What is Protein C Deficiency?
Protein C deficiency is a rare condition where there’s not enough protein C activity in the body. Protein C is a type of protein in our blood that helps control blood clotting. When protein C is activated (known as activated protein C or APC), it works as a strong preventer of blood clotting. If there’s a deficiency in protein C, the body can’t regulate the clotting process properly, leading to an increased risk of blood clots, a condition known as thrombophilia.
What Causes Protein C Deficiency?
Protein C deficiency can be either acquired in life or present from birth, known as congenital. It is caused by mutations in the PROC gene. There are over 160 known changes to this PROC gene that can result in protein C deficiency. These mutations can cause two types of issues:
- Type I: Decreased levels of protein C
- Type II: The creation of an altered protein C molecule that isn’t as effective as it ought to be
Protein C deficiency is an “autosomal dominant” condition, which means it’s largely determined by a single mutated gene from either parent. If a person inherits one copy of the mutated gene (created from one parent’s egg or sperm), this leads to a mild form of protein C deficiency. However, if a person has the mutation in both of their copies of this specific gene (inherited from both parents), they end up with a severe form of protein C deficiency.
Risk Factors and Frequency for Protein C Deficiency
Mild protein C deficiency is a bit common, with estimates suggesting it affects between 1 in 200 to 1 in 500 people. However, serious cases of protein C deficiency are significantly less common – it’s estimated that only 1 in 20,000 people have a clinically substantial form of the deficiency. The severe protein C deficiency is very rare, occurring in about 1 in 4 million infants. However, these estimate may be inaccurate due to possible underdiagnosis or under-reporting of cases.
- Mild protein C deficiency affects approximately 1 in 200 to 1 in 500 individuals.
- Clinically substantial protein C deficiency is more rare, affecting about 1 in 20,000 people.
- Severe protein C deficiency, which mainly affects infants, is incredibly rare, with estimates putting it at 1 in 4 million infants.
- The actual numbers might be higher due to underdiagnosis or under-reporting.
Signs and Symptoms of Protein C Deficiency
Severe protein C deficiency is a genetic condition that will show itself in newborns shortly after they are born. It’s primarily characterized by conditions known as disseminated intravascular coagulation (DIC), which is a condition that affects the blood’s ability to clot, and purpura fulminans (PF), which is marked by discolored patches on the skin. These individuals often suffer recurring instances of PF, which can be triggered by things like infections, injuries, or operations.
Those who have a moderately severe protein C deficiency might not exhibit any notable symptoms until they reach their teenage years. The symptoms they experience frequently involve recurrent episodes of blood clotting, which can result in conditions like deep vein thrombosis (DVT), clots in the lungs (pulmonary emboli or PE), clots within organs, and a predisposition for DIC.
In individuals who have a mild deficiency in protein C activity stemming from a heterozygous protein C deficiency, symptoms can come in a range of severities. Some people might not experience any symptoms at all, while others might end up with recurring blood clots that can lead to conditions known as post-thrombotic syndrome. Aside from DVT and PE, these patients might also suffer complications like strokes from a lack of blood supply to the brain, and blood clots associated with pregnancy. The risk of developing thrombotic events in individuals carrying protein C mutations can vary, and might be influenced by factors like how fully the gene is expressed, as well as environmental or other genetic factors.
Testing for Protein C Deficiency
If your doctor suspects that you may have a condition called protein C deficiency, they will use a variety of tests to check your levels of protein C. These tests can include clotting tests, and more specialized tests such as enzyme-linked immunosorbent assays (ELISA) – a type of blood test – and chromogenic tests, which measure specific proteins.
They might also check for changes in the PROC gene – the gene that instructs your body how to make protein C.
In a healthy newborn baby, the usual amount of protein C in the blood is 40 IU (International Units) per dL (deciliter) of blood. This typically increases to around 60 IU/dL by the time the baby is 6 months old. For healthy adults, the normal range is between 65 to 135 IU/dL.
If you have mild protein C deficiency, you’ll have lower levels, between 20 IU/dL and the lowest limit of the normal range – this varies depending on age. If the condition is a bit worse, you’ll find protein C levels between 1 and 20 IU/dL. In severe cases, activity levels can go below 1 IU/dL.
These protein C activity levels can also be described in terms of functional percentages. These percentages help doctors to understand how well the protein is working in your body.
Treatment Options for Protein C Deficiency
There are currently no widely accepted guidelines for treating protein C deficiency, a rare genetic disorder that increases the risk of developing blood clots. Most of the current understanding about protein C deficiency treatment comes from individual case studies and medical practitioners’ experiences, not large, controlled studies.
The treatment for protein C deficiency often involves replacing the missing protein C. In newborns with severe symptoms, this replacement can be done using a substance referred to as ‘protein C concentrate’, which comes from fresh frozen plasma or specially-treated human plasma. Once the immediate risk has been managed, regularly scheduled protein C replacements may be used as a preventive measure.
Medications that prevent blood clotting (anticoagulants) such as warfarin or low-molecular-weight heparin may also be used for treating this condition. The use of these medications may be especially beneficial when there’s a need to manage specific situations like blood clot events in children. One reason for choosing these medications over protein C replacement might be their lower cost, as protein C replacement therapy may be expensive.
What else can Protein C Deficiency be?
If a patient is inclined to develop blood clots (a condition known as thrombophilia) and doesn’t have any other risk factors, their condition could be due to a lack of a protein in their blood called protein C. However, the tendency to form blood clots can also be due to other inherent abnormalities in the blood clotting process, or a mix of the lack of protein C and other risk factors. Some of these inherent abnormalities could be:
- A mutation in the blood clotting protein called factor V Leiden
- A deficiency of another protein in the blood known as protein S
- A lack of a protein called antithrombin, which prevents blood clots
- A mutation in the gene for a protein called prothrombin, specifically at position G20210A
Besides this, the deficiency of protein C could be a developed condition and not something a person is born with (not congenital). This could happen because of several conditions such as:
- A type of medication called warfarin therapy used to prevent blood clots
- A lack of vitamin K necessary for blood clotting
- Severe liver dysfunction, affecting the production of clotting proteins
- Bacterial infections in children
What to expect with Protein C Deficiency
Newborn babies with severe protein C deficiency often face serious challenges. Their condition can get worse due to complications from frequent plasma infusions, like fluid overload, that can lead to a high rate of infant death. Unfortunately, there’s not enough data to clearly understand the long-term outcomes for patients with severe congenital protein C deficiency.
On the other hand, patients with mild protein C deficiency are susceptible to repeated episodes of venous thromboembolism (VTEs), which includes deep vein thrombosis (DVT). These conditions may cause something called post-thrombotic syndrome and conditions like venous stasis ulcers, which are wounds that occur due to improper functioning of blood vessels in the lower leg. Repeated clotting events in patients with thrombophilia (a condition that increases the risk of blood clots) can be influenced by factors like family history of clots, obesity, underlying inflammatory disorders, and having multiple thrombophilia qualities.
Possible Complications When Diagnosed with Protein C Deficiency
Therapy using fresh frozen plasma (FFP) can cause fluid overload, which might lead to high infant mortality rates in severe cases of protein C deficiency. This is due to the large volume of plasma needed for an FFP procedure. Moreover, not all hospitals have access to FFP that is free of viruses. With regular transfusions, there’s also a risk of viral infections. Like all transfusions, there’s always a risk of negative immune responses to foreign molecules present in the FFP. However, using protein C concentrate tends to lower the risk of viral contamination and allergic reactions. Treatment of protein C deficiency in newborns often requires the insertion of devices into the central vein, and this can sometimes lead to complications like blood clotting or infections.
For teenagers and adults, long-term anticoagulation therapy (a therapy that helps prevent blood clots) may raise the overall risk of severe forms of bleeding, such as ruptured ovarian cysts and resulting pelvic bleeding in women. If protein C levels are not properly replaced, traditional treatments with estrogens are not advisable. Protein C concentrate replacement can be used to manage bleeding and blood clot complications during certain surgical procedures. It is still under review whether screening patients at risk is effective, and more evidence is needed.
- Fluid overload in infants due to FFP therapy
- Risk of viral infection and immune reactions from transfusions
- Potential complications like blood clotting or infections from protein C treatment in newborns
- Increased risk of severe bleeding with long-term anticoagulation therapy in teenagers and adults
- Risk of complications with traditional estrogen treatments if protein C levels are not properly replaced
- The effectiveness of screening at-risk patients is still under review
Preventing Protein C Deficiency
Home-based patient monitoring tools, or point-of-care testing (POCT), have made it easier to manage people with severe protein C deficiency, a condition that affects how the body clots blood. These tools mainly measure the international normalized ratio (INR), which indicates how quickly the blood clots. Combining this with short-term treatments like blood-thinning medications or protein C replacement, patients can proactively manage their condition. This strategy helps prevent multiple episodes of blood clots that would typically require hospital care.
