Dr. Imad Hassan El-SadekKuwaiti Board of Anesthesia (PGY3)           March 21st, 2012
Outline•   Definition &Types•   Incidence•   Pathophysiology•   Diagnosis•   Treatment•   HIT in CABG patients•   Protocol
Definition• HIT is an antibody-mediated adverse drug reaction to heparin  that can lead to devastating thromboembolic comp...
Heparin or Heparin/PF4 complex: trigger an antibody response (IgG, IgM, and IgA).                                Pathogene...
WHO WOULD GET HIT?
Risk factors for developing HIT    Risk Factor                                                                            ...
Cardiac and Orthopedic Population          Patient                        Days of                        Frequency of HIT ...
Iceberg Model of HIT
HOW DOES HIT PRESENT
Diagnosis of HIT  HIT is a clinico-pathologic syndrome• Onset Variations  – Typical-onset HIT: 5-10 days  – Rapid-onset HI...
Diagnosis of HIT        Thrombocytopenia                        90% to 95%                                                ...
Differential DiagnosisDIC              ITP         TTP-HUS    Drug-induced  Thrombocytopenia     SLE
4T’s for Diagnosis of HITPretestProbability   6-8Very likely   4-5 Possible   0-3 Unlikely
Laboratory Diagnosis of HITAntigen                  FunctionalAssays                     Assays                           ...
MANAGEMENT OF HIT
Management of HITT             ACCP 2012 Recommendations1. Stop Heparin2. Treatment With Nonheparin Anticoagulants        ...
Characteristics of Anticoagulants Used      to Treat Patients with HIT
Management of Clinically suspected HIT           Pharmacological Treatment    • Two DTIs are available in the United State...
Dosing of Heparin Alternatives
Management of HITT             ACCP 2012 Recommendations• Treatment With Nonheparin Anticoagulants Recommendation         ...
Management of Clinically suspected HIT     Pharmacological TreatmentFor how long?• HIT  – Therapeutic anticoagulation: Unt...
SUSPECTED HIT MANAGEMENTPROTOCOL
• 4T’s: - Low: May continue Heparin, consider alternative diagnosisConfirm     •       - Intermediate:  immunoassay, if p...
MANAGEMENT OF HIT IN PATIENTSUNDERGOING CARDIAC SURGERY
Factors Influencing HIT Management    Options in Cardiac Surgery PatientsDisease Activity • Acute, Subacute, history of HI...
Management of HIT     in Patients Undergoing Cardiac Surgery                                                      Cardiac ...
Management of HIT           in Patients Undergoing Cardiac Surgery                 Recommendation                         ...
Possible Treatment Options for HIT         patients Undergoing CBPHeparin Based • Non-urgent: Postpone • Semi-Urgent: Brie...
Heparin Based Treatment  1. Non-Urgent CPB: Postponement• Rationale:  – A secondary immune response after reexposure to   ...
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  • Heparin-induced thrombocytopenia +/- thrombosis (HITT)Occurs 5-10 days after a first exposure to heparin (more quickly in patients with prior exposure).Can also occur within 1-2 weeks of a hospital stay.Platelets nadir at 30,000-60,000/mL.Frequency of 0.2-5%.Thromboembolic events occur in 30-80% of affected individuals.Risk factorsFemaleSurgicalUse of unfractionated heparin (risk of HIT 2.6% with UFH and 0.2% with LMWH)
  • Heparin exposure leads to the formationof IgG antibodies that recognize multimolecular complexesof platelet factor 4 (PF4) and heparin that form on the surface ofplatelets. 7,8 These complexes bind to the FcIIa (IgG) receptorsof platelets, 9,10 resulting in platelet activation and release ofprocoagulant, platelet-derived microparticles. 11,12 The end resultis marked generation of thrombin and the formation of venousand arterial thromboses that are the clinical hallmark of HIT.
  • A platelet count which has fallen 50 percent or more from a prior value, even if absolute thrombocytopenia is not present
  • A platelet count which has fallen 50 percent or more from a prior value, even if absolute thrombocytopenia is not present
  • "4 Ts" score introduced in 2003. A score of 0–8 points is generated; if the score is 0-3, HIT is unlikely. A score of 4–5 indicates intermediate probability, while a score of 6–
  • HIPA most used.. Less sensitive than SRA
  • Hit cdh

    1. 1. Dr. Imad Hassan El-SadekKuwaiti Board of Anesthesia (PGY3) March 21st, 2012
    2. 2. Outline• Definition &Types• Incidence• Pathophysiology• Diagnosis• Treatment• HIT in CABG patients• Protocol
    3. 3. Definition• HIT is an antibody-mediated adverse drug reaction to heparin that can lead to devastating thromboembolic complications Types Type 1 Type 2Nature Non immune Immune-mediatedOnset 1-4 5-10Incidence 10-20% 0.2-5%.Pathophysiology Heparin-induced platelet aggregationPlatelet Count nadir 100,000 30,000-60,000Manifestation Asymptomatic Thrombosis (30-80%): venous-arterial (3– 4:1)Management Strategy Observation; improves while Heparin alternatives on heparin
    4. 4. Heparin or Heparin/PF4 complex: trigger an antibody response (IgG, IgM, and IgA). Pathogenesis
    5. 5. WHO WOULD GET HIT?
    6. 6. Risk factors for developing HIT Risk Factor Risk Prolonged Heparin use UFH > LMWH (2.6% with UFH and 0.2% with LMWH) RR 5.3; 95% CI 2.8-9.9 Surgical > medical patients RR 3.2; 95% CI 2.0-5.4 Female > male patients RR 2.4; 95% CI 1.4-4.1 The highest risk for HIT was seen in female surgical patients RR 17; 95% CI 4.2-72 receiving UFH Prior Exposure to Heparin (UFH or LMWH) 1.7 vs 0.3%, OR 4.9; 95% CI 1.5-16 Cardiac and Orthopedic Surgery have a higher risk of HIT (1%-5%) than medical or obstetric patients (0.1%-1%)• Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108:2937.• Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703.• Prandoni P, Siragusa S, Girolami B, et al. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Blood 2005; 106:3049.
    7. 7. Cardiac and Orthopedic Population Patient Days of Frequency of HIT antibodies Frequency of population treatment clinical HIT Activation Antigen assay assay Cardiac, UFH 5.1 ± 2.2 (SD) 20.0 % 50.0 % 1.0 % Orthopedic, 9.2 ± 2.2 9.3 % 14.1 % 4.9 % UFH Orthopedic, 9.5 ± 3.0 3.2 % 7.5 % 0.9 % LMWHWarkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703.
    8. 8. Iceberg Model of HIT
    9. 9. HOW DOES HIT PRESENT
    10. 10. Diagnosis of HIT HIT is a clinico-pathologic syndrome• Onset Variations – Typical-onset HIT: 5-10 days – Rapid-onset HIT: within 24 hrs – Delayed-onset HIT: as long as 3 weeks after cessation of heparin
    11. 11. Diagnosis of HIT Thrombocytopenia 90% to 95% <150,000 or 30-50% fall • Rarely severe, platelet counts typically >20,000/µL; median platelet count nadir of about 60,000/µL • Cardiac Surgical Patients: “a secondary fall in the platelet count ≥50 percent that begins between the 5th-10th postop day appears to be highly predictive of HIT” Thrombosis 30-80% • venous-arterial (3-4:1) • Manifestations: DVT, PE, distal ischemic necrosis following DVT, cerebral sinus thrombosis, adrenal hemorrhage secondary to adrenal vein thrombosis, and transient global amnesia. • Necrotic skin lesions at heparin injection sites. Acute Systemic Reactions Within 30min of exposure • fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest occurring after IV heparin bolus administration.Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocypenia after cardiac surgery. JThromb Haemost 2010; 8:27.
    12. 12. Differential DiagnosisDIC ITP TTP-HUS Drug-induced Thrombocytopenia SLE
    13. 13. 4T’s for Diagnosis of HITPretestProbability 6-8Very likely 4-5 Possible 0-3 Unlikely
    14. 14. Laboratory Diagnosis of HITAntigen FunctionalAssays Assays SRA ELISA serotonin release assay particle gel HIPA immunoassay Heparin-induced platelet activation
    15. 15. MANAGEMENT OF HIT
    16. 16. Management of HITT ACCP 2012 Recommendations1. Stop Heparin2. Treatment With Nonheparin Anticoagulants Danaparoid Fondaparinux Desirudin BivalirudinRecommendation LoEIn patients with HIT/HITT, we recommend the use 1Cof nonheparin anticoagulants, in particular argatrobanlepirudin, argatroban, and danaparoid, over thefurther use of heparin or LMWH orinitiation/continuation of VKA No prospective head-to-head trials comparing one agent with another
    17. 17. Characteristics of Anticoagulants Used to Treat Patients with HIT
    18. 18. Management of Clinically suspected HIT Pharmacological Treatment • Two DTIs are available in the United States: Lepirudin Argatroban Caution Prolonged in Renal Failure Prolonged in liver dysfunction (decrease by 75%) Initial Dose: IVI: 0.10 mg/kg/h Recommended: 2mcg/kg/min ACCP: 0.5-1.2 mcg/kg/min Dose adjustment aPTT: 1.5-2.0 x baseline aPTT: 1.5-3 x baseline Effect on INR Minimal Substantial Adverse Effects Anaphylaxis (1st: 0.015%; re-exposure:0.16%)According to systematic review (2004):• Lepirudin results in RRR of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls.• Argatroban showed a RRR of the above clinical outcomes to be 0.20 and 0.18.[8]
    19. 19. Dosing of Heparin Alternatives
    20. 20. Management of HITT ACCP 2012 Recommendations• Treatment With Nonheparin Anticoagulants Recommendation LoE In patients with HIT/ HITT who have normal renal function, we suggest the use of 2C argatroban or lepirudin or danaparoid over other nonheparin anticoagulants In patients with HIT/HITT and renal insufficiency, we suggest the use of argatroban 2C over other nonheparin anticoagulants2. Platelet Transfusions LoE In patients with HIT and severe thrombocytopenia, we suggest giving platelet 2C transfusions only if bleeding or during the performance of an invasive procedure with a high risk of bleeding.
    21. 21. Management of Clinically suspected HIT Pharmacological TreatmentFor how long?• HIT – Therapeutic anticoagulation: Until platelet count recovers to stable plateau. – Prophylactic anticoagulation: for up to 4 weeks • Risk of thrombosis for 2-4 weeks after initiation of Rx.• HITT – Transition to warfarin after platelet count > 150 – Overlap warfarin with DTI for >= 5 days, with >= 48 hrs INR >2
    22. 22. SUSPECTED HIT MANAGEMENTPROTOCOL
    23. 23. • 4T’s: - Low: May continue Heparin, consider alternative diagnosisConfirm • - Intermediate:  immunoassay, if positive  Send functional assay HIT • - High: Stop Heparin and initiate alternative • Stop all heparin or LMWH, including flushes or locks Stop • Label all IV sites or catheters as “NO HEPARIN”Heparin • Order bilateral lower extremity ultrasound for DVT Rule-outThrombus • HIT/HITT: lepirudin, argatroban, and danaparoid • Renal impairment: Argatroban; RRT: argatroban or danaparoid Heparinalternative • Pregnant: danaparoid. lepirudin or fondaparinux only if danaparoid is not available • Initiate late (Plt >150,000) and low( Max 5mg/d)Overlap • Overlap with nonheparin anticoagulant for >=5days and Target INR reachedwarfarin • If already on warfarin when HIT  Reverse with Vitamin K • Usually no bleeding Avoid • Can result in acute thrombosisPlatelets
    24. 24. MANAGEMENT OF HIT IN PATIENTSUNDERGOING CARDIAC SURGERY
    25. 25. Factors Influencing HIT Management Options in Cardiac Surgery PatientsDisease Activity • Acute, Subacute, history of HITPatient’s Co-morbidities • Renal Impairment, liver impairmentDrug Availability • UFH, Heparin Alternatives, PlasmapheresisSurgical Urgency • Postponement vs. ProceedingDrug Monitoring • ACT, aPTT, ECT
    26. 26. Management of HIT in Patients Undergoing Cardiac Surgery Cardiac Surgery Acute or Subacute HIT History of HIT Urgent Non-Urgent Ab Negative Ab Positive Bivalirudin Delaying Short-term Non Heparin over other nonheparinanticoagulants and over heparin the surgery until HIT has resolved and HIT antibodies are negative Heparin anticoagulant plus antiplatelet agents
    27. 27. Management of HIT in Patients Undergoing Cardiac Surgery Recommendation LoE In patients with acute HIT (thrombocytopenic, HIT antibody positive) or 2C subacute HIT (platelets recovered, but still HIT antibody positive) who requireAcute HIT urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants and over heparin plus antiplatelet agents In patients with acute HIT who require nonurgent cardiac surgery, we 2C recommend delaying the surgery (if possible) until HIT has resolved and HIT antibodies are negative In patients with a history of HIT in whom heparin antibodies have been shown 2CHistory of HIT to be absent who require cardiac surgery, we suggest the use of heparin (short- term use only) over nonheparin anticoagulants In patients with a history of HIT in whom heparin antibodies are still present 2C who require cardiac surgery, we suggest the use of nonheparin anticoagulants over heparin or LMWH
    28. 28. Possible Treatment Options for HIT patients Undergoing CBPHeparin Based • Non-urgent: Postpone • Semi-Urgent: Brief intra-op UFH • Urgent: UFH with intra-op PlasmapheresisHeparin with Antiplatelets • Heparin + Iloprost • Drawback: severe hypotension • Hepain + Tirofebam (Glycoprotein IIb-IIIa antagonist) • In renal imapirment patients (2001)Hepain Alternatives • DTI: Lepirudin, Argatroban • Danaparoid • Defibrinogenating Agent (ancorod)
    29. 29. Heparin Based Treatment 1. Non-Urgent CPB: Postponement• Rationale: – A secondary immune response after reexposure to heparin should not occur until at least three days after exposure. – Thus, a brief exposure to heparin during CPB should not immediately elicit HIT antibodies. – Furthermore, since the heparin would be rapidly cleared after the procedure, even if antibodies appeared, they would not be thrombogenic in the absence of heparin.

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