune-mediated

adverse effect of heparin that

paradoxically increases risk of thrombosis


HIT is a clinico-pathological syndrome

• Thrombocytopenia and/or

• Thrombosis

Warkentin TE, Chong BH, Greinacher A. Thromb Haemost 1998;79:1-7.Greinacher et al. Blood 2005;106:2921-2922.Greinacher et al. Thromb Haemost 2005;94:132-135.

Clinical

Pathological

• Heparin-dependent, platelet-activating IgG antibodies

• Anaphylactoid reaction after i.v. heparin bolus

• Skin lesions at s.c. heparin injection sites

• Overt (decompensated) disseminated intravascular coagulation (DIC)

Heparin-induced thrombocytopenia (HIT)

Less frequent clinical manifestations

Approach to diagnose HIT

Thrombocytopenia (> 50% decrease)

Timing 5-14 days after starting heparin

Unusual thromboembolism;skín lesions; anaphylaxis

OTher cause not apparent

Test for HIT antibodies positive(usually strongly positive)

+

+

+

+

+

+

Yes HIT

Strongly Suspected

Possible

Thrombosis

Confirmed when positive in context of strong

clinical suspicion

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%)

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)

Ring of positive charge

HIT: a link between immune system and hemostasis

FcRIIa Heparansulfate

PF4

Heparin

B-L

Warkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7

ThrombinTissue factorEC

Li et al, Blood 2002; 99:1230

Thrombosis

PF4 tetramer

Sequence of eventsin the development of HIT

• 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

Initiation

Sequence of events in the development of HIT

• 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

Development of a hypercoagulable state

HIT - a vicious cycle of platelet activation and coagulation

PF4/Heparin/HIT-IgGPF4/Heparin/HIT-IgG

Platelet ActivationPlatelet Activation

CoagulationCoagulation


Release PF4Release PF4

Monocyte ActivationMonocyte Activation

CoagulationCoagulation

Endothelial Cell Endothelial Cell InjuryInjury

ThrombosisThrombosis Embolism Embolism

MorbidityMorbidity

&&

DeathDeath


Release PF4

/HIT-IgGPF4PF4 /HIT-IgG

Factors influencing frequency of HIT

Factor Influence

Type of heparinBovine UFH > porcine UFH > LMWH

Patient populationPost-surgery > medical > obstetrical

Duration of heparin5 or more days heparin use > 1-4 days

Dose of heparinChange from low to full dose can lead abrupt platelet in immunized patient

Gender Female > male

Definition of thrombocytopeniaProportional platelet count fall (e.g. >50%) more sensitive than absolute platelet

“Iceberg model” of HIT

ThrombocytopeniaPositivewashedplatelet activationassay

PositivePF4 antigenassay

Thrombosis

HITsyndrome

Numbers of Patients

Adapted from Warkentin TE. Br J Haematol 2003,121:535

HIT and associated thrombosis occurs in the subset of patients with platelet-activating anti-PF4/H antibodies

Platelet count nadir distribution in HIT

Adapted from Warkentin TE. Br J Haematol 2003,121:535

Median platelet count nadir55 x 10 9/L

Platelet fall <50%

Platelet Count Nadir (x 109/L)

Num

ber

of P

atie

nts

Type of HIT-associated thrombosis

Nil (N=72)

Venous (N=132)

Venous & arterial (N=6)

Arterial (N=24)

60

50

40

30

20

10

0

5

6-10

11-1

516

-20

21-3

0

31-4

5

46-7

071

-100

101-

150

151-

200

201-

300

301-

400

>400

Management of HIT – diagnosisThree different clinical presentations

Adapted from Warkentin TE. Br J Haematol 2003, 121: 535

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


Specificity (%)

Diagnostic assay Sensitivity (%) Early platelet Late platelet

Serotonin release assay (SRA)

90-98 >95 80-97

Heparin-induced platelet activation assay (HIPA)

90-98 >95 80-97

Platelet aggregation (PRP) 35-85 90 82

PF4/heparin EIA >90 >95 50-93

Combination of platelet activation assay & PF4 antigen EIA

100 >95 80-97

Adapted from 7th. ACCP Conference 2004 Chest 126, 311S


• 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 >50% 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

Clinical signs of HIT

Erythematous plaques 1

Skin necrosis 1 Venous gangrene 2

Deep venous thrombosis 1

1 Reproduced with permission Blackwell Publishing (Warkentin TE. Br J Haematol 1996 2 Warkentin TE et al. Ann Intern Med 1997

Clinical signs of HIT

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

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

Acute reactions after intravenous heparin bolus

Venous and/or arterial thrombosis

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

Platelet count monitoring is recommended in patients at risk of HIT > 0.1%*

Platelet count monitoring

Patient population Yes/No Frequency

Risk for HIT common (>1%)

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 Yesimmediate – 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 < 0.1%. Medical/obstetric patients on LMWH No -

* 7th. ACCP Conference 2004 Chest, 126: 311S

2 1 0

Thrombocytopenia> 50% platelet count fall to nadir ≥ 20

30-50% platelet count fall to nadir 10-19

<30% platelet count fall to nadir ≤ 10

Timing of fall in platelet count or other sequelae

Onset d 5-10 or < 1 d (if heparin exposure within 30 d)

> d 10, or timing unclear, or < d 1 with recent heparin 31-100 d

Platelet count fall < 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:

Diagnosis - pretest probability: the 4 T’s

A

B

C

D

Adapted from Lo et al. J Thromb Haemost 2006, in press

Diagnosis - pretest probabilityInterpretation of 4 T’s score

• Score 0-3: very unlikely to be HIT (<5%)

• Score 4 - 5: a minority have HIT (10-30%)

• Score 6 – 8: 20 to >80% have HIT, depending on the clinical

setting and scorer´s experience: these patients usually require an alternative, non-heparin anticoagulant in therapeutic doses

Adapted from Lo et al. J Thromb Haemost 2006, in press

Management of HIT – treatment

• 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

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)

When HIT is strongly-suspected:

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


• 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

When the diagnosis of HIT is confirmed:

* 7th. ACCP Conference 2004 Chest, 126, 311S-337S


• 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.

When HIT is clinically possible but platelet count decrease is more likely caused by other reasons:

Selleng K and Greinacher A: Intensiv up-2-date 2005;1:329-341

Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

Occurrence of symptomatic thrombosis after stopping heparin in patients confirmed to have isolated HIT

Cumulative thrombotic event-rate (%)

Days after isolated HIT recognized

52.8%

100

90

80

70

60

50

40

30

20

10

00 2 4 6 10 12 14 168 18 22 26 28 302420

N = 62

14-year retrospective study

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 1995;11(Suppl. C):29C-34CWarkentin TE. Thromb Res; 2003; 110:73-82


• Danaparoid – Xa/IIa inhibitor (anti-Xa >> anti-IIa)

• Direct thrombin inhibitor (DTI):

• Lepirudin

• Argatroban

• Bivalirudin

Suitable alternative non-heparin antithrombotic therapies are:

* 7th. ACCP Conference 2004 Chest 126: 311S-337S

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

4. Binding of HIT antibodies to PF4/heparin complexes on the platelet surface results in platelet activation, thrombocytopenia and increased risk of arterial thrombosis

5. Platelet, monocyte, and endothelial cell activation results in a hypercoagulable state, and increased risk of venous thrombosis

6. HIT-associated thrombosis occurs in some patients 1 – 2 days before platelet counts decrease


7. Platelet count monitoring is important to diagnose isolated HIT and thus has the potential to prevent thrombosis

8. Recognizing a relative decrease of platelet count is important since platelets do not always fall below 150 x 109/L

9. Platelet count monitoring is recommended in most patients receiving UFH and in some patients receiving LMWH.


9. Heparin should be stopped immediately in all situations where HIT is strongly suspected

10. 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

11. Danaparoid provides an option for anticoagulation in either prophylactic or therapeutic doses



Documents

Heparin-Induced Thrombocytopenia (HIT)