ArticlePDF Available

Abstract

Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins, that act as natural anticoagulants. The proteolytic activation of PC by thrombin occurs on the surface of endothelial cells and involves thrombomodulin and endothelial PC receptor. In the presence of PS, phospholipids and calcium, activated PC (APC) inactivates membrane bound factors V (FVa) and FVIIIa by their cleavage at the specific arginine residues. PC and PS deficiencies are inherited as autosomal dominant disorders associated with recurrent venous thromboembolism (VTE) and, in most cases, derived from heterozygous missense mutations (78% and 63%, respectively). Heterozygous PC deficiency is found in 6% of families with inherited thrombophilia, in 3% of patients with a first-time deep vein thrombosis (DVT) and 0.2-0.3% of healthy individuals. The PS deficiency is detected more commonly than PC deficiency and its prevalence has been estimated with a less than 0.5% in the general European population and 2% to 12% of selected groups of thrombophilic patients. Approximately 75% of PC-deficient patients have type I deficiency and 95% of PS-deficient patients develop type I and type III of PS deficiency. The diagnosis of PC and PS deficiencies is challenging, many preanalytical and analytical factors may affect the PC/PS levels. Molecular analysis of the PC and PS genes (PROC and PROS1, respectively) involves direct gene sequencing and if negative, multiplex ligation-dependent probe amplification (MLPA) method. Patients with low PC and PS levels and the known mutation within PROC or PROS1 genes combined with other genetic or environmental thrombosis factors are at increased risk of recurrent thromboembolic events and require lifelong oral anticoagulation.
EW
1, 2, A–D
, A U
1, 2, A, C, E, F
Protein C and Protein S Deficiency
Practical Diagnostic Issues
Niedobór białka C i białka S praktyczne problemy diagnostyczne
1
The John Paul II Hospital, Kraków, Poland
2
Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
Aresearch concept and design; B collection and/or assembly of data; C – data analysis and interpretation;
Dwriting the article; Ecritical revision of the article; F final approval of article; Gother
Abstract
Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins, that act as natural anticoagulants. The
proteolytic activation of PC by thrombin occurs on the surface of endothelial cells and involves thrombomodulin
and endothelial PC receptor. In the presence of PS, phospholipids and calcium, activated PC (APC) inactivates
membrane bound factor V (FVa) and FVIIIa by their cleavage at the specific arginine residues. PC and PS defi-
ciencies are inherited as autosomal dominant disorders associated with recurrent venous thromboembolism (VTE)
and, in most cases, derived from heterozygous missense mutations (78% and 63%, respectively). Heterozygous PC
deficiency is found in 6% of families with inherited thrombophilia, in 3% of patients with a first-time deep vein
thrombosis (DVT) and in 0.2–0.3% of healthy individuals. The PS deficiency is detected more commonly than PC
deficiency and its prevalence has been estimated with a less than 0.5% in the general European population and
2% to 12% of selected groups of thrombophilic patients. Approximately 75% of PC-deficient patients have type
I deficiency and 95% of PS-deficient patients develop type I and type III of PS deficiency. The diagnosis of PC and
PS deficiencies is challenging due to many preanalytical and analytical factors affecting the PC/PS levels. Molecular
analysis of the PC and PS genes (PROC and PROS1, respectively) involves direct gene sequencing and if nega-
tive, multiplex ligation-dependent probe amplification (MLPA) method is performed. Patients with low PC and
PS levels and the known mutation within PROC or PROS1 genes combined with other genetic or environmental
thrombosis factors are at increased risk of recurrent thromboembolic events and require lifelong oral anticoagula-
tion (Adv Clin Exp Med 2013, 22, 4, 459–467).
Key words: protein C, protein S, deficiency, venous thromboembolism, mutation.
Streszczenie
Białko C (protein C, PC) i białko S (protein S, PS) to zależne od witaminy K glikoproteiny będące naturalnymi inhi-
bitorami krzepnięcia krwi. Proteolityczna aktywacja PC przez trombinę zachodzi na powierzchni komórek śród-
błonka w obecności trombomoduliny i śródbłonkowego receptora PC. Aktywne PC (APC) z udziałem kofaktora,
którym jest PS, w obecności fosfolipidów i wapnia, degraduje czynnik Va i FVIIIa przez ich cięcie w specyficznych
resztach argininowych. Niedobory PC i PS podłożem występowania i nawrotów żylnej choroby zakrzepowo-
zatorowej (ż.ch.z.z.). Niedobory PC/PS dziedziczone w sposób autosomalny dominujący i w większości przy-
padków pochodzą z heterozygotycznych mutacji typu zmiany sensu (odpowiednio: 78 i 63%). Heterozygotyczny
niedobór PC występuje u 6% rodzin z trombofilią, u 3% pacjentów, z pierwszym epizodem zakrzepicy żył głębokich
oraz u 0,2–0,3% osób zdrowych. Niedobór PS pojawia się częściej niż niedobór PC, a jego występowanie szacuje
się na mniej niż 0,5% w zdrowej populacji europejskiej i 2–12% u pacjentów z zakrzepicą. U około 75% pacjentów
z niedoborem PC występuje niedobór typu I, a u 95% pacjentów z niedoborem PS rozwija się typ I i typ III niedo-
boru. Diagnostyka niedoborów PC i PS jest trudna ze względu na występowanie wielu czynników fazy przed- i ana-
litycznej wpływających na stężenia PC i PS. Analiza molekularna genów PC i PS (odpowiednio: PROC i PROS1)
obejmuje ich bezpośrednie sekwencjonowanie genów, a w przypadku wyniku negatywnego stosuje się metodę
multipleksowej amplifikacji sondy zależnej od ligacji (multiplex ligation-dependent probe amplification, MLPA).
Pacjenci z małymi stężeniami PC i PS oraz mutacją w genach PROC lub PROS1 w połączeniu z innymi genetycz-
Adv Clin Exp Med 2013, 22, 4, 459–467
ISSN 1899–5276
EDITORIAL
© Copyright by Wroclaw Medical University
E. W, A. U
460
Protein C (PC) and protein S (PS) are vitamin
K-dependent glycoproteins that act as natural an-
ticoagulants. Basic characteristics of PC ad PS are
summarized in Table 1.
Role of Protein C and
Protein S in Human
Physiology
PC is a precursor of the serine protease, acti-
vated protein C (APC). Its proteolytic activation
by thrombin occurs on the surface of endothelial
cells and involves thrombomodulin and endothe-
lial PC receptor (EPCR). PC activation is enhanced
approximately 20-fold in vivo when PC is bound to
the EPCR [1]. In the presence of PS, phospholipids
and calcium, APC inactivates membrane bound
activated factor (F)V and FVIII by their cleavage
at the specific arginine residues [2]. Only free PS
that constitutes 40% of the total protein amount
possesses APC cofactor activity [3].
Protein S also exerts a direct APC-indepen-
dent inhibitory effect on the prothrombinase com-
plex by binding to FXa and to FVa, and thus results
in impaired prothrombin activation [4]. In addi-
tion, PS stimulates tissue factor pathway inhibitor
(TFPI) in the inactivation of FXa [5].
Growing evidence indicates that PC, APC and
PS, besides their known anticoagulant properties,
have multiple actions such as anti-apoptotic and
anti-inflammatory activities, regulation of gene
expression and stabilization of endothelial barrier
protection [6, 7]. This activity appears to be medi-
ated by two key receptors, protease activated re-
ceptor 1 (PAR1) and EPCR [6, 8]. Cytoprotective
signaling induced by APC can be observed not on-
ly in the endothelium but also in many other cell
types therein neurons, which may be a very prom-
ising tool for providing neuroprotective acute and
chronic therapies [9].
PC and PS Deficiencies
Low levels of PC were first described by Grif-
fin et al. in 1981 [10]. PS deficiency was first re-
ported in 1984 by Comp and Esmon [11]. Both
deficiencies were associated with recurrent venous
thromboembolism (VTE). PC and PS deficien-
cies are inherited as autosomal dominant disor-
ders and, in most cases, derived from heterozy-
gous mutations.
Heterozygous PC deficiency is found in 6%
of families with inherited thrombophilia, in 3%
of patients with a first-time deep vein thrombosis
(DVT) and in 0.2–0.3% of healthy individuals [12–
14]. PC/PS homozygosity or compound heterozy-
gosity is extremely rare (1/4 million of living in-
fants) and results in neonatal purpura fulminans
(PF) and disseminated intravascular coagulation
(DIC) presented within hours of birth [15, 16].
PC deficiency is classified as type I (quantita-
tive defects of PC: low antigen levels, reduced ac-
tivity) and type II (qualitative defects: IIa, normal
antigen concentrations, reduced activity in both
amidolytic and clotting functional assays, and IIb,
normal antigen concentrations, reduced clotting
activity) [12, 17]. Approximately 75% of PC-defi-
cient patients have type I deficiency and 95% of the
remainding have type IIa deficiency, but type IIb is
very rare [18].
The PS deficiency prevalence has been esti-
mated with a less than 0.5% in the general Euro-
pean population and 2% to 12% of selected groups
of thrombophilic patients [19]. Currently, PS de-
ficiency is detected more commonly than PC de-
ficiency in the general population and among pa-
tients with VTE.
PS deficiency is classified as type I (low total
and free antigen, reduced activity), type II (normal
total and free antigen, reduced activity) and type
III (normal total antigen, reduced free antigen and
activity) [12, 20]. Type I and type III deficiencies
account for 95% of cases of PS deficiency.
Acquired PC and PS deficiency can develop
with vitamin K deficiency, liver disease, treatment
with vitamin K antagonists, severe and chronic in-
flammation, autoimmune syndromes, nephritic
syndrome, or DIC [14, 21]. Of note, PC and PS
deficiency cannot be reliably measured in patients
receiving warfarin or acenocoumarol. Important-
ly, PS deficiency, but not PC deficiency, is com-
monly observed during pregnancy starting from
the first weeks. Moreover, low PS levels can be
found in patients with AIDS [22] and acute vari-
cella infection [23].
nymi i środowiskowymi czynnikami sprzyjającymi zakrzepicy narażeni na zwiększone ryzyko nawracających
epizodów zakrzepowo-zatorowych, co jest wskazaniem do stosowania przewlekłej antykoagulacji (Adv Clin Exp
Med 2013, 22, 4, 459–467).
Słowa kluczowe: białko C, białko S, niedobór, zakrzepica żylna, mutacja.
Protein C and Protein S Deficiency
461
Genetic Background of PC
and PS Deficiencies
Recently, Caspers et al. have shown that PC
and PS deficiencies exhibit similar mutation pro-
files and are most frequently caused by missense
mutations (78% and 63%, respectively) followed
by nonsense mutations (11% and 9%), splice-site
mutations (7% and 13%), small duplications/in-
sertions/deletions (2% and 9%) and large deletions
(3% and 6%) [13]. These data are in concordance
with data published in the HGMD mutation data-
base (http://www.hgmd.org). The detection rate of
Table 1. Main characteristics of protein C (PC) and protein S (PS) [3, 14, 18, 26]
Tabela 1. Charakterystyka białka C (PC) i białka S (PS) [3, 14, 18, 26]
PC PS
History
(Historia odkrycia)
isolated from bovine plasma by Johan
Stenflo in 1976 and named protein
C because it was the third protein to elute
from DEAE-Sepharose
described by Di Scipio in 1977, named
protein S in reference to its isolation and
characterization in Seattle
Gene characterization
(Charakterystyka genu)
gene PROC located on chromosome 2, posi-
tion 2q13-q14, spans 11kb long including
9 exons and 8 introns and encodes a 461
amino acids protein
active gene PROS1 (or PSa) and tran-
scriptionally inactive pseudogene PROS2
(or PSa) both located on chromosome 3,
position 3p11.1-3q11.2 and share approxi-
mately 97% similarity; PROS1 gene spans
80 kb long including 15 exons and 14
introns and encodes a 672 amino acid
protein
Synthesis
(Synteza)
hepatocytes, endothelial cells, mouse renal
tubular cells
hepatocytes, endothelial cells, human tes-
tis Leydig cells, vascular smooth muscle
cells and megakaryocytes
Molecular weight
(Masa cząsteczkowa)
62 kDa 71 kDa
Protein
(Białko)
the zymogenic form of plasma PC is
activated by thrombin in the presence of
thrombomodulin and endothelial protein
C receptor leding to activated PC (APC)
generation
60% bound to C4bBP-β chain (inactive),
40% free PS (physiologically active),
together total PS
Concentration in plasma
(Stężenie w osoczu)
3–5 µg/ml 20–25 µg/ml
Half-life
(Okres półtrwania)
6–8 hours 42 hours
Reference range
(Zakres referencyjny)
PC 70–140% free PS: female 55–124%, male 74–146%;
total PS: female 60–140%, male 75–140%
Assays
(Testy)
amidolytic PC assays for routine screen-
ing for PC deficiency, more specific than
coagulation assays; immunoassays (turbidi-
metric, nefelometric, ELISA)
immunoassays for free and total PS, and
clotting assays for PS activity
Physiological variability
(Zmienność fizjologiczna)
early childchood PC = 40%; increase by
more than 20% in pregnancy and in the
old age; remain elevated in the postpartum
period
early childhood PS=60%, total PS is
increasing with age; free PS levels are
independent of age; pregnancy free PS
30–50%, lower level in women than men
Pathophysiological
variability
(Zmienność
patofizjologiczna)
VKA-based anticoagulant therapy, vitamin
K deficiency, DIC, severe infections, liver
disease, fresh thrombosis, oral contracep-
tive use, autoantibody presence
VKA-based anticoagulant therapy, vita-
min K deficiency, DIC, liver disease, oral
contraceptive use, autoantibody presence
APC – activated PC. APC – aktywowane PC.
DIC – disseminated intravascular coagulation. DIC – zespół rozsianego wewnątrznaczyniowego krzepnięcia.
VKA – vitamin K antagonist. VKA – antagonista witaminy K.
E. W, A. U
462
mutations is 70–80% for PC deficiency and around
50% in families with PS deficiency [13, 24, 25].
The lower mutation rate detection within the
PROS1 gene may be explained by the fact that PS
levels are also influenced by non-genetic factors
like age, sex, pregnancy, oral contraceptive use, or
vitamin K intake [13, 26]. Moreover, some poly-
morphisms within the PROC and PROS1 genes,
or within vitamin K-dependent gamma-carboxy-
lation-related genes, may affect PC and PS activity
or antigen concentrations [27, 28].
Clinical Manifestations
and Treatment of PC
and PS Deficiencies
The risk of developing thrombosis among in-
dividuals with genetic defect in PROC or PROS1
genes varies significantly and depends on multiple
gene-gene or gene-environment interactions. Peo-
ple with hereditary PC/PS deficiency have about
a 2- to 11-fold increased risk for VTE developing,
with its main clinical presentations of DVT and
pulmonary embolism (PE) in comparison with
those without a deficiency [29]. This means that
DVT or PE will occur in approximately 1 of every
100 to 500 people with one of these deficiencies an-
nually [29]. Less common manifestations of PC/PS
deficiency are superficial, cerebral, visceral, or axil-
lary vein thrombosis [26].
Depending on the phenotype, approximately
half of the PC/PS deficient subjects become symp-
tomatic at 55 years of age, whereas others will
never experience any complications [26, 30]. The
development of VTE in PC/PS deficient patients
may be provoked by concomitant thrombophilic
defects (FV Leiden, prothrombin G20210A, in-
creased levels of FVIII, IX, and XI, hyperhomo-
cysteinemia) and exposure to transient risk fac-
tors (obesity, surgery, trauma, immobilization,
chronic illnesses, pregnancy, or female hormone
intake) [29, 31].
The large European Prospective Cohort on
Thrombophilia (EPCOT) study has shown that
4.5% of asymptomatic relatives of patients with
confirmed thrombophilia, developed first VTE
during the 5.7 years of follow-up [32]. The annu-
al incidence of VTE in PC- (0.7%) and PS- (0.8%)
deficient patients was higher than in cases of FV
Leiden [32].
Patients with provoked episodes are labeled as
a low risk category and receive time-limited anti-
coagulation, usually 3 to 6 months of warfarin [33].
Warfarin should be administered initially with an
additional injectable anticoagulant (usually low-
molecular-weight heparin, LMWH) until an in-
ternational normalized ratio (INR) of 2.0–3.0 is
reached on two consecutive days. Heparin should
be given for at least 5 days to prevent skin necro-
sis, which is a rare adverse effect that occurs dur-
ing early warfarin treatment in patients with PS/
/PC deficiency [26]. Patients with idiopathic events
are considered at high risk for VTE recurrence
and benefit from indefinite duration anticoagula-
tion [33, 34].
Patients with hereditary PC/PS deficiency have
a high risk of VTE recurrence. A retrospective study
in a large cohort of families has shown that annu-
al incidences of first recurrence after a first episode
of VTE were 6.0% (95% CI, 3.9–8.7) in PC-defi-
cient patients and 8.4% (95% CI, 5.8–11.7) in PS-
deficient patients [30]. This risk has been increased
1.4-fold by concomitance of other thrombophil-
ic defects e.g. FV Leiden, prothrombin G20210A
compared to patients without concomitant throm-
bophilic defects [30].
Severe PC/PS deficiency when plasma PC/
/PS concentrations are almost undetectable is as-
sociated with PC/PS homozygosity or compound
heterozygosity. This extremely rare condition
causes PF and DIC and is characterized by gen-
eral clotting in the microvasculature [15, 16]. PF
originates with red or purpuric lesions which rap-
idly progress to form palpable black eschars on the
back of the head and buttocks. Coagulation stud-
ies have shown markedly elevated D-dimer, an
undetectable plasma PC activity, thrombocytope-
nia, hypofibrinogenaemia, and prolongation of the
prothrombin time [15].
Neonatal PF can be monitored only with PC
replacement in the form of fresh frozen plasma
(FFP) or a human plasma-derived, viral inacti-
vated PC concentrate (Ceprotin) [15]. Ceprotin
is manufactured by Baxter BioScience (Glendale,
CA, USA) and has been licensed in the United
States and Europe.
Replacement therapy with PC concentrate can
be used at a dose of 100 U/kg followed by 50 U/kg
every 6 hours to maintain a PC level of about 50%.
If PC concentrate is unavailable, FFP is recom-
mended at a dose 10–15 ml/kg every 8–12 h. The
most affected infants have been managed for long-
term secondary prophylaxis with PC concentrate
or therapeutic anticoagulation using either LMWH
or high-intensity warfarin [15]. Monitoring with
D-dimer levels for evidence of coagulation activa-
tion is useful to confirm adequate replacement or
anticoagulation therapy [35].
Recombinant APC (Xigris; Eli Lilly, India-
napolis, IN, USA) has also been used to treat PF
in a child with severe PC deficiency and 24 µg/
/kg/h dose has been administrated [36]. However,
Protein C and Protein S Deficiency
463
potential hemorrhagic risk may be involved during
this treatment [37].
Although PC/PS deficiency is associated pri-
marily with an increased risk for VTE, some stud-
ies have shown that arterial thrombosis manifested
by myocardial infarction (MI) or ischemic stroke
may be caused by PC/PS deficiency with other pre-
disposing factors involvement [38–40]. Sayin et al.
has found that left main coronary artery (LMCA)
thrombus accompanied by embolization of the left
anterior descending artery (LAD) in a 37-year-old
man with normal coronary arteries was caused by
PC and PS deficiency [38]. In this case cigarette
smoking was considered to be a contributory fac-
tor leading to endothelial dysfunction. A large
family cohort study demonstrated that heredi-
tary PC (PC antigen < 63% and/or activity < 64%)
or PS (PS antigen < 68%) deficiency is associated
with increased risk of arterial thrombosis, defined
as MI, ischemic stroke or transient ischemic attack,
before age 55 years, but not in older subjects [40].
Indications for PC/PS
Deficiencies Diagnostic
Testing
1. VTE without obvious cause < 45–50 years.
2. VTE in patients with a family history of
thrombosis.
3. Recurrent VTE.
4. Thrombosis at an unusual location.
5. Developing VTE during pregnancy, use
of oral contraceptives or hormone replacement
therapy.
In asymptomatic patients with PC/PS deficien-
cy thromboprophylaxis is not recommended.
Blood Sample Collection
and Processing for PC/PS
Deficiency Testing
For routine screening of PC deficiency the ami-
dolytic PC assay is recommended as more func-
tional and specific than coagulation assays [41].
PC antigen is generally assayed by ELISA [18]. Im-
munoassays for free and total PS are preferred for
screening, and clotting assays for PS activity (Ta-
ble 1). If the results of functional and antigenic as-
says do not confirm the diagnosis unequivocally,
genetic testing is indicated [14].
Testing should be done at least several weeks
(3–6 months) after an acute clotting event to allow
acute-phase reactant proteins to return to base-
line [29, 42].
PC/PS deficiency should not be diagnosed or
excluded on the basis of assays performed when the
patient is taking vitamin K antagonist (VKA) [18].
To avoid false-positive test results, plasma samples
should be taken after temporary interruption of oral
anticoagulant therapy for at least 10 days [42] and,
in some cases, bridging anticoagulation with alterna-
tive agents such as LMWH [26]. Positive test results
should be confirmed by a second blood sample.
In pregnant women, positive test results should
be established after the postpartum period [42]. To
prove inherited deficiency, testing of family mem-
bers is recommended.
Both patient and family members should re-
ceive genetic counseling prior to genetic testing,
and such testing should only be performed after
obtaining consent.
Additional factors influencing plasma PC/PS
levels are summarized in Table 1.
Molecular Diagnosis
Genetic analysis by DNA sequencing is the im-
portant tool in the diagnosis of PC and PS defi-
ciencies. The presence of the PS pseudogene re-
quires careful primer design to avoid amplification
of pseudogene fragments [14]. When no point mu-
tations within PROC or PROS1 genes have been
found by routine methods, the multiplex ligation-
dependent probe amplification (MLPA) is a use-
ful technique for the detection copy number vari-
ation involving duplication or deletions from one
or more exons to the whole gene [24, 25]. It should
be noted, however, that genetic analysis of patients
with PC levels above 70% and PS levels above 55%
is not recommended because of the very low like-
lihood of detection a mutation associated with in-
herited PC or PS deficiencies [13].
Thromboprophylaxis with LMWH
(Dalteparin, Enoxaparin and
Nadroparin) or Unfractionated
Heparin (UFH) According to Polish
Guidelines for the Prevention
and Treatment of Venous
Thromboembolism, 2012
Both suggested thromboprophylaxis in asymp-
tomatic individuals with a PC/PS deficiency and
thromboprophylaxis indicated after VTE event in-
cludes following groups of patients:
- in pregnancy and puerperium,
- in the perioperative period,
- at the time of internal medicine hospitaliza-
tion (thromboprophylaxis should not be used in
patients at high-risk of bleeding, e.g., liver damage
E. W, A. U
464
INR > 1.5, thrombocytopenia < 50 × 10
3
/ul, serious
bleeding in last 3 months).
After VTE event prophylactic or intermediate
doses of LMWH should be used in patients who
have previously interrupted anticoagulation. Ther-
apeutic doses (after two incidents), adjusted or in-
termediate, should be used in patients who have
previously applied anticoagulation.
Prophylactic PC concentrate should be admin-
istrated prior the invasive procedures with high
risk of thrombosis, bleeding or prior the child-
birth, at the initial dose of 100 U/kg followed by
30–50 U/kg every 12–24 h until PC > 100% (mini-
mal PC activity 20–50%).
Indications for extended anticoagulation after
one episode of VTE:
anticoagulant therapy for up to 2 years with-
out other thrombophilia,
life-long if other thrombophilia is present
(coexistence of PC/PS heterozygous deficiency
with FV Leiden or prothrombin 20210A).
PS and PC Deficiencies with
Known Genetic Background
in Polish Patients
So far the authors identified two mutations re-
sponsible for PC deficiency and two mutations re-
sponsible for PS deficiency in Polish patients who
have been referred to the Centre for Coagulation
Disorders, John Paul II Hospital, Krakow, Poland.
A missense mutation in a PROC gene, a het-
erozygous nucleotide substitution G > C in codon
109 resulting in the replacement of glycine for argi-
nine (G109R) associated with PC deficiency was de-
scribed for the first time in a 28-year-old male Pol-
ish patient, who was admitted due to acute MI with
anterior wall ST-segment elevation (STEMI) 8 h af-
ter the pain onset. Coronary angiography revealed
a thrombus in the LMCA leading to an 80% diame-
ter stenosis and distal embolization of LAD; whereas
the remaining vessels were normal. The patient re-
ceived clopidogrel with a glycoprotein IIb/IIIa in-
hibitor (abciximab) and unfractionated heparin
with the subsequent intravenous infusion. Twenty-
four hours after angiography enoxaparin at thera-
peutic doses was initiated with clopidogrel and as-
pirin. After 7 days, a repeat coronary angiography
showed no evidence of residual thrombus in LMCA
or LAD. The patient was discharged on dual anti-
platelet therapy with enoxaparin (maintained for
6 months) and after a year clopidogrel was discon-
tinued. The patient remains on aspirin indefinite-
ly. PC antigen values were reduced to 46% and 59%
on the two respective occasions (reference range,
65–140%). In this case the patient’s risk factors in-
cluding heavy smoking, hypercholesterolemia, and
obesity in combination with genetic thrombophilic
factor caused the LMCA thrombus [43].
The second PROC mutation discovered in
a Polish patient was a heterozygous nucleotide
T > C substitution in codon 106 resulting in the
replacement of cysteine by arginine (C106R)
which has not been reported so far in the liter-
ature. A 29-year-old, obese male patient experi-
enced first-ever proximal DVT of the left leg fol-
lowing trauma and the subsequent high-risk PE
with hypotonia that was successfully treated with
tenecteplase, a fibrinolytic agent. The patient
started therapy with acenocoumarol with a tar-
get INR value of 2 to 3. His family history of was
negative. On two separate occasions PC activ-
ity was 42% (reference range, 70–140%), while
PC antigen were 44% and 41% (reference range,
65–140%), respectively. The diagnosis of the type
I PC deficiency was established (Wypasek 2013,
unpublished data).
The first Polish case of PS deficiency with ge-
netic characterization has been reported in a young
male patient, who experienced idiopathic DVT at
the age of 24 and was treated with enoxaparin for
5 months. A few months later he developed ede-
ma of the right calf and right popliteal vein throm-
bosis was diagnosed. He started acenocoumarol at
a daily dose of 2–3 mg with a target INR of 2 to 3.
Family history revealed idiopathic DVT complicat-
ed with post-thrombotic syndrome in the patient’s
mother at the age of 45 and two episodes of DVT in
her sister. The free PS level was 18.9% in the patient
(male reference range 74–146%) and 17.6% in the
patient’s mother (female reference range 55–124%).
Similar results were obtained on two separate occa-
sions. Total PS in both patients were reduced to 40
and 44%, respectively (reference range 70–120%).
Type I PS deficiency was diagnosed. MLPA analysis
profile suggested a large deletion involving exons 1
to 12 of the PROS1 gene, present at the heterozygous
state in both the proband and his mother [44].
Another report associated with PS deficiency
was the Heerlen polymorphism, a missense ser-
ine 501 to proline exchange (S501P) resulting in
thymine to cytosine transition in exon 13 of the
PROS1 gene. The association between the PS Heer-
len and venous thromboembolism (VTE) is not
clearly established. The prevalence of the S501P
mutation is high in the healthy European popu-
lation (0.5%) and data on the association between
PS Heerlen and thrombosis are inconsistent [45].
It was shown that the PS Heerlen may be involved
in the occurrence of VTE when other genetic risk
factors like FV Leiden, prothrombin G20210A or
antiphospholipid antibodies are present [46].
Protein C and Protein S Deficiency
465
PS Heerlen has been reported in a 50-year-
-old man with several thrombotic episodes of
deep and superficial veins and a highly positive
thrombotic family history. He was successfully
treated with enoxaparin for 3 months but refused
anticoagulation with VKA taking only low-dose
aspirin. The free PS levels were reduced to 52.8%
and 55.8% on the two separate occasions (refer-
ence range 74–146%). Total PS was 110.5% (ref-
erence range 75–140%). Type III PS deficiency
combined with FV Leiden and primary antiphos-
pholipid syndrome was diagnosed [47].
The current evidence indicates that screen-
ing for inherited thrombophilia, including defi-
ciencies in natural anticoagulants like PC and PS,
should be conducted in young patients with VTE
and in selected cases of stroke or MI in particular if
a family history for thrombosis is positive. Patients
with low PC and PS levels and the known muta-
tion within PROC or PROS1 genes combined with
other genetic or environmental thrombosis factors
are at increased risk of recurrent thromboembol-
ic events and require lifelong oral anticoagulation
even after the first episode. Given positive family
history including deaths from VTE among first de-
gree relatives, genetic counseling in such families
should be implemented and appropriate thrombo-
prophylaxis in high-risk states should be consid-
ered in asymptomatic carriers.
References
[1] Esmon CT: The protein C pathway. Chest 2003, 124, 26S–32S.
[2] Dahlbäck B: Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008, 112,
19–27.
[3] Dahlback B: Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein.
J Biol Chem 1986, 261, 12022–12027.
[4] Hackeng TM, van’t Veer C, Meijers JCM, Bouma BN: Human protein S inhibits prothrombinase complex activ-
ity on endothelial cells via a direct interaction of protein S with factor Va and Xa. Evidence for an activated protein
C independant anticoagulant function of protein S in plasma. J Biol Chem 1994, 269, 21051–21058.
[5] Hackeng T, Sere KM, Tans G, Rosing J: Protein S stimulates inhibition of the tissue factor pathway by tissue factor
pathway inhibitor. Proc Natl Acad Sci 2006, 103, 3106–3111.
[6] Griffin JH, Zlokovic BV, Mosnier LO: Protein C anticoagulant and cytoprotective pathways. Int J Hematol 2012,
95, 333–345.
[7] Dahlbäck B, Villoutreix BO: Regulation of blood coagulation by the protein C anticoagulant pathway: novel
insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005, 25,
1311–1320.
[8] Mosnier LO, Zlokovic BV, Griffin JH: The cytoprotective protein C pathway. Blood 2007, 109, 3161–3172.
[9] Cheng T, Liu D, Griffin JH, Fernández JA, Castellino FJ, Rosen ED, Fukudome K, Zlokovic BV: Activated
protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med
2003, 9, 338–342.
[10] Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C: Deficiency of protein C in congenital thrombotic
disease. J Clin Invest 1981, 68, 1370–1373.
[11] Comp PC, Esmon CT: Recurrent venous thromboembolism in patients with a partial deficiency of protein S.
N Engl J Med 1984, 311, 1525–1528.
[12] Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology Investigation and
management of heritable thrombophilia. Br J Haematol 2001, 114, 512–528.
[13] Caspers M, Pavlova A, Driesen J, Harbrecht U, Klamroth R, Kadar J, Fischer R, Kemkes-Matthes B, Oldenburg J:
Deficiencies of antithrombin, protein C and protein S practical experience in genetic analysis of a large patient
cohort. Thromb Haemost 2012, 108, 247–57.
[14] Bereczky Z, Kovács KB, Muszbek L: Protein C and protein S deficiencies: similarities and differences between two
brothers playing in the same game. Clin Chem Lab Med 2010, 48, S53–66.
[15] Goldenberg NA, Manco-Johnson MJ: Protein C deficiency. Haemophilia 2008, 14, 1214–1221.
[16] Estelles A, Garcia-Plaza I, Dasi A, Aznar J, Duart M, Sanz G, Pérez-Requejo JL, Espana F, Jimenez C, Abeledo G:
Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984, 52, 53–56.
[17] Reitsma PH, Poort SR, Bernardi F, Gandrille S, Long GL, Sala N, Cooper DN: Protein C deficiency: a data-
base of mutations. For the Protein C & S Subcommittee of the Scientific and Standardization Committee of the
International Society on Thrombosis and Haemostasis. Thromb Haemost 1993, 69, 77–84.
[18] Mackie I, Cooper P, Lawrie A, Kitchen S, Gray E, Laffan M: British Committee for Standards in Haematology:
Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Int J Lab Hematol 2013, 35, 1–13.
[19] García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N: Molecular basis of protein S deficiency. Thromb Haemost
2007, 98, 543–556.
[20] Borgel D, Duchemin J, Alhenc-Gelas M, Matheron C, Aiach M, Gandrille S: Molecular basis for protein S hered-
itary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network
on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies. J Lab Clin Med 1996, 128,
218–227.
E. W, A. U
466
[21] Mulder R, Tichelaar VY, Lijfering WM, Kluin-Nelemans HC, Mulder AB, Meijer K: Decreased free protein
S levels and venous thrombosis in the acute setting, a case-control study. Thromb Res 2011, 128, 501–502.
[22] Bissuel F, Berruyer M, Causse X, Dechavanne M, Trepo C: Acquired protein S deficiency: correlation with
advanced disease in HIV-1-infected patients. J Acquir Immune Defic Syndr 1992, 5, 484–489.
[23] Regnault V, Boehlen F, Ozsahin H, Wahl D, de Groot PG, Lecompte T, de Moerloose P: Anti-protein S anti-
bodies following a varicella infection: detection, characterization and influence on thrombin generation. J Thromb
Haemost 2005, 3, 243–249.
[24] Lind-Halldén C, Dahlen A, Hillarp A, Zöller B, Dahlbäck B, Halldén C: Small and large PROS1 deletions but no
other types of rearrangements detected in patients with protein S deficiency. Thromb Haemost 2012, 108, 94–100.
[25] Pintao MC, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, de Visser MC, Gandrille S, Reitsma PH: Gross
deletions/duplications in PROS1 are relatively common in point mutation negative hereditary protein S deficiency.
Hum Genet 2009, 126, 449–456.
[26] ten Kate MK, van der Meer J: Protein S deficiency: a clinical perspective. Haemophilia 2008, 14, 1222–1228.
[27] Kimura R, Kokubo Y, Miyashita K, Otsubo R, Nagatsuka K, Otsuki T, Sakata T, Nagura J, Okayama A,
Minematsu K, Naritomi H, Honda S, Sato K, Tomoike H, Miyata T: Polymorphisms in vitamin K-dependent
gamma-carboxylation-related genes influence interindividual variability in plasma protein C and protein S activi-
ties in the general population. Int J Hematol 2006, 84, 387–397.
[28] Aiach M, Nicaud V, Alhenc-Gelas M, Gandrille S, Arnaud E, Amiral J, Guize L, Fiessinger JN, Emmerich J:
Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic
risk. Arterioscler Thromb Vasc Biol 1999, 19, 1573–1576.
[29] Lipe B, Ornstein DL: Deficiencies of natural anticoagulants, protein C, protein S, and antithrombin. Circulation
2011, 124, e365–368.
[30] Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J: High long-term
absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein
C or antithrombin. Thromb Haemost 2009, 101, 93–99.
[31] Brouwer JL, Veeger NJ, Kluin-Nelemans HC, van der Meer J: The pathogenesis of venous thromboembolism:
evidence for multiple interrelated causes. Ann Intern Med 2006, 145, 807–815.
[32] Vossen CY, Conard J, Fontcuberta J, Makris M, van der Meer FJ, Pabinger I, Palareti G, Preston FE, Scharrer I,
Souto JC, Svensson P, Walker ID, Rosendaal FR: Risk of a first venous thrombotic event in carriers of a familial throm-
bophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005, 3, 459–464.
[33] Goldhaber SZ, Piazza G: Optimal duration of anticoagulation after venous thromboembolism. Circulation 2011,
123, 664–667.
[34] Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM,
Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ: Long-term,
low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003, 348,
1425–1434.
[35] Monagle P, Andrew M, Halton J, Marlar R, Jardine L, Vegh P, Johnston M, Webber C, Massicotte MP:
Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular
weight heparin. Thromb Haemost 1998, 79, 756–761.
[36] Manco-Johnson MJ, Knapp-Clevenger R: Activated protein C concentrate reverses purpura fulminans in severe
genetic protein C deficiency. J Pediatr Hematol Oncol 2004, 26, 25–27.
[37] Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R,
Wang D, Sundin DP, Giroir B: REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspec-
tive (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III
randomised controlled trial. Lancet 2007, 369, 836–843.
[38] Sayin MR, Akpinar I, Karabag T, Aydin M, Dogan SM, Cil C: Left main coronary artery thrombus resulting from
combined protein C and S deficiency. Intern Med 2012, 51, 3041–3044.
[39] Sadiq A, Ahmed S, Karim A, Spivak J, Mattana J: Acute myocardial infarction: a rare complication of protein
C deficiency. Am J Med 2001, 110, 414.
[40] Mahmoodi BK, Brouwer JL, Veeger NJ, van der Meer J: Hereditary deficiency of protein C or protein S con-
fers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study.
Circulation 2008, 118, 1659–1667.
[41] Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC,
Walker I, Watson H: Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010, 149, 209–220.
[42] Heit JA: Thrombophilia: common questions on laboratory assessment and management. Hematology Am Soc
Hematol Educ Program 2007, 127–135.
[43] Wypasek E, Pankiw-Bembenek O, Potaczek DP, Alhenc-Gelas M, Trebacz J, Undas A: A missense mutation
G109R in the PROC gene associated with type I protein C deficiency in a young Polish man with acute myocardial
infarction. Int J Cardiol 2013, May 2.
[44] Wypasek E, Alhenc-Gelas M, Undas A: First report of a large PROS1 deletion from exon 1 through 12 detected
in Polish patients with deep-vein thrombosis. Thromb Res 2013, Mar 6.
[45] Bertina RM, Ploos van Amstel HK, van Wijngaarden A, Coenen J, Leemhuis MP, Deutz-Terlouw PP, van der
Linden IK, Reitsma PH: Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism
of residue 460. Blood 1990, 76, 538–548.
Protein C and Protein S Deficiency
467
[46] Giri TK, Yamazaki T, Sala N, Dahlba¨ck B, de Frutos PG: Deficient APC-cofactor activity of protein S Heerlen
in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factors. Blood
2000, 96, 523–531.
[47] Wypasek E, Potaczek PD, Alhenc-Gelas M, Undas A: Heerlen polymorphism associated with type III pro-
tein S deficiency and factor V mutation in a Polish patient with deep vein thrombosis. Blood Coagul Fibrinolysis
(in press).
Address for correspondence:
Anetta Undas
Institute of Cardiology
Jagiellonian University Medical College
80 Prądnicka St.
31-202 Kraków
Poland
Tel.: +48 12 614 30 04
E-mail: mmundas@cyf-kr.edu.pl
Conflict of interest: None declared
Received: 4.06.2013
Accepted: 12.08.2013
... The anticoagulant effect of PC (autoprothrombin IIA and blood coagulation factor XIX) was first demonstrated in 1960 [38]. PC deficiency is detected in 0.5-6% of patients presenting with venous thromboembolism [39]. Consisting of two subunits linked by disulphide bonds, this protein is 62 kDa in size and is synthesized in the liver [40]. ...
... Activated protein C (APC), active FV and FVIII causes its inactivation. In addition to its anti-coagulant effects, PC also has different biological effects such as anti-inflammatory and cellprotective effects [39,43]. ...
Article
Full-text available
COVID-19 is the most devastating pandemic situation we have experienced in our age, affecting all systems. Although it affects all systems, it shows its most important effect through thrombophilia. Therefore, the possible cause of sudden death due to COVID-19 may be embolism caused by thrombophilia. D-dimer amounts increase due to COVID-19. The thrombosis is associated with sudden death in COVID-19 disease in populations. Since individuals with thrombophilia will be more prone to death due to COVID-19, it may be appropriate to administer low doses of Clexane ( Enoxaparin sodium ) or low-weight heparin for prophylactic purposes in order to consider these individuals at high risk and to prevent deaths. Moreover, in order not to risk the lives of healthcare professionals with thrombophilia, it would be appropriate to keep them away from individuals with COVID-19 disease and to employ them in different healthcare services according to their fields of expertise. It should also not be forgotten that different symptoms related to COVID-19 appear day by day, these different symptoms probably show that the virus has undergone mutations in order to survive, but no matter what, its effect on thrombophilia has not been eliminated yet. This compilation aims to present the reasons and causes of death due to COVID-19, possible treatment options, and thrombophilia panel tests and new parameters that may have a place in the meticulous interpretation of these tests and possible etiopathology in the light of current information. Therefore, presenting this information in a rational manner and keeping the parameters of the thrombophilia panel under strict control predict that the deaths due to the virus will be partially reduced.
... Protein S (PS) also known as S-protein is a 70 kDa VK-dependent plasma glycoprotein (Wypasek & Undas, 2013) synthesized primarily in the liver apart from endothelial cells (Fair et al., 1986), testicular Leydig cells and osteoclasts (Griffin et al., 2007). PS inhibits blood coagulation by serving as a non-enzymatic cofactor for activated protein C (PC), factor V (FVa) and activated factor VIII (FVIIIa) in the anticoagulant pathway (De Wolf et al., 2006), and PS further showing anticoagulant activity that is independent from activated PC (Sere et al., 2004). ...
... In the circulation, PS exists in two forms, a free form and a complex form bound to complement protein C4b-binding protein (C4BP) (Dahlbäck & Villoutreix, 2005) with its deficiency leading to venous thromboembolism. In humans, PS is encoded by the PROS1 gene, with an inherent mutation causing PS deficiency leading to an increased risk of deep venous thrombosis (Wypasek & Undas, 2013), however at times PS deficiency may also be acquired as a result of pregnancy (Lalan et al., 2012), kidney disease (D'Angelo et al., 1988), or due to the usage of oral contraceptives (Boerger et al., 1987;Mackie et al., 2001). ...
Article
Background Vitamins play an essential role in various physiological and biological processes, and their deficiency causes several health consequences in humans. Unlike vitamins A, B, C, D, E, the vitamin K (VK) deficiency is not dealt with profusely keeping in view of its inherent dietary sources and its health implications in human physiology such as blood coagulation. The VK family belongs to a variety of distinct subtypes in the length of side chains composed of isoprenoid families, and is important for various biological functions while much of the behaviour is not unknown. Scope and approach In the recent past, a lot of knowledge has been derived from the VK deficiency and its comorbidities. This review emphasizes on the nutrigenomics perspective of VK deficiency as we throw light on diagnostic challenges of VK. Key findings and conclusions We highlight the molecular physiological perspectives of VK using systems/nutri-genomics approaches and explore the human health effects of VK deficiency besides giving a gist of food-omics technologies.
... Proteins C and S are vitamin K-dependent glycoproteins. Protein S, the cofactor for protein C, supports the activated protein C in the presence of phospholipids and calcium in the inactivation of membrane-bound factors V (FVa) and FVIIIa (9). The mechanistic pathways through which protein C exerts its effects on the coagulation cascades include degrading factors V/ Va and VIII/VIIIa, releasing a tissue-type plasminogen activator, and stimulating fibrinolysis by interacting with the plasminogen activator inhibitor (10). ...
Article
Full-text available
Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PT CRT (15.014) and PT SVR (13.846) (PT CRL = 13.383, p < 0.001), PTT CRT (42.923) and PTT SVR (37.8) (PTT CRL = 36.494, p < 0.001), LAC CRT (49.414) and LAC SVR (47.046) (LAC CRL = 40.763, p < 0.001), FIB CRT (537.66) and FIB SVR (480.29) (FIB CRL = 283.57, p < 0.001), ProC CRT (85.57%) and ProC SVR (99.34%) (ProC CRL = 94.31%, p = 0.04), ProS CRT (62.91%) and ProS SVR (65.06%) (ProS CRL = 75.03%, p < 0.001), D-dimer ( p < 0.0001, χ ² = 34.812), and FDP ( p < 0.002, χ ² = 15.205). No significant association was found in the ATIII results in groups (ATIII CRT = 95.71% and ATIII SVR = 99.63%; ATIII CRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p -values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.
... In patients diagnosed with venous thrombosis, long-term anticoagulants should be used to ensure that the treatment is effective and the disease does not recur. Lifelong treatment should be considered especially in thrombophilic patients with atypical localization [43,44]. In a study comparing LMWH (tinzaparin sodium) and continuous IV heparin in the treatment of proximal DVT, patients treated with LMWH had better results in terms of survival and major bleeding compared to SH patients, and LMWHs were at least as effective and safe as classical heparins, It has been stated that it is easy to use and will provide outpatient treatment for patients with uncomplicated proximal DVT [45]. ...
Article
Full-text available
Introduction: Deep vein thrombosis is an important health problem that is frequently encountered in the general population and especially in surgical clinics and has a negative impact on quality of life. In this study, treatment options and results of patients with deep vein thrombosis who have been hospitalized for 12 years in Atatürk University and Erzurum Regional Hospital were examined and discussed. Methods: In our clinic, 412 cases of deep vein thrombosis (211 female, 201 male) were hospitalized between 2009 and 2021. The mean age of the patients was 49 ± 19 years. While medical treatment with heparin was given to all 412 patients; thrombolytic therapy, surgical embolectomy (vascular and pulmoner), and pharmaco-mechanical thrombectomy were applied to some of these patients. Results: Deep vein thrombosis was more common in the lower extremity (n=322, 78.2%). All patients had at least one of the complaints of pain, swelling and redness. All cases were diagnosed by color Doppler ultrasonography. Medically, standard and low molecular weight heparin therapy was given to all patients after hospitalization. Thrombolytic therapy was applied to 66 (16,1%) of the cases, pulmonary embolectomy to 8 (1,9%), surgical thrombectomy to 10 (2,4%) and pharmacomechanical thrombectomy to 44 (10,7%) patients. In addition to these 120 patients (29.1%), a vena cava filter was placed for prophylactic purposes. Conclusions: In patients diagnosed with deep vein thrombosis and hospitalized, the diagnosis should be supported by Doppler ultrasound in addition to clinical diagnosis after an etiology investigation. Early diagnosis, rapid and effective treatment methods are important for the subsequent quality of life of patients. In addition to low molecular weight heparins being the first choice agents, standard heparin administration still needs to be applied in some clinical pictures. In addition, we believe that pharmacomechanical thrombectomy can be applied in appropriate acute cases. Keywords: Deep vein thrombosis; anticoagulant treatment; heparin therapy; low-molecular-weight heparin; mechanical thrombectomy.
... Blood tests showed no hereditary hypercoagulability disorder such as protein C and S deficiency, as the possible cause of the thrombus. 5 She had no history of thrombophilia. ...
Article
Full-text available
A 99-year-old woman with atrial fibrillation bradycardia and symptomatic long pauses underwent a leadless pacemaker implantation after red blood cell transfusion due to anaemia. The patient’s blood tests after transfusion showed hypercoagulability; haematocrit, haemoglobin and fibrinogen levels were increased from 24.5% to 33.2%, 76 g/L to 111g/L, and 346 mg/dL to 646 mg/dL, respectively. Blood tests showed no hereditary hypercoagulability disorder and she had no history of thrombophilia. A leadless pacemaker was implanted in the correct position in the right ventricle. Heparin was administered after sheath insertion and the leadless pacemaker system was thoroughly flushed with heparinised saline before the tether was cut; however, removing the tether after leadless pacemaker implantation was difficult because clots had formed on the tether.
... On the other hand, PS also serves as a cofactor of tissue factor pathway inhibitor (TFPI), which inhibits the activity of tissue factors by promoting the binding interaction of TFPI and FXa [4]. Hereditary protein S deficiency (PSD) is an autosomal dominant hereditary disease, which may be caused by genetic and acquired factors [5]. It is classified into three subtypes: Type I (total PS, free PS levels, and PS activity are decreased), type II (total PS and free PS levels are normal, but PS activity is decreased), and type III (total PS level is normal, but free PS level and PS activity are decreased) [6]. ...
Article
Full-text available
Background Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S ( PROS1 ) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown. Methods The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1 . Results In this family, the proband with venous thrombosis of both lower extremities, the proband’s mother with pulmonary embolism and venous thrombosis of both lower extremities, and the proband’s younger brother had significantly lower PS activity and carried a PROS1 c. 1820 T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation. Conclusions The analysis of family phenotype, gene association, and cell function tests suggest that the PROS1 Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.
... On the other hand, PS also serves as a cofactor of tissue factor pathway inhibitor (TFPI), which inhibits the activity of tissue factors by promoting the binding interaction of TFPI and FXa [4]. Hereditary protein S de ciency (PSD) is an autosomal dominant hereditary disease, which may be caused by genetic and acquired factors [5]. It is classi ed into three subtypes: Type I (total PS, free PS levels, and PS activity are to "sudden chest pain with loss of consciousness" and was diagnosed with "pulmonary embolism." ...
Preprint
Full-text available
Background: Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S (PROS1) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown. Methods: The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1. Results: In this family, the proband with venous thrombosis of both lower extremities, the proband’s mother with pulmonary thrombosis and venous thrombosis of both lower extremities, and the proband’s younger brother had significantly lower PS activity and carried a PROS1 c. 1820T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation. Conclusions: The analysis of family phenotype, gene association, and cell function tests suggest that the PROS Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.
... Activated protein C inhibits thrombosis by deactivating activated factors V and VIII. Protein S serves as a co-factor during this process (110)(111)(112). Patients with hepatic cirrhosis usually have low levels of protein C and high levels of factor VIII. ...
Article
Full-text available
Mycoplasma pneumoniae is a common pathogen causing respiratory infections in children and adults. In addition to respiratory diseases, Mycoplasma pneumoniae is also involved in numerous extrapulmonary diseases. Thrombosis is an extrapulmonary manifestation associated with Mycoplasma pneumoniae infection. In recent years, an increasing number of case reports have been published identifying thrombosis secondary to Mycoplasma pneumoniae infection. In the present study, the available relevant literature in English available on PubMed, Medline and Web of Science was consulted. The results of the present study demonstrated that in patients with thrombosis caused by Mycoplasma pneumoniae infection, some of the factors causing thrombosis are transient and some are due to hereditary thrombophilia. Following timely treatment, the majority of patients recovered completely but some patients had a poor prognosis. The present review focuses on the pathogenesis, clinical features, treatment and prognosis of this crucial issue, which contributes toward the understanding of the disease.
Article
The interest in the role of the gravitational factor during landing after long-term space flights (SF) leads to the search for various innovative approaches to assessing the compliance of external changes observed by clinicians. The results of special research methods such as Omics technologies that may reflect physiological responses to the conditions created during landing are of great interest. Our purpose is to compare the blood plasma proteome changes associated with the trauma and endothelial dysfunction processes prior to launch and on the day of landing, as well as the groups of cosmonauts with and without the secondary hemorrhagic purpura. In our study, the concentrations of 125 plasma proteins in 18 Russian cosmonauts, measured using targeted proteomic analysis based on liquid chromatography and tandem mass spectrometry were analyzed. The results reveal the trends of 12 proteins participating in the processes that trigger hemorrhagic purpura under the effect of re-entry g-forces. Exposure to intense g-forces and return to the gravity are the key factors for external manifestations of changes in the body systems induced by a long-term stay in space microgravity. Our results may be useful for further research to experts in gravitational physiology, aviation and space medicine.
Article
The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.
Article
Protein S is one of the major natural anticoagulants. A missense serine 501 to proline (S501P) Heerlen polymorphism is associated with reduced levels of free protein S. Heerlen polymorphism, especially when combined with other thrombophilia risk factors, can lead to thromboembolic complications. To our knowledge, we report here the first Polish case associated with heterozygous Heerlen polymorphism resulting in type III protein S deficiency, detected in a 50-year-old man with several thrombotic episodes of deep and superficial veins and a highly positive thrombotic family history. The patient also had factor V Leiden mutation and persistently elevated anticardiolipin antibodies. It seems that increased risk of thrombotic complications could be explained in the patient by a synergy between the effects of Heerlen polymorphism, factor V Leiden heterozygous status and antiphospholipid syndrome.
Article
Inherited hypercoagulopathies such as protein C and S deficiency usually lead to the formation of venous thrombi in clinical practice; however, they rarely lead to arterial thrombosis. It has been demonstrated that both protein C and S deficiency may lead to myocardial infarctions. However, our literature review revealed no reports of left main coronary artery thrombi caused by protein C and S deficiency. This paper presents a case of a left main coronary artery thrombus resulting from protein C and S deficiency in a young patient with normal coronary arteries.
Article
Keywords:heritable thrombophilia;case finding;thromboprophylaxis;venous thromboembolism