Protein C & S

Deficiency

Definition of Protein C deficiency

Protein C deficiency is a congenital or acquired
condition that leads to increased risk for thrombosis.
Congenital protein C deficiency is one of several
inherited thrombophilias, which are a heterogeneous
group of genetic disorders associated with an elevated
risk of venous thromboembolism

Pathophysiology
Protein C is a 62-kD, vitamin Kdependent glycoprotein
synthesized in the liver. It
circulates in the blood as an
inactive zymogen at a
concentration of 4 g/mL.
Its activation into the serineprotease-like enzyme, activated
protein C (aPC), is catalyzed by
thrombin when it is bound to the
endothelial proteoglycan
thrombomodulin.

 Activated protein C (aPC) exerts its anticoagulant

activity primarily through inactivation of coagulation
factors Va and VIIIa, which are required for factor X
activation and thrombin generation.
The catalytic activity of activated protein C (aPC) is
greatly enhanced by the vitamin K-dependent cofactor
protein S.

 A deficiency of activated protein C (aPC) disturbs the

delicate balance between procoagulant and
anticoagulant proteins and engenders a prothrombotic
environment.
The role of activated protein C (aPC) and other
anticoagulant proteins in this balance appears to be
especially important in the slow-flowing venous
circulation, in which there is prolonged exposure of
procoagulant proteins and platelet phospholipids to the
vessel wall.
This may explain, in part, why protein C deficiency
appears to be associated primarily with venous

Clinical manifestation
History should be asked:
1. Does the patient have a previous history of venous
thromboembolism (VTE)?
2. Has the patient been treated with anticoagulation in the
past? Is there a history of warfarin-induced skin necrosis
(WISN)? Was there bleeding or other complications of
anticoagulation therapy?
3. Is there a family history of VTE?
4. Is there a family history of neonatal purpura fulminans (NPF)?

Physical examination
1. Venous thromboembolism
2. Warfarin-induced skin
necrosis
The skin lesions of WISN occur on the
extremities, torso, breasts, and penis.
They begin as erythematous macules
and, if appropriate therapy is not
initiated promptly, evolve to become
purpuric and necrotic bullae. A patient
with warfarin-induced skin necrosis.

3. Neonatal purpura
fulminans
Affected neonates present with
diffuse ecchymoses which,
similar to the lesions of WISN,
progress to form necrotic
bullae if appropriate therapy is
not rapidly instituted.

Etiology
Causes of acquired protein C deficiency include:

Acute thrombosis
Warfarin therapy
Liver disease
Vitamin K deficiency
Sepsis
Disseminated intravascular coagulation (DIC)
Certain chemotherapeutic agents (eg, L-asparaginase)

Investigation
Assays
Immunologic assays
enzyme-linked immunosorbent assays (ELISAs)
radioimmunoassays (RIAs), and
electroimmunoassays.

Functional assays

Screening protein C level

Management
A substantial proportion of individuals with protein C
deficiency remain asymptomatic throughout life and
require no specific therapy. However,
thromboprophylaxis may be considered in such
individuals, particularly if there is a strong family history
of thrombosis, for situations associated with a high
thrombotic risk such as pregnancy and the postpartum
state, surgery, and trauma.
For those patients who do develop clinical
manifestations of hereditary protein C deficiency,
treatment depends on the particular clinical syndrome:
venous thromboembolism (VTE), warfarin-induced skin

 VTE
Anticoagulation is the mainstay of therapy for the treatment and prevention of
venous thromboembolism (VTE)

WISN
Therapy consists of immediate discontinuation of warfarin,
Administration of vitamin K, and initiation of therapeutic doses of heparin.
If the patient is protein C deficient, administration of exogenous protein C should
be administered, either in the form of fresh frozen plasma (FFP) or, preferably, as
purified protein C concentrate (Ceprotin)

NPF
Fresh frozen plasma highly purified protein C concentrate (Ceprotin)
Anticoagulation therapy
Warfarin

Definition of Protein S deficiency

Protein S deficiency may be hereditary or acquired; the
latter is usually due to hepatic diseases or a vitamin K
deficiency.
Protein S deficiency usually manifests clinically as
venous thromboembolism (VTE).

Pathophysiology
Protein S is part of a system of anticoagulant
proteins that regulate normal coagulation
mechanisms in the body. Under most normal
circumstances, the anticoagulant proteins
prevail and blood remains in a liquid
nonthrombotic state. Whenever procoagulant
forces are locally activated to form a physiologic
or pathologic clot, protein S participates as part
of one mechanism of controlling clot formation
Protein S functions predominantly as a
nonenzymatic cofactor for the action of another
anticoagulant protein, activated protein C (APC).
This activity occurs via a coordinated system of
proteins, termed the protein C system.

Clinical Manifestation
History
1. Symptoms related to protein S deficiency are those associated
with deep venous thrombosis (DVT), thrombophlebitis, or
pulmonary embolus.
2. Venous thrombosis of the lower limbs: Lower limb swelling and
discomfort are the usual symptoms.
3. A family history of thrombosis, eg inherited thrombophilia.
4. Thrombosis at an early age (eg, usually < 55 y) or recurrent
thrombosis is also frequently indicative of an inherited
thrombophilic state (eg, protein S deficiency).

Physical examination
DVT
1. Venous thrombosis of the lower extremities
2. Superficial thrombophlebitis
3. The classic presentation of DVT is a triad of calf pain,
edema, and pain on dorsiflexion of the foot (ie, Homan sign).

Pulmonary embolism
Dyspnea, chest pain, syncope, cardiac palpitations,
tachypnea
Syncope or cyanosis
Classic pleuritic chest pain, cough, or hemoptysis suggests
an embolism with pleural involvement
Right-sided heart failure sign
Findings of right ventricular dysfunction include bulging
neck veins, a left parasternal lift, and an accentuated
pulmonic component of the second heart sound

Etiology
Rarely, an acquired disorder causes protein S deficiency.
Acquired deficiencies of protein S occur with liver
disease, vitamin K deficiency, or as a result of
antagonism with oral warfarin anticoagulants.
Protein S levels decrease in pregnancy and can fall into
the abnormal-low laboratory range. These low levels of
protein S in pregnancy do not cause thrombosis by
themselves.

Investigation
Protein S deficiency is diagnosed using laboratory tests
for the protein S antigen and by using other tests for
functional protein S activity (based on clotting assays)
measured by ELISA methods

Management
Management of protein S deficiency takes place in the
event of acute venous thromboembolism (VTE), include:
1. Heparin
2. Warfarin
3. Prophylaxis
In such patients, avoid drugs that predispose to thrombosis, including
oral contraceptives. In these patients, if surgery or orthopedic injury
occurs, prophylaxis with heparin is mandatory.
In pregnancy, experts recommend prophylaxis with heparin