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Heparin induced thrombocytopenia

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Heparin induced thrombocytopenia

  1. 1. Heparin-Induced Thrombocytopenia Paul Basciano, MD November 21, 2013
  2. 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. 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. 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. 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. 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. 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. 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. 10. The Four T’s LOW: 0-3 points INTERMEDIATE: 4-5 points HIGH: 6-8 points Lo et al., JThrombHaemost 2006
  11. 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. 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. 13. The oTher T’s: Thrombosis and oTher causes  More on these later
  14. 14. The 4 T’s: Clinical Score Experts Everyone Else Experts Lo et al., JThrombHaemost 2006
  15. 15. The 4 T’s: Correlation with Labs Experts Everyone Else Lo et al., JThrombHaemost 2006
  16. 16. 4Ts in other studies
  17. 17. 4Ts in Real Life
  18. 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. 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. 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. 22. ACCP Guidelines, Chest 2008
  23. 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. 24. Laboratory Methods: Activation Assays
  25. 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. 26. EIA and SRA
  27. 27. HIT: TREATMENT
  28. 28. How to Treat HIT  Heparin: Stop it.  Alternative Anticoagulation: Start it.  Warfarin: Reverse it, delay it, and overlap it.
  29. 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. 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. 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. 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. 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. 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. 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. 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. 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. 38. HIT: Decision-Making Guidelines
  39. 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. 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. 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. 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. 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

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