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Acute Leukemia and Intracerebral Hemorrhage

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Acute Leukemia and Intracerebral Hemorrhage Powered By Docstoc
					Acute Leukemia and
   Intracerebral
   Hemorrhage
     Tanya Wildes
     April 22, 2006
Disclosure: Tanya Wildes,
          M.D.
Dr. Tanya Wildes has no relevant financial
          interests to disclose.
  Disclosure: <insert name>,
             M.D.
Tanya Wildes, M.D. has financial interests to
disclose. Potential conflicts of interest have been
resolved.
    Research Support / Grants          None
    Stock/Equity (any amount)          None
    Consulting / Employment            None
    Speakers Bureau / Honoraria        None
    Other                              None
                                                      3
                     Case #1
   31 year old female with AML M5 presents with
    neutropenic fevers after her first cycle of
    consolidation chemotherapy.
   She also complains of intermittent headaches
    since she underwent intrathecal chemotherapy
    two weeks ago. Headaches are aching, bifrontal,
    worse when supine.
                    Case #1
   Physical Exam
     Temp 38.6 P 116
     Neuro exam was nonfocal

   Labs:
     WBC 0.1
     Hgb 9.3
     Plt 22
     PT 15.3
     PTT 36.0
Brain MRI
                       Case #1
   MRI demonstrates parenchymal hemorrhage left frontal
    lobe that measures 10 x 7 mm x 7 mm.
   Neurosurgery was consulted; they recommended
    transfusion of platelets with goal platelet count over
    100,000.
   Neutropenic fevers were treated with cefepime and
    supportive care.
   Follow-up head CT two weeks later showed no increase
    in the size of hemorrhage.
   The patient was discharged home once neutropenic
    fevers resolved.
                      Case #2
   42 year old female with       Initial labs:
    HTN, DM presented                 WBC 218.4
    with 1 week of headache.          Hgb 9.7
   No history of trauma.             Platelet 20
   She was conversant and            PT 19.0
    neurologically intact             PTT 39.9
    upon arrival to ED.
Head CT
             Head CT
  IMPRESSION:
1. SMALL (10.7 x 8.5 mm) PARENCHYMAL
   HEMORRHAGE AT THE LEFT PARIETAL
   GREY-WHITE MATTER JUNCTION.
2. SUGGESTION OF VERY MILD EDEMA IN
   LEFT HEMISPHERE WITH 5MM
   MIDLINESHIFT TOWARDS THE RIGHT.
                    Case #2
   Patient was transferred to BJH BMT service.
   On arrival, patient was conversant with normal
    vital signs.
   Peripheral smear revealed abundant blasts, some
    with bilobed nuclei, minimal granulation,
    occasional auer rods.
                      Case #2
   Neurosurgery was consulted.
   They recommended correction of her
    thrombocytopenia and coagulopathy.
    Within 3 hours of arrival, the patient’s level of
    consciousness declined.
   She was intubated for airway protection.
   A repeat head CT was performed.
Head CT
                      Head CT
   FINDINGS:
   Intraparenchymal hemorrhage in the right parietal lobe
    has intervally increased in size, measuring
    approximately 5 cm x 3.3 cm with extensive
    surrounding vasogenic edema.
   Interval development of a new, smaller foci of
    intraparenchymal hemorrhage within the bilateral
    frontal lobes and right temporal lobe, as well.
   Mass effect upon the left ventricle, with near
    effacement of the temporal and occipital horns. There
    is slight rightward midline shift.
                    Case #2
   Neurosurgery then recommended recombinant
    activated factor VII.
   Despite aggressive medical intervention, the
    patient expired within hours of her initial
    presentation.
             Patient 1        Patient 1     Patient 2
             (at diagnosis)   (at time of
                              hemorrhage)
WBC          249.7            0.1           218.4    297
Plt          64               22            20
PT           21.4             15.3          19.0    22.4
INR          1.75             1.16          1.55    1.85
PTT          46.1             36.0          39.9
Fibrinogen   138                            90
Uric Acid    10.1                           5.9
             Clinical questions
   How common is intracranial hemorrhage among
    leukemia patients?
   What clinical factors account for differences in
    severity of intracranial hemorrhage?
   Is there evidence to support the use of
    recombinant factor VII in our patient
    population?
      Fatal Intracranial Hemorrhage in
                 Blast Crisis
                                                    NEJM 1957
    Case series N=100
    81 deaths
    18 deaths due to intracranial hemorrhage (22%)


Cause of death WBC >300                                       WBC<300
ICH                            9 (69%)                        9 (13%)                        18 p<0.001
Other                          4                              59                             63
                               13                             68                             81
Fritz, RD, et al. The association of fatal intracranial hemorrhage and “blastic crisis” in patients with acute leukemia.
NEJM 1959; 261(2): 59-64.
    Fatal Intracranial Hemorrhage in
               Blast Crisis
                                  NEJM 1957

                          WBC > 300                     WBC <300

>90% blasts               8/9 (89%)                     2/9 (22%)      P = 0.015


Platelet                  Range 8-205                   Range 4-10      P<0.01


Other sites of bleeding   4/9 (44%)                     9/9 (100%)      P = 0.03


Uric Acid                 10.5                          3.8   P<0.05


Time from diagnosis to    6 weeks (0-14 months)         11 months (3-15 months)
hemorrhage                                              P<0.05

Autopsy                   Leukemic nodules associated   Subdural or subarachnoid
                          with intraparenchymal         hemorrhage
                          hemorrhages in white matter
       ICH in the contemporary era
   Autopsy series of 3426 patients with non-CNS
    cancer
      453 patients with leukemia were autopsied
      69/453 (15.2%) patients with leukemia had ICH
            71% of ICH were symptomatic
            7% (9/129) of ALL patients had ICH
                    55.5% were petechial or small hemorrhages
              22.4% (43/192)of AML patients had ICH
                    23.3% were petechial or small hemorrhages


Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine 1985; 64(1): 16-35.
                               Symptoms
   Petechial or small (<2cm) hemorrhages
        Usually asymptomatic
   Large (>2cm) hemorrhages
        Single
             Acute headache, vomiting, focal deficits, obtundation,
              transtentorial herniation
        Multiple
             Sudden lethargy without focal deficits


Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine 1985;
64(1): 16-35.
Hemorrhage               without CNS              with CNS leukemic infiltration
                           leukemic
                                             Parenchymal             Meningeal
                          infiltration
                                             infiltrates with        involvement without
                                             leukostasis             leukostasis
# patients            50                     13                      6

# symptomatic 38 (76%)                       8 (61%)                 3 (50%)

Hemorrhage at 7 (18.4%)                      5 (62.5%)               0
diagnosis     (86% APL)
Fever                 68.4%                  37.5%                   100%

WBC                   8 (0.1-104)             No median given   (70- 36 (1-97)
                                             730)
Plt                   13.5 (2-52)            36 (10-50)              32 (3-65)
Multiple hematomas    12%                    62.5%                   16.6%
Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine 1985;
64(1): 16-35.
                          Summary
   Patients with high WBC count at diagnosis and
    hemorrhage tend to have higher platelet counts and
    multiple hemorrhages.
       Pathophysiology likely related to leukemic infiltration with
        ischemic, hypoxic vasodilation and vessel rupture.
   Patients who develop hemorrhage after diagnosis tend
    to do so in the setting of sepsis, fever and marked
    thrombocytopenia; they tend to have solitary
    hemorrhages.
       Pathophysiology likely related to multiple abnormalities of
        coagnulation.
                 Subdural Hematoma
   25/453 (5.5%) patients with leukemia suffered
    subdural hematomas
      Acute confusion and lethargy were the presenting
       signs on all patients
      Thrombocytopenia with or without DIC and sepsis
       were present in all patients with leukemia and SDH
      None were diagnosed pre-mortem

      3/25 had meningeal leukemic infiltration



Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine 1985;
64(1): 16-35.
                         Treatment
   Randomized controlled trials:
       rFVIIa for intracranial hemorrhage in patients with normal
        coagulation parameters
       rFVIIa for bleeding following hematopoietic stem cell
        transplantation
   Prospective:
       Bleeding times after rFVIIa in thrombocytopenic patients
   Case reports:
       rFVIIa for intracranial hemorrhage in patient with refractory
        ITP
       rFVIIa for subdural hemorrhage in AML patient with platelet
        alloimmunization
                                       Treatment
      RCT: rFVIIa in intracranial hemorrhage
   N=399                                                    Exclusion criteria
   Inclusion criteria                                             Thrombocytopenia
        Age >18                                                   Coagulopathy or DIC
        ICH documented by CT                                      Sepsis
         within 3 hours of                                         Planned surgical
         symptom onset                                              evacuation
                                                                   Known AVMs, trauma,
                                                                    aneurysm
                                                                   Use of oral anticoagulants
                                                                   Thrombosis (MI, DVT,
                                                                    CVA) within 30 days

Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352(8): 777-785.
                                       Treatment
      RCT: rFVIIa in intracranial hemorrhage
   Intervention
        Patients randomized to 40 mcg/kg rFVIIa, 80 mcg/kg rFVIIa, 160
         mcg/kg rFVIIa or placebo
        Dose was given within 1 hour of CT scan and no more than 4 hours after
         symptom onset
   Endpoints
        Hematoma size by head CT at 24 hours and 72 hours
        Clinical Assessment
              Glasgow Coma Scale
              Rankin Scale: global outcomes
              National Institutes of Health Stroke Scale: neurologic impairment
              Barthel Index: activities of daily living
              Extended Glasgow Outcomes Scale: ability for self-care and independence


Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352(8): 777-785.
                                       Treatment
      RCT: rFVIIa in intracranial hemorrhage




Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352(8): 777-785.
                                       Treatment
      RCT: rFVIIa in intracranial hemorrhage
   Results:
        Clinical Outcomes
            Mortality in placebo arm 29% vs 18% in treatment arm
            Patients treated with rFVIIa showed dose-dependent
             improvement in outcomes on all four outcomes scales
             (Rankin Scale, National Institutes of Health Stroke Scale,
             Barthel Index and Extended Glasgow Outcomes Scale).
            Thromboembolic events occurred in 2% of placebo
             treated patients and 7% of rFVIIa treated patients


Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. NEJM 2005; 352(8): 777-785.
rFVIIa in thrombocytopenic patients
   Mayer study of rFVIIa in intracerebral
    hemorrhage patients may not be applicable to
    our patients as they excluded patients with
    thrombocytopenia, coagulopathy and sepsis.
   What evidence is there for efficacy of rFVIIa in
    thrombocytopenic patients?
                       Treatment
              rFVIIa in thrombocytopenia
   N=74
       Group A: 47 patients with decreased platelet
        production
       Group B: 27 patients with immune destruction

   Dose: 50mcg/kg or 100mcg/kg
   Positive response: Decrease in Bleeding time >2
    minutes between 2 hours before and 30 minutes
    after rFVIIa

Kristensen, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis
1996; 26S1:159-164.
                       Treatment
              rFVIIa in thrombocytopenia
Platelet Count                                             Positive Response

<20 x 10^9/l                                               12/37 (32%)

21-39 x 10^9/l                                             15/27 (56%)

>40 x 10^9/l                                               28/41 (68%)

Overall                                                    55/105 (52%)

Kristensen, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis
1996; 26S1:159-164.
                       Treatment
              rFVIIa in thrombocytopenia
   Median reduction in bleeding time
         Decreased platelet production: 14 minutes
         Increased platelet destruction: 5 minutes
   8 patients had thrombocytopenia and active bleeding
         Bleeding stopped in 6 patients
   Theory:
         Though thrombocytopenic patients have an intact intrinsic
          coagulation pathway, exogenous FVIIa ensures that the few
          platelets available are maximally activated.


Kristensen, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis
1996; 26S1:159-164.
                                         Treatment
 rFVIIa in hematopoietic stem cell transplant
              patients with bleeding
 Prospective, randomized trial of patients
  undergoing autologous or allogeneic transplant
 N=100
 Inclusion: Mild bleeding (score 2) x 3 days or
  severe to serious bleeding (score 3 or 4)
 Exclusion: atherosclerotic disease, stroke or
  DVT within 3 months, DIC, thrombotic
  microangiopathy, VOD, active AML M3, M4 or
  M5 or recent granulocyte infusion.
Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic
stem cell transplantation. 2005; 3:1935-1944.
                                         Treatment
 rFVIIa in hematopoietic stem cell transplant
             patients with bleeding
 Treatment:
       rFVIIa dose 40, 80 or 160 mcg/kg or placebo IV q 6
        hours x 6 doses
       “Standard management practices”
             RBC transfusion if Hgb<8
             Platelet transfusion if plt <20x 10^9

             If diffuse alveolar hemorrhage or hemorrhagic cystitis,
              platelets were transfused if <75 x 10^9
             Use of antifibrinolytic agents was discouraged


Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic
stem cell transplantation. 2005; 3:1935-1944.
                                         Treatment
 rFVIIa in hematopoietic stem cell transplant
              patients with bleeding
 Primary endpoint: change in bleeding score 2
  hours after final dose of rFVIIa
 Secondary endpoints:
       change in bleeding score at 24, 48, 72 and 96 hours
        after initial dose
       RBC, platelet and FFP transfusion requirements
        during 96 hour follow-up


Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic
stem cell transplantation. 2005; 3:1935-1944.
                                         Treatment
        RCT: rFVIIa in hematopoietic stem cell
          transplant patients with bleeding




Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic
stem cell transplantation. 2005; 3:1935-1944.
                                         Treatment
        RCT: rFVIIa in hematopoietic stem cell
          transplant patients with bleeding




Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic
stem cell transplantation. 2005; 3:1935-1944.
                                          Treatment
       Case report: rFVIIa in ITP patient with ICH
      16 y.o. F with ITP refractory to IVIg, steroids,
       cyclophosphamide anti-CD20 and anti-TNFalpha monoclonal
       antibiodies
      Presented with severe headache, N/V x 36 hours; no trauma.
      Platelet count - 4 x 10^9
      HCT demonstrated large intraparenchymal hemorrhage.
      Treated with platelet transfusion, FFP, IV tranexamic acid.
      Started on rFVIIa 122mcg/kg q 2 hours, weaned to q 8 hours,
       then q day x 5 days.
      Despite transfusion of 98 u of plt, highest platelet count was 35.
      Serial neuro-imaging demonstrated no further hemorrhage. She
       was discharged after 3 weeks with no residual neurologic deficits.

Barnes, C. Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia
unresponsive to platelet-enhancing treatment. Transfusion Medicine 2005; 15: 145-150.
                                     Treatment
 Case report: rFVIIa in platelet refractory AML
                 patient with ICH
 27 y.o. F with MDS evolved into AML. She was
  refractory to platelets at time of induction
  chemotherapy
 Day +7: Subdural Hemorrhage
       Treated with tranexamic acid and platelet transfusion
   Day +21: Head CT with stable hematoma
   Day +23: hemoptysis, periorbital hematoma
   Day +27: left hemiparesis; head CT
    demonstrated progression of SDH
Vidarsson B. Recombinant Factor VIIa for bleeding in refractory thrombocytopenia. Thromb Haemost 2001;
83:634-5.
                                     Treatment
Case report: rFVIIa in platelet refractory AML
              patient with ICH
   Day +32-33: rFVIIa 100 mcg/kg q 2 hours x 5
    doses, then q4 hours x 6 doses.
   Day +33: headache resolved, periorbital
    hematomas stable, no left sided weakness
   Patient had no further bleeding for remainder of
    her course.
   Patient died on Day +81 of persistent disease.

Vidarsson B. Recombinant Factor VIIa for bleeding in refractory thrombocytopenia. Thromb Haemost 2001;
83:634-5.
                       Summary
   Intracerebral hemorrhage is common in acute
    leukemia
     Blast crisis – related to leukostasis
     Coagulopathy

   Mainstay of treatment is supportive therapy
   Further study needed to determine the role of
    rFVIIa in patients with leukemia and
    intracerebral hemorrhage
                                References
   Barnes, C. Recombinant FVIIa in the management of intracerebral haemorrhage in
    severe thrombocytopenia unresponsive to platelet-enhancing treatment. Transfusion
    Medicine 2005; 15: 145-150.
   Fritz, RD, et al. The association of fatal intracranial hemorrhage and “blastic crisis” in
    patients with acute leukemia. NEJM 1959; 261(2): 59-64.
   Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine 1985;
    64(1): 16-35.
   Kristensen, et al. Clinical experience with recombinant factor VIIa in patients with
    thrombocytopenia. Haemostasis 1996; 26S1:159-164.
   Mayer SA, et al. Recombinant activated factor VII for acute intracerebral hemorrhage.
    NEJM 2005; 352(8): 777-785.
   Pihusch M, et al. Recombinant activated factor VII in treatment of bleeding
    complications following hematopoietic stem cell transplantation. 2005; 3:1935-1944.
   Quinones-Hinojosa, et al. Spontaneous intracerebral hemorrhage due to coagulation
    disorders. Neurosurg Focus 2003; 15(4): 1-17.
   Vidarsson B. Recombinant Factor VIIa for bleeding in refractory thrombocytopenia.
    Thromb Haemost 2001; 83:634-5.
    Fatal Intracranial Hemorrhage in
               Blast Crisis
                            NEJM 1957
   Of those with WBC>300, there were 2 distinct
    subgroups:
       Subgroup A: WBC exceeded 300 >8 days before ICH,
        peaked at 450-850
       Subgroup B: WBC rose abruptly <2 days before ICH.

                  A (N=5)        B (N=4)
Type              5/5 ALL        3/4 AML
Plt            8-17            20-200            P<0.05
No difference in uric acid or survival.

				
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