Heparin Induced Thrombocytopenia (HIT) - Renal Perspective

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Heparin-Induced Thrombocytopenia (HIT) Renal Perspective:

Heparin-Induced Thrombocytopenia (HIT) Renal P erspective Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria – EGY drgawad@gmail.com 14 th KUC Club – 20 Aug 2015

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To download the lecture please contact me on drgawad @gmail.com For more lectures, visit www.NephroTubeCNE.com

HIT Overview of Presentation:

HIT Overview of Presentation Case 1 Male on maintenance hemodialysis UFH as anticoagulant Develops thrombocytopenia No clinical evidence of thrombosis All causes of thrombocytopenia are excluded A diagnosis of HIT is confirmed Case 2 Male on maintenance hemodialysis UFH as anticoagulant Develops thrombocytopenia C linical evidence of thrombosis (DVT) All causes of thrombocytopenia are excluded A diagnosis of HIT is confirmed HIT = Heparin exposure + Thrombocytopenia ± Thrombosis

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

HIT Pathogenesis:

Heparin Platelet Fc Receptor α granule PF 4 HIT Pathogenesis Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Animation: M. Gawad. Aug, 2015. www.NephroTubeCNE.com

HIT Pathogenesis:

Y Y Marginal B Lymphocytes Heparin HIT Pathogenesis Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Animation: M. Gawad. Aug, 2015. www.NephroTubeCNE.com IgG Ab

HIT Pathogenesis:

Y HIT Pathogenesis Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Animation: M. Gawad. Aug, 2015. www.NephroTubeCNE.com

HIT Pathogenesis:

Platelet aggregation = Thrombosis + Thrombocytopenia Y Endothelial cells Tissue Factor Thrombin HIT Pathogenesis Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Animation: M. Gawad. Aug, 2015. www.NephroTubeCNE.com Heparan Sulphate

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Presentation – Thrombocytopenia Platelet Count :

Presentation – Thrombocytopenia Platelet Count Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Linkins LA et al. American College of Chest Physicians. Chest . 2012;141(2 Suppl):e495S . 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT

Presentation – Thrombocytopenia Platelet Nadir :

Presentation – Thrombocytopenia Platelet Nadir Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Linkins LA et al. American College of Chest Physicians. Chest . 2012;141(2 Suppl):e495S . 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Timing (the mean nadir is approximately  60 X 109L)

Presentation – Thrombocytopenia HD Patients - Specific Issues :

Presentation – Thrombocytopenia HD Patients - Specific Issues Matsuo. J Blood Disord Transfus . 2011, S2 No dialytic session day may give a chance of recovering the platelet count The timing of thrombocytopenia is usually delayed over 10 days D efinition of HD-HIT may be less strict, in the range of a >30% fall in the platelet count and below 150×109 /L

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Presentation - Thrombosis 1- History and Physical Examination :

Presentation - Thrombosis 1- History and Physical Examination "white clots "

Presentation – Thrombosis HD Patients - Specific Issues:

Clotting of the dialysis lines and/or dialyzer ( v isible clotting in the extracorporeal circulation may provide a clue to suspect HIT) Fistula thrombosis Presentation – Thrombosis HD Patients - Specific Issues Nakamoto H et al. (2005 ) Hemodial Int 9: S2-S7.

Presentation – Thrombosis Thrombosis-Thrombocytopenia Relationship 1- History and Physical Examination :

Presentation – Thrombosis Thrombosis-Thrombocytopenia Relationship 1- History and Physical Examination Nakamoto H et al. (2005 ) Hemodial Int 9: S2-S7. Major clinical manifestations are primary thrombocytopenia and new thrombosis The complication of thrombosis sometimes develops before thrombocytopenia emerges 5-10 days after starting heparin

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Presentation – Acute Systemic Reaction HD Patients - Specific Issues:

Presentation – Acute Systemic Reaction HD Patients - Specific Issues Hartman et al. Nephron Clin. Pract. 104, c143–c148 (2006). Fever and chills Hypotension Tachycardia Tachypnea Flushing Headache 5–30 min after an IV bolus of UFH Chest pain. Dyspnea (can be so severe that it mimics a pulmonary embolism “ pseudopulmonary embolism syndrome”) Collapse & death

Presentation – Acute Systemic Reaction HD Patients - Specific Issues:

Presentation – Acute Systemic Reaction HD Patients - Specific Issues Hartman et al. Nephron Clin. Pract. 104, c143–c148 (2006). Fever and chills Hypotension Tachycardia Tachypnea Flushing Headache 5–30 min after an IV bolus of UFH Chest pain. Dyspnea (can be so severe that it mimics a pulmonary embolism “ pseudopulmonary embolism syndrome”) Collapse & death It can masquerade as an acute dialyzer reaction Thrombocytopenia in this setting is often transient → platelet count should be checked as soon as possible after symptoms appear.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Presentation - Frequency Hemodialysis Patients:

Presentation - Frequency Hemodialysis Patients Matsuo T et al. Pathophysiol Haemost Thromb . 2006;35(6): 445-50 Matsuo. J Blood Disord Transfus . 2011, S2 Newly treated subjects receiving dialysis in 3 months Frequency of 2.3% Chronic dialysis patients treated for over 3 months Frequency of 0.6% Usually due to changes in immunological tolerance: cardiovascular surgery orthopedic surgery high-dose administration of erythropoietin with an adverse platelet-stimulating reaction

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Diagnosis Suspicion:

Diagnosis Suspicion Thrombocytopenia (with its different specific characteristics: % of fall, nadir, timing) ± Thrombosis ± Acute systemic reaction

Diagnosis Suspicion – Post Surgical:

Diagnosis Suspicion – Post Surgical Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Diagnosis Suspicion – Post Surgical:

Diagnosis Suspicion – Post Surgical Surgery Post operative platelets follow up Obstetric, Cardiopulmonary bypass every 2–3 d from days 4 to 14 or until heparin is stopped (2C) Post-operative patients and cardiopulmonary bypass patients who have been exposed to heparin in the previous 100 d and are receiving any type of heparin 24 h after starting heparin (2C).

Diagnosis 4T’s Score - Probability:

Diagnosis 4T’s Score - Probability Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Hicks LK et al. Blood . 2014 Dec;124(24):3524-8

Diagnosis 4T’s Score - Probability:

Diagnosis 4T’s Score - Probability http://www.mdcalc.com/4ts-score-heparin-induced-thrombocytopenia/#next-steps

Diagnosis 4T’s Score:

Very high negative predictive value (97 to 99 %) P ositive predictive value is low (10 to 20% for an intermediate score [ 4 or 5 points] and 40 to 80% for a high score [ 6 to 8 points ]) Blood 2012; 120: 4160-7 J Thromb Haemost 2010; 8: 2642-50. Andreas Greinacher . N Engl J Med , July 16, 2015;373:252-61 Diagnosis 4T’s Score

Diagnosis :

Andreas Greinacher . N Engl J Med , July 16, 2015;373:252-61 Diagnosis

Diagnosis :

Andreas Greinacher . N Engl J Med , July 16, 2015;373:252-61 Diagnosis

Diagnosis HD Patients – Special Issues:

Diagnosis HD Patients – Special Issues C hronic heparin exposure → high incidence of heparin-induced antibodies (the clinical significance of which is uncertain) Asmis LM et al. Thromb Haemost 2008; 100:498.

Diagnosis HD Patients – Special Issues:

Diagnosis HD Patients – Special Issues C hronic heparin exposure → high incidence of heparin-induced antibodies (the clinical significance of which is uncertain) Asmis LM et al. Thromb Haemost 2008; 100:498. Do not routinely test patients undergoing dialysis for HIT antibodies, except in the appropriate clinical setting i.e. clinical suspicion of HIT

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Distinguishing Characteristics of the Two Types of HIT:

Distinguishing Characteristics of the Two Types of HIT >20,000/ l Adapted from: Brieger DB et al. J Am Coll Cardiol 1998; 31:1449. H eparin causes non-immune-mediated platelet aggregation

Delayed-onset HIT:

Rice L et al. Ann Intern Med. 2002;136(3):210. Thrombocytopenia and/or thrombosis occur after heparin has been withdrawn Timing: occurring at a median time of 14 days after discharge from the hospital (range: 9 to 40 days) High-titer HIT antibodies High morbidity if not recognized → re-treatment with UFH or LMWH → decrease in platelet counts more → clinical deterioration Delayed-onset HIT

Spontaneous HIT :

Warkentin TE et al. Blood 2014; 123:3651. HIT-like syndrome without prior heparin exposure Positive immunoassay for HIT antibodies Positive functional assay Secondary to infectious or inflammatory event (eg, gram negative bacteremia, orthopedic surgery) Spontaneous HIT

Spontaneous HIT :

Andreas Greinacher . N Engl J Med, July 16, 2015;373:252-61 Spontaneous HIT

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Is it HIT?:

Is it HIT ? Differentiation between HIT and other causes of thrombocytopenia is important

Thrombcytopenia www.NephroTubeCNE.com:

Thrombcytopenia www. N ephro T ube CNE .com

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Treatment General Population - Not on HD:

Treatment General Population - Not on HD Stop Heparin Start non-heparin anticoagulant Whether or not complicated by thrombosis Use therapeutic rather than prophylactic dosing due to the risk of thrombosis associated with HIT, and possibly also for the condition for which heparin was administered originally Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Treatment HD Patients – Special Issues:

Treatment HD Patients – Special Issues Davenport. Semin Dial. 2011;24:382-385.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Available in Egypt 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Davenport. Semin Dial. 2011;24:382-385.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Davenport. Semin Dial. 2011;24:382-385.

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Recombinant H irudin ( L epirudin )

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Recombinant H irudin – RB variant Available in Egypt

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Recombinant H irudin – RB variant

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic Recombinant H irudin – RB variant

Treatment Non Heparin Anticoagulants - Systemic:

Treatment Non Heparin Anticoagulants - Systemic If all systemic anticoagulants are available at you local work area, so the following general approach is preferred Patient condition Best approach Normal renal and hepatic function Any of the alternative anticoagulants can be used Generally use IV argatroban  infusion;  Fondparinux  can be used if there is a need for a subcutaneous agent. Renal insufficiency Argatroban  at therapeutic doses since it is metabolized hepatically . Hepatic impairment Fondaparinux  at therapeutic doses Renal and hepatic impairment Argatroban  or  bivalirudin  at reduced doses.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Treatment Non Heparin Anticoagulants – Extracorporeal HD:

Treatment Non Heparin Anticoagulants – Extracorporeal HD Davenport. Semin Dial. 2011;24:382-385. Available in Egypt

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Treatment Non Heparin Anticoagulants – Catheter Lock:

Treatment Non Heparin Anticoagulants – Catheter Lock Davenport. Semin Dial. 2011;24:382-385 Davenport A. Hemodial Int 4:78–82, 2000 Schenk P, et al. Am J Kidney Dis 35:130–136 , 2000 Willicombe MK , et al. Am J Kidney Dis 55:348–351, 2010 Don’t use heparin for catheter locks or flushes Alternative locks Recombinant tissue plasminogen activator (1–2 mg⁄ml up to 2– 4 mg⁄ lumen) Urokinase (1250–2500 IU⁄ ml) Fondaparinux (1 mg) Lepirudin (1–5 mg ⁄ ml) Hypertonic trisodium citrate (4% or higher concentrations, up to 46% [Citra-Lock]) Taurolidine

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Treatment Thrombocytopenia/HIT-Ab Resolution:

Treatment Thrombocytopenia/HIT- Ab Resolution Warkentin TE, Kelton J. N Engl J Med. 2001;344(17 ):1286

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Transitioning to Warfarin:

Transitioning to Warfarin HIT patients are at risk of venous limb gangrene and skin necrosis during initiation of warfarin . Warfarin should not be initiated until platelet count is ≥ 150 x 109/L (Grade 1C ). Initial warfarin dose should be ≤ 5 mg/day. Larger loading doses should be avoided (Grade 1C). A parenteral non-heparin anticoagulant should be overlapped with warfarin for ≥ 5 days and until INR has reached intended target (Grade 1C ). 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT Linkins LA et al. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e495S.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Duration of anticoagulation:

Duration of anticoagulation For patients with HIT-associated thrombosis (i.e. HITT ), anticoagulate for 3 months. For patients with HIT without thrombosis (i.e. isolated HIT), anticoagulation for up to 4 weeks should be considered.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Platelet transfusion:

Platelet transfusion Prophylactic platelet transfusions should be avoided in patients with HIT. The risk of bleeding is very low, and such transfusions can increase the risk of thrombosis. Platelets should not be given for prophylaxis (1C) but may be used in the event of bleeding (2C ) !!!! Blood 2015; 125: 1470-6.

Talk Outline:

Talk Outline Pathogenesis Presentation Thrombocytopenia Thrombosis Acute systemic reaction Frequency Diagnosis Other HIT Forms Is it HIT? Treatment General Approach Non Heparin Systemic Anticoagulants Non Heparin Extracorporeal Anticoagulants Non Heparin Catheter-Lock Anticoagulants Response to therapy Transformation to Warfarin Duration of Anticoagulation Platelet Transfusion Heparin Re-Challenge

Heparin Re-Challenge:

Heparin Re-Challenge Davenport. Semin Dial. 2011;24:382-385.

Heparin Re-Challenge:

Heparin Re-Challenge Nephron Clin Pract 2006;104:c143–c148 Never Tried Did well for 12 mo Did well for 7 mo Did well for 1 mo Heparin Re-Challenge

Heparin Re-Challenge:

Heparin Re-Challenge 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT

Heparin Re-Challenge:

Heparin Re-Challenge 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected HIT

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Gawad Thank You

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