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Acute Leukemia and Intracerebral Hemorrhage

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31 year old female with AML M5 presents with neutropenic fevers ... Headaches are aching, bifrontal, worse when supine. Case #1. Physical Exam. Temp 38.6 P 116 ... – PowerPoint PPT presentation

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Title: Acute Leukemia and Intracerebral Hemorrhage


1
Acute Leukemia and Intracerebral Hemorrhage
  • Tanya Wildes
  • April 22, 2006

2
Disclosure Tanya Wildes, M.D.
Dr. Tanya Wildes has no relevant financial
interests to disclose.
3
Disclosure ltinsert namegt, 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

4
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.

5
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

6
Brain MRI
7
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.

8
Case 2
  • 42 year old female with HTN, DM presented with 1
    week of headache.
  • No history of trauma.
  • She was conversant and neurologically intact upon
    arrival to ED.
  • Initial labs
  • WBC 218.4
  • Hgb 9.7
  • Platelet 20
  • PT 19.0
  • PTT 39.9

9
Head CT
10
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.

11
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.

12
Case 2
  • Neurosurgery was consulted.
  • They recommended correction of her
    thrombocytopenia and coagulopathy.
  • Within 3 hours of arrival, the patients level
    of consciousness declined.
  • She was intubated for airway protection.
  • A repeat head CT was performed.

13
Head CT
14
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.

15
Case 2
  • Neurosurgery then recommended recombinant
    activated factor VII.
  • Despite aggressive medical intervention, the
    patient expired within hours of her initial
    presentation.

16
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17
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?

18
Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957
  • Case series N100
  • 81 deaths
  • 18 deaths due to intracranial hemorrhage (22)

Fritz, RD, et al. The association of fatal
intracranial hemorrhage and blastic crisis in
patients with acute leukemia. NEJM 1959 261(2)
59-64.
19
Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957
20
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.
21
Symptoms
  • Petechial or small (lt2cm) hemorrhages
  • Usually asymptomatic
  • Large (gt2cm) 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.
22
Graus F, et al. Cerebrovascular complications in
patients with cancer. Medicine 1985 64(1)
16-35.
23
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.

24
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.
25
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

26
TreatmentRCT rFVIIa in intracranial hemorrhage
  • N399
  • Inclusion criteria
  • Age gt18
  • ICH documented by CT within 3 hours of symptom
    onset
  • Exclusion criteria
  • Thrombocytopenia
  • Coagulopathy or DIC
  • Sepsis
  • Planned surgical 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.
27
TreatmentRCT 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.
28
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29
TreatmentRCT rFVIIa in intracranial hemorrhage
Mayer SA, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. NEJM 2005
352(8) 777-785.
30
TreatmentRCT 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.
31
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32
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?

33
TreatmentrFVIIa in thrombocytopenia
  • N74
  • 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 gt2
    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 26S1159-164.
34
TreatmentrFVIIa in thrombocytopenia
Kristensen, et al. Clinical experience with
recombinant factor VIIa in patients with
thrombocytopenia. Haemostasis 1996 26S1159-164.
35
TreatmentrFVIIa 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 26S1159-164.
36
Treatment rFVIIa in hematopoietic stem cell
transplant patients with bleeding
  • Prospective, randomized trial of patients
    undergoing autologous or allogeneic transplant
  • N100
  • 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 31935-1944.
37
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 Hgblt8
  • Platelet transfusion if plt lt20x 109
  • If diffuse alveolar hemorrhage or hemorrhagic
    cystitis, platelets were transfused if lt75 x 109
  • 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 31935-1944.
38
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 31935-1944.
39
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 31935-1944.
40
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 31935-1944.
41
TreatmentCase 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 109
  • 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.
42
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 83634-5.
43
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 83634-5.
44
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

45
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 26S1159-164.
  • 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 31935-1944.
  • 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 83634-5.

46
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47
Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957
  • Of those with WBCgt300, there were 2 distinct
    subgroups
  • Subgroup A WBC exceeded 300 gt8 days before ICH,
    peaked at 450-850
  • Subgroup B WBC rose abruptly lt2 days before ICH.
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