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1. Heparin-Induced
Thrombocytopenia (HIT)
Renal Perspective
Mohammed Abdel Gawad
Nephrologist
Alexandria – EGY
NephroTube Chairman
drgawad@gmail.com

3. 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
• Clinical evidence of thrombosis
(DVT)
• All causes of thrombocytopenia
are excluded
• A diagnosis of HIT is confirmed
HIT = Heparin exposure + Thrombocytopenia ± Thrombosis

4. 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

21. 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

22. 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
Platelets count
Most of patients
Thrombocytopenia
+
Fall in platelet
count  50%
+
clinical evidence of
HIT
10% of patients
Thrombocytopenia
+
Fall in platelet
count 30-50%
+
clinical evidence of
HIT
5% of patients
No Thrombocytopenia
But
Fall in platelet count
30-50%
+
clinical evidence of HIT

23. 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)

24. 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
Definition of HD-HIT may be
less strict, in the range of a
>30% fall in the platelet count
and below 150×109 /L

25. 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

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

27. • Clotting of the dialysis lines and/or dialyzer
(visible 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.

28. 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

29. 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

30. 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.

31. 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

32. 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

33. 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

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

35. 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.

36. 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).

37. 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

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

39. Andreas Greinacher. N Engl J Med,
July 16, 2015;373:252-61 Diagnosis
4T’s Score

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

41. • Very high negative predictive value (97 to 99%)
• Positive 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

42. Diagnosis
HD Patients – Special Issues
Chronic heparin exposure → high incidence of heparin-induced
antibodies (the clinical significance of which is uncertain)
740 patients (HD & PD)
1st 90 days: heparin-induced antibodies by immunoassay in 20%
By 6 months: 9% of patients had antibodies
9 % (1.2%) patients develop clinical HIT
during the study
Asmis LM et al. Thromb Haemost 2008; 100:498.

43. Diagnosis
HD Patients – Special Issues
Chronic 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

44. 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

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

46. 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

47. 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

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

49. 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

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

51. Thrombcytopenia
www.NephroTubeCNE.com

52. 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

53. 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.

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

55. 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

56. 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.

57. 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.

58. 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.

59. 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.

60. 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.

61. 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.

62. 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.

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

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

65. Treatment
Non Heparin Anticoagulants - Systemic
Recombinant Hirudin (Lepirudin)

66. Treatment
Non Heparin Anticoagulants - Systemic
Recombinant Hirudin – RB variant
Available
in Egypt

67. Treatment
Non Heparin Anticoagulants - Systemic
Recombinant Hirudin – RB variant

68. Treatment
Non Heparin Anticoagulants - Systemic
Recombinant Hirudin – RB variant

69. 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.

70. 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

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

72. 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

73. 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

74. 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

75. Treatment
Thrombocytopenia/HIT-Ab Resolution
Resolution of thrombocytopenia
following withdrawal of heparin
typically occurs within 7 days
If no improvement within 3-4 days of
heparin withdrawal → Check continued
exposure to heparin or an additional
cause of thrombocytopenia
Warkentin TE, Kelton J. N Engl J Med. 2001;344(17):1286
HIT antibodies can
persist for 2-3
months, depending
on the assay used to
detect them

76. 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

77. 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.

78. 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

79. 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.

80. 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

81. 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.

82. 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

83. Heparin Re-Challenge
Davenport. Semin Dial. 2011;24:382-385.
HIT antibodies disappear with the passage of time
If on retesting both functional and ELISA assays remain
negative
Patients can be cautiously re-challenged with heparins, with
appropriate monitoring

84. 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

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

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

87. Thank You