Heparin Induced Thrombocytopenia Jennifer Howard D.O. June 4, 2002

Heparin Induced Thrombocytopenia

Jennifer Howard D.O.

June 4, 2002

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.

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.

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?

Introduction

• Thrombocytopenia is a well-recognized complication of heparin treatment

• Two types of heparin induced thrombocytopenia

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

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

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


• 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


• HIT antibodies also react with the heparin-PF4 complex on endothelial cells and monocytes

• Leads to tissue factor expression

• Procoagulant response


• 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


• 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

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

• <1% in medical pts- prophylactic or therapeutic doses


• 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


• 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


• Most pts who develop HIT have received IV or SQ heparin

• Cases reported from hepflush or use of heparin-coated catheter

Thrombocytopenia

• Normal platelet counts in adults 150,000-450,000

• Mean values: 237,000 in men 266,000 in women

• Definition: platelet count <150,000 per microliter

• 2.5% of the normal population have platelets < 150,000

Thrombocytopenia

• Surgical bleeding due solely to thrombocytopenia does not occur until plts < 50,000

• Clinical or spontaneous bleeding does not occur until plts <10,000-20,000

Thrombocytopenia- Clinical Presentation

• Most cases of thrombocytopenia are asymptomatic

• Most common symptomatic presentation is bleeding– Mucosal- epistaxis, gingival bleeding– Cutaneous- petechiae, superficial ecchymoses

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

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

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

Thrombocytopenia- Mechanisms

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

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

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

Thrombocytopenia- Dilutional/Distributional

• After massive blood loss and transfusions with PRBC’s

• Splenic sequestration can increase from Nl 30% to 90% – Seen in extreme splenomegally– Platelet mass and survival remain normal

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

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

Thrombocytopenia- Physical Exam

• Check ocular fundus for bleeding

• Lymphadenopathy

• Hepatosplenomegaly

• Stool for occult blood

• Skin- petechiae in dependent areas

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

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

Thrombocytopenia- Decreased Production

• Circulating blasts-> acute leukemia

• Leukoerythroblastic picture-> BM invasion by tumor, fibrosis, granulomata

• Other cytopenias-> myelodysplasia

• Normal size or small platelet-> absence of effective BM response to the increased need

Thrombocytopenia- Increased Destruction

• Microangiopathic picture with fragmented RBC’c, hemolytic anemia-> DIC, TTP-HUS

• Large platelets-> young platelets that are hemostatically active without bleeding

• Associated autoimmune disease (SLE)

Thrombocytopenia-BM Biopsy

• Indicated in virtually all pts with unexplained thrombocytopenia

• May exclude healthy people under 60

• Normal or increased megakaryocytes-> increased peripheral destruction

• Absent or decreased megakaryocytes with hypocellularity-> decreased production

Thrombocytopenia- BM Biopsy

• Hypercellular marrow- myelodysplasia or B12/folate def

• Granulomata, fibrosis or malignant cells-> marrow invasion

Thrombocytopenia

• Incidental Thrombocytopenia of Pregnancy

• ITP-> exclude all other causes

HIT- Clinical Manifestations

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

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 <30,000– 20% mild >100,000

• Typical drug-induced thrombocytopenia <20,000

Clinical Manifestations- Thrombosis

• In >50% 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

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

Thrombosis

• Since flow and shear are high in arterial circulation, thrombosis is rich in platelets

• Clots appear white due to platelet aggregates

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

“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

“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”


• 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


• 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

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

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

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

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

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

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

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

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

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 >100,000 due

to risk of venous limb gangrene

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


• 10% cross-reactivity with anti-heparin Ab but the clinical significance is uncertain

• Renally cleared• Monitoring with Anti Xa levels recommended for:

– Pts <55 or >90 kg

– Renal insufficiency

– After 2-3d of treatment

– During CP bypass


• No antidote for bleeding

• Long half life 17-24 hrs

• No readily available test to monitor anticoagulant effect

• Incidence of major bleeding 3.1%


• Acute thrombosis- IV bolus 1250-3700u – Then 400u/hr x 4hrs– Then 300u/hr x 4 hrs– Then 150-200u/hr

• Thrombosis >5d ago: bolus 1250u IV then 750-1250u SQ q8-12hrs

• DVT prophylaxis:– <90kg: 750u SQ q8hr acute HIT, q12hr recent HIT– >90kg: 1250u SQ q8hr or q12hr

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


• 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


• 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

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

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

HIT Treatment- Bivalirudin

• Brand: Angiomax

• Has been used in pts with HIT undergoing PTCA

• Use has been limited to date

HIT Treatment on the Horizon

• Desirudin

• Melagatran

• Fondaparinux

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

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 <5d• 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

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

Thank You for you Attention

Have a great day!

A copy of this presentation will be made available in the library for anyone interested

References

• Warkentin,T. Heparin-induced thrombocytopenia, Part 1: The diagnostic clues. Journal of Critical Illness. 2002;17(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.

References

• Rice, Lawrence et al. Delayed-Onset Heparin-Induced Thrombocytopenia. Ann Intern Med 2002;136:210-215.

• Warkentin MD, T and John Kelton MD. Delayed-Onset Heparin- Induced Thrombocytopenia and Thrombosis. Ann Intern Med 2001;135:502-506.

• 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. 2002116:887-891.

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. 2002;89: 979-981.

References

• Dager, William and Richard White. Treatment of Heparin-Induced Thrombocytopenia. The Annals of Pharmacotherapy. 2002;36:489-503.

• Willey, Michelle, deDenus, Simon and Sarah Spinler. Removal of Lepirudin, a Recombinant Hirudin, by Hemodialysis, Hemofiltration, or Plasmapheresis. Pharmacotherapy 2002;22(4):492-499.

Documents

Heparin Induced Thrombocytopenia Jennifer Howard D.O. June 4, 2002