高亮:Traumatic Brain Injury Associated Coagulopathy

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  • DDimer < 0.5 PT 10.2-15.0 Fibrinogen 214-474 INR of 1.0 indicates 100% and an INR of 1.4-1.6 indicates 40%. I will use an INR of 1.2 to indicate 60% prothrombin activity
  • 高亮:Traumatic Brain Injury Associated Coagulopathy

    1. 1. Dept. of Neurosurgery. Huashan Hospital. Fudan University. Shanghai Neurosurgical emergency center Liang Gao ( 高亮 ) Traumatic Brain Injury Associated Coagulopathy
    2. 3. Case File <ul><li>20 year old, female, student. </li></ul><ul><li>Suffered from traffic accident and loss of consciousness immediately, transferred to local hospital 30’ later, CT scan showed brain swelling, right occipital bone fracture.2009/06/30 </li></ul><ul><li>PE: 3mm, light reflex(+), babinski sign (+) ,GCS13. a </li></ul>
    3. 4. 2009.06.30 2:17PM
    4. 5. 2009.06.30 2:17PM
    5. 7. DIAGONOSIS <ul><li>Mild TBI </li></ul><ul><li>Right skull base fracture </li></ul><ul><li>Small subdural hemorrhage </li></ul><ul><li>t-SAH </li></ul>
    6. 8. DIAGNOSIS- Marshall classification <ul><li>Computed tomography classification system of head injury </li></ul><ul><li>Diffuse injury I No visible pathology seen on CT </li></ul><ul><li>Diffuse injury II Cisterns are present with shift 0-5 mm. No high- or mixed-density lesion >25 cc.May include bone fragments and foreign bodies </li></ul><ul><li>Diffuse injury III (swelling) Cisterns compressed or absent. Shift 0-5 mm. No high- or mixed-density lesion >25 cc </li></ul><ul><li>Diffuse injury IV (shift)-Shift >5 mm. No high- or mixed-density lesion >25 cc </li></ul><ul><li>Evacuated mass lesion -Any lesion surgically evacuated </li></ul><ul><li>Nonevacuated mass lesion-High- or mixed-density lesion >25 cc not surgically evacuated </li></ul>HIGH RISK !!!!!
    7. 9. 2009.07.01 <ul><li>Coma, GCS decrease to 9, pupil diameter 3mm in both sides, light reflex (+), babinski sign in both sides (+); </li></ul>
    8. 10. 2009.07.01 18:15PM
    9. 11. 2009.07.02 11:12PM
    10. 12. 2009.07.02 11:12PM
    11. 13. Initial management <ul><li>GCS decreased to 7 </li></ul><ul><li>Pupil 3mm, light reaction(+) </li></ul><ul><li>Dehydration </li></ul><ul><li>DIC management </li></ul>
    12. 14. 2009.07.03 10:41AM
    13. 15. <ul><li>Continuous CSF drainage via lumbar puncture !??? </li></ul><ul><li>GCS decreased to 3. </li></ul><ul><li>Pupils 1mm, light reaction (+/-) </li></ul><ul><li>Ventilator support </li></ul>
    14. 16. Traumatic Coagulapathy <ul><li>Mechanism </li></ul><ul><li>Diagnosis </li></ul><ul><li>Management???? </li></ul>
    15. 17. 2009.07.04 0:45AM
    16. 18. 2009.07.07 10:12AM
    17. 19. 2009.07.09 0:04AM
    18. 20. Transfer to Shanghai 2009.07.10 <ul><li>GCS3, High fever, support with ventilalar </li></ul><ul><li>SOS </li></ul><ul><li>Reasons </li></ul><ul><li>????? </li></ul>
    19. 21. 二 00 九年七月十三日
    20. 22. 二 00 九年七月十三日
    21. 23. 2009.07.20
    22. 24. 2009.08.20
    23. 29. Coagulopathy and TBI <ul><li>Concepts of hemostasis </li></ul><ul><li>Coagulopathy in traumatic brain injury </li></ul><ul><li>Review some treatments for TBI associated coagulopathy </li></ul>
    24. 30. Coagulopathy and TBI <ul><li>Primary hemostasis </li></ul><ul><li>Initial clot </li></ul><ul><li>Function of platelets </li></ul><ul><li>Secondary hemostasis </li></ul><ul><li>Thrombin generation via the coagulation cascade </li></ul><ul><li>Cross-linking of fibrin </li></ul><ul><li>Fibrinolysis </li></ul><ul><li>Activation of Plasminogen to Plasmin </li></ul><ul><li>tPA </li></ul>
    25. 31. Coagulation Cascade
    26. 32. Cell-based Model of Hemostasis Components Endothelial Injury Tissue Factor release Thrombin generation Platelet activation Coagulation factor activation Mathews Neurocritical Care , 2006
    27. 33. Coagulopathy and TBI <ul><li>Coagulopathy is common in TBI </li></ul><ul><li>Dilutional </li></ul><ul><li>Pre-existing coagulation abnormalities </li></ul><ul><li>Anticoagulant use </li></ul><ul><li>Warfarin, ASA, NSAIDS, Plavix </li></ul><ul><li>Hypothermia (30-34 degrees) </li></ul><ul><li>Increased fibrinolysis </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Impaired platelet function </li></ul>
    28. 34. Coagulopathy Score SCORE PT(S) aPTT ( S ) Platelet Fibrinogen ( mg/dl ) D-dimer (ng/ml ) 1 <13.5 28~41 > 150 > 180 < 1000 2 >=13.5 <28, >41 ≦ 150 ≦ 180 < 2000 3 >15 ≦ 24, ≧ 46 ≦ 100 ≦ 150 <4000 4 >18 ≧ 61 ≦ 60 ≦ 100 ≧ 4000
    29. 35. Scoring system for diagnosing DIC Prothrombin Index: the percentage of the present prothrombin complex to its normal level
    30. 38. Time course of coagulopathy in isolated s-TBI
    31. 39. Coagulopathy and TBI <ul><li>Coagulopathy is more frequent in TBI </li></ul><ul><li>Review of 276 Isolated head injury on CT had a 17% rate of coagulopathy. </li></ul><ul><li>Coagulopathy is highly associated with poor outcome in TBI. </li></ul><ul><li>Review of 8K TBI pts revealed elevated INR to be a powerful independent prognostic sign of poor outcome. </li></ul><ul><li>Coagulopathy is highly associated with DTICH. </li></ul><ul><li>Murray, Steyerberg et al, J Neurotrauma, 2007 </li></ul><ul><li>Zehtabchi,Sinert et al, Resuscitation, 2008 </li></ul>
    32. 40. Coagulopathy and TBI <ul><li>TBI induced coagulopathy </li></ul><ul><li>Injury mediated release of Tissue Factor </li></ul><ul><li>Related to amount of tissue injured </li></ul><ul><li>Fibrinolysis abnormalities </li></ul><ul><li>Hypocoagulable state </li></ul><ul><li>Increase in size of intracranial hemorrhage </li></ul><ul><li>Hypercoagulable state </li></ul><ul><li>Increase in microthrombosis causing local ischemia </li></ul>
    33. 41. TBI and Platelet Dysfunction <ul><li>Compared to non - TBI trauma and healthy volunteers, TBI patients had: </li></ul><ul><li>Platelet count lower (180 vs 230 and 256) </li></ul><ul><li>Longer bleeding time (674 s vs 350/320 s) </li></ul><ul><li>Diminished platelet function using thromboelastography </li></ul>
    34. 42. TBI and Hypoperfusion <ul><li>Challenge to concept that TF release is source of TBI coagulopathy. </li></ul><ul><li>Prospective cohort study (n=39) </li></ul><ul><li>AIS of brain ,Protein C, Thyromodulin (Anticoagulants) PT, PTT,ABG(BD>6) </li></ul><ul><li>Cohen, Pittett et al, J of Trauma, Dec 2007 </li></ul>
    35. 43. TBI and Hypoperfusion <ul><li>28 of 39 with normal BD </li></ul><ul><li>None developed coagulopathy </li></ul><ul><li>11 of 39 with BD >6 </li></ul><ul><li>Elevated INR </li></ul>
    36. 44. TBI and Hypoperfusion <ul><li>Increasing brain AIS had little effect on PT/PTT. </li></ul>Cohen, Pittett et al, J of Trauma, 2007
    37. 45. TBI and Hypoperfusion <ul><li>Increasing brain AIS had little effect on Protein C or Thrombomodulin . </li></ul>Cohen, Pittett et al, J of Trauma, 2007
    38. 46. TBI and Hypoperfusion <ul><li>Increasing base deficit had significant effect on PT/PTT. </li></ul>Cohen, Pittett et al, J of Trauma, 2007
    39. 47. TBI and Hypoperfusion <ul><li>Increasing base deficit had significant effect on Protein C and Thyromodulin (anticoagulants). </li></ul>Cohen, Pittett et al, J of Trauma, 2007
    40. 48. TBI and Hypoperfusion <ul><li>Hypoperfusion may be significant contributor to coagulopathy in TBI. </li></ul><ul><li>Give additional support to hypotension worsens outcome in why TBI. </li></ul><ul><li>Adequate and early resuscitation field as well as the ED is critical. </li></ul>
    41. 49. Warfarin and TBI <ul><li>TBI in patients using warfarin. </li></ul><ul><li>ICH in warfarin users had 48% mortality. </li></ul><ul><li>Compared to ICH w/o warfarin mortality of 10%. </li></ul>
    42. 50. Warfarin and TBI <ul><li>All trauma patients on warfarin were quickly evaluated and treated by protocol with 4-6 units FFP . </li></ul>
    43. 51. Warfarin and TBI <ul><li>Protocol driven warfarin reversal decreased time to INR correction (INR <1.6). </li></ul>
    44. 52. Warfarin and TBI <ul><li>Protocol driven warfarin reversal decreased incidence of ICH progression . </li></ul>
    45. 53. Warfarin and TBI <ul><li>Protocol driven warfarin reversal decreased mortality from 48% to 10% . </li></ul>Both deaths in the treatment group had >10 hour delay in initiation due to transfer issues
    46. 54. Warfarin-related hemorrhage
    47. 55. Warfarin-related hemorrhage <ul><li>Warfarin doubles ICH mortality. </li></ul><ul><li>Warfarin increases risk of hematoma expansion. Bleeding continues </li></ul><ul><li>over a longer period. </li></ul>Flibotte et al. Neurology , 2004
    48. 56. Warfarin and TBI <ul><li>Increasing use of warfarin for stroke prevention in elderly </li></ul><ul><li>Less studied than warfarin-related non- traumatic ICH </li></ul><ul><li>Progression of hematoma common, even when initially small </li></ul><ul><li>Progression increases mortality risk </li></ul><ul><li>Reversal seems to decrease progression </li></ul><ul><li>No randomized trials </li></ul><ul><li>What’s the smallest amount of traumatic intracranial hemorrhage that doesn’t need to be reversed? Location specific ? </li></ul>
    49. 57. Warfarin and TBI Ivascu Journal of Trauma 2005
    50. 58. FFP REVERSAL PROTOCAL INR corrected within 24 hours (< 1.4) – Shorter median time to FFP initiation (90 v. 210 min) – 12 of 69 (17%) not reversed by 24 hours This experience neither unique nor acceptable Logistics of FFP or reversal agent itself?
    51. 59. Coagulopathy Reversal <ul><li>Principle : </li></ul><ul><li>any intracranial hemorrhage in patient on warfarin (with INR > 1.4) should be considered “life-threatening”. </li></ul><ul><li>Goal – normalize coagulation </li></ul><ul><li>– (not hypercoaguable) </li></ul><ul><li>– Practical approach: normal INR ASAP </li></ul>
    52. 60. Warfarin Reversal Agents <ul><li>Warfarin </li></ul><ul><li>– Vitamin K antagonist </li></ul><ul><li>– Vit K is cofactor in g –carboxylation of coagulation factors II, VII, IX, X (and Pro C & S) </li></ul><ul><li>Options </li></ul><ul><li>– Directly compete by giving Vitamin K </li></ul><ul><li>– Replace native coagulation factors (FFP, PCC) </li></ul><ul><li>– Bypass central part of coagulation cascade (rVIIa) </li></ul><ul><li>Schulman. Anticoagulants and their reversal. Transfusion Medicine Reviews 21;2007 </li></ul><ul><li>Steiner. Intracerebral hemorrhage associated with oral antiocoagulant therapy. Stroke 37;2006 </li></ul>
    53. 61. Vitamin K <ul><li>Oral or parenteral </li></ul><ul><li>Plasma half-life 1.5-3 hours </li></ul><ul><li>Full effect at 12-24 hours after administration </li></ul><ul><li>Dose – 10 mg oral, sc, or IV </li></ul><ul><li>Cost -cheap </li></ul><ul><li>Utility for urgent warfarin reversal – poor </li></ul><ul><li>Due to short duration of other replacement agents should be given as part of all reversal protocols </li></ul>
    54. 62. Fresh Frozen Plasma <ul><li>“ Standard approach” </li></ul><ul><li>All coagulation factors in non-concentrated form </li></ul><ul><li>Must do: ABO compatibility testing, Thawing (~20 min) </li></ul><ul><li>Difficult to give enough volume to correct INR > 5 </li></ul><ul><li>Volume load (800-3500 ml for full correction) </li></ul><ul><li>Cost – moderate, ~200 cc unit </li></ul><ul><li>Utility for urgent warfarin reversal – poor due to logistics (time and volume) </li></ul><ul><li>Should still probably be given as part of all reversal protocols because it contains all factors </li></ul>
    55. 63. Prothrombin Complex Concentrate <ul><li>Dry preparation – ~20 min to reconstitute; no compatibility testing or thawing </li></ul><ul><li>At least 16 different preps worldwide </li></ul><ul><li>Some with relatively less VII or IX </li></ul><ul><li>Dose – various recs 30-50 IU/kg; single bolus dose (~50 ml) </li></ul><ul><li>Cost – expensive </li></ul><ul><li>Utility for urgent warfarin reversal – good </li></ul><ul><li>Problems – availability; risk of thrombosis; </li></ul><ul><li>viral reduction does not eliminate prions </li></ul>
    56. 64. rFVIIa <ul><li>Off-label use </li></ul><ul><li>Works in non-warfarin ICH? </li></ul><ul><li>Rapid reconstitution, low volume </li></ul><ul><li>Dose - ???, reports have used 5-320 µg/kg </li></ul><ul><li>Cost – very expensive </li></ul><ul><li>Utility for urgent warfarin reversal – good </li></ul><ul><li>• Problems – risk of thrombosis, INR correction without eliminating bleeding risk (thromboelastography better?) </li></ul>
    57. 65. rFVIIa in TBI <ul><li>Level I trauma, retrospective, 4 years. </li></ul><ul><li>681 severe TBI patients. </li></ul><ul><li>63 initially coagulopathic (INR >1.4) . </li></ul><ul><li>29 received rFVIIa vs. 34 no rFVIIa. </li></ul><ul><li>Mean age, ISS, GCS, INR </li></ul>Stein, Scalea et al, J Trauma, 2008
    58. 66. rFVIIa in TBI <ul><li>Time to intervention (median) </li></ul><ul><li>rFVIIa 144 minutes </li></ul><ul><li>no rFVIIa 446 minutes (p = 0.0003) </li></ul>Stein, Scalea et al, J Trauma, 2008
    59. 67. rFVIIa in TBI <ul><li>FFP given prior to intervention (median) </li></ul><ul><li>rFVIIa 2 </li></ul><ul><li>no rFVIIa 6 (p = 0.0006) </li></ul>Stein, Scalea et al, J Trauma, 2008
    60. 68. rFVIIa in TBI <ul><li>Mortality in isolated TBI </li></ul><ul><li>rFVIIa 33.3% </li></ul><ul><li>no rFVIIa 52.9% (p = 0.24) </li></ul>Stein, Scalea et al, J Trauma, 2008
    61. 69. rFVIIa in TBI <ul><li>Thromboebolic comlictions </li></ul><ul><li>rFVIIa --6 </li></ul><ul><li>no rFVIIa --6 (p= 0.759 ) </li></ul>Stein, Scalea et al, J Trauma, 2008
    62. 70. Guidelines for Warfarin Reversal <ul><li>US - Chest 133 (Suppl 175S), 2008: </li></ul><ul><li>In patients with life-threatening bleeding “hold warfarin therapy and give FFP, PCC, or rVIIa supplemented with vitamin K (10 mg by slow IV infusion). Repeat, if necessary, depending on INR (Grade 1c).” </li></ul>
    63. 71. Reversing heparin <ul><li>Unfractionated heparin </li></ul><ul><li>– Acts at IIa/Xa </li></ul><ul><li>– Protamine 1 mg per 100 U heparin received within last 2 hours (max 50 mg) </li></ul><ul><li>Low molecular weight heparin </li></ul><ul><li>– Acts at Xa </li></ul><ul><li>– No direct reversal agent </li></ul><ul><li>Protamine 1 mg per 1 mg enoxaparin received within past 8 hours (max dose 50 mg)? </li></ul><ul><li>Check factor Xa level </li></ul><ul><li>-rFVIIa? Few case reports </li></ul><ul><li>Direct thrombin inhibitors (e.g argatroban) </li></ul><ul><li>– No reversal agent </li></ul>
    64. 72. Antiplatelet Agents <ul><li>Extremely widely used agents – ASA, clopidogrel, ASA + DP </li></ul><ul><li>ICH – the word is still out </li></ul><ul><li>– Studies conflict regarding impact on hematoma growth and outcome---- Independent predictor of death, likely due to hematoma enlargement </li></ul><ul><li>--No effect on outcome or hematoma expansion in </li></ul><ul><li>CHANT placebo group </li></ul><ul><li>TBI – even less known than with ICH </li></ul><ul><li>– May be associated with ongoing bleeding and ↑ mortality, esp in elderly </li></ul><ul><li>– Everybody’s afraid of clopidogrel and surgery </li></ul>Saloheimo Stroke 2006; Neurology 2009
    65. 73. Antiplatelet agents – What to Do? <ul><li>You get to pick </li></ul><ul><li>1. Nothing </li></ul><ul><li>2. Give platelet transfusion </li></ul><ul><li>3. Give DDAVP </li></ul><ul><li>4. Give rFVIIa </li></ul><ul><li>5. Check platelet function assay and do 2/3/4 if abnormal </li></ul><ul><li>6. Check bleeding time and do 2/3/4 if abnormal </li></ul><ul><li>7. Rescan and do 2/3/4 if hematoma expands </li></ul><ul><li>8. Check platelet function assay (PFA-10 ) </li></ul>
    66. 74. TBI-induced Coagulopathy <ul><li>TBI-initiated consumptive coagulopathy (DIC) </li></ul><ul><li>– Balance between thrombosis and hemostasis </li></ul><ul><li>– Acutely, hemostasis and prevention of ongoing bleeding is priority </li></ul>
    67. 75. INR & TBI craniotomy <ul><li>Methods: We performed a 2-year (2005-2006) retrospective study of adult blunt trauma patients with traumatic brain injury who presented coagulopathic (international normalized ratio [INR] >1.3) and required emergent craniotomy. We compared patients who did (rFVIIa group) and did not (no-rFVIIa group) receive rFVIIa to correct coagulopathy before craniotomy . </li></ul>Brown et al. Recombinant Factor VIIa for the Correction of Coagulopathy Before Emergent Craniotomy in Blunt Trauma Patients. Journal of Trauma-Injury Infection & Critical Care,2010
    68. 76. INR & TBI craniotomy <ul><li>METHODS: The clinical and laboratory features of a prospectively followed up case-series of 15 patients with traumatic ICB (mainly isolated SDHs) and coagulopathy (INR) >1.3 treated with rFVIIa in our institution are presented, along with a review of the literature regarding the role of rFVIIa in neurosurgical patients with ICB. </li></ul><ul><li>RESULTS: All 15 patients suffered a SDH (4 of 15 had a combined ICB) and coagulopathy (mean INR, 2.34 +/- 0.83; thrombocytopenia rate, 20%), which was attributed to anticoagulants in 46.7%. The mean INR decreased to 1.5 +/- 0.14 after standard therapy and 0.92 +/- 0.1 after rFVIIa therapy. </li></ul>Bartal C. J Trauma. 2007 Oct;63(4):725-32.
    69. 77. rFVIIa INR & emergency Craniotomy <ul><li>METHODS: nine patients with coagulopathy requiring urgent neurosurgical intervention were reviewed retrospectively. Each patient was given a dose ranging from 40 to 90 microg/kg of rFVIIa before undergoing surgery. Pre-rFVIIa coagulation and post-rFVIIa coagulation parameters were obtained. Once correction of the coagulopathy was verified, each patient underwent the appropriate neurosurgical procedure. 20 minutes after infusion of the medication showed normalization of values. </li></ul>Park P. Neurosurgery. 2003 Jul;53(1):34-8;
    70. 78. INR & TBI craniotomy <ul><li>METHODS: The trauma registry was used to identify patients with severe TBI who were admitted during a 4-year period and were coagulopathic at admission (international normalized ratio, INR >/=1.4) and required a neurosurgical procedure. </li></ul>Stein. J Trauma. 2008 Mar;64(3):620-7;
    71. 79. Coagulopathy & PLT <ul><li>PLT </li></ul>
    72. 80. 谢谢!

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