Supplementary Table S1. Panel composition
Panel member
Specialty
Affiliation
Ira Shulman, MD
Transfusion Medicine
University of Southern
California, Los Angeles, CA
Aryeh Shander, MD FCCM
FCCP
Anesthesiology and Critical
care
Englewood Hospital and
Medical Center, Englewood,
NJ
Phillip Bahramipour, MD
Radiology
University of Medicine and
Dentistry of New Jersey,
Newark, NJ
Michael Diringer, MD
Neurology
Washington University
School of Medicine, Saint
Louis, MO
Matthew Flaherty, MD
Neurology
University of Cincinnati
Academic health Center,
Cincinnati, OH
Edward Michelson, MD
FACEP
Emergency Medicine
Case Western Reserve
University School of
Medicine and University
Hospitals Case Medical
Center, Cleveland, OH
Babak Sarani, MD FACS
FCCM
Trauma and Surgical Critical
Care
George Washington
University, Washington, DC
Independent post hoc review panel
Neil Blumberg, MD
Laboratory Medicine
University of Rochester
Medical Center, School of
Medicine and Dentistry,
Rochester, NY
Maureane Hoffman, MD PhD
Clinical pathology
Duke University, Durham VA
Medical Center, Durham, NC
Lewis Kaplan, MD FACS
FCCM FCCP
Trauma Surgery
Yale University School of
Medicine, New Haven, CT
Majed Refaai, MD
Transfusion Medicine
University of Rochester
Medical Center, School of
Medicine and Dentistry,
Rochester, NY
Johnathan Waters, MD
Anesthesiology
University of Pittsburgh,
Pittsburgh, PA
John Peter Gruen, MD
Neurosurgery
Keck School of Medicine,
University of Southern
California, Los Angeles, CA
Supplementary Table S2. Composition of search phrases for literature searches
Terms included in
plasma search phrase
Terms included in
bleeding search phrase
Terms included in
CNS search phrase
plasma [Mesh]
fresh frozen plasma
fresh-frozen plasma
FFP
thawed plasma
liquid plasma
(plasma AND 24 AND phlebotomy)
FP24
FP-24
PF24
PF-24
cryoprecipitate-poor plasma
(solvent AND detergent AND
plasma)
(solvent/detergent AND plasma)
(S/D AND plasma)
Octaplas
(methylene blue AND plasma)
(psoralen AND ultraviolet AND
plasma)
(amotosalen AND ultraviolet AND
plasma)
INTERCEPT plasma
(riboflavin AND ultraviolet AND
plasma)
Mirasol plasma
bleed
bleeding
blood loss
hemorrhage
hemorrhagic
haemorrhage
haemorrhagic
hematoma
haematoma
coagulopathy
coagulopathic
coagulation
central nervous system
neurology
neurological
neurosurgery
neurosurgical
neuropathy
neuropathology
neuropathological
brain
cranium
cranial
intracranial
cerebrum
cerebellum
cerebral
intracerebral
craniocerebral
subdural
epidural
extradural
arachnoid
subarachnoid
parenchymal
intraparenchymal
ventricular
intraventricular
meningeal
meninges
basilar artery
cerebellar artery
carotid artery
communicating artery
basal ganglia
(continued next page)
(continued from
previous)
basal ganglionic
pontine
putaminal
spine
spinal
intraspinal
paraspinal
cauda equina
vertebral
vertebrae
lumbar
Supplementary Table S3. Inclusion and exclusion criteria used for manual literature screen.
Inclusion criteria for manual screening of literature search
1
Plasma was administered to patients to prevent or treat bleeding or
coagulopathy associated with the CNS
2
Plasma transfusion was a possible treatment option, even if plasma was not
given or if alternative therapy was administered instead (to prevent or treat
bleeding or coagulopathy associated with the CNS)
3
Efficacy, safety, or clinical and long-term outcomes (such as controlling
bleeding, survival, recovery of functional independence, quality of life, and
overall healthcare costs) were reported after plasma transfusion or equivalent
therapy.
Exclusion criteria for manual screening of literature search
1
“Not CNS-related”—bleeding or coagulopathy reported in the study
was not associated with the CNS
2
“No outcomes of interest”—outcomes were not reported following
plasma transfusion or equivalent therapy, or plasma transfusion was
reported as an outcome rather than an intervention (e.g. transfusion
requirements following different surgical approaches)
3
“Pediatrics”—study population consisted mainly of patients below 18
years of age
4
“Non-analytical reports”— Studies of limited statistical value; case reports
and case series with ≤ 6 patients, where patients are presented case-by-case
rather than being analyzed as a group
5
“Other studies”—animal model studies, in vitro or ex vivo
experimental studies, non-systematic review articles, editorials, letters
and opinion-based articles were all excluded
CNS, central nervous system
Supplementary Table S4. Evidence list for each clinical scenario
Level of
evidence
Article
Clinical scenario 1: Spontaneous bleeding with oral VKA therapy
Original research articles
1+
Boulis et al., 1999 Neurosurgery.[1]
2+
Guest et al., 2010 Clin Ther.[2]
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Goldstein et al., 2006 Stroke.[4]
2+
Huttner et al., 2006 Stroke.[5]
2+
Roitberg et al., 2005 Neurosurgery.[6]
2+
Cartmill et al., 2000 Br J Neurosurg.[7]
2+
Makris et al., 1997 Thromb Haemost.[8]
2+
Fredriksson et al., 1992 Stroke.[9]
2-
Stead et al., 2010 Clin Neurol Neurosurg.[10]
2-
Siddiq et al., 2008 Neurocrit Care.[11]
2-
Brody et al., 2005 Neurocrit Care.[12]
2-
Yasaka et al., 2003 Thromb Haemost.[13]
3
Maeda et al., 2012 J Neurol Sci.[14]
3
Appelboam and Thomas 2007 Intensive Care Med.[15]
3
Bobbitt et al., 2011 Thromb Res.[16]
3
Barillari et al., 2012 Blood Transfus.[17]
3
Menzin et al., 2012 J Thromb Haemost.[18]
3
Ouirke et la., 2007 Ir Med J.[19]
3
Sjöblom et al., 2001 Stroke.[20]
3
Bertram et al., 2000 J Neurol.[21]
3
Wijdicks et al., 1998 Neurosurgery.[22]
3
Amin et al., 2012 Neurocrit Care.[23]
3
Menzin et al., 2012 Thromb Haemost.[24]
3
Chong et al., 2010 Anaesth Intensive Care.[25]
3
Fernlöf et al., 2009 Blood Coagul Fibrinolysis.[26]
3
Lee et al., 2006 Neurology.[27]
3
Park et al., 2003 Neurosurgery.[28]
3
Sørensen et al., 2003 Blood Coagul Fibrinolysis.[29]
3
Ananthasubramaniam et al, 2001 Chest.[30]
3
Pindur and Mörsdorf 1999 Thromb Res.[31]
3
Pindur et al., 1999 Semin Thromb Hemost.[32]
3
Zingale et al., 1999 J Neurosurg Sci.[33]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Bechtel et al., 2011 Int J Emerg Med.[35]
2++
Dentali et al., 2011 Thromb Haemost.[36]
2++
Keeling et al., 2011 Br J Haematol.[37]
2++
Morgenstern et al., 2010 Stroke.[38]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 2: Spontaneous bleeding in the absence of oral VKA therapy
Original research articles
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Roitberg et al., 2005 Neurosurgery.[6]
2-
Stead et al., 2010 Clin Neurol Neurosurg.[10]
3
Pindur and Mörsdorf 1999 Thromb Res.[31]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Morgenstern et al., 2010 Stroke.[38]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 3: Isolated trauma-related CNS bleeding with oral VKA therapy
Original research articles
1+
Boulis et al., 1999 Neurosurgery.[1]
2++
Ivascu et al., 2005 J Trauma.[41]
2+
Guest et al., 2010 Clin Ther.[2]
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Makris et al., 1997 Thromb Haemost.[8]
2-
Senft et al., 2009 Neurol Res.[42]
2-
Stein et al., 2009 J Trauma.[43]
2-
Kalina et al., 2008 Am Surg.[44]
3
Coimbra et al., 2005 J Trauma.[45]
3
Barillari et al., 2012 Blood Transfus.[17]
3
Menzin et al., 2012 J Thromb Haemost.[18]
3
Mountain et al., 2010 Med J Aust.[46]
3
Safaoui et al., 2009 Am J Surg.[47]
3
Wijdicks et al., 1998 Neurosurgery.[22]
3
Amin et al., 2012 Neurocrit Care.[23]
3
Menzin et al., 2012 Thromb Haemost.[24]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Bechtel et al., 2011 Int J Emerg Med.[35]
2++
Dentali et al., 2011 Thromb Haemost.[36]
2++
Keeling et al., 2011 Br J Haematol.[37]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 4: Isolated trauma-related CNS bleeding in the absence of oral VKA therapy
Original research articles
1+
Etemadrezaie et al., 2007 Clin Neurol Neurosurg.[48]
2++
Peiniger et al., 2011 Crit Care.[49]
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Winter et al., 1989 Ann Emerg Med.[50]
2-
Stein et al., 2009 J Trauma.[43]
3
Schöchl et al., 2010 Crit Care.[51]
3
May et al., 1997 Am Surg.[52]
3
Touho et al., 1986 Neurosurgery.[53]
3
Bauer et al., 2011 J Trauma.[54]
3
Park et al., 2003 Neurosurgery.[28]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
2+
Lier et al., 2011 Intensive Care Med.[55]
Clinical scenario 5: Surgical bleeding with oral VKA therapy
Original research articles
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Horlocker et al., 2001 Anesth Analg.[56]
3
Amin et al., 2012 Neurocrit Care.[23]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Dentali et al., 2011 Thromb Haemost.[36]
2++
Keeling et al., 2011 Br J Haematol.[37]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 6: Surgical bleeding in the absence of oral VKA therapy
Original research articles
1+
Xu et al., 2012 Arch Orthop Trauma Surg.[57]
2+
Bershad et al., 2008 J Neurosurg.[3]
2+
Horlocker et al., 2001 Anesth Analg.[56]
2-
Friedman and Sussman 1989 Clin Lab Haematol.[58]
3
Watson et al., 2011 Transfus Med.[59]
3
Pull ter Gunne et al., 2010 Spine J.[60]
3
Blanchette et al., 2007 Eur Spine J.[61]
3
Davis et al., 2004 J Trauma.[62]
3
Bauer et al., 2011 J Trauma.[54]
3
Goldstein et al., 2010 Arch Neurol.[63]
3
Park et al., 2003 Neurosurgery.[28]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Krisl et al., 2011 Ann Pharmacother.[64]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 7: Prophylactic transfusion of plasma in patients on oral VKA therapy1
Original research articles
1+
Yiu et al., 2006 Am J Cardiol.[65]
2-
Stein et al., 2009 J Trauma.[43]
3
Bobbitt et al., 2011 Thromb Res.[16]
3
Ouirke et al., Ir Med J.[19]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Dentali et al., 2011 Thromb Haemost.[36]
2++
Keeling et al., 2011 Br J Haematol.[37]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
Clinical scenario 8: Prophylactic transfusion of plasma in patients in the absence of oral VKA
therapy1
Original research articles
1+
Etemadrezaie et al., 2007 Clin Neurol Neurosurg.[48]
2+
Winter et al., 1989 Ann Emerg Med.[50]
2-
Stein et al., 2009 J Trauma.[43]
3
Watson et al., 2011 Transfus med.[59]
3
Davis et al., 2004 J Trauma.[62]
3
May et al., 1997 Am Surg.[52]
3
Touho et al., 1986 Neurosurgery.[53]
Systematic reviews, meta-analyses, guidelines
1++
Stanworth et al., 2004 Br J Haematol.[34]
2++
Murad et al., 2010 Transfusion.[39]
2++
Roback et al., 2010 Transfusion.[40]
1
Prophylaxis was defined as administration of plasma in non-bleeding patients, either to normalize
abnormal coagulation parameters, or as early intervention to reduce the risk of bleeding before
invasive procedures or following injury. CNS, central nervous system; INR, international normalized
ratio; VKA, vitamin K antagonist
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5. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated
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