heparin induced thrombocytopenia.ppt

Heparin-Induced Heparin-Induced ThrombocytopeniThrombocytopeni

aa

Learning ObjectivesLearning Objectives Understand the etiology and Understand the etiology and

pathogenesis of Heparin-Induced pathogenesis of Heparin-Induced ThrombocytopeniaThrombocytopenia

Be able to differentiate the two types of Be able to differentiate the two types of HIT; Type I and Type II.HIT; Type I and Type II.

Recognize the signs and symptoms of Recognize the signs and symptoms of Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and institute appropriate treatmentinstitute appropriate treatment

Gain the knowledge necessary to Gain the knowledge necessary to minimize the occurence heparin-induced minimize the occurence heparin-induced thrombocytopenia.thrombocytopenia.

Case QuestionCase Question

55 yo Female patient with history of 55 yo Female patient with history of HTN, Osteoarthritis is s/p Right knee HTN, Osteoarthritis is s/p Right knee replacement POD #6. The primary replacement POD #6. The primary service noticed a platelet count of service noticed a platelet count of 50,000 today (on admission it was 50,000 today (on admission it was 200,000). You suspect HIT, and 200,000). You suspect HIT, and start Argatroban. You also send start Argatroban. You also send serological work-up for HIT. What is serological work-up for HIT. What is the next important step?the next important step?

Case QuestionCase Question

A) Immediately start Coumadin with A) Immediately start Coumadin with ArgatrobanArgatroban

B) Lower extremity Doppler B) Lower extremity Doppler C) V/Q scanC) V/Q scan D) Nothing currently indicatedD) Nothing currently indicated

Case AnswerCase Answer

A) Immediately start Coumadin with A) Immediately start Coumadin with ArgatrobanArgatroban

B) Lower extremity DopplerB) Lower extremity Doppler C) V/Q scanC) V/Q scan D) Nothing currently indicatedD) Nothing currently indicated

Definition of HITDefinition of HIT

Heparin-induced thrombocytopenia is an Heparin-induced thrombocytopenia is an antibody mediated pro-thrombotic antibody mediated pro-thrombotic disorder. disorder.

Diagnosis can be difficult.Diagnosis can be difficult.

Heparin-Induced Thrombocytopenia

HIT Type I HIT Type II

Classificaiton of Type I and Classificaiton of Type I and Type II HITType II HIT

Type I HITType I HIT Non-immuneNon-immune Decrease in Decrease in

platelets is b/w 10-platelets is b/w 10-30,000/ml30,000/ml

Do not discontinue Do not discontinue heparin heparin

Type II HITType II HIT Focus of this talkFocus of this talk ImmuneImmune Decrease in Decrease in

platelets by 50% or platelets by 50% or less than 150,000less than 150,000

Heparin needs to Heparin needs to be stoppedbe stopped

Alternative Alternative anticoagulation anticoagulation needs to be startedneeds to be started

Type I HITType I HIT Non-immuneNon-immune Platelet drop due to direct effect of Platelet drop due to direct effect of

heparin on platelet activationheparin on platelet activation Of no clinical consequenceOf no clinical consequence

Chong BH and Castaldi Pa. Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated Possible mechanism for non-immune heparin associated thrombocytopeniathrombocytopenia. Aust N Z J Med 1986.. Aust N Z J Med 1986.

Arepally G and Ortel T. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia.Heparin-Induced Thrombocytopenia. The New England Journal of The New England Journal of Medicine. Medicine.

Schematic of HIT (Schematic of HIT (TYPE IITYPE II) ) immune activationimmune activation

A Theory for ThrombosisA Theory for Thrombosis

Formation of platelet plugFormation of platelet plug HIT antibodies also bind to HIT antibodies also bind to

endothelial cellsendothelial cells endothelial cell endothelial cell injuryinjury

Blank M, Shoenfeld Y, Tavor S, et al. Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor Anti-platelet factor 4/heparin antibodies from patients with heparin-induced 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular thrombocytopenia provoke direct activation of microvascular endothelial cells.endothelial cells. Int Immunol 2002. Int Immunol 2002.

Occurs in 3% of those treated with Occurs in 3% of those treated with unfractionated heparin unfractionated heparin

Type of Heparin usedType of Heparin used bovine > porcine > low-molecular weightbovine > porcine > low-molecular weight Frequency of HITFrequency of HIT Surgical > Medical > Obstetric patientsSurgical > Medical > Obstetric patients

Epidemiology of HITEpidemiology of HIT

Complications of HITComplications of HIT

--ThThrombocytopenia (bleeding rarely occurs) rombocytopenia (bleeding rarely occurs) by spleenby spleen

-Platelet activation -Platelet activation binding to endothelial binding to endothelial cells cells

Leading to Leading to thrombosisthrombosis -DIC-DIC -Anaphylactic type reactions-Anaphylactic type reactions

Thrombotic risk is 30x control.Thrombotic risk is 30x control. Arepally G and Ortel T. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia.Heparin-Induced Thrombocytopenia. The New The New

England Journal of Medicine.England Journal of Medicine.

Thrombosis LocationThrombosis Location

Venous or ArterialVenous or Arterial Retrospective review of 127 patients Retrospective review of 127 patients

with confirmed HIT: venous with confirmed HIT: venous thrombosis occurred in 78 patients, thrombosis occurred in 78 patients, vs 18 patients with arterial vs 18 patients with arterial thrombosis (61% and 14%)thrombosis (61% and 14%)

Warkentin TE and Kelton JG. A 14-year study of heparin-induced Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.

Risk of ThrombosisRisk of Thrombosis

Same study; those with only Same study; those with only thrombocytopenia, had a 30-day thrombocytopenia, had a 30-day thrombotic event was 53%.thrombotic event was 53%.

Warkentin TE and Kelton JG. A 14-year study of heparin-induced Warkentin TE and Kelton JG. A 14-year study of heparin-induced

thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502..

Thrombosis from HITThrombosis from HIT

Venous thrombosis and pulmonary Venous thrombosis and pulmonary embolismembolism

Less frequently arterial thrombosisLess frequently arterial thrombosis Other: skin, coronary, CNS, adrenalOther: skin, coronary, CNS, adrenal

DVTDVT

Onset of HITOnset of HIT

HIT usually occurs within 5-10 days HIT usually occurs within 5-10 days Delayed-onset HIT occurs up to 2 Delayed-onset HIT occurs up to 2

weeks after treatment with heparinweeks after treatment with heparin Rapid onset HIT occurs less than 5 Rapid onset HIT occurs less than 5

daysdays

Due to pre-existing antibodies.Due to pre-existing antibodies.

Recognizing HITRecognizing HIT

In any patient receiving In any patient receiving heparin/LMWHheparin/LMWH

Unexplained thrombocytopeniaUnexplained thrombocytopenia Thrombosis with thrombocytopeniaThrombosis with thrombocytopenia Necrotic skin lesions at site of Necrotic skin lesions at site of

heparin skin injectionheparin skin injection

Pre-test probabilityPre-test probability

Multiple causes of thrombocytopenia Multiple causes of thrombocytopenia in medical/surgical patientsin medical/surgical patients

Potential for false-positives with Potential for false-positives with ELISAELISA

The use of the “4 T’s”The use of the “4 T’s”

Pre-test probabilityPre-test probability

Validation of the 4 T’sValidation of the 4 T’s

Among 111 patients with low pre-Among 111 patients with low pre-test probability; one had HIT (0.9%)test probability; one had HIT (0.9%)

Intermediate scores: 11.4% with HITIntermediate scores: 11.4% with HIT High scores: 34% with HITHigh scores: 34% with HIT

Lo GK, Julh D, Warkentin TE, et al. Evaluation of Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006.settings. J Thromb Haemost 2006.

Diagnosis of HITDiagnosis of HIT

A decrease in platelet count by 50%, A decrease in platelet count by 50%, or platelet level less than 150,000.or platelet level less than 150,000.

Absence of other causes of Absence of other causes of thrombocytopeniathrombocytopenia

May be with or without thrombosisMay be with or without thrombosis Platelet do not drop below 30,000/mlPlatelet do not drop below 30,000/ml

Arepally G and Ortel T. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia.Heparin-Induced Thrombocytopenia. The New England The New England

Journal of Medicine. Journal of Medicine.

Differential Diagnosis of Differential Diagnosis of ThrombocytopeniaThrombocytopenia

Drug InducedDrug Induced heparinheparin procainamideprocainamide diuretics (furosemide)diuretics (furosemide) HH22 blockers blockers

(cimetidine)(cimetidine) thrombolytic therapythrombolytic therapy GP IIb/IIIa antagonistsGP IIb/IIIa antagonists

MechinicalMechinical membrane oxygenatormembrane oxygenator intra-aortic balloon intra-aortic balloon

pumppump PseudothrombocytopeniPseudothrombocytopeni

aa platelet clumpingplatelet clumping hemodilutionhemodilution

Associated disordersAssociated disorders hypersplenismhypersplenism infections/sepsisinfections/sepsis hypotension and hypotension and

subsequent subsequent disseminated disseminated intravascular intravascular coagulationcoagulation

Other causesOther causes chronic idiopathic chronic idiopathic

thrombocytopenia thrombocytopenia purpura with purpura with exacerbationexacerbation

antiphospholipid antiphospholipid antibody syndromeantibody syndrome

HIT without clinical HIT without clinical symptoms of thrombosissymptoms of thrombosis

Silent DVT’sSilent DVT’s

Serologic StudiesSerologic Studies

ImmunoassayImmunoassay

-ELISA-ELISA Functional AssaysFunctional Assays

-Serotonin release assay-Serotonin release assay

-Heparin-Induced platelet -Heparin-Induced platelet aggregationaggregation

First Lab Test is First Lab Test is ImmunoassayImmunoassay

ELISAELISA - measures binding of HIT antibodies - measures binding of HIT antibodies

from patient serum to PF4-heparin from patient serum to PF4-heparin complex coated on the wells of the plate.complex coated on the wells of the plate.

-Sensitivity >97%-Sensitivity >97% -Specificity 74-86%-Specificity 74-86% -High NPV-High NPV If high suspicion and with a positive test If high suspicion and with a positive test

result; no further diagnositic work-up result; no further diagnositic work-up neededneeded

Need for functional assayNeed for functional assay

If positive immunoassay, but intermediate If positive immunoassay, but intermediate suspicion of HITsuspicion of HIT

Up to 50% of patients after open heart Up to 50% of patients after open heart surgery; 10% of medical patients have surgery; 10% of medical patients have reactive anti-bodies against heparin-PF4 reactive anti-bodies against heparin-PF4 without HITwithout HIT

Aster RH and Davoren A. Aster RH and Davoren A. Heparin-Induced Thrombocytopenia Heparin-Induced Thrombocytopenia and Thrombosis.and Thrombosis. American Journal of Hematology. American Journal of Hematology.

Functional AssaysFunctional Assays

Heparin-Induced Platelet Heparin-Induced Platelet aggregationaggregation

-donor platelets mixed with patient -donor platelets mixed with patient serum; measure aggregation with serum; measure aggregation with and without heparinand without heparin

-Sensitivity >90%-Sensitivity >90%

-Specificity 77-100%-Specificity 77-100%

Functional AssaysFunctional Assays

14-C Serotonin Release Assay14-C Serotonin Release Assay Gold StandardGold Standard

-Donor platelets radio-labaled with 14-C -Donor platelets radio-labaled with 14-C radiocarbon, patient serum added, serotonin radiocarbon, patient serum added, serotonin quantified quantified

-mixed with low and high concentration of -mixed with low and high concentration of heparinheparin

-Sensitivity and Specificity >95%-Sensitivity and Specificity >95%

-cost, technical demands, not widely available-cost, technical demands, not widely available Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-

induced thrombocytopenia. Blood 1986.induced thrombocytopenia. Blood 1986.

TreatmentTreatment

When clinical criteria are met, start When clinical criteria are met, start treatment while awaiting laboratory treatment while awaiting laboratory resultsresults

Increase in platelet count after Increase in platelet count after stopping heparin in the absence of stopping heparin in the absence of other causes, may be diagnostic in other causes, may be diagnostic in the absence of confirmatory labsthe absence of confirmatory labs

Treatment of HITTreatment of HIT Stop any heparin treatment, including Stop any heparin treatment, including

heparin line flushes or use of heparin heparin line flushes or use of heparin coated catheterscoated catheters

Platelet transfusions contraindicatedPlatelet transfusions contraindicated LMWH contraindicated due to cross-LMWH contraindicated due to cross-

reactivityreactivity Warfarin contraindicated initiallyWarfarin contraindicated initially Start alternative anti-coagulation, even Start alternative anti-coagulation, even

without any signs of thrombosis without any signs of thrombosis -Argatroban-Argatroban -Lepirudin-Lepirudin -Fondaparinux -Fondaparinux case report of HIT case report of HIT

Coumadin not used Coumadin not used initiallyinitially

Report of 8 patients with HIT, at Report of 8 patients with HIT, at which point heparin stopped and which point heparin stopped and Coumadin startedCoumadin started

Developed venous limb gangrene Developed venous limb gangrene and full-thickness skin necrosisand full-thickness skin necrosis

Warkentin TE, Elavathil LJ, Hayward CP, et al. Warkentin TE, Elavathil LJ, Hayward CP, et al. The The pathogenesis of venous limb gangrene associated with pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopeniaheparin-induced thrombocytopenia. Ann Intern Med 1997.. Ann Intern Med 1997.

Thrombin InhibitorsThrombin Inhibitors


Lepirudin:Lepirudin:

-direct thrombin inhibitor-direct thrombin inhibitor

-goal aPTT of 1.5-2.5x-goal aPTT of 1.5-2.5x

-use another agent if there is renal -use another agent if there is renal insufficiency as it is renally excretedinsufficiency as it is renally excreted

-side-effects: bleeding (18%)-side-effects: bleeding (18%)

-anti-dote-anti-dote


Lepirudin Lepirudin

-Lepirudin in 403 patients and 120 -Lepirudin in 403 patients and 120 controls. Rate outcome of death, controls. Rate outcome of death, amputation, and thrombosis (at 35 amputation, and thrombosis (at 35 days) lower vs control (20.3%, 43%; P days) lower vs control (20.3%, 43%; P value of <0.001).value of <0.001).

Lubenow N. Eichler P, Lietz T, et al. Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of Lepirudin for prophylaxis of thrombosis in patients with acute isolated thrombosis in patients with acute isolated heparinheparin--induced induced thrombocytopeniathrombocytopenia: an analysis of 3 prospective studies: an analysis of 3 prospective studies. Blood . Blood 2004.2004.

ArgatrobanArgatroban

-direct thrombin inhibitor, interefers at -direct thrombin inhibitor, interefers at thrombin active sitethrombin active site

-adjusted to aPTT of 1.5-3x-adjusted to aPTT of 1.5-3x

-hepatic clearance so avoid in -hepatic clearance so avoid in hepatobiliary diseasehepatobiliary disease

-side-effect: bleeding (7%), anaphylaxis-side-effect: bleeding (7%), anaphylaxis

-anti-dote-anti-dote


Thrombin InhibitorsThrombin Inhibitors Argatroban Argatroban Multicenter study of 722 patients with HITMulticenter study of 722 patients with HIT - outcome of death, amputation, - outcome of death, amputation,

thrombosis at 37 days lower vs control (34-thrombosis at 37 days lower vs control (34-35% vs 43%)35% vs 43%)

- Reduction in new thromboembolic - Reduction in new thromboembolic complications (10-14% vs 25%; P value complications (10-14% vs 25%; P value <0.05)<0.05)

Lewis BE, Wallis DE, Leya F, et al. Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.with heparin-induced thrombocytopenia. Arch Intern Med 2003. Arch Intern Med 2003.

Lewis BE, Wallis DE, Berkowitz SD, et al. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.in patients with heparin-induced thrombocytopenia. Circulation 2001. Circulation 2001.


Bivalirudin- not fully investigated for Bivalirudin- not fully investigated for HIT in most settingsHIT in most settings

Synthetic Synthetic PentasaccharidePentasaccharide

Fondaparinux: inhibitor of XaFondaparinux: inhibitor of Xa

Case study of Fondaparinux not Case study of Fondaparinux not preventing HITpreventing HIT

Alsaleh KA, Al-Nasser SM, Bates SM et al. Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT Delayed-onset HIT caused by low-molecular-weight heparin manifesting during caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxisFondaparinux prophylaxis. Am J Hematol. 2008; Epub ahead of . Am J Hematol. 2008; Epub ahead of print.print.

Case study associated with episode of Case study associated with episode of HIT, when used as prophylaxis.HIT, when used as prophylaxis.

Warkentin T, Maurer B, Aster R, et al. Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Heparin-Induced Thrombocytopenia associated with Fondaparinux.Thrombocytopenia associated with Fondaparinux. The New England The New England Journal of Medicine. Boston: June 2007. Vol 356.Journal of Medicine. Boston: June 2007. Vol 356.

Persistent and Worsening Persistent and Worsening Thrombosis despite HIT Thrombosis despite HIT

treatmenttreatment Can use IVIG, plasma exchange, and Can use IVIG, plasma exchange, and

aspirin if life-threatening thrombosis aspirin if life-threatening thrombosis are worsening/persistant despite are worsening/persistant despite alternative anticoagulationalternative anticoagulation

ThrombolysisThrombolysis ThromboembolectomyThromboembolectomy

Course of TreatmentCourse of TreatmentHIT without ThrombosisHIT without Thrombosis

HIT without any thrombosis: HIT without any thrombosis: continue alternative anticoagulation continue alternative anticoagulation for at least until platelet count for at least until platelet count normalnormal

Increased risk of thrombosis for 2-4 Increased risk of thrombosis for 2-4 weeksweeks

Coumadin for 1-3 monthCoumadin for 1-3 month Studies required Studies required

Course of TreatmentCourse of TreatmentHIT with THROMBOSISHIT with THROMBOSIS

HIT with thrombosis: initiate HIT with thrombosis: initiate coumadin once platelet count normal coumadin once platelet count normal (overlap for 5 days with thrombin (overlap for 5 days with thrombin inhibitor until INR therapeutic); inhibitor until INR therapeutic); Continue coumadin for 3-6 months Continue coumadin for 3-6 months at INR of at INR of

2-3.2-3.

Re-treatment with Heparin Re-treatment with Heparin in those with prior HITin those with prior HIT

HIT antibodies (IgG to PF4/heparin) HIT antibodies (IgG to PF4/heparin) persist 100 days/3 monthspersist 100 days/3 months

Use alternative anticoagulationUse alternative anticoagulation Heparin should still be avoided if Heparin should still be avoided if

possiblepossible If heparin is essential (cardio-If heparin is essential (cardio-

pulmonary bypass); need to confirm pulmonary bypass); need to confirm absence of HIT antibodies; and its use absence of HIT antibodies; and its use should be limited to procedure onlyshould be limited to procedure only

As Prophylaxis:As Prophylaxis:UFH vs LMWHUFH vs LMWH

In a randomized, double blind clinical In a randomized, double blind clinical trial of 665 patients receiving DVT trial of 665 patients receiving DVT prophylaxis after hip surgery:prophylaxis after hip surgery:

9/332 patients with UHF 9/332 patients with UHF HITHIT None of 333 patients with LMWHNone of 333 patients with LMWH 2.7% vs 0%; P value 0.00182.7% vs 0%; P value 0.0018 Warkentin T, Levine M, Hirsh J, et al. Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Heparin-Induced

Thrombocytopenia in Patients Treated with Low-Molecular-Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated HeparinWeight Heparin or Unfractionated Heparin. The New . The New England Journal of Medicine. England Journal of Medicine.

Other prevention Other prevention StrategiesStrategies

Limit heparin duration; start Limit heparin duration; start Coumadin early in transitioning Coumadin early in transitioning

In someone with history of HIT, In someone with history of HIT, heparin should be listed as an heparin should be listed as an allergyallergy

Areas of UncertaintyAreas of Uncertainty

Argatroban vs LepirudinArgatroban vs Lepirudin HIT antibodies are also present in HIT antibodies are also present in

patients that do not have any clinical patients that do not have any clinical manifestations. Uncertain why manifestations. Uncertain why complications occur in some.complications occur in some.

Arepally G and Ortel T. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia.Heparin-Induced Thrombocytopenia. The New The New England Journal of Medicine. England Journal of Medicine.

References IReferences I 1) Arepally G and Ortel T. 1) Arepally G and Ortel T. Heparin-Induced Thrombocytopenia.Heparin-Induced Thrombocytopenia. The New The New

England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819.England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819. 2) Warkentin T, Maurer B, Aster R, et al. 2) Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Heparin-Induced

Thrombocytopenia associated with Fondaparinux.Thrombocytopenia associated with Fondaparinux. The New England The New England Journal of Medicine. Boston: June 2007. Vol 356 (25); Pg 2653.Journal of Medicine. Boston: June 2007. Vol 356 (25); Pg 2653.

3) Aster RH and Davoren A. 3) Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis.Thrombosis. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44.

4) Warkentin T, Levine M, Hirsh J, et al. 4) Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated HeparinHeparin or Unfractionated Heparin. The New England Journal of . The New England Journal of Medicine. Boston: May 1995. Vol 332 (20); Pgs 1330-1336.Medicine. Boston: May 1995. Vol 332 (20); Pgs 1330-1336.

5) Muslimani A, Basma R and Daw H. 5) Muslimani A, Basma R and Daw H. Immune Heparin-Induced Immune Heparin-Induced Thrombocytopenia Resulting from Preceding Exposure to Heparin Thrombocytopenia Resulting from Preceding Exposure to Heparin Catheter Flushes.Catheter Flushes. American Journal of Hematology. 2007. Vol 82; Pgs 652- American Journal of Hematology. 2007. Vol 82; Pgs 652-655.655.

6) Selleng K, Warkentin T and Greinacher A. 6) Selleng K, Warkentin T and Greinacher A. Heparin-induced Heparin-induced thrombocytopenia in intensive care patientsthrombocytopenia in intensive care patients. Critical Care Med 2007. Vol . Critical Care Med 2007. Vol 35 (4); Pgs 1165-1176.35 (4); Pgs 1165-1176.

7) Cines D, Rauova L, Arepally G, et al. 7) Cines D, Rauova L, Arepally G, et al. Heparin-Induced Heparin-Induced Thrombocytopenia: An autoimmune Disorder Regulated Through Dynamic Thrombocytopenia: An autoimmune Disorder Regulated Through Dynamic Autoantigen Assembly/DisassemblyAutoantigen Assembly/Disassembly. Journal of Clinical Apheresis. 2007. . Journal of Clinical Apheresis. 2007. Vol 22; Pgs 31-36.Vol 22; Pgs 31-36.

References IIReferences II 8) Lubenow N. Eichler P, Lietz T, et al. 8) Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of Lepirudin for prophylaxis of

thrombosis in patients with acute isolated heparin-induced thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studiesthrombocytopenia: an analysis of 3 prospective studies. Blood 2004; . Blood 2004; Vol 104: Pgs 3072-7. Vol 104: Pgs 3072-7.

9) Lewis BE, Wallis DE, Leya F, et al. 9) Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.patients with heparin-induced thrombocytopenia. Arch Intern Med Arch Intern Med 2003; Vol 163: Pgs1849-56. 2003; Vol 163: Pgs1849-56.

10) Lewis BE, Wallis DE, Berkowitz SD, et al. 10) Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; Vol. 103: Pgs 1838-43. Circulation 2001; Vol. 103: Pgs 1838-43.

11) Chong BH and Castaldi Pa. 11) Chong BH and Castaldi Pa. Platelet proaggregating effect of Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated heparin: Possible mechanism for non-immune heparin associated thrombocytopeniathrombocytopenia. Aust N Z J Med 1986; Vol 16; Pgs 715.. Aust N Z J Med 1986; Vol 16; Pgs 715.

12) Martel N, Lee J and Wells PS. 12) Martel N, Lee J and Wells PS. Risk for heparin-induced Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a metanalysisweight heparin thromboprophylaxis: a metanalysis. Blood 2005; Vol . Blood 2005; Vol (106); Pg 2710.(106); Pg 2710.

References IIIReferences III 13) Blank M, Shoenfeld Y, Tavor S, et al. 13) Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor Anti-platelet factor

4/heparin antibodies from patients with heparin-induced 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular thrombocytopenia provoke direct activation of microvascular endothelial cells.endothelial cells. Int Immunol 2002; Vol 12: Pg 121. Int Immunol 2002; Vol 12: Pg 121.

14) Warkentin TE and Kelton JG. 14) Warkentin TE and Kelton JG. A 14-year study of heparin-A 14-year study of heparin-induced thrombocytopeniainduced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.. Am J Medicine 1992; Vol (101): Pg 502.

15) Warkentin TE, Elavathil LJ, Hayward CP, et al. 15) Warkentin TE, Elavathil LJ, Hayward CP, et al. The The pathogenesis of venous limb gangrene associated with heparin-pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopeniainduced thrombocytopenia. Ann Intern Med 1997; Vol 127: Pg 804.. Ann Intern Med 1997; Vol 127: Pg 804.

16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for 16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27.heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27.

17) Lo GK, Julh D, Warkentin TE, et al. 17) Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settingsin two clinical settings. J Thromb Haemost 2006; Vol 4: 759.. J Thromb Haemost 2006; Vol 4: 759.

18) Alsaleh KA, Al-Nasser SM, Bates SM et al. 18) Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT Delayed-onset HIT caused by low-molecular-weight heparin manifesting during caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxisFondaparinux prophylaxis. Am J Hematol. 2008; Epub ahead of . Am J Hematol. 2008; Epub ahead of print.print.

Questions?Questions?

heparin induced thrombocytopenia.ppt

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