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Heparin induced thrombocytopenia
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Heparin induced thrombocytopenia






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  • -Not so easy to apply accurately: the criteria are stringent
  • Evaluated in two clinical settings:Experts—authors at a single tertiary care centerEveryone Else: Anyone ordering an ELISA, mandatory part of test orderingNote:Distribution of patients is differentResults of the scores are different

Heparin induced thrombocytopenia Presentation Transcript

  • 1. Heparin-Induced Thrombocytopenia Paul Basciano, MD November 21, 2013
  • 2. Overview  The Immunology of HIT  Clinical Presentations     Laboratory Diagnosis    Timing and degree of thrombocytopenia Presence of thrombosis and implications for management Rarer presentations Heparin/PF-4 antibodies Serotonin release assay, HIPA Therapeutic Management       DTIs, fondaparinux Vitamin K antagonism With or without thrombosis Cardiovascular surgery Heparin re-challenge Spontaneous HIT, Fondaparinux-induced thrombocytopenia, and others  ACP Guidelines 8th Edition, 2008  Warkentin recent reviews   ASH Educational Session Paradigms and Paradoxes, J Thromb Haemost 2011; 9 (Suppl 1):105-117
  • 3. HIT: Features  An atypical, drug-induced immune response with platelet- activating IgG antibodies against a novel epitope of PF4 induced by stoichiometric amounts of heparin  A hypercoaguable state with a high risk of thrombosis, amputation, and death due to activation of platelets, endothelium, and WBC  A disease requiring a clinicopathologic diagnosis
  • 4. HIT Immunology  PF4 and chondroitin sulfate released from activated platelets  PF4 forms dimers and tetramers—tetramers bind to surface of platelets and to endothelial cells via GAGs  The presence of long chains of heparin allow for ultra-large aggregates of PF4 tetramers to form  These ultra-large PF4 tetramers allows for the binding of IgG abs which in turn bind to FcRγIIA receptors on platelets and endothelium, leading to activation
  • 5. The Immunology of HIT 2days 2days Unpredictable •The HIT ab is detectable a full 4 days before the platelet count cross the 50% reduction line •Therefore re-testing is unnecessary, although this doesn’t rule out human error Warkentin et al. Blood 2009
  • 6. Immunoglobulin Subtypes •IgG elevation occurred later in the non-HIT group •No significant differences in IgA or IgM levels between HIT and non-HIT patients Warkentin et al. Blood 2009
  • 7. Immunology of HIT •PF4/Hep abs increase quickly like a secondary immune response •Unlike a true secondary immune response, the antibodies are relatively short-lived • Cleared within 40-100days •There is also no anamnestic response
  • 8. The Immunology of HIT: Summary  Difference in levels of antibody formation between HIT and non-HIT was due to IgG levels  OD values are approximately 80% of maximal at the start of platelet fall (before clinical susupicion), and higher at the time of 50% reduction  Very rapid antibody response: median 4 days from heparin administration  No typical Ig class switch response (e.g. IgM ->IgG)  No association between previous heparin exposure and timing of antibody development  No anamnestic response in HIT; rapid reactions are from circulating antibody  Relatively rapid loss of antibody titers. Warkentin et al. Blood 2009
  • 10. The Four T’s LOW: 0-3 points INTERMEDIATE: 4-5 points HIGH: 6-8 points Lo et al., JThrombHaemost 2006
  • 11. The First T: Thrombocytopenia  Initial studies used an absolute platelet count cut-off  Improved sensitivity with preserved specificity for using a relative 50% drop (some suggest even 30%--the Brittish)  Platelet count may be normal even when dropping; consider especially thrombocytosis  The relative drop is based on the platelet count at initiation of heparin; especially important in the post-surgical patient (the double dip)  The thrombocytopenia of HIT also tends to be more mild than that seen with other drug reactions
  • 12. The Second T: Timing  For most patients, the drop will begin 5-10d after the initiation of heparin (nadir 10-14d)  Upwards of 20% of patients will have drops after heparin is stopped (delayed-onset HIT)  Some will have thrombosis prior to platelet drop  Early drops occur in patients with recent exposure to heparin  Generally within 30-100days prior  Due to remaining PF4/heparin abs, NOT an anamnestic response
  • 13. The oTher T’s: Thrombosis and oTher causes  More on these later
  • 14. The 4 T’s: Clinical Score Experts Everyone Else Experts Lo et al., JThrombHaemost 2006
  • 15. The 4 T’s: Correlation with Labs Experts Everyone Else Lo et al., JThrombHaemost 2006
  • 16. 4Ts in other studies
  • 17. 4Ts in Real Life
  • 18. 4 T’s: Summary  A low clinical score reliably rules out HIT  No need for lab testing  No need to stop heparin  A high score has a poor positive predictive value (in the wrong hands…)  May depend on the population  Doesn’t reflect two main clinical parameters: patient population and type of heparin  Needs to be strictly applied
  • 19. Rarer presentations of HIT  Anaphylactic reactions to heparin infusion  N.b. anaphylactoid reactions to OSCS in 2008  Necrotizing skin lesions at injection sites  Platelets in the normal range  Especially, pts with ET and other MPDs  Continued thrombosis despite heparin
  • 20. Over-diagnosis of a problem worth worrying about  “Within the past 10-20 years, recognition of HIT has evolved from gross underdiagnosis to wild overdiagnosis”  “In essence, the widespread detection of anti-PF4/heparin antidoies by commerically-available PF-4 dependent immunoassays has prompted an over-diagnosis of HIT”  However, given the clinical importance of diagnosis true HIT (as relatively rare as it is), it is imperative to always consider it and reassure oneself that it is not occurring.
  • 22. ACCP Guidelines, Chest 2008
  • 23. Laboratory Methods: Ig Detection Assays •Confirm assay can also be performed with addition of excess heparin Excess heparin should inhibit antibody binding and reduce OD
  • 24. Laboratory Methods: Activation Assays
  • 25. •Clinically irrelevant antibodies detected by EIAs (IgGAM>>>IgG) •Note even SRA% is greater than clinical HIT positivity •This is why HIT is a clinicopathologic diagnosis, and not a pathologic diagnosis alone •>50% of CT surgery patients will have ab positivity even though 1% will have HIT
  • 26. EIA and SRA
  • 28. How to Treat HIT  Heparin: Stop it.  Alternative Anticoagulation: Start it.  Warfarin: Reverse it, delay it, and overlap it.
  • 29. (Isolated)HIT and HITT  The difference is based on the presence of overt thrombosis  With i-HIT, 4 limb dopplers should be performed on all patients (50% silent VTE found)  Isolated HIT requires at least cessation of heparin plus alternative anticoagulation until platelet recovery; warfarin use and duration is uncertain
  • 30. Risk of Thrombosis in Isolated HIT •High risk of thrombosis mandates treatment with non-heparin anticoagulant, likely beyond prophylactic dosing AACP Guidelines, Chest 2008
  • 31. Argatroban  2mcg/kg/min  For Bilirubin >1.5, 0.5mcg/kg/min  Likely for all severe illness  PTT based assay—will be confounded by elevations associated with DIC seen in HIT as well as by re-warfarinization  No studies outside of HIT
  • 32. Lepirudin  Renally cleared  High incidence of antibodies after treatment; re- treatment is not recommended  Maybe more effective than argatroban?  Limb loss: 5% with lepirudin, 13% with argatroban  Likely not more bleeding than argatroban  Dosing is a major issue, and should be based on manufacturer and not trials:  Infusion rate of 0.1mg/kg/h  No bolus unless life or limb-threat: 0.2mg/kg  Same PTT goals
  • 33. Bivalrudin  Only approved for use with PCI and cardiac surgery  Lower antigenicity and less dependence on renal clearnece than lepirudin  less effects on INR than argatroban  Only reports about use outside of PCI and CT surgery in HIT; other studies outside of HIT
  • 34. Fondaparinux  Some concern about cross-reactivity, but rare  Renally cleared  Long half life  No monitoring required, but anti-Xa can be used and will not be confounded like PTT  Warkentin loves it
  • 35. Cardiac Surgery and PCI  Cardiac surgery options:  Re-challenge with heparin (esp >100d since HIT, negative SRA); use only during procedure  Use Bivalrudin  Use Heparin + Tirofiban or Epoprostenol  Use Lepirudin  Use Argatroban  PCI options:  Argatroban  Bivalrudin  Lepirudin  (Note: no heparin re-challenge; may need later for surgery)
  • 36. Warfarin  Not to be restarted until platelets >150 or ‘significantly improved’  Argatroban and Lepirudin will affect INR  Fondaparinux and Bivalrudin will not  May be possible to use DTI and then change to fondaparinux when platelets have recovered in preparation for warfarin
  • 37. Platelet Transfusions  Not absolutely contraindicated  Some concern regarding safety and precipitation of thrombosis  May be more of an association than causal  Have a higher threshold to transfuse patients with confirmed HIT, but give as needed for significant bleeding and/or risk of bleeding  Usually platelets >30 with HIT and no bleeding attributable to HIT  Co-existing conditions (DIC etc) may lower platelet count more
  • 38. HIT: Decision-Making Guidelines
  • 39. Low Clinical Likelihood of HIT, No Active Thrombosis  Do not send EIA or SRA and continue heparin  OR  If EIA/SRA sent-> switch to prophylactic dosing of alternative (esp fondaparinux) and wait for results (CYA)
  • 40. Int/High Possibility of HIT, Active Thrombosis  Send appropriate tests (EIA, SRA)  Reverse any warfarin with IV or PO vitamin K  Change to alternative anticoagulation based on clinical setting  Wait for platelet recovery and then begin warfarin with overlap if HIT confirmed
  • 41. Low Likelihood of HIT with Thrombosis or Int/High without Thrombosis  More difficult clinical situations  Trust the 4Ts– if truly low likelihood, continue heparin  If Int/High and no renal failure or bleeding, single dose of treatment dose fondaparinux until EIA results may be good intermediate
  • 42. Isolated HIT  Perform LE dopplers to assess for silent thrombosis  Begin alternative anticoagulation based on clinical setting  ?Begin warfarin when platelets recover and continue for…
  • 43. A History of HIT  First, confirm the history is true (retrospective 4T analysis, review ELISA and look for prior SRA)  Check ELISA  If negative can rechallenge  If positive, check SRA  Can re-use heparin in situations such as cariopulmonary bypass for brief periods  Use alternative anticoagulation in all other settings, including pre- and post-operative