heparin-induced thrombocytopenia …a diagnostic and
TRANSCRIPT
Royal North ShoreHospital
Heparin-induced thrombocytopenia
…a diagnostic and therapeutic challenge
Christopher M Ward
Northern Blood Research Centre Royal North Shore Hospital
ISTH Bangkok November 2017SydneyMedicalSchool
ISTH Advanced Training CourseDubai, UAE
Disclosures for Christopher Ward In compliance with COI policy, ISTH requires the following disclosures to the session audience:
Research Support/P.I. Bayer, CSL, Pharmion
Employee No relevant conflicts of interest to declare
Consultant No relevant conflicts of interest to declare
Major Stockholder No relevant conflicts of interest to declare
Speakers Bureau Alexion, Amgen, Bayer, Boehringer Ingelheim, Celgene, IL, Pfizer-BMS, Sanofi
HonorariaAmgen, Bayer, Boehringer Ingelheim, Celgene, GSK,
IL, Janssen, Novartis, Pharmacia, SpecialisedTherapeutics
Scientific Advisory BoardAlexion, Amgen, Astra-Zeneca, Bayer, Boehringer
Ingelheim, Celgene, GSK, IL, Janssen, Pfizer-BMS, Sanofi, Specialised Therapeutics
Presentation includes discussion of the following off-label use of a drug or medical device:
HIT testing using Multiplate aggregometer, alternate anticoagulants for HIT
When good drugs turn “bad”….
Paradoxical effects of an anticoagulant
HITS remains a diagnostic and clinical challenge
What is HIT?
Clinical features of HIT
Laboratory testing – screening assays
- functional assays
Treatment options
Heparin-induced Thrombocytopenia/Thrombosis
Heparin-dependent antibodies (recognise heparin-PF4)Antibodies not uncommon ?10%
1-5% develop thrombocytopenia - after several daysWatch for significant drops within normal range
Thrombosis in 10-20% (HITTS) with high morbidity/mortality
Venous > arterial, also skin necrosis at injection sites
Increased risk with His131 FcR polymorphism
Diagnosis must be clinical, poor assay sensitivity
STOP heparin treat with alternative anticoagulantDO NOT USE warfarin until platelets recovered
Thrombosis
Thrombocytopenia
Heparin-dependentantibodies ?5% of popn
5% exposed
HITTS : pathogenesis
Endothelium
Heparin
PF4
HeparansPF4
ThrombosisPlatelet clearance
Anti-heparin/PF4 Abs
Why is HIT an unusual immune response?
Rapid appearance of PF4-heparin antibodies
Most are IgG rather than IgM
PF4-heparin antibodies present in those not exposed to heparin, and asymptomatic – high prevalence after cardiothoracic surgery
PF4-heparin antibodies do not persist – failure of memory B cells?
Is HIT a misdirected immune response?
Heparin
PF4
Infection:Platelets release PF4
PF4 binds surface glycans on bacteria
B
PF4-glycan forms a neoepitope
Antibodies to PF4-glycan produced, enhance phagocytosis
Subsequent exposure to heparin andplatelet activation
Antibodies cross-react with PF4-heparin
Adaptive immune response
HIT
Krauel et al Blood 2011
HITS remains a diagnostic and clinical challenge
What is HIT?
Clinical features of HIT
Laboratory testing – screening assays
- functional assays
Treatment options
Clinical events associated with HIT...
Venous thrombosis (30-70%) – DVT or PE
Adrenal necrosis/haemorrhage
Cerebral sinus thrombosis
Venous limb gangrene (esp with VKA)
Arterial thrombosis (15-30%) incl limb gangrene
Stroke or myocardial infarction
Skin lesions at injection sites (10%), skin necrosis
Acute reactions to iv heparin (10%)
DIC (10%)
HIT Ab +ve
Dia +Agg -
Dia -Agg +TKJR
Clexane 40mg/d
UFH/Clexane
Adrenal Haem.
PE
Delayed diagnosis of HIT is not uncommon...
Danaparoid
Skin lesions in HIT
can include local necrosis at sites of heparin injection
Digital gangrene is one of the most striking complications of HIT
High rates of limb amputation in many series
Reflects acute arterial thromboembolism
Can be triggered by addition of warfarin – adds PC, PS depletion to the hypercoagulable state
“4T” Pretest Probability Score for HIT
Warkentin et al Br J Haematol 2003Low 0-3, Intermediate 4-5, High 6-8
Clinical utility of 4T score: a metaanalysis
Cuker et al Blood 2012
Systemic review of literature – 13 studies included both 4T and reference “standard” (SRA, HIPA or platelet aggregation) in 3068 patients
55.8% (1712) classified as low probability by 4TN.B. 13 of these patients had a positive functional test...Negative predictive value 0.998 (95% CI 0.97-1.00)
Positive predictive value of intermediate 4T 0.14 (0.09-0.22)
Positive predictive value of high 4T (8%) 0.64 (0.40-0.82)
“Low probability 4T appears... a robust means of excluding HIT”Interassessor variability and no standard assay used
Timing of platelet fall after surgery and heparin –typical patterns of HIT
Warkentin and Greinacher Ann Thorac Surg 2003
A: typical, gradual fall on heparin after 5-10 daysB: acute fall, often with systemic reactionC: delayed onset, fall in platelets after heparin ceased
Thrombosis in HITTS can occur at low-normal platelet counts
Warkentin Semin Hematol 1998
Uncommon variants of HIT
“Spontaneous” HIT without heparin exposure –may occur postop, after infection
Delayed-onset HIT – triggered by potent “autoimmune-like” antibodies activating platelets in the absence of heparin. Higher morbidity/mortality and prolonged time to platelet recovery
HIT-associated consumptive coagulopathy – DIC causing problems if therapy is monitored by APTT
Coumarin necrosis – caused by extreme hypercoagulability (platelet procoagulantresponse, macro- and microvascular thrombosis)
Warkentin J Thromb Haemost 2011
“Autoimmune HIT: a puzzling entity
Warkentin & Greinacher Curr Opin Hematol 2016
Some patients develop “autoimmune” strong antibodies that activate platelets in vitro and in vivo without heparin being present
Can be detected in functional assays by platelet aggregation in the “no heparin” control
Leads to “delayed onset HIT” – begins or worsens after stopping heparin, or “persistent HIT” – low platelets for more than 30d after stopping heparin, or even “spontaneous” HIT with a typical clinical and laboratory picture but no heparin exposure…
Believed due to PF4 binding to non-heparin platelet glycosaminoglycans, including chondroitin sulfate, triggering “heparin-PF4” antibodies
Practice point
When should we suspect HIT?
Unexpected drop in platelet count (but may remain in normal range) in a patient with current or recent heparin exposure
Most common in “sick” patients, where platelets are activated by sepsis, inflammation, surgery – rarely seen in routine prophylaxis or pregnancy
Occurs after LMWH as well as UFH
Diagnosis and management of HIT
… a work in progress
Why is HIT over-diagnosed?
Thrombocytopenia is common in hospitalisedpatients, especially in ICU
(LMW) heparin use is widespread in this group
Heparin-PF4 antibodies have a high prevalence in older patients, esp after cardiothoracic surgery
BUT...most Ab positive patients do not have true HIT
Why does it matter?
A putative diagnosis of HIT mandates a switch to alternative anticoagulants
These anticoagulants are expensive, difficult to use and expose patients to higher risks of bleeding (esp the direct thrombin inhibitors)
Patients with this diagnosis may have to use alternative anticoagulants longterm
Overdiagnosis of HIT is putting many patients at unnecessary risk... and markedly increasing treatment costs
HITS remains a diagnostic and clinical challenge
What is HIT?
Clinical features of HIT
Laboratory testing – screening assays
- functional assays
Treatment options
Warkentin Hematology (ASH) 2011
The “iceberg” model of HIT
PaGIAs (Diamed)qualitative assay, simple and rapidSerum or plasma similarFalse negatives higher than EIAs, many false positives
ELISA assays (GTI, Stago, Hyphen)heparin-PF4 or polyvinylsulfate-PF4 as target antigenhighly sensitive but high false positive rates (incl APL)semiquantitative, expensive – usually batchedimprove specificity with IgG-specific cf. IgGAM, OD>1.00
Nanoparticle flow - STic (Stago)Rapid immunoassay designed for fresh samples
Rapid automated assays – HemosIL HIT-Ab (IL)Potential for similar performance to ELISA, but on demand
Anti-Heparin-PFA immunoassays
PaGIA assay for Heparin-PF4 antibodies (Diamed)
Particle gel immunoassay
Rapid test, convenient
Previous issues with assay quality, many “false positives”
Clinical–laboratory algorithm to predict HIT
Ruf et al Thromb Haemost 2011
Combined algorithm for HIT diagnosis – incorporates 4T score, ELISA and OD value
Patients with a 4T score >3 and OD>1.0 were considered positive
Tested against a retrospective cohort of 83 patients (9 SRA positive) – algorithm indicated DTI therapy in 22 patients
Sensitivity of algorithm was 90%, specificity of 82% - better than 4T alone, or ELISA alone
Practice point
When should we test for HIT?
Clinical picture (including 4T score) cannot make the diagnosis, score is less reliable in medical and ICU patients
Need access to a rapid “screen” assay or ELISA
Think before ordering assays in those with a high likelihood of heparin-PF4 antibodies (e.g. post-cardiothoracic surgery)
Negative screening assay is useful in excluding HIT – but a positive result will lead to a change in therapy
HITS remains a diagnostic and clinical challenge
What is HIT?
Clinical features of HIT
Laboratory testing – screening assays
- functional assays
Treatment options
HIT functional assaysAntibodies only bind to stoichiometric PF4-heparin complexes:→ Heparin must be stopped the day before blood collection for functional investigation
Functional assays must include low and high heparin concentrations
PRP 0.5 IU/ml 100 IU/ml
Washed platelets 0.1 - 0.2 IU/ml 100 IU/ml
Thrombocytopenia in hospitalised patients is very common AND(LMW) heparin use in hospitalised patients is very common
Hep-PF4 antibodies are common – most are “false positive”True HIT, with platelet activation is uncommon
A positive functional assay mandates alternate anticoagulation, ?indefinitely
A negative functional assay provides more options –e.g. transient heparin for bypass in a frail patient
Why perform a functional assay?…
(Light transmission aggregometry)Better performance from washed platelet assays:
Serotonin release assay (SRA) Warkentin
Heparin-induced platelet aggregation (HIPA) Greinacher
Whole-blood impedance aggregometry (HIMEA) Morel-Kopp
(Flow cytometry for platelet activation)
(Thrombin generation)Tan et al Semin Thromb Haemost 2012
Functional assays for HITS
The way forward….
… a faster path to confirming HIT
Consensus method paper using whole-blood impedance aggregometry to detect platelet activating HIT antibodies
A rapid, non-radioactive alternative to serotonin release assay –does require HIT-sensitive donor platelets
Functional assay to distinguish “true” HIT from false positive samples
single use test cell with twin impedancesensor
sample volume0.3 ml/test
firm adhesion and aggregation of platelets on the sensor surface enhances the electrical resistance between the 2 sensor wires
Multiplate® test cell
HIMEA assay to detect platelet-activating HIT antibodies
Negative False positive
Weak positive
Strong positive
1 U/mL
200 U/mL
Morel-Kopp et al J Thromb Haemost 2016
HIT excluded –resume heparin
Cease heparin exposure
HIT possible – change anticoagulant
negative positive
Clinical suspicion of HIT - ?4T score
Screening immunoassay for PF4-heparin – IgG specific preferred
Functional assay to confirm HITnegative?
HIT more likely if high OD
HITS remains a diagnostic and clinical challenge
What is HIT?
Clinical features of HIT
Laboratory testing – screening assays
- functional assays
Treatment options
Key principles of therapy in HIT
Cease all exposure to heparin(s)
Avoid platelet transfusion
Anticoagulation is required to counter hypercoagulable state – prophylactic if no thrombosis, therapeutic if thrombosis
Continue alternate anticoagulant until platelet count normalised
Defer warfarin until platelet count normalised (at least 5 days)
Alternative anticoagulants in HITS – now…
Lepirudin direct thrombin inhibitor
Danaparoid heparinoid
Fondaparinux pentasaccharide
Argatroban direct thrombin inhibitor
Bivalirudin direct thrombin inhibitor
In future… dabigatran, rivaroxaban, apixaban?
The ideal anticoagulant for HIT would have…
Flexible dosing prophylactic and therapeutic
SC option allow outpatient treatment
Assay to monitor allows dose adjustments
Not affect INRs to simplify switch to warfarin
Stable dosing
Short half-life many patients are unstable
Non-renal clearance
Low bleeding risk
Low cost
The conventional options…Danaparoid Hirudins Argatroban
Flexible dosing + + +
SC option + - -
Assay to monitor + +? +?
Not affect INRs + -- ?
Stable dosing + - ?
Short half-life - + +
Non-renal cl. - --- +
Low bleeding risk ? -- ?
Low cost - - -
newer options…Fondaparinux NOACs
Flexible dosing + +
SC option + - (PO)
Assay to monitor +? +
Not affect INRs + ?
Stable dosing + +
Short half-life - -
Non-renal cl. - ?
Low bleeding risk ? ?
Low cost + +
Anticoagulation in HIT
Necessary until platelets have normalised
Prophylactic – 750U BD sc danaparoid or 2.5mg fondaparinux if no thrombosis
Therapeutic – consider danaparoidinfusion (monitor anti-Xa) or 7.5mg fondaparinux
Direct thrombin inhibitors (hirudins) may have higher bleeding risk – caution with dosing and renal impairment
NOACs an unproven alternative…
Diagnosis and management of HITFunctional assays (e.g. SRA) are superior to immunoassays in identifying clinically relevant heparin-induced Abs;
A positive functional assay makes a definitive diagnosis of HIT
Only ~10% of suspected HIT are Ab positive; of those with positive PF4 immunoassays, only10-50% are functional positive
Recommend use of danaparoid or fondaparinux(indirect thrombin inhibitors) rather than DTIs because :
• proven effective in HIT, also in non-HIT thrombosis, • available in prophylactic and therapeutic doses, weight-adjusted• monitor with anti-Xa levels (less risk of over/underdosing than APTT-based monitoring of lepirudin, argatroban), • longer half-lives, easier to overlap with warfarin• likely lower bleeding rates than DTIs (cf inappropriate dosing of lepirudin in the literature)
Warkentin Hematology (ASH) 2011
Practice point
Alternate anticoagulants in HIT?
Simple if no thrombosis – cover with fondaparinux, danaparoid or NOAC, at least until platelets recovered
Patients with thrombosis are often unstable and complex – prefer parenteral options such as danaparoid or argatroban
Caution with monitoring, especially when transitioning to warfarin – bleeding risks are high with direct thrombin inhibitors
Growing clinical experience with NOACs, but little published to date. If using rivaroxaban or apixaban, start with higher dose as per acute VTE
Avoid warfarin until platelets fully recovered, no progressive thrombosis
Can we re-expose HIT patients to heparin?
Blood 2016
HIT antibodies are usually transient
If a patient with prior HIT needs bypass or other high-risk procedure, they can be briefly exposed to heparin again (provided heparin-PF4 antibodies are negative)
Very low risk of recurrence, even though antibodies will be induced
Cover postoperative course with an alternative anticoagulant
HIT : a continuing challenge
Most thrombocytopenia on heparin is not HIT, but always consider the diagnosis
Clinical features can be helpful – but laboratory testing is needed to either exclude or confirm “true” HIT
Consider functional testing to confirm Abpositive cases
Caution with alternate anticoagulants – do not start warfarin too early and avoid platelet transfusion