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