virtual lecture - insights...• heparin exposure results in formation of igg antibodies that...

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© MFMER© MFMER

Virtual Lecture

How Can Your Laboratory Minimize Over-Diagnosis of HIT?

© MFMER

Our speaker for this program is Dr. Jill Adamski, an Associate Professor of Laboratory Medicine and Pathology for the Mayo Clinic College of Medicine and Science, and a Consultant in Laboratory Medicine for the Department of Laboratory Medicine and Pathology in Phoenix, Arizona.

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© MFMER

Virtual Lectures Planning Committee Disclosure Summary As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of these relevant financial relationships will be published in activity materials so those participants in the activity may formulate their own judgments regarding the presentation.

Listed below are individuals with control of the content of this program who have disclosed…

Relevant financial relationship(s) with industry:None

No relevant financial relationship(s) with industry:Jill Adamski, MD, PhD – program presenterCurtis Hanson, MD – program planning committeeMelissa Peterson – program planning committeeSharon Preuss – program planning committeeBobbi Pritt, MD, MSc, DTMH – program planning committee

References to off-label and/or investigational usage(s) of pharmaceuticals or instruments in their presentation:

None

©2016 MFMER | slide-4

How can your Laboratory Minimize over-diagnosis of HIT?Practical Approaches for Improving HIT Diagnostic Accuracy

Jill Adamski MD, PhDAssociate Professor, Transfusion Medicine

Department of Laboratory Medicine and Pathology

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“Within the past 10‐20 years, recognition of HIT has evolved from a gross under

diagnosis to wild over diagnosis”

-TE Warkentin

Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011;9 Suppl 1:105-117.


Disclosures

• No relevant financial disclosures

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Objectives

• Define clinical features characteristic of HIT and understand implications of diagnosis.

• Use pre‐test scoring systems to estimate probability of HIT.

• State the pros and cons associated with the various laboratory tests for HIT.

• Apply this knowledge towards effective lab medicine consultation to help improve diagnostic accuracy of HIT.


Clinical Features of HIT

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Heparin Induced Thrombocytopenia

• Serious, potentially life‐threatening complication due to an adverse immune mediated drug reaction

• Associated with increased risk of thrombosis

• Heparin exposure results in formation of IgG antibodies that recognize multimolecular PF4:Heparin complexes

• Clinical diagnosis that is supported by laboratory testing

• Consequences of HIT diagnosis (real or false) are significant


Why are we concerned about false positive results?

• Change anticoagulation management for the patient for the rest of their lives

• Unnecessary exposure of thrombocytopenic patients to prolonged anticoagulation

• Unnecessary procedures, delay to surgery

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True story…Does this patient have HIT?

• 54 year old male with history of Grave’s disease admitted for treatment of metastatic ampullary cancer

• UFH for DVT prevention

• On day 6 patient platelet count dropped from baseline 200’s to 89.7


Diagnosis of HIT

• Thrombocytopenia is most common presenting feature

• Degree of thrombocytopenia• Decrease from baseline of 30% to 50%, nadir

>20,000/ul• Median platelet count 60,000/uL, +/- thrombosis

(n=142)• Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia.

Semin Hematol. 1998;35(4 Suppl 5):9-16.

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Diagnosis of HIT



>20,000/ul

• Timing of thrombocytopenia• 5 to 14 days after initiation of heparin, except in

patients with recent heparin exposure • Thrombocytopenia <24h with heparin re-exposure

• Other causes of thrombocytopenia excluded


Other Causes of Thrombocytopenia

• Sepsis

• DIC

• Cancer‐associated DIC

• Hemodilution post‐surgery

• Severe pulmonary embolism

• Antiphospholipid syndrome

• Thrombolytic therapy

• EDTA‐induced pseudothrombocytopenia

• GP IIb/IIIa inhibitor‐induced thrombocytopenia

• Drug‐induced thrombocytopenia (other than heparin)

• Post‐transfusion purpura

• Thrombotic thrombocytopenic purpura

• Non‐immune heparin‐associated thrombocytopenia

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Diagnosis of HIT



>20,000/ul

• Timing of thrombocytopenia• 5 to 14 days after initiation of heparin, except in

patients with recent heparin exposure • Thrombocytopenia <24h with heparin re-exposure

• Other causes of thrombocytopenia excluded

• With or without thrombosis


Pre-Test Probability to Assess Risk for HIT

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• Pre‐test probability assessment important because:

• The delay in laboratory testing• Isolated HIT antibodies are frequent and not diagnostic of HIT

• Probability scoring systems:

• Warkentin’s 4Ts

• HIT Expert Probability (HEP)

Pre-Test Evaluation


Pre‐test Probability: The 4 T’sScore 0, 1 or 2 for each category

2 1 0

Thrombocytopenia> 50% platelet count fall to nadir ≥ 20

30‐50% platelet count fall to nadir 10‐19

<30% platelet count fall to nadir ≤ 10

Timing of fall in

platelet count or other sequelae

Onset d 5‐10 or < 1 d (if heparin exposure

within 30 d)

> d 10, or timing unclear, or < d 1 with recent heparin 31‐100 d

Platelet count fall < d 4 (without recent heparin exposure)

Thrombosis or

other sequelae

New thrombosis; skin necrosis; post‐heparin bolus acute systemic

reaction

Progressive or recurrent thrombosis;

erythematous skin lesions; suspected thrombosis – not

confirmed

None

OTher cause for thrombocytopenia

No other cause for platelet count fall is

evident

Possible other cause is evident

Definite other cause is present

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Pre-Test Probability: Interpretation of 4T Score

• Score 0-3: • Very unlikely to be HIT

• NPV = 99%

• Score 4 - 5:• A minority have HIT

• PPV = 14%

• Score 6 – 8:• PPV = 64%

Cuker et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systemic review and meta-analysis. Blood. 2012;120:4160-4167.


26 HIT experts (selected from the Transfusion Medicine Hemostasis Clinical Trials Network)

diagnostic “weight” to 8 clinical features (‐3 to 3)median weights incorporated into a novel pre‐test

probability model

The HIT Expert Probability (HEP) Score: a novel pre-test probability model for HIT

based on broad expert opinionCuker, A et al. J of Thromb Hemostasis. 2010;8:2642-2650

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• 4T score = 4


Laboratory Assays for HIT

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HIT ELISA

• Patient sample added to microtiter plate coated with heparin:PF4 (or other negatively charged substrate:PF4.

• Secondary antibodies – often IgG, IgA, IgM but only IgG thought to be clinically relevant

1. High Sensitivity2. Technically Easy3. Relatively quick results

Pros

1. Poor specificity2. Clinically insignificant Ab3. Many interferences

Cons


Serotonin Release Assay (SRA)

• Activity assay, confirmation test

• Patient’s sample is incubated with healthy donor platelets that have been loaded with radiolabeled serotonin.

• Heparin:PF4 binding to “HIT”-IgG crosslink platelet FcRIIA, activating and release of serotonin.

1. “Gold” Standard2. Relatively high sens/spec

Pros

1. Technically demanding2. Not readily available3. Some interferences

Cons

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Other Assays

• Heparin induced platelet aggregation assay• Functional assay

• Measures platelet aggregation in the presence of patient serum and therapeutic levels of heparin

• Heparin:PF4 rapid assay• Point of care immunoassay


• False positive ELISA: sepsis, circulating antibody complexes, antibodies to PF4, bovine antibodies

• False positive SRA: anti‐heparin:PF4 of IgM/IgA isotype, anti‐platelet or HLA antibodies

• False negative ELISA and SRA: low affinity/avidity antibodies may not be detected, interfering antibodies

• Specimen contaminated with heparin!!!

• Consider liability if test ordered and patient still receiving heparin

• Testing delays and pre‐analytical error = missed diagnosis

Pitfalls of HIT testing

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• 4T score = 4

• ELISA OD = 2.039

• Sent to reference lab for SRA


Laboratory Medicine Consultation (Intervention!) to Improve Diagnosis of HIT

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Old HIT Testing and Diagnostic Protocol

• All ordered HIT tests were run, if OD>0.4 patient diagnosed with HIT

• IRB approved study of physician ordering practices, validation of pre‐test scoring in our patient population

• 157 orders for HIT testing (25 positive ELISA tests)

• Based on probability scores, ~ 60 % of tests would not be run!

• ~1% “positive” ELISAs would have been missed

• None of the 3 cases had clinically relevant results (IgM)

• 15% of all orders were requested on heparin naïve patients!

• Usually ordered for thrombocytopenia work‐up


New HIT Testing and Diagnostic Protocol

• All orders are reviewed for appropriateness and require approval by Laboratory Medicine or Hematology physician

• UFH d/c for minimum of 6 h

• If either score is above threshold test is approved• Score thresholds: 4Ts = 4 and HEP = 2

• Positive ELISA reflex to reference lab for ELISA (isotype determination) and SRA

• No repeat tests on patients once they have a (+) result• Exceptions will be made if plan to expose patient to heparin (CPB)

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Comparison Before and After HIT Testing Policy

PRE‐18 months POST‐18 months

HIT tests performed Total = 1904Unique patients = 1197

Total = 408Unique patients = 400

HIT tests not approved 0257

Tested = 12 (all negative)Hep naïve or >100 d = 32

Previous (+) = 11

Patients with +HIT ELISA result

Total = 406195 unique patients diagnosed with HIT

Total = 31

Avg # tests after +HIT result 2.1 0

Confirmation and functional test at ref lab

0 31

Diagnosis of HIT based on clinical and laboratory findings

Unknown

6 patients with clinical and laboratory HIT

3 patients dx without supporting SRA+


Global Approach to HIT Diagnosis

• General reliance on ELISA test have lead to over diagnosis of HIT

• Positive ELISA in a patient with low pre‐test probability should not be interpreted as diagnostic

• Functional assays should be used to confirm clinical significance of antibody

• HIT diagnosis should not be based solely on laboratory data

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True story…Does this patient have HIT?• 54 year old male with history of Grave’s disease

admitted for treatment of metastatic ampullary cancer, UFH for DVT prevention


• 4T score = 4

• ELISA OD = 2.039• Negative IgG, but positive IgM (+inhibition),

IgA (-inhibition)

• SRA negative – not diagnosed with HIT, patient had DIC associated with metastatic cancer


Summary• Serious, potentially life‐threatening complication due to an adverse immune response to heparin

• Awareness of the clinical presentation of HIT and the ability to distinguish it from other causes of platelet count reduction are keys to avoiding serious sequelae

• Vast majority of antibodies detected by ELISA do not cause HIT; including pre‐test evaluation and functional assays will reduce false positive diagnosis

• Clinical Pathology staff can play an active role for increasing diagnostic accuracy of HIT and ensuring appropriate use of laboratory resources

• The consequence of a HIT diagnosis – real or false – have tremendous impact on the patient for the rest of their lives

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Questions & Discussion

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