11

Heparin-Induced Heparin-Induced ThrombocytopeniaThrombocytopenia

(HIT)(HIT)

Ashraf WarsiAshraf Warsi

(R4) hematology(R4) hematology

22

Heparin & HIT historyHeparin & HIT history 1916 heparin discovered by Mclean and Howell1916 heparin discovered by Mclean and Howell 1950s established as a therapy for venous and 1950s established as a therapy for venous and

arterial thrombosisarterial thrombosis 1957 Weismann and tobin describe 10 patients 1957 Weismann and tobin describe 10 patients

who developed unexpected arterial thrombosis who developed unexpected arterial thrombosis after starting heparinafter starting heparin

1966-1972 Roberts and Colleagues described similar findings, speculating that the etiology could represent an antigen-antibody mechanism

1979 Towne describes the white clot syndrome 1989 Chong and Berndt, HIT type 1 & type 2

33

HITHIT

HIT, HIT type II, Immune HIT: HIT, HIT type II, Immune HIT:

is an immune mediated transient disorder is an immune mediated transient disorder which is an adverse event of using heparin which is an adverse event of using heparin during which there is an increase in risk of during which there is an increase in risk of thrombosis. It may also occur with the thrombosis. It may also occur with the usage of highly sulfated polysaccharides usage of highly sulfated polysaccharides like hypersulfated chondroitin sulfatelike hypersulfated chondroitin sulfate

Incidence:Incidence:

44Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2006;355:809-17

55

66

Clinical events in HITClinical events in HIT

Venous thrombosisVenous thrombosis (30-70%): (30-70%):

DVT/PE, cerebral sinus thrombosis, DVT/PE, cerebral sinus thrombosis, adrenal necrosis, venous limb gangreneadrenal necrosis, venous limb gangrene

Arterial thrombosisArterial thrombosis (15-30%): (15-30%):

stroke, M.I., arterial ischemiastroke, M.I., arterial ischemia Skin lesions at heparin injection sitesSkin lesions at heparin injection sites (10%): (10%):

Skin necrosis, erythematous plaquesSkin necrosis, erythematous plaques acute reactionacute reaction (anaphylactoid) after (anaphylactoid) after

heparin bolus (10%)heparin bolus (10%) Disseminated intravascular coagulationDisseminated intravascular coagulation

(10%)(10%)

77

Necrotic lesions in HIT patient receiving LMWH injections

88

L arm

99

Risk of thrombosis in HITRisk of thrombosis in HIT

Warkentin and Kelton. Am J Med. 1996;101:502-507

1010

1111

PathophysiologyPathophysiology

In a proposed explanation for heparin-induced thrombocytopenia, IgG antibodies recognize platelet factor 4 (PF4)-heparin complexes. The resulting PF4-heparin-IgG immune complexes bind to Fc receptors on circulating platelets. Fc-mediated platelet activation releases PF4 from a-granules in platelets, establishing a cycle of platelet activation and formation of prothrombotic platelet microparticles. Removal of immune complex-coated platelets by the reticuloendothelial system results in thrombocytopenia. PF4 also binds to heparan sulfate on the surface of endothelial cells, leading to immune-mediated injury, thrombosis, and disseminated intravascular coagulation.

1212

HIT = Thrombin HIT = Thrombin GenerationGeneration

The Actions of ThrombinThe Actions of Thrombin

Releases from endothelium: NO PGI2 t-PA von Willebrand ADP

Prothrombin thrombin

Fibrinogen fibrinActivation of platelets

Factor XIII XIIIa cross-linked

fibrin

Factor V Va Factor VIII VIIIa

Thrombin

1313

Diagnosis Diagnosis

HIT is a HIT is a clinicoclinico--pathologicalpathological diagnosis diagnosis

Clinical: Clinical:

thrombosis/ ischemiathrombosis/ ischemia

Pathological:Pathological:

thrombocytopenia and a positive thrombocytopenia and a positive serological assay for IgG antibodiesserological assay for IgG antibodies

1414

Thrombocytopenia…Thrombocytopenia…

<150,000 &/or<150,000 &/or a proportional (relative) platelet

count fall of 50% or more from the postoperative peak.

Probability of HIT ???

1515

4 Ts4 Ts

TThrombocytopeniahrombocytopenia TTiming of onset of platelet falliming of onset of platelet fall TThrombosis or other sequelaehrombosis or other sequelae ooTTher causes of platelet fall her causes of platelet fall

1616

4 Ts

Lo GK, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759–65

1717Warkentin, T. E. Hematology 2006;2006:408-414

Figure 1. Platelet count nadirs in heparin-induced thrombocytopenia (HIT), quinine-induced immune thrombocytopenic purpura (Q-ITP), and thrombotic

thrombocytopenic purpura (TTP) with absent ADAMTS-13 activity

1818

Delayed-onset HIT and/orDelayed Platelet Count Recovery

from HIT

Delayed onset of HIT ( thrombocytopenia &/or thrombosis after stopping heparin )

Delayed recovery (median time to platelet count recovery is 4 days, and 90% of patients recover to a platelet count of > 150,000 within 1 week)

Spontaneous HIT: rarely, an illness that resembles HIT without preceeding exposure to heparin

1919

Thrombosis without Thrombocytopenia butTiming Consistent with HIT

Relation of onset of platelet count decrease and onset of HIT-associated thrombosis.The data summarize 209 patients with HITassociated thrombosis. About one quarter (26.3%) of patients develop thrombosis on the same day that the thrombocytopenia occurs (defined arbitrarily as the day the platelet counthas fallen by more than 50%), and in 33.5% the platelet count reached thrombocytopenia levels only after the occurrence of thrombosis.

2020

Detection of HIT antibodiesDetection of HIT antibodies Platelet activation assays:Platelet activation assays: sertonin release assay (SRA)sertonin release assay (SRA) heparin induced platelet aggregation assay (HIPAA)heparin induced platelet aggregation assay (HIPAA) platelet-rich plasma (PRP) aggregationplatelet-rich plasma (PRP) aggregation platelet microparticlesplatelet microparticles

Antigen assays:Antigen assays: PF4/heparin EIAPF4/heparin EIA pf4/polyvinyl sulfonate EIApf4/polyvinyl sulfonate EIA fluid phase EIAfluid phase EIA particle gel immunoassayparticle gel immunoassay

2121

HIT assaysHIT assays

2222

Laboratory Testing for HITLaboratory Testing for HITTestTest AdvantagesAdvantages Disadvantages Disadvantages

SRA Sensitivity: high Technically demandingSpecificity: high (radioisotopes)

(false positives rare) Not readily available

Platelet (HIPA) Specificity: high Sensitivity: low aggregation Technique-dependent

Immunoassay Sensitivity: high Specificity: low (false (ELISA) Technically easy positives common for

Rapid turnaround time some populations)

2323

HIT assaysHIT assays

Diagnostic Diagnostic assayassay

Sensitivity Sensitivity (%)(%)

Specificity (%)Specificity (%)

SRASRA 90-9890-98 >95>95

HIPAAHIPAA 90-9890-98 >95>95

PRPPRP 35-8535-85 9090

PF4/heparin EIAPF4/heparin EIA >90>90 8585

Platelet Platelet activation + activation +

enzyme assayenzyme assay

100100 >95>95

2424

Differential diagnosisDifferential diagnosis SepsisSepsis DICDIC APSAPS EDTA- induced thrombocytopeniaEDTA- induced thrombocytopenia GP IIb/IIIa inhibitor induced thrombocytopeniaGP IIb/IIIa inhibitor induced thrombocytopenia TTPTTP Other drug induced thrombocytopeniaOther drug induced thrombocytopenia HIT type IHIT type I Post transfusion purpuraPost transfusion purpura hemodilutionhemodilution

2525

Treatment of Suspected Treatment of Suspected HITHIT

Discontinue ALL heparin immediatelyDiscontinue ALL heparin immediately

Initiate alternative anticoagulationInitiate alternative anticoagulation

Monitor carefully for thrombosisMonitor carefully for thrombosis

Avoid prophylactic platelet transfusionsAvoid prophylactic platelet transfusions

Document HIT in medical recordsDocument HIT in medical records

Laboratory evaluationLaboratory evaluation

Monitor platelet counts recoveryMonitor platelet counts recovery

2626

treatmenttreatment

Once the platelet count is above Once the platelet count is above 150,000 warfarin should be started150,000 warfarin should be started

Duration of anticoagulation ????Duration of anticoagulation ????

6-8 weeks6-8 weeks

2727

Heparin Alternatives

2828

2929

3030

Take home messageTake home message

HIT is a potentially fatal side effect of HIT is a potentially fatal side effect of heparin that is more common with UFH heparin that is more common with UFH than LMWHthan LMWH

HIT is a clinico-pathological diagnosisHIT is a clinico-pathological diagnosis HIT has a high risk of arterial HIT has a high risk of arterial

thrombosisthrombosis High risk patients on heparin require High risk patients on heparin require

monitoring of their plateletsmonitoring of their platelets Plan of management is : Plan of management is :

3131

Take home messageTake home message 2 Do’s:2 Do’s: stop heparinstop heparin

start alternative anticoagulant in therapeutic start alternative anticoagulant in therapeutic dosesdoses

2 Don’ts:2 Don’ts: avoid platelet transfusionavoid platelet transfusion

avoid warfarin and if started reverse with avoid warfarin and if started reverse with vitamin Kvitamin K

2 Tests:2 Tests: test for HIT antibodiestest for HIT antibodies

lower limb duplex ultrasonographylower limb duplex ultrasonography

3232

Heparin-Induced Heparin-Induced ThrombocytopeniaThrombocytopenia

(HIT)(HIT)

3333