ORIGINAL ARTICLE

Protein C deciency
N. A. GOLDENBERG* and M. J. MANCO-JOHNSON*
*Hemophilia & Thrombosis Center, Section of Hematology, Oncology, and Bone Marrow Transplantation, Department
of Pediatrics, University of Colorado Denver and The Childrens Hospital, Aurora, CO; and Division of Hematology/
Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
Summary. Severe protein C deciency (i.e. protein C
activity <1 IU dL
)1
) is a rare autosomal recessive
disorder that usually presents in the neonatal period
with purpura fulminans (PF) and severe disseminated
intravascular coagulation (DIC), often with concom-
itant venous thromboembolism (VTE). Recurrent
thrombotic episodes (PF, DIC, or VTE) are common.
Homozygotes and compound heterozygotes often
possess a similar phenotype of severe protein C
deciency. Mild (i.e. simple heterozygous) protein C
deciency, by contrast, is often asymptomatic but
may involve recurrent VTE episodes, most often
triggered by clinical risk factors. The coagulopathy in
protein C deciency is caused by impaired inactiva-
tion of factors Va and VIIIa by activated protein C
after the propagation phase of coagulation activa-
tion. Mutational analysis of symptomatic patients
shows a wide range of genetic mutations. Manage-
ment of acute thrombotic events in severe protein C
deciency typically requires replacement with pro-
tein C concentrate while maintaining therapeutic
anticoagulation; protein C replacement is also used
for prevention of these complications around sur-
gery. Long-term management in severe protein C
deciency involves anticoagulation with or without a
protein C replacement regimen. Although many
patients with severe protein C deciency are born
with evidence of in utero thrombosis and experience
multiple further events, intensive treatment and
monitoring can enable these individuals to thrive.
Further research is needed to better delineate optimal
preventive and therapeutic strategies.
Keywords: disseminated intravascular coagulation,
neonatal thrombosis, protein C, purpura fulminans,
thrombophilia
Introduction
Protein C was isolated from bovine plasma by Johan
Steno in 1976 and named C because it was the
third protein to elute from DEAE-Sepharose [1].
However, the function of protein C in the physio-
logical regulation of coagulation was not delineated
until several years thereafter. Low levels of plasma
protein C were rst associated with venous throm-
bosis in a family study by Grifn et al. in 1982 [2].
The dramatic neonatal presentation of homozygous
protein C deciency with disseminated intravascular
coagulation (DIC) and purpura fulminans (PF)
within hours of birth was reported by several groups
in 1984 [35]. These infants and those others
subsequently recognized were determined to have a
critical defect in coagulation regulation in associa-
tion with undetectable levels of protein C. Affected
infants often died despite frequent infusions of
plasma, sometimes because of complications of uid
overload from the amount of plasma required to
reverse DIC. Knowledge regarding the molecular and
cellular biology of protein C has unfolded over the
subsequent years.
Materials and methods
This article was prepared using published reviews
and sentinel source publications. In addition, the
authors have personally cared for three persons with
severe, moderately severe congenital protein C de-
ciency from the neonatal period through young
Correspondence: Marilyn J. Manco-Johnson, Mountain States
Regional Hemophilia & Thrombosis Ctr, MS F-416, PO Box
6507, Fitzsimons Bldg 500, Room WG 109, 13001 E. 17th Place,
Aurora, CO 80045, USA.
Tel.: 303 724 0365; fax: 303 724 0947;
e-mail: marilyn.manco-johnson@uchsc.edu
Accepted after revision 7 July 2008
Haemophilia (2008), 14, 12141221 DOI: 10.1111/j.1365-2516.2008.01838.x
2008 The Authors
1214 Journal compilation 2008 Blackwell Publishing Ltd
adulthood and a large number of children and adults
with symptomatic or asymptomatic heterozygous
protein C deciency.
Epidemiology and genetics
The incidence of asymptomatic protein C deciency
has been reported to be between 1 in 200 and 1 in
500 healthy individuals, whereas the incidence of
clinically signicant protein C deciency has been
estimated at 1 in 20 000 [6]. There is no apparent
racial or ethnic predilection for genetic protein C
deciency. Where specic mutations are reported
from widely dispersed geographic areas, these
reports appear to reect recurrent mutations related
to CG TG and CG CA transitions that arise
de novo at the highest frequency [7].
Based on a carrier rate of 0.2%, a homozygous or
compound heterozygous (i.e. two different allelic
mutations) protein C deciency incidence of 1 per 4
million births could be predicted. However, a recent
survey for an FDA pre licensure study of a protein C
concentrate (Baxter BioScience, Glendate, CA, USA)
identied only 12 living patients with levels of
protein C less than 20 IU dL
)1
in North America.
Potential explanations for the low prevalence of
patients with severe genetic protein C deciency
includes excess foetal demise, early postnatal deaths
before diagnosis, heterogeneity in the cause of low
levels of protein C in the healthy population, and
under-reporting.
Cases of individuals with decreased levels of
protein C showing familial transmission consistent
with heterozygous deciency have been found among
healthy blood donors who had no personal or family
history of venous thrombotic events (VTEs) [8,9]. By
contrast, two prospective studies of asymptomatic
protein C-decient relatives of protein C-decient
probands showed an increased risk of VTE [10,11].
An investigation based on protein C mutational
analysis reported a 50% risk for thrombosis in
carriers from symptomatic families by the age of
45 years [12].
The variability in risk of symptomatic VTE in
carriers of protein C mutations may be because of
incomplete gene penetrance and environmental or
genetic cofactors necessary to trigger thrombotic
events. Because of the overlap in protein C plasma
activity in healthy individuals with those carrying
heterozygous protein C gene mutations, it is often
difcult to assign carrier status based on a single
plasma determination. It has been postulated that a
second gene mutation could explain the discrepancy
between symptomatic and asymptomatic families
with protein C mutations [6,13]. Assayed protein C
activity explains some aspects, but not all, of the
phenotype. The factor V Leiden mutation accounts
for 20% of the variance in white families and
investigations are actively exploring other candidate
genes.
Most genetic protein C mutations result in type 1
deciencies in which the decreases in protein C
antigen and functional activity are equivalent. Type 2
deciencies with protein C activity lower than the
antigen account for 15% of symptomatic deciencies
[6,13]. To date, there have been more than 160
protein C gene mutations reported [14,15]. There is
no single gene mutation that serves as a founder
effect causing protein C deciency in a large number
of families. Worldwide, most infants with homozy-
gous protein C deciency have been born of consan-
guineous unions and compound heterozygous
mutations are more common.
Biology and pathophysiology
Protein C is a vitamin K-dependent coagulation
protein that serves a critical role in the regulation of
thrombin [see reviews: 6,1619]. Protein C is syn-
thesized in hepatocytes and circulates in plasma in a
very low concentration of approximately 70 nm.
Plasma protein C is activated after complex forma-
tion with thrombin on the endothelial cell receptor
thrombomodulin; this activation is facilitated by
protein C binding to the endothelial protein C
receptor (EPCR). Activated protein C (APC), aug-
mented by protein cofactors (protein S and factor V)
and lipid cofactors (high-density lipoprotein and
anionic phospholipids), cleaves critical sites in the
activated procoagulant factors V and VIII, thus
inactivating these enzymes. Patients with protein C
deciency have a decreased capacity to down-regu-
late the propagation of thrombin generation by
factor Va and VIIIa once they have been activated
by the small amounts of thrombin generated in the
initiation phase of coagulation activation.
Activated protein C also functions in the regulation
of inammation. During sepsis, signalling by inam-
matory cytokines interleukin-1 and tumour necrosis
factor mediates altered protein transcription in the
systemic inammatory response (SIR). SIR results in
decreased synthesis of the regulatory proteins anti-
thrombin, protein C and protein S, with increased
synthesis of prothrombotic proteins factor VIII, von
Willebrand factor, and brinogen. APC bound to
EPCR cleaves the endothelial cell protease activated
receptor-1 and, in addition to altered coagulation
proles, causes down-regulation of proinammatory
PROTEIN C DEFICIENCY 1215
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Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 12141221
and proapoptotic mediators, up-regulation of anti-
inammatory and antiapoptotic pathways, and sta-
bilization of endothelial cell barrier functions [16].
The clinical inuence of SIRin the pathophysiology of
sepsis and the importance of APC in dampening this
pathway was demonstrated in the PROWESS trial, in
which infusions of recombinant APC resulted in a
signicant decrease in the mortality of adults with
sepsis [20]. Of note, patients with genetic protein C
deciency are not known to have increased suscepti-
bility to sepsis or an altered inammatory response.
Levels of protein C mature later than many other
coagulation proteins. The mean plasma concentra-
tion of protein C in a healthy term infant is
40 IU dL
)1
, with a lower limit of normal of
25 IU dL
)1
. Protein C concentration increases from
birth until 6 months of age when the 50th percentile
of paediatric level is equivalent to the 10th percentile
of healthy adults (approximately 60 IU dL
)1
). Pro-
tein C concentration remains slightly low through
childhood and achieves the adult range after puberty
[21]. Healthy adults show a wide observed range of
plasma protein C activity of approximately
65135 IU dL
)1
[13]. Authors of this review employ
a nomenclature of mild protein C deciency to
indicate activity levels greater than 20 IU dL
)1
but
below the age-appropriate lower limit of normal
values, moderately severe protein C deciency as
activity levels in the range of 120 IU dL
)1
, and
severe deciency for activity levels less than
1 IU dL
)1
. Most neonatal presentations occur in
infants with severe protein C deciency in whom
protein C activity is undetectable. However, rarely,
patients with moderate protein C activity have also
presented with neonatal PF [22].
Protein Cdeciency may be acquired and caused by
increased consumption (e.g. overt DIC, severe infec-
tion without overt DIC, acute VTE) or by decreased
synthesis of the active carboxylated protein (e.g.
administration of vitamin K antagonists, severe
hepatic synthetic dysfunction, complications of pre-
maturity). Ill preterminfants may have very lowlevels
of protein Cactivity (e.g. <10 IU dL
)1
) as an acquired
deciency superimposed on physiologically decreased
levels at this age; these low levels may contribute to
thrombotic complications in intensively supported
preterm infants [21,23]. Rarely, antiphospholipid
antibodies (APA) may also cause acquired protein C
deciency via antibody-mediated clearance.
Clinical manifestations
Infants with severe genetic protein C deciency
usually present within hours of birth with rapidly
progressive PF and DIC [24]. PF originates with red
or purpuric lesions at pressure points, such as the
back of the head and buttocks, as shown in Fig. 1.
The lesions rapidly progress to form palpable black
eschars that are exquisitely painful. Histologically,
PF lesions consist of brin clots in small venules of
the subcutaneous fat. Coagulation studies are often
normal at the outset of skin lesions, except for a
markedly elevated D-dimer and an undetectable
plasma protein C activity. However, thrombocyto-
penia, hypobrinogenaemia, and prolongation of the
prothrombin time develop rapidly after onset of PF,
if not immediately observed. Other coagulation
proteins may be decreased acutely, secondary to
consumptive coagulopathy, but normalize to age-
appropriate levels after resolution of DIC. Most
affected infants manifest white light reexes and are
congenitally blind from thrombosis into the devel-
oping vitreal vein and many show evidence of
prenatal arterial ischaemic stroke on magnetic reso-
nance imaging of the brain. Large vessel thromboses,
including renal vein thrombosis, have been reported
Fig. 1. Compound heterozygous protein C deciency with unde-
tectable protein C activity. Purpura fulminans in severe protein C
deciency often presents within hours of birth at points of minimal
pressure.
1216 N. A. GOLDENBERG and M. J. MANCO-JOHNSON
2008 The Authors
Haemophilia (2008), 14, 12141221 Journal compilation 2008 Blackwell Publishing Ltd
in some affected infants. Persons with severe protein
C deciency experience recurrent episodes of
PF triggered by infection, trauma, and even minor
decreases in goal levels of therapeutic anticoagula-
tion.
A delayed presentation may be observed in ado-
lescents and adults with moderately severe protein C
deciency [25]. The clinical course includes recurrent
VTE, including extremity deep vein thrombosis
(DVT), pulmonary emboli (PE), parenchymal throm-
bi and a proclivity to DIC. Although individuals with
low levels of detectable protein C often have a
clinical presentation that is delayed until puberty,
vulnerability of affected individuals to DIC and
thrombosis thereafter may be similar to that seen in
patients with neonatal presentation.
The clinical phenotype of simple heterozygous
protein C deciency, characterized by mild deciency
in measured protein C activity, can range from
asymptomatic to a potent thrombophilic state with
recurrent thromboses resulting in severe venous insuf-
ciency fromthe post-thrombotic syndrome, as shown
in Fig. 2. In addition to DVTand PE, the patients with
heterozygous protein C deciency may develop
ischaemic arterial stroke, mesenteric thrombi and
pregnancy-associated thrombosis [2628]. Patients
with a signicant positive family history, multiple
thrombophilia traits, APA, or underlying inamma-
tory disorders are more likely to develop thrombotic
manifestations, while more benign personal and fam-
ily histories are often characterized by mild protein C
deciency as a single thrombophilic defect.
Diagnosis
Diagnostic testing for protein C deciency typically
uses functional assays. Chromogenic assays for
protein C that use activation by snake venom in an
activating reagent (Protac; Aniara Corp, Mason,
OH, USA) are widely available. Clotting assays and
enzyme-linked immunosorbent assays are also com-
mercially available. Given the occurrence of acquired
deciency, retesting of patients with low protein C
levels to exclude a transient deciency is recom-
mended after resolution of acute consumptive states
and when not receiving oral anticoagulant therapy.
Patients with APA and low levels of protein C can be
tested for antiprotein C antibodies to determine
whether protein C deciency is congenital or
acquired. Quality assurance issues in sample collec-
tion, assay performance, and interpretation (i.e.
preanalytic and analytic conditions) are extremely
important in the determination of protein C activity
[29].
In the case of suspected homozygous or compound
heterozygous protein C deciency, testing both
parents and all grandparents can be helpful. Most
parents of infants with severe protein C deciency
are asymptomatic and have protein C levels com-
patible with heterozygous status.
Protein C mutational analysis is available in a few
laboratories; see persons interested in protein C
sequencing below. Results of DNA studies can be
useful for conrmation of carrier status or for
prenatal diagnosis. Prenatal diagnosis can be made
by mutational analysis of the protein C gene using
chorionic villous sampling material or amniotic cells.
For the protein C mutation database, readers are
referred to the Web site of the Scientic Standard-
ization Committee of the International Society for
Thrombosis and Haemostasis, Subcommittee on
Plasma Coagulation Inhibitors, currently chaired by
Dr. Elaine Gray (http://www.med.unc.edu/isth/
ssc_home.htm).
Management
Neonatal PF can be controlled only with protein C
replacement in the form of fresh frozen plasma (FFP)
or a human plasmaderived, viral inactivated protein
C concentrate [3032]. A human plasma-derived,
viral-inactivated protein C concentrate manufactured
by Baxter (Ceprotin

; Baxter BioScience, Glendale,

CA, USA) has been licensed in the United States and
Europe. A second plasma-derived concentrate (Prot-
exel

; LFB, Lille, France) is also available in Europe.

Protein C replacement dosing is similar to that for
other vitamin K-dependent proteins, such as factor
IX. A total of 1 IU kg
)1
of protein C concentrate or
1 mL kg
)1
of FFP will increase the plasma concen-
tration by 1 U dL
)1
. Based on a 6- to 10-h half-life of
protein C in plasma in the steady state, patients with
Fig. 2. Symptomatic heterozygous protein C deciency. Individu-
als with recurrent venous thromboembolism secondary to hetero-
zygous protein C deciency are at risk for post-thrombotic
syndrome. This patient manifests venous stasis ulcers.
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Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 12141221
severe protein C deciency who have DIC or acute
thrombosis can be treated acutely with an initial
bolus of 100 IU kg
)1
followed by 50 IU kg
)1
every
6 h. Author recommendations for management of
patients with severe protein C deciency are given in
Table 1.
Outside of DIC, PF, or an acute VTE event, most
affected infants have been managed for long-term
secondary prophylaxis with protein C concentrate or
therapeutic anticoagulation using either low-molec-
ular-weight heparin or high-intensity warfarin [30
34]. Warfarinization should always be preceded by
several days of therapeutic heparin administration to
avoid warfarin skin necrosis and other progressive or
recurrent thrombotic complications, including VTE,
PF, or DIC. Alternatively, children can be managed
with a combination of the two approaches (e.g.
protein C replacement, approximately 50 U kg
)1
,
given every other day or three times weekly in
combination with less intensive anticoagulation).
Monitoring for evidence of coagulation activation
with D-dimer is useful to conrm adequate replace-
ment or anticoagulation therapy; in the authors
experience, and as previously published in the
neonate [33], a markedly elevated or rapidly rising
D-dimer has often heralded the onset of recurrent
VTE, PF, or DIC in young patients with severe
protein C deciency.
Recombinant APC (Xigris; Eli Lilly, Indianapolis,
IN, USA) has been used by the authors to treat PF in
a child with severe protein C deciency. Recombi-
nant APC, administered at a dose of 24 lg kg
)1
h
)1
(the regimen recommended for sepsis), resulted in a
plasma protein C activity of 5 IU dL
)1
and has
been variably effective in controlling PF [35].
However, a non-signicant trend to increase in
major bleeding episodes in a paediatric randomized
controlled trial of recombinant APC in sepsis
(particularly among young infants) [36] has raised
concern regarding the potential haemorrhagic risk
of this agent in children.
Complications of therapy
The use of FFP can be complicated by uid overload,
as noted above. In addition, FFP is not available in
the USA as a viral-inactivated product. Furthermore,
exposure to large numbers of donors over time
increases the cumulative risk for transfusion-associ-
ated viral infection and allergic reaction to donor
proteins in FFP. By contrast, protein C concentrate
has a small theoretical risk of viral contamination,
similar to other Food and Drug Administration-
approved human plasma-derived, viral inactivated
protein concentrates. Allergic reactions and alloan-
tibody formation are potential complications of any
Table 1. Author recommendations for management of patients with severe genetic protein C deciency.
Condition Treatment product Dosing Target therapeutic indicator
DIC, PF, acute VTE Protein C concentrate 100 U kg
)1
initial bolus; 50 U kg
)1
every 612 h (every 6 h acutely)
Protein C activity 50 IU dL
)1
trough;
decreasing (or normalization of)
D-dimer
Fresh frozen plasma 1015 mL kg
)1
, every 812 h, until
protein C concentrate available
Protein C activity >10 IU dL
)1
trough,
until protein C concentrate available;
decreasing (or normalization of)
D-dimer
Unfractionated heparin* 1520 U kg
)1
h
)1
with protein C
replacement
Anti-Xa activity 0.30.7 U mL
)1
Low-molecular-weight heparin* 1.01.5 mg kg
)1
every 12 h with
protein C replacement
Anti-Xa activity 0.51.0 U mL
)1
Prophylaxis for
invasive procedures
Protein C concentrate 100 U kg
)1
initial bolus;
3050 U kg
)1
every 1224 h
Protein C activity 2050 IU dL
)1
trough; negative (or rapidly
decreasing) D-dimer in
postoperative period
Maintenance Protein C concentrate
(typically with
oral anticoagulation, below)
3050 IU kg
)1
every 13 days D-dimer negative
Warfarin 0.10.2 mg kg
)1
orally every day
(without protein C replacement);
0.050.1 mg kg
)1
orally every day
with protein C replacement
INR 2.53.5, higher INR typically
required in adolescents, INR 1.52.5
with protein C replacement
DIC, disseminated intravascular coagulation; INR, international normalized ratio; PF, purpura fulminans; VTE, venous thromboembo-
lism.
*May pose an increased bleeding risk in the setting of thrombocytopenia in DIC.
1218 N. A. GOLDENBERG and M. J. MANCO-JOHNSON
2008 The Authors
Haemophilia (2008), 14, 12141221 Journal compilation 2008 Blackwell Publishing Ltd
protein replacement therapy but have not been
described in patients to date.
Long-term replacement therapy in small infants
has required placement of central venous access
devices. Because of the inherent hypercoagulability
of affected patients, thrombotic and infectious com-
plications of central venous access devices present
limitations to continuous replacement therapy and
must be accompanied by strict adherence to the
protein C replacement regimen, in addition to any
concomitant low-dose anticoagulation. Routine
instillation of a brinolytic agent into the central
venous access device may be helpful to prevent
catheter occlusions and infections, but there is no
evidence to support this practice.
Prognosis
Published data on the long-term outcome of persons
affected with severe genetic protein C deciency are
limited. For this reason, at present, information on
outcomes is principally limited to anecdotal experi-
ences. Point-of-care testing for international normal-
ized ratio with home monitors has greatly facilitated
care of patients with severe genetic protein C
deciency. Early recognition of subtherapeutic inter-
national normalized ratios (INR), accompanied by
institution of short-term bridging anticoagulation
with low-molecular-weight heparin or protein C
replacement with concentrate, can successfully pre-
vent recurrent episodes of VTE, DIC and PF. With
proactive home monitoring and patient-directed
management, the need for hospitalization can
become infrequent. For example, a 20-year-old
woman managed by the authors with severe protein
C deciency and congenital blindness because of
bilateral vitreal vein thrombosis in utero, who
adeptly uses a home INR monitoring device, has
been hospitalized three times in the past six years
including twice for bleeding episodes on high-dose
warfarin (target INR: 3.53.8), and once for Med-
iport placement to permit regular protein C replace-
ment as a means of reducing chronic anticoagulant
dose and, hence, the risk of future bleeds. This
patient has been free of hospitalization for the past
2 years while on a prophylactic thrice-weekly protein
C replacement regimen in conjunction with low-dose
warfarin.
The cumulative likelihood of severe bleeding
complications increases with the duration of long-
term anticoagulation. Of considerable concern is
the risk of ruptured ovarian cyst with resultant
signicant pelvic haemorrhage among adolescent
and young adult females receiving long-term anti-
coagulation, and traditional suppressive therapy
with oestrogens is contraindicated in patients with
protein C deciency, unless protein C is being
adequately replaced. In addition, surgical interven-
tion for the management of viscous thromboembo-
lic complications, such as bowel infarct, also poses
a challenge with regard to the simultaneous risks
of severe haemorrhage and recurrent thrombotic
events. The availability of protein C concentrate
has been judged to be life-saving in such
circumstances.
Each of three children with severe/moderately
severe genetic protein C deciency managed and
followed long-term by the authors has been
adequately supported through major surgery with
protein C replacement. No anticoagulation has
been required when plasma protein C concentra-
tions have been maintained above a nadir of 50%
around surgery and above 20% during baseline
conditions; this has enabled invasive surgical pro-
cedures to be performed with low risk of major
haemorrhage.
Some patients with simple heterozygous protein C
deciency, including one followed by the authors,
have experienced recurrent severe episodes of DVT,
leading to advanced post-thrombotic syndrome with
venous stasis ulcers that heal poorly and are difcult
to manage. The coexistence of obesity is an impor-
tant candidate prognostic factor for the development
of post-thrombotic syndrome in patients with
thrombophilia.
The lupus anticoagulant has developed in
patients with protein C deciency and recurrent
thrombosis, including two of the three severe/
moderately severe protein C-decient patients man-
aged by the authors. Although the relationship of
thrombophilia to development of APA is unknown,
it is possible that vascular damage contributes to
the development of the antibodies. Our experience
suggests that APA may exacerbate the prothrom-
botic state and clinical course in protein C-decient
individuals.
It is worthy of note that osteoporosis has devel-
oped in the 20-year-old woman described earlier,
maintained on life-long intensive oral anticoagula-
tion with warfarin. Given that oral anticoagulation
with vitamin K antagonists is not associated with
osteoporosis, it is likely that long-term decreases in
normal impact physical activities because of congen-
ital blindness contributed to decreased bone density
in this patient. Heightened surveillance of bone
mineral density in congenitally blind protein C-
decient patients and early institution of isometric
exercise regimens and medication for osteoporosis
PROTEIN C DEFICIENCY 1219
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Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 12141221
may be warranted to prevent fractures in such
patients, who are at risk for both thrombotic and
haemorrhagic complications with orthopaedic
injury.
With regard to physical and cognitive develop-
ment, all three children with severe/moderately
severe protein C deciency managed by the authors
with intensive anticoagulation and/or protein C
replacement have exhibited normal growth in long-
term follow-up. Furthermore, although some
reported children with severe protein C deciency
have manifest developmental delays and/or cognitive
impairment, these three patients have achieved above
average academic success in university and graduate
school programmes.
Individuals with interest in the area
Paediatric haematology
Marilyn J. Manco-Johnson, MD; email: marilyn.
manco-johnson@uchsc.edu; Neil A. Goldenberg,
MD, PhD; email: neil.goldenberg@uchsc.edu; Tel.
(both) 303 724 0365.
Protein C gene sequencing
Craig Hooper, PhD, United States Centers for Disease
Control andPrevention, 1600ClintonRd., Bldg1Room
1332, Atlanta, GA 30333, USA; Tel.: 404 639 3750;
Fax: 404 639 1638; email: woh1@cdc.gov. Dr Hooper
could provide mutation analysis as part of a research/
registry project. The time to results is dependent on the
number of samples submitted for analysis.
The laboratory of Dr Christine Mannhalter is
licensed for genetic testing and can provide mutation
analysis for protein C deciency. The time to results
ranges between two and three weeks per sample.
Contact information for Dr Mannhalter is as fol-
lows: Univ.-Prof. Dr Christine Mannhalter,
Klinisches Institut fu r Medizinische & Chemische
Labordiagnostik, Medizinische Universita t Wien,
Allgemeines Krankenhaus, Wien. Wa hringer Gu rtel
18-20, A-1090 Wien, Tel.: (+43/1) 40 400 20 85,
Fax: (+43/1) 40 400 20 97, e-mail: christine.mann-
halter@meduniwien.ac.at.
Links to organizations that can provide information,
referrals and support
National Alliance for Thrombosis and Thrombo-
philia (NATT) is an advocacy society for persons and
families dealing with thrombosis and thrombophilia:
http://www.nattinfo.org.
The Anticoagulation Forum is a network of health
care professionals committed to the therapy of
thromboembolic disorders predominantly through
the venue of anticoagulation management service:
http://www.acforum.org.
The United States Centers for Disease Control and
Prevention Pilot Program in Thrombophilia and
Thrombosis: http://www.cdc.gov/ncbddd/hbd/throm
b_center_list.htm and http://www.cdc.gov/ncbddd/
hbd/clotting.htm.
Conclusions and future directions
Severe protein C deciency remains a rarely diag-
nosed condition. It is possible that affected indi-
viduals may experience excess foetal demise or that
affected infants die from DIC before assignment of
the diagnosis. Given the availability of safe, effec-
tive replacement proteins, renewed educational
outreaches to paediatricians, obstetricians, and
primary care physicians may help to identify
affected infants who would benet from such
therapies. At the same time, future study of dosing,
efcacy, and safety of protein C replacement for
both prophylaxis and therapy in identied individ-
uals with severe and moderately severe protein C
deciencies is urgently needed. Given the rarity of
these protein C deciency states, and yet their
frequently severe impact on longevity and quality
of life, strong advocacy efforts will likely be
necessary to continue active research efforts (both
observational and interventional) directed toward
an ultimate goal of optimizing care of affected
patients.
Disclosures
The authors stated that they had no interests which
might be perceived as posing a conict or bias.
References
1 Steno J. A new vitamin K-dependent protein: puri-
cation from bovine plasma and preliminary character-
ization. J Biol Chem 1976; 251: 35563.
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PROTEIN C DEFICIENCY 1221
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