Protein C deficiency is a rare disorder that results in abnormal blood clotting due to a low level or low activity of protein C, which is a protein found in the blood that acts as an anticoagulant. Protein C deficiency could either be congenital (present at birth) or acquired (occurs later in life due to certain conditions, e.g. severe liver disease). 

Read on to learn about what causes the deficiency in protein C, the main signs and symptoms of protein C deficiency, the group of people with the highest risk of developing protein C deficiency, their prognosis (outlook) and much, much more! 

Introduction

Protein C deficiency is a rare disorder that causes excessive blood clotting.¹ 

Importance of protein C in the body

Protein C acts as an anticoagulant, meaning that it prevents blood clotting. Blood clotting is an important process in the body because it prevents excessive internal bleeding from an injury such as a deep cut or even a mild scratch. Therefore, not having enough protein C in the body, as is the case in people with protein C deficiency, can increase the risk of developing serious blood clotting abnormalities including deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ Pulmonary embolism happens following deep vein thrombosis when a blood clot that is usually located deep within the leg breaks loose and lodges itself into the lung. This can quickly deprive the lungs of oxygen and blood flow, which can lead to death, if not treated promptly. 

Prevalence 

According to research studies, protein C deficiency is rare, with mild protein C deficiency affecting approximately 1 in 200 to 500 people and severe protein C deficiency affecting approximately 1 in 4 million infants.² However, it is suggested that more people are affected by protein C deficiency as the disorder is hugely underdiagnosed and underreported. 

Causes and inheritance  

Protein C deficiency is mainly caused by mutations (changes in the DNA sequence) in the PROC gene.¹ The PROC gene is important for the production of protein C, a protein found in the blood that regulates blood clotting by inactivating (‘turning off’ or blocking) certain proteins that promote blood clotting. 

Protein C deficiency is inherited in an autosomal dominant manner, meaning that one copy of the mutated PROC gene is required to develop the mild form of protein C deficiency.³ People who have two copies of the mutated PROC gene develop severe protein C deficiency.

A child who has one parent with the mutated PROC gene has a 50% chance of inheriting a single copy of the mutated PROC gene. A child with both parents having the mutated PROC gene has a 25% chance of inheriting both copies of the mutated PROC gene. 

It is important to note that protein C deficiency is not just congenital (develops during birth) but can also be acquired and developed from certain conditions later in life including:¹

• Vitamin K deficiency
• Warfarin therapy (prevent blood clots)
• Severe liver disease
• Disseminated intravascular coagulation (DIC)
• Severe bacterial infection (sepsis)

Risk factors 

Certain factors may increase the risk of developing protein C deficiency including:¹ 

• Medications: especially those containing estrogen (e.g. oral contraceptive pills)
• Smoking
• Obesity
• Pregnancy
• Sedentary lifestyle (inactivity)
• Traumatic injury (e.g. car accident) 
• Surgery 

Signs and symptoms 

Mild protein C deficiency 

People with mild protein C deficiency usually develop no signs and symptoms (asymptomatic).¹ Mild protein C deficiency has two main types: 

• Type I: characterised by low levels of protein C 

• Type II: characterised by normal levels of protein C but with low activity 

Regardless of the type of mild protein C deficiency and the absence of symptoms in most patients, mild protein C deficiency increases the risk of developing the following conditions: 

• Venous thromboembolism
  • Deep vein thrombosis (DVT) 
  • Pulmonary embolism (PE)
• Blood clots in other parts of the body including the brain, small, and/or large intestines 

Severe protein C deficiency 

On the other hand, babies born with severe protein C deficiency develop signs and symptoms shortly following birth (within hours to days).¹ Signs and symptoms may include:

• Blood clots in veins throughout the body including the arms or legs (purpura fulminans and disseminated intravascular coagulation)
• Excessive internal bleeding into affected areas
• Large purple patches or spots throughout the body 

Diagnosis

A healthcare provider will diagnose a suspected patient with protein C deficiency by performing a series of tests in the following order:¹

1. Physical examination, medical, and family history: to determine the clotting risk of the patient 

2. Blood tests: to identify the levels of protein C in the patient’s blood as well as its activity. An ideal (normal) protein C activity in healthy adults ranges between 65 to 135 IU dL-1. Depending on severity of signs and symptoms, blood tests of patients with protein C deficiency will show protein C activity levels as follows:²

• Mild protein C deficiency: between 20 IU dL-1

• Moderate-severe protein C deficiency: between 1–20 IU dL-1 

• Severe protein C deficiency: less than 1 IU dL-1

3. Functional assays including:

• Clotting assays²

• Enzyme-linked immunosorbent assays (ELISA)²

4. Genetic testing: to check whether the patient has a mutation in the PROC gene. However, it is important to note that having a mutation in the PROC gene does NOT confirm the diagnosis of protein C deficiency. 

Management and treatment 

Management and treatment of protein C deficiency depends on the form of protein C deficiency and the severity of signs and symptoms.¹ 

Mild protein C deficiency 

Patients with mild protein C deficiency may either receive: 

• No treatment: patients with mild protein C deficiency often do not require treatment unless they:

• Are physically inactive (sedentary)
• Have obesity 
• Are smokers 
• Are pregnant
• Experienced trauma e.g. car accident 
• Had recent surgery 

• Treatment with anticoagulant therapy: usually provided if the patient developed thrombosis (blood clots). An example of an anticoagulant that could be used for treatment includes warfarin (high-intensity). However, if warfarin is used, the healthcare provider will usually use heparin first to prevent complications which can lead to death of skin and tissues. 

Severe protein C deficiency 

Infants with severe protein C deficiency who have purpura fulminans, for example, may be treated with protein C concentrate or fresh frozen plasma (FFP). 

Prevention strategies 

The congenital form of protein C deficiency cannot be prevented because it is a disorder that babies inherit and are born with.¹ 

The acquired form of protein C deficiency may or may not be preventable depending on its severity and cause.¹ Anticoagulant therapy may be provided in certain cases to decrease their risk of clotting. These cases are people with obesity, a history of smoking, and/or a sedentary lifestyle as well as women who are pregnant or on oral contraceptive pills. 

Prognosis and outlook

The prognosis of protein C deficiency varies depending on its form. Patients with mild protein C deficiency have an increased risk of developing venous thromboembolism and pulmonary embolism (PE).¹ As mentioned above, PE can quickly become fatal. 

Infants with severe protein C deficiency have a poor prognosis and die quickly after birth. Infants often die due to fluid overload from frequent infusions of plasma. 

Summary 

Protein C deficiency is a rare congenital or acquired disorder that causes excessive blood clotting and therefore increases the risk of developing life-threatening blood clotting problems including venous thromboembolism, deep vein thrombosis (DVT), and pulmonary embolism (PE).

Protein C acts as an anticoagulant by inactivating proteins that promote blood clotting. 

Mutations in the PROC gene are responsible for the congenital form of protein C deficiency, which causes infants to be born with a low level or activity of protein C. The acquired form of protein C, on the other hand, occurs later in life due to certain conditions such as: 

• Vitamin K deficiency
• Warfarin therapy
• Severe liver disease
• Sepsis

Protein C deficiency has two main forms, each of which varies in the signs and symptoms it presents with and therefore the treatment provided:

1. Mild protein C deficiency: 

• Often results in no signs and symptoms (asymptomatic)
• Most people with this form receive no treatment 
• Anticoagulant therapy with warfarin may be offered to pregnant women, people with obesity, traumatic injury, history of smoking, and/or sedentary lifestyle 

2. Severe protein C deficiency causes infants to present with:

• Purpura fulminans and disseminated intravascular coagulation 
• Excessive internal bleeding into affected areas 
• Large purple patches or spots throughout the body 
• Treatment usually involves protein C concentrate or fresh frozen plasma (FFP) 

At present, mild and severe protein C deficiency are diagnosed via a physical examination, medical examination, family history evaluation, blood tests, functional assays (e.g. ELISA), and/or genetic testing.