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HEPARIN
INDUCED
THROMBO
CYTOPENIA
Vivian Yang (MS4)
Anna Nguyen, MD (PGY4)
Blood Bank and
Transfusion Medicine
https://s3.amazonaws.com/lowres.cartoonstock.com/myths-legends-blood-blood_donation-blood_donor-vampires-sucking_blood-gckn70_low.jpg
HIT TYPES
➤ Type 1
➤ non-immune mediated, not
clinically significant
➤ Type 2
➤ immune-mediated, life-
threatening
➤ Subclinical
➤ previous exposure with persistent
antibodies, higher risk if re-exposed
➤ Spontaneous
➤ inflammatory disease
➤ Heparin-induced antibodies
➤ no clinical symptoms but positive
cross reaction in lab
https://online.epocrates.com/data_dx/reg/1202/img/1202-1-hlight.jpg
https://patentimages.storage.googleapis.com/EP1861039B1/imgb0001.png
PATHOPHYSIOLOGY
➤ Neoantigen
➤ heparin + platelet factor 4
➤ HIT autoantibody (IgG) to
neoantigen
➤ Immune-mediated activation
of platelets
➤ Thrombocytopenia
➤ Reticuloendothelial system
➤ Thrombosis
https://www.uptodate.com/contents/image?imageKey=HEME%2F50473&topicKey=HEME%2F90261&rank=1~150&source=see_link&search=heparin%20induced%20thrombocytopenia
RISK FACTORS
➤ Molecular weight
➤ unfractionated vs low
molecular weight
➤ Dose
➤ therapeutic vs high vs low
➤ Gender
➤ male vs female
➤ Endogenous PF4 level
➤ Age?
http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2006/Dec3(4)/PublishingImages/31_fig2.jpg
http://www.medline.com/media/catalog/sku/BHL/300x300/BHL2B0944CS_PRI01.JPG
http://images.medscape.com/pi/features/drugdirectory/octupdate/HOS14021.jpg
CLINICAL MANIFESTATIONS
➤ Thrombocytopenia: platelets
<150, >50% decrease from
baseline, mean nadir ~60
➤ Thrombosis: venous >
arterial, 50% incidence with
HIT
➤ Skin necrosis
➤ Limb gangrene
➤ Organ ischemia/infarction
➤ Timing: 5-10 days after
exposure, resolves in 7 days
http://argatroban.eu/admin/editor/uploads/media/Picture1.jpg
http://www.bloodspecialistclinic.com/wp-content/uploads/2015/03/Thrombocytopenia-e1433829294708-600x409.jpg
https://www.researchgate.net/profile/Sai-Ching_Yeung2/publication/45709851/figure/fig1/AS:281121020497958@1444035882885/Figure-1-Clinical-course-of-heparin-induced-thrombocytopenia-The-graph-charts-the-time.png
https://s3.amazonaws.com/lowres.cartoonstock.com/money-banking-sell_blood-donate_blood-give_blood-plasma-blood_plasma-jcon676_low.jpg
EVALUATION
➤ DO NOT WAIT FOR
THROMBOSIS
➤ Calculate 4 T’s score
➤ 0-3: low risk (<1%)
➤ 4-5: intermediate risk (14%)
➤ 6-8: high risk (64%)
➤ Other pre-test probability
scores
➤ Lillo-Le Louet
➤ HIT Expert Probability
(HEP)
http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2006.01787.x/epdf
DIFFERENTIAL DIAGNOSIS
➤ Disseminated Intravascular
Coagulation (DIC), sepsis,
infection
➤ Immune thrombocytopenia
purpura (ITP)
➤ Post transfusion purpura (PTP)
➤ Thrombotic microangiopathy:
TTP/HUS
➤ Drug-induced thrombocytopenia
➤ Venous thromboembolism
➤ Lupus +/- antiphospholipid
antibody syndrome
http://thelancet.com/cms/attachment/2001010017/2003786503/gr2_lrg.jpg
http://www.lymphedemapeople.com/images/2549.jpg
https://healthimpactnews.com/wp-content/uploads/sites/2/2013/04/ITP-1.jpg
LABORATORY TESTING
➤ Immunoassay
➤ Detects presence of HIT
antibodies in patient serum
➤ EIA
➤ Functional Assay
➤ Detects ability of HIT
antibody from patient serum
to activate platelets
➤ Serotonin Release Assay, SRA
➤ Future
➤ PF4 dependent P selectin
expression (PEA)
https://i.ytimg.com/vi/RRbuz3VQ100/hqdefault.jpg
https://media.licdn.com/mpr/mpr/shrinknp_800_800/AAEAAQAAAAAAAAJwAAAAJDkxYWZmOGI0LTU1M2MtNGIxZi05MjhhLTY2MTBiZmU2NGNiYg.png
HIT EIA
➤ Platelet Factor 4 Assay (Immucor)
➤ Solid-phase enzyme linked
immunosorbent assay
➤ Detects antibodies to PF4 when
complexed with polyanionic
compounds (polyvinyl sulfonate,
PVS)
➤ (1) Wells are coated with PF4 with
PVS. Add patient serum. (2) Add Anti-
Human Globulin. Incubate. (3) Add
PNPP. Incubate. (4) Add stopping
reagent. If there is a reaction, color
change will occur. (5) Measure optical
density on spectrophotometer. Positive
is OD>0.4. Add into Sunquest. (6)
Wells 1,2 have OD of 0.317 (patient).
Wells 5,6 are positive control.
1
2 3 4
5
6
HIT SRA
➤ Functional assay measuring
heparin-dependent platelet
activation
➤ Patient serum + donor
platelets (14-C serotonin)
+ heparin at varying
concentrations
➤ Positive is 14-C serotonin
release > 20% with low
dose heparin (therapeutic,
0.1U/mL)
https://image.slidesharecdn.com/coagulationassayspart2boct2014-1a-141017095053-conversion-gate01/95/coagulation-assays-28-638.jpg?cb=1413539540
https://www.theanswerpage.com/uploaded/images/heparin/4-2.png
http://chakrigajula.com/wp-content/uploads/2011/08/misc_cartoon116.jpg
MANAGEMENT
➤ Consult a hematologist
➤ Stop all forms of heparin
➤ Anticoagulate with non-heparin
agent if high risk of thrombosis
➤ Argatroban
➤ Fondaparinux
➤ Bivalirudin
➤ Danaparoid, lepirudin
➤ Monitor platelets.
➤ Consider platelet transfusion.
➤ Bridge to warfarin or other
➤ Avoid heparin for life
http://circ.ahajournals.org/content/circulationaha/121/13/1523/F1.large.jpg
http://my.clevelandclinic.org/ccf/media/Images/anticoagulation-clinics/warfarin.jpg?la=en
SUMMARY
➤ Monitor platelets and clinical signs daily. Consult early.
➤ If HIT is highly suspected, stop all heparin products.
➤ Use ELISA to screen for intermediate-high suspicion.
➤ Use SRA to confirm.
➤ Avoid heparin forever.
THANK YOU!http://theawkwardyeti.com/wp-content/uploads/2014/03/Screen-shot-2014-03-20-at-8.45.51-AM.png

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Heparin Induced Thrombocytopenia

  • 1. HEPARIN INDUCED THROMBO CYTOPENIA Vivian Yang (MS4) Anna Nguyen, MD (PGY4) Blood Bank and Transfusion Medicine https://s3.amazonaws.com/lowres.cartoonstock.com/myths-legends-blood-blood_donation-blood_donor-vampires-sucking_blood-gckn70_low.jpg
  • 2. HIT TYPES ➤ Type 1 ➤ non-immune mediated, not clinically significant ➤ Type 2 ➤ immune-mediated, life- threatening ➤ Subclinical ➤ previous exposure with persistent antibodies, higher risk if re-exposed ➤ Spontaneous ➤ inflammatory disease ➤ Heparin-induced antibodies ➤ no clinical symptoms but positive cross reaction in lab https://online.epocrates.com/data_dx/reg/1202/img/1202-1-hlight.jpg https://patentimages.storage.googleapis.com/EP1861039B1/imgb0001.png
  • 3. PATHOPHYSIOLOGY ➤ Neoantigen ➤ heparin + platelet factor 4 ➤ HIT autoantibody (IgG) to neoantigen ➤ Immune-mediated activation of platelets ➤ Thrombocytopenia ➤ Reticuloendothelial system ➤ Thrombosis https://www.uptodate.com/contents/image?imageKey=HEME%2F50473&topicKey=HEME%2F90261&rank=1~150&source=see_link&search=heparin%20induced%20thrombocytopenia
  • 4. RISK FACTORS ➤ Molecular weight ➤ unfractionated vs low molecular weight ➤ Dose ➤ therapeutic vs high vs low ➤ Gender ➤ male vs female ➤ Endogenous PF4 level ➤ Age? http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2006/Dec3(4)/PublishingImages/31_fig2.jpg http://www.medline.com/media/catalog/sku/BHL/300x300/BHL2B0944CS_PRI01.JPG http://images.medscape.com/pi/features/drugdirectory/octupdate/HOS14021.jpg
  • 5. CLINICAL MANIFESTATIONS ➤ Thrombocytopenia: platelets <150, >50% decrease from baseline, mean nadir ~60 ➤ Thrombosis: venous > arterial, 50% incidence with HIT ➤ Skin necrosis ➤ Limb gangrene ➤ Organ ischemia/infarction ➤ Timing: 5-10 days after exposure, resolves in 7 days http://argatroban.eu/admin/editor/uploads/media/Picture1.jpg http://www.bloodspecialistclinic.com/wp-content/uploads/2015/03/Thrombocytopenia-e1433829294708-600x409.jpg https://www.researchgate.net/profile/Sai-Ching_Yeung2/publication/45709851/figure/fig1/AS:281121020497958@1444035882885/Figure-1-Clinical-course-of-heparin-induced-thrombocytopenia-The-graph-charts-the-time.png
  • 7. EVALUATION ➤ DO NOT WAIT FOR THROMBOSIS ➤ Calculate 4 T’s score ➤ 0-3: low risk (<1%) ➤ 4-5: intermediate risk (14%) ➤ 6-8: high risk (64%) ➤ Other pre-test probability scores ➤ Lillo-Le Louet ➤ HIT Expert Probability (HEP) http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2006.01787.x/epdf
  • 8. DIFFERENTIAL DIAGNOSIS ➤ Disseminated Intravascular Coagulation (DIC), sepsis, infection ➤ Immune thrombocytopenia purpura (ITP) ➤ Post transfusion purpura (PTP) ➤ Thrombotic microangiopathy: TTP/HUS ➤ Drug-induced thrombocytopenia ➤ Venous thromboembolism ➤ Lupus +/- antiphospholipid antibody syndrome http://thelancet.com/cms/attachment/2001010017/2003786503/gr2_lrg.jpg http://www.lymphedemapeople.com/images/2549.jpg https://healthimpactnews.com/wp-content/uploads/sites/2/2013/04/ITP-1.jpg
  • 9. LABORATORY TESTING ➤ Immunoassay ➤ Detects presence of HIT antibodies in patient serum ➤ EIA ➤ Functional Assay ➤ Detects ability of HIT antibody from patient serum to activate platelets ➤ Serotonin Release Assay, SRA ➤ Future ➤ PF4 dependent P selectin expression (PEA) https://i.ytimg.com/vi/RRbuz3VQ100/hqdefault.jpg https://media.licdn.com/mpr/mpr/shrinknp_800_800/AAEAAQAAAAAAAAJwAAAAJDkxYWZmOGI0LTU1M2MtNGIxZi05MjhhLTY2MTBiZmU2NGNiYg.png
  • 10. HIT EIA ➤ Platelet Factor 4 Assay (Immucor) ➤ Solid-phase enzyme linked immunosorbent assay ➤ Detects antibodies to PF4 when complexed with polyanionic compounds (polyvinyl sulfonate, PVS) ➤ (1) Wells are coated with PF4 with PVS. Add patient serum. (2) Add Anti- Human Globulin. Incubate. (3) Add PNPP. Incubate. (4) Add stopping reagent. If there is a reaction, color change will occur. (5) Measure optical density on spectrophotometer. Positive is OD>0.4. Add into Sunquest. (6) Wells 1,2 have OD of 0.317 (patient). Wells 5,6 are positive control. 1 2 3 4 5 6
  • 11. HIT SRA ➤ Functional assay measuring heparin-dependent platelet activation ➤ Patient serum + donor platelets (14-C serotonin) + heparin at varying concentrations ➤ Positive is 14-C serotonin release > 20% with low dose heparin (therapeutic, 0.1U/mL) https://image.slidesharecdn.com/coagulationassayspart2boct2014-1a-141017095053-conversion-gate01/95/coagulation-assays-28-638.jpg?cb=1413539540 https://www.theanswerpage.com/uploaded/images/heparin/4-2.png
  • 13. MANAGEMENT ➤ Consult a hematologist ➤ Stop all forms of heparin ➤ Anticoagulate with non-heparin agent if high risk of thrombosis ➤ Argatroban ➤ Fondaparinux ➤ Bivalirudin ➤ Danaparoid, lepirudin ➤ Monitor platelets. ➤ Consider platelet transfusion. ➤ Bridge to warfarin or other ➤ Avoid heparin for life http://circ.ahajournals.org/content/circulationaha/121/13/1523/F1.large.jpg http://my.clevelandclinic.org/ccf/media/Images/anticoagulation-clinics/warfarin.jpg?la=en
  • 14. SUMMARY ➤ Monitor platelets and clinical signs daily. Consult early. ➤ If HIT is highly suspected, stop all heparin products. ➤ Use ELISA to screen for intermediate-high suspicion. ➤ Use SRA to confirm. ➤ Avoid heparin forever.