Heparin Induced Thrombocytopenia

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Heparin Induced Thrombocytopenia

• Jennifer Howard D.O.
• June 4, 2002

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Case

• 68 yo WF with hx of HTN and DM presents to ER
  after a fall. She is found to have a hip fracture
  and the plan is to go to surgery after medical
  clearance. Prophylactic SQ unfractionated heparin
  is started and continued for 3d while pt is
  cleared for surgery.

3
Case

• After surgery the heparin is restarted and 2 days
  later the patient is moved to rehab. After
  transfer the patient complains of redness and
  swelling of arm near site of subclavian TLC.
  Labs reveal mild leukocytosis and Platelets of
  85,000. Doppler US shows an acute DVT of the arm.

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Case

• Med list Insulin SS, Demerol, HCTZ, Captopril,
  Heparin SQ, and Tylenol
• Questions
• Why does she have thrombocytopenia?
• Why does she have a DVT?
• Is this HIT?
• How do we treat her now?

5
Introduction

• Thrombocytopenia is a well-recognized
  complication of heparin treatment
• Two types of heparin induced thrombocytopenia

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Type 1 HIT

• Less serious
• Less severe decrease in platelet count
• Occurs 1-2 days after heparin initiation
• Usually returns to baseline with continued
  heparin administration
• No clinical consequence
• Non-immune, due to a direct effect of heparin on
  platelet activation

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Type 2 HIT

• More serious
• Immune-mediated disorder with formation of
  antibodies against heparin-PF4 complex
• Aka heparin associated thrombocytopenia and white
  clot syndrome
• white clot is a platelet rich arterial
  thrombosis

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HIT- Pathophysiology

• Antigen of HIT
• Tetrameric glycoprotein found in platelet alpha
  granules
• Platelet Factor 4 (PF4)
• PF4 is positively charged and binds negatively
  charged sulfated polysaccharide chains of heparin
• A conformational change occurs producing an
  immunoglobulin response to the altered PF4 in
  some pts

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HIT- Pathophysiology

• PF4, heparin, and IgG antibodies form
  multimolecular complexes and bind to the platelet
  surface
• Platelet activation occurs
• Releases more PF4
• Leads to thrombin generation and procoagulant
  effect

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HIT- Pathophysiology

• HIT antibodies also react with the heparin-PF4
  complex on endothelial cells and monocytes
• Leads to tissue factor expression
• Procoagulant response

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HIT- Pathophysiology

• Activated platelets aggregate and are removed
  prematurely from the circulation, causing
  thrombocytopenia
• HIT is uniquely assoc with platelet activation
• May explain assoc with thrombosis rather than
  bleeding

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HIT- Pathophysiology

• LMWH is smaller in size than UFH but can still
  complex with PF4
• HIT may recur or persist if LMWH is used to treat
  HIT triggered by UFH

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HIT-Incidence and Frequency

• Frequency of HIT varies from 1-5 of pts
  receiving UFH
• Highest frequency 3-5 reported in post op
  orthopedic pts who received prophylactic UFH for
  10-14days
• lt1 in medical pts- prophylactic or therapeutic
  doses

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HIT-Incidence and Frequency

• Highest frequency of HIT Ab in cardiac surgical
  pts but lower risk of HIT
• Risk of LMWH-induced HIT very low in medical pts
  but up to .5 in ortho pts receiving LMWH for
  10-14d

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HIT-Incidence and Frequency

• 10-20 of pts receiving UFH have 50 drop in
  platelets or drop to below normal range
• In one study of 665 hip surgery pts receiving
  heparin prophylaxis
• UFH- 7.8 had anti-heparin Ab, 2.7 developed HIT
• LMWH- 2.2 had anti-heparin Ab, 0 developed HIT

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HIT-Incidence and Frequency

• Most pts who develop HIT have received IV or SQ
  heparin
• Cases reported from hepflush or use of
  heparin-coated catheter

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Thrombocytopenia

• Normal platelet counts in adults 150,000-450,000
• Mean values 237,000 in men 266,000 in
  women
• Definition platelet count lt150,000 per
  microliter
• 2.5 of the normal population have platelets lt
  150,000

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Thrombocytopenia

• Surgical bleeding due solely to thrombocytopenia
  does not occur until plts lt 50,000
• Clinical or spontaneous bleeding does not occur
  until plts lt10,000-20,000

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Thrombocytopenia- Clinical Presentation

• Most cases of thrombocytopenia are asymptomatic
• Most common symptomatic presentation is bleeding
• Mucosal- epistaxis, gingival bleeding
• Cutaneous- petechiae, superficial ecchymoses

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Thrombocytopenia- Clinical Presentation

• Bleeding with platelet abnormalities occurs
  immediately after vascular trauma
• Rarely have delayed bleeding in contrast to
  coagulation disorders
• CNS bleeding is uncommon but it is the most
  common cause of death due to thrombocytopenia

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Thrombocytopenia

• Platelets are produced in the bone marrow from
  megakaryocytes
• The megakaryocyte produces plts by cytoplasmic
  shedding directly into marrow sinusoids
• Normal platelet production is 35,000-50,000 per
  mcL per day- can be increased 8x if increased
  demand

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Thrombocytopenia

• Once in circulation, plts survive 8-10 days
• Plts are removed from circulation by the
  monocyte-macrophage system
• One third of the platelet mass is in the spleen
  is equilibrium with the circulating pool

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Thrombocytopenia- Mechanisms

• 4 mechanisms explain reduced platelets
• 1- decreased production
• 2- increased destruction
• 3- spurious
• 4- dilutional or distributional

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Thrombocytopenia- Decreased Production

• Decreased production by bone marrow occurs when
  the marrow is suppressed or damaged
• After viral infection
• After chemotherapy or radiation
• Congenital or acquired BM aplasia/ hypoplasia
• Direct alcohol toxicity
• Vitamin B12/ folate deficiency

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Thrombocytopenia- Increased Destruction

• Seen in may conditions
• Certain viral infections like mono and CMV
• Physical destruction during CP bypass
• ITP
• DIC
• HELLP
• Drugs
• TTP-HUS

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Thrombocytopenia- Dilutional/Distributional

• After massive blood loss and transfusions with
  PRBCs
• Splenic sequestration can increase from Nl 30 to
  90
• Seen in extreme splenomegally
• Platelet mass and survival remain normal

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Thrombocytopenia- Spurious

• If anticoagulation of the blood sample is
  inadequate platelets clump and are counted as
  leukocytes
• .1 of normal people have EDTA-dependent
  agglutinins which lead to clumping and spurious
  leukocytosis

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Thrombocytopenia- Initial Approach

• If the platelet count does not make sense, repeat
  it
• History- recent viral infection, alcoholism,
  pregnancy, etc
• Bleeding history- past bleeding problems, iron
  def anemia, bleeding after dental work, menses,
  etc
• Drug ingestion- heparin, valproic acid, gold
  salts, bactrim, quinine, etc

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Thrombocytopenia- Physical Exam

• Check ocular fundus for bleeding
• Lymphadenopathy
• Hepatosplenomegaly
• Stool for occult blood
• Skin- petechiae in dependent areas

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Thrombocytopenia- CBC Peripheral Smear

• Need to do this fairly quickly since TTP and
  acute leukemia need quick treatment
• Pseudothrombocytopenia can be confirmed by
  presence of clumps on smear

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Thrombocytopenia- Peripheral Smear

• Abnormal platelet morphology
• Small number of congenital disorders that can be
  diagnosed by abnormal morphology
• May- Hegglin anomaly
• Bernard-Soulier Syndrome
• Alport Syndrome
• Wiskott-Aldrich syndrome

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Thrombocytopenia- Decreased Production

• Circulating blasts-gt acute leukemia
• Leukoerythroblastic picture-gt BM invasion by
  tumor, fibrosis, granulomata
• Other cytopenias-gt myelodysplasia
• Normal size or small platelet-gt absence of
  effective BM response to the increased need

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Thrombocytopenia- Increased Destruction

• Microangiopathic picture with fragmented RBCc,
  hemolytic anemia-gt DIC, TTP-HUS
• Large platelets-gt young platelets that are
  hemostatically active without bleeding
• Associated autoimmune disease (SLE)

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Thrombocytopenia-BM Biopsy

• Indicated in virtually all pts with unexplained
  thrombocytopenia
• May exclude healthy people under 60
• Normal or increased megakaryocytes-gt increased
  peripheral destruction
• Absent or decreased megakaryocytes with
  hypocellularity-gt decreased production

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Thrombocytopenia- BM Biopsy

• Hypercellular marrow- myelodysplasia or
  B12/folate def
• Granulomata, fibrosis or malignant cells-gt marrow
  invasion

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Thrombocytopenia

• Incidental Thrombocytopenia of Pregnancy
• ITP-gt exclude all other causes

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HIT- Clinical Manifestations

• HIT is a clinicopathologic syndrome
• Clinical criterion thrombocytopenia
• Pathologic criterion HIT antibodies

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Clinical Manifestations- Thrombocytopenia

• Thrombocytopenia is usually mild-mod
• Often complicated by thrombosis
• Platelet count begins to fall 5-10 days after
  receiving heparin
• Median platelet count falls to 60,000/mcL
• 60 moderate 30,000-100,000
• 20 severe lt30,000
• 20 mild gt100,000
• Typical drug-induced thrombocytopenia lt20,000

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Clinical Manifestations- Thrombosis

• In gt50 thrombosis occurs
• new, recurrent or progressive
• Especially pts with severe thrombocytopenia
• Thrombosis can be venous or arterial
• Highest occurrence DVT 50, PE 25
• Other reactions skin, transient global amnesia,
  acute systemic reaction

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Thrombosis

• Mechanism not known but several theories
• Release of procoagulants from activated platelets
• Generation of platelet microparticles
• Increased tissue factor generation from
  endothelial cell injury
• Fragments of platelet membrane serve as catalyst
  for clotting

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Thrombosis

• Since flow and shear are high in arterial
  circulation, thrombosis is rich in platelets
• Clots appear white due to platelet aggregates

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Onset of HIT

• 70- typical presentation is fall n platelets
  beginning 5-10d after starting heparin
• 30- rapid fall in platelets following
  reinstitution of heparin therapy leads to HIT
  diagnosis retrospectively
• Most often occurs in post-op pts whose platelet
  counts should be rising

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Rapid Onset HIT

• Seen in 30 of pts with persistent anti-heparin
  Ab
• Associated with prior heparin therapy in last 100
  days
• Anti-heparin antibodies are transient
• If rapid onset of thrombocytopenia and no recent
  heparin, look for another cause

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Delayed Onset HIT

• Typically affects pts with high titers of
  platelet-activating IgG Ab
• HIT occurs on average 9 days after withdrawing
  heparin
• May actually be delayed-recognition

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Delayed Onset HIT

• Study published in Annals Int Med 2/2002
• 14 pts re-admitted with TEC after benign hospital
  course heparin therapy
• 12 had venous thrombosis, 4 arterial thrombosis
• Plts mildly decreased on admission
• 11 received heparin on readmission with decrease
  in plts to mean 39,000
• All 14 had anti-heparin Ab

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Delayed Onset HIT

• Study published in Annals Int Med 10/2001
• 12 pts with thrombosis avg 9 days after
  withdrawing heparin
• 9 pts received heparin on readmission with
  further decrease in platelet count
• One patient suffered cardiac arrest after heparin
  dose

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HIT- Diagnosis

• Since thrombocytopenia is so common in
  hospitalized pts, specific lab tests need to be
  ordered
• Always check serial platelets to determine when
  platelets fall in relation to starting heparin
  therapy

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HIT- Diagnosis

• First, must recognize the syndrome
• Otherwise unexplained thrombocytopenia
• Thrombosis assoc with thrombocytopenia
• Platelet count drop 50 from prior value
• Heparin initiation must have been within 5-10days
• First make diagnosis clinically as labs may have
  slow turnaround time

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HIT- Diagnosis

• Two major groups of assays exist
• Activation or functional assays- detect Ab by
  their characteristic heparin-dependent platelet
  activating properties
• Antigen assays- detect reactivity against PF4 by
  immunoassay

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Activation/ Functional Assays

• C14-Serotonin Release Assay- gold standard
• Platelet aggregation test
• Heparin induced platelet aggregation assay
• Measurement of microparticle release by flow
  cytometry
• use plts from healthy donors with patient serum
  and heparin to measure plt activation

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Antigen Assays

• Immunoassays for measurement of Ab
• ELISA with PF4-heparin complexes
• ELISA with PF4-polyvinylsulphate complexes
• New assay for rapid detection of HIT Ab
• Agglutination assay with PF4-heparin complexes
• Adapted to the gel technique of the
  ID-microtyping system

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ID-Microtyping System

• British Journal of Haematology 2002
• 100 pts with HIT by HIPA PF4-heparin ELISA
• 20 suspected HIT with neg tests
• 20 healthy people
• Purpose- to compare new ID-Heparin PF4 to other
  assays

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ID-Microtyping System- Results

• ELISA had highest sensitivity but lowest
  specificity
• ID-HPF4 did fairly well
• Authors suggest using it with a functional test
  for now and doing a prospective study

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HIT- Treatment

• First- immediate cessation f all exposure to
  heparin
• Includes hepflush
• Avoid LMWH since it may cross-react with the
  anti-heparin Ab
• Heparin cessation alone usually not enough since
  these pts remain at risk for thrombosis
• One study of 62 pts showed 53 risk of thrombosis
  at 30 days

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HIT- Treatment

• Two recommended alternatives to treat thrombosis
  or pts requiring anticoagulation
• Danaparoid
• Direct thrombin inhibitor
• These should also be used for prophylaxis in HIT
• Avoid warfarin until platelet count gt100,000 due
  to risk of venous limb gangrene

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HIT Treatment- Danaparoid

• Brand Orgaran
• Heparinoid composed of heparan sulfate, dermatan
  sulfate,and chondroitin sulfate
• FDA approved for prophylaxis in hip replacement
• Not approved for HIT but extensive experience in
  HIT

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HIT Treatment- Danaparoid

• 10 cross-reactivity with anti-heparin Ab but the
  clinical significance is uncertain
• Renally cleared
• Monitoring with Anti Xa levels recommended for
• Pts lt55 or gt90 kg
• Renal insufficiency
• After 2-3d of treatment
• During CP bypass

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HIT Treatment- Danaparoid

• No antidote for bleeding
• Long half life 17-24 hrs
• No readily available test to monitor
  anticoagulant effect
• Incidence of major bleeding 3.1

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HIT Treatment- Danaparoid

• Acute thrombosis- IV bolus 1250-3700u
• Then 400u/hr x 4hrs
• Then 300u/hr x 4 hrs
• Then 150-200u/hr
• Thrombosis gt5d ago bolus 1250u IV then 750-1250u
  SQ q8-12hrs
• DVT prophylaxis
• lt90kg 750u SQ q8hr acute HIT, q12hr recent HIT
• gt90kg 1250u SQ q8hr or q12hr

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HIT Treatment- Lepirudin

• Brand Refludan
• Recombinant hirudin produced from leech salivary
  glands
• FDA approved for tx of HIT with thrombosis (first
  approved HIT drug)
• Acts directly on circulating and clot-bound
  thrombin

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HIT Treatment- Lepirudin

• Renally cleared- specialized dosing based on CrCl
• Anticoagulant effect lasts 40 min in Nl pts
• Adequate circulating levels documented by PTT
• Target PTT 1.5-2.5 x control
• Slow IV bolus .4mg/kg up to 110 kg then infusion
  .15mg/kg

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HIT Treatment- Lepirudin

• Anti-lepirudin Ab develop commonly
• may impair renal clearance of active drug
• Monitor frequent PTT
• Has been successfully administered SQ after
  thrombosis stabilized by IV treatment

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HIT Treatment- Argatroban

• Direct thrombin inhibitor
• Recently FDA approved for HIT
• Short half-life of 24min
• Monitored by PTT or ACT
• PTT returns to Nl 2hr after stopping it
• Steady state reached in 1-3 hrs
• No antidote to bleeding

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HIT Treatment- Argatroban

• Hepatically cleared- specialized dosing in
  hepatic insufficiency
• Start 2mcg/kg/min IV and adjust to maintain PTT
  1.5-3 x control
• Can also increase PT so must stop infusion for
  4-6 hrs remeasure PT to assess coumadin therapy

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HIT Treatment- Bivalirudin

• Brand Angiomax
• Has been used in pts with HIT undergoing PTCA
• Use has been limited to date

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HIT Treatment on the Horizon

• Desirudin
• Melagatran
• Fondaparinux

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HIT- Renal Failure

• Best choice is argatroban for HIT tx but no
  studies for use in hemodialysis in place of
  heparin
• Recent article in Pharmacotherapy reviewed
  studies to date suggestion lepirudin my be
  removed by hemodialysis, hemofiltration, or
  plasmapheresis using specific membrane materials

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HIT- Prevention

• LMWH and heparinoids are associated with much
  lower incidence of HIT
• Best prevention is judicious use of UFH or
  substitution of LMWH when appropriate
• Limit heparin tx to lt5d
• Start coumadin early to minimize heparin tx
• Do not start coumadin in pts with HIT until
  thrombocytopenia resolves
• Do not give LMWH after HIT develops with UFH

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Use of Heparin after HIT

• Can use heparin if
• HIT Ab no longer detectable
• Heparin used for short duration during surgery
  only (ex CP bypass) with other anticoagulants
  postop

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Thank You for you Attention

• Have a great day!
• A copy of this presentation will be made
  available in the library for anyone interested

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References

• Warkentin,T. Heparin-induced thrombocytopenia,
  Part 1 The diagnostic clues. Journal of Critical
  Illness. 200217(5)172-178.
• Coutre MD, Steven. Heparin-Induced
  Thrombocytopenia. UpToDate online 10.1. Nov 30,
  2001.
• Landaw MD, Stephen. Approach to the patient with
  Thrombocytopenia. UpToDate 9.1. Sept 22, 2000.

91
References

• Rice, Lawrence et al. Delayed-Onset
  Heparin-Induced Thrombocytopenia. Ann Intern Med
  2002136210-215.
• Warkentin MD, T and John Kelton MD.
  Delayed-Onset Heparin- Induced Thrombocytopenia
  and Thrombosis. Ann Intern Med
  2001135502-506.
• Eichler, Petra, et al. The New ID-Heparin/PF4
  Antibody test for rapid detection of
  heparin-induced antibodies in comparison with
  functional and antigenic assays. British Journal
  of Haematology. 2002116887-891.

92
References

• Cines MD, Douglas. Heparin-Induced
  Thrombocytopenia and Thrombosis. Platelets An
  Update on Diagnosis and Management of
  Thrombocytopenia disorders. American Society of
  Hematology. Hematology. 2001. 295-305.
• Liu MD, Jayson, et al. Patency of Coronary
  Artery Bypass Grafts in Patients with
  Heparin-Induced Thrombocytopenia. The American
  Journal of Cardiology. 200289 979-981.

93
References

• Dager, William and Richard White. Treatment of
  Heparin-Induced Thrombocytopenia. The Annals of
  Pharmacotherapy. 200236489-503.
• Willey, Michelle, deDenus, Simon and Sarah
  Spinler. Removal of Lepirudin, a Recombinant
  Hirudin, by Hemodialysis, Hemofiltration, or
  Plasmapheresis. Pharmacotherapy
  200222(4)492-499.