What is Protein S Deficiency?
Protein S deficiency is a rare health condition where there is a lower activity of something called protein S, a special protein in the blood. This protein has a complex but crucial job – it helps to regulate blood clotting, inflammation, and a process called apoptosis, or ‘cell death’. Protein S was first discovered in Seattle back in 1979 and contributes by aiding another protein called activated protein C (APC) to control factors that help the blood to clot.
If someone lacks sufficient protein S, their body has trouble managing blood clotting. This can result in creating too many blood clots, a condition known as thrombophilia, and a serious issue called venous thromboembolism (VTE) where a blood clot blocks a vein.
Protein S deficiency can either be inherited, which means it’s passed on from your parents through genes, or you can acquire it. Acquired deficiency is usually due to liver disease, a kidney disorder called nephrotic syndrome, or a lack of vitamin K. When inherited, it follows a pattern called an ‘autosomal dominant trait’, meaning that you only need to get the abnormal gene from one parent in order to inherit the disease. With this kind of protein S deficiency, blood clotting problems can happen whether you inherit just one copy or two copies of the faulty gene.
Typically, those with protein S deficiency have problems with VTE. While there have been cases where protein S deficiency and arterial thrombosis – clots that form in the arteries – have occurred together, these seem to be more of a coincidence or a weak link. Further, there’s limited evidence of these types of clots happening in related inherited disorders. Overall, Protein S deficiency is a rare but serious condition that primarily influences blood clotting.
What Causes Protein S Deficiency?
Protein S deficiency is a condition that can be inherited (congenital) or can develop later in life (acquired). This condition occurs due to changes or mutations in the PROS1 gene.
The most common types of mutations are point mutations, which can stop the formation of the protein S molecule too early, leaving it incomplete. Over 200 different mutations of this gene have been identified and can lead to three different forms of Protein S deficiency:
1. Type 1: This presents with lower levels of total protein S and free protein S, as well as decreased protein S activity.
2. Type 2, also known as Type 2b: This involves normal total protein S and free protein S levels, but a decrease in protein S activity.
3. Type 3, also known as Type 2a: In this type, there are normal levels of total protein S but lower levels of free protein S and reduced protein S activity.
Protein S deficiency is usually inherited in an autosomal dominant manner. This means if a person has a mutation in just one copy of the gene from either parent, they may have mild protein S deficiency. Those who inherit mutations from both parents tend to have severe protein S deficiency.
There are also factors that can cause changes in protein S levels later in life, including:
1. Use of vitamin K-blocking medications
2. Chronic infections
3. Severe liver disease
4. Systemic lupus erythematosus (an autoimmune disease)
5. Disorders that increase blood cell production (myeloproliferative disorders)
6. Kidney disease that cause high levels of protein in the body (Nephritic syndrome)
7. Severe, widespread clotting in the blood vessels (Disseminated intravascular coagulation, or DIC)
Risk of a type of blood clot called venous thromboembolism (VTE) can also increase in people with protein S deficiency who are taking birth control pills or are pregnant.
Risk Factors and Frequency for Protein S Deficiency
Congenital protein S deficiency is a condition that is passed down through families, but its effects can vary. Half of the individuals who carry one copy of the gene causing protein S deficiency can develop any abnormal blood clotting, known as Venous Thromboembolism (VTE). The other half do not show any disease symptoms and never develop VTE. The average rate of abnormal blood clotting is about 1.90% every year, and it most often starts around the age of 29.
Some people might inherit two copies of this gene, which will cause them to develop a condition called ‘purpura fulminans’. Babies with this condition will have abnormal blood clotting resulting in skin and tissue under the skin dying.
- A mild form of protein S deficiency occurs in approximately 1 out of every 500 individuals.
- Severe protein S deficiency is much rarer and it’s hard to know how common it is because it’s difficult to diagnose.
Healthy individuals usually don’t have protein S deficiency. In a study involving healthy individuals who donated blood, familial protein S deficiency (passed down in families) showed a prevalence between 0.03 to 0.13%. However, in a group of patients who had either repetitive abnormal blood clotting or had a family history of abnormal blood clotting, the presence of protein S deficiency was between 3 to 5%.
Based on some studies, there were suggestions to lower the required protein S levels for diagnosing the deficiency. There is no difference in the occurrence of protein S deficiency based on data from the US and European studies. However, it was found to be more prevalent in the Japanese population, with rates as high as 12.7% in people with abnormal blood clotting, and around 0.48% to 0.63% in the general population.
In a similar study involving 3788 participants, the prevalence of familial protein S deficiency was found to be between 0.03 to 0.13%. In patients who had a family history of abnormal blood clotting or recurrent abnormal blood clotting, the occurrence of protein S deficiency increased to 3% to 5%.
- Protein S deficiency is found to be 5 to 10 times more common among Japanese than in white population.
- Men tend to have higher levels of protein S antigen.
- The age at which abnormal blood clotting commences varies if one carries one (heterozygous) or two (homozygous) copies of the gene. For individuals with one copy of the gene, abnormal blood clotting often starts between the ages of 40 to 45. The rare individuals who have two copies of the gene usually show symptoms in early childhood.
Signs and Symptoms of Protein S Deficiency
Protein S deficiency, a condition that can potentially cause blood clots, manifests differently among patients. Symptoms and severity of this condition differ greatly. People may experience symptoms before the age of 55, with some common indicators being deep vein thrombosis, pulmonary embolism, and an increased likelihood of developing disseminated intravascular coagulation. Some patients might develop unusual blood clots in the brain or other areas. Women may experience repeated miscarriages, which could sometimes be the only symptom. Despite being predisposed to blood clots, around half of the cases occur in the absence of standard risk factors for blood clotting. Family history may increase the risk, pointing towards an inherited condition.
- Common symptoms debut before 55 years of age
- Deep vein thrombosis and pulmonary embolism are frequent signs
- Some women might only experience repeated miscarriages
- Atypical locations of blood clots can occur
- Family history of blood clots might indicate a hereditary pattern
Severe protein S deficiency, a rare condition that arises from congenital mutations, appears in newborns shortly after birth with an issue called purpura fulminans. Without early diagnosis and intervention, children with this condition rarely survive beyond their childhood years.
The physical signs of this condition aren’t typically specific and often misleadingly suggest deep vein thrombosis. Sites of blood clots in less common locations are unusual.
Deep vein thrombosis is the most common presentation, affecting almost 90% of cases. Its typical signs include calf pain, swelling, and pain when bending the foot upward. However, only about a third of deep vein thrombosis cases demonstrate all three symptoms. The most common sign is swelling in one leg or calf, accompanied by mild or moderate discomfort.
People experiencing a pulmonary embolism, a serious condition where a blood clot gets lodged in an artery in the lung, typically present with shortness of breath, chest pain, fainting, and racing heartbeat. Rapid breathing is often the most common sign. A large pulmonary embolism can cause fainting or bluish skin and can also result in acute right-sided heart failure. This causes bulging neck veins, a lift in the area next to the left breastbone, and an intensified “lub-dub” heart sound.
Testing for Protein S Deficiency
Testing for Protein S deficiency, a condition that affects the body’s ability to clot blood, involves various tests to measure the activity of Protein S in the body. There are two types of tests – clotting tests (which check how well the blood clots) and enzyme-linked immunosorbent assays (ELISA) (a test that measures the amount of a specific protein).
The ‘Protein S antigen’, a part of protein S, can be detected in two forms – as a total antigen and as free protein S antigen. The free form of Protein S is the one that’s actually involved in preventing clot formation. So, the levels of both – free and total Protein S – can be measured through the ELISA test.
The ‘Functional Protein S’ tests work by measuring the time it takes for blood to clot. They involve the formation of a substance called activated protein C (APC).
Several conditions can lower Protein S levels in the body. Some of these include vitamin K deficiency, liver disease, acute thrombosis (blood clot formation), pregnancy, and use of the drug, warfarin.
The levels of Protein S in the blood can vary due to age, gender, hormonal status, lipid metabolism, and genetic or other influences. Women generally have lower levels of total and free Protein S compared to men. However, as women age, their total Protein S levels increase due to changes in hormone levels. Interestingly, the levels of free Protein S do not seem to change with age. A noteworthy point is that a certain disorder called factor V Leiden can lead to falsely low levels of functional Protein S. There are newly developed testing methods that accurately measure protein S deficiency in these situations.
There are three different types (phenotypes) of Protein S deficiency. These are based on the levels of free and total protein S and how functionally active protein S is. Types 1 and 3 are most common. Total protein S tests are excellent but can’t detect types 2 and 3 Protein S deficiency. To detect these, one may use “free protein S assays”, but they lack consistency in results.
Sometimes, the healthcare professional might also want to examine if there are any mutations present in the gene that makes Protein S (known as the PROS1 gene). The International Society on Thrombosis and Hemostasis (ISTH) maintains a registry of such documented mutations. This detection of mutations is typically done through something called DNA sequencing or amplification, and analysis through a process called polymerase chain reaction (PCR).
Treatment Options for Protein S Deficiency
If someone has protein S deficiency but hasn’t experienced a blood clot, doctors may prescribe preventative treatment to reduce the risk. However, if the person has suffered from an acute blood clot in the veins, or venous thromboembolism (VTE), doctors will employ the standard treatment for such situations.
Treatment of VTE often involves the use of anticoagulant medications, which are drugs that prevent blood from clotting too quickly or easily. These can include types of heparin, a naturally occurring anticoagulant; VKA (Vitamin K antagonist), which works by reducing the action of Vitamin K that helps blood to clot; and DOAC (direct oral anticoagulant), which directly inhibits the enzyme involved in blood clotting. The type of heparin used initially can be delivered differently, some via an IV and others under the skin, and is typically given for a minimum of 5 days. After that, treatment continues with either a VKA or a DOAC, depending on the patient’s preference and convenience.
In the past, VKA was the go-to drug for blood clots, but with the introduction of DOACs, the preference is shifting. This is due to the effective and safe profile of DOACs. In a study, DOACs were found to be as effective as the combination of heparin and VKA for inherited clotting disorders, with fewer risks.
As for people born with protein S deficiency, they usually receive anticoagulation therapy until their blood coagulation has stabilized for two consecutive days. Preventive anticoagulation therapy is maintained for 3 to 6 months after a thrombotic episode and may be extended for patients with additional clotting conditions. If the initial blood clotting event was life threatening or occurred in multiple or unusual places, lifelong therapy may be needed.
But if the blood clotting event was prompted by a major event like trauma or surgery and was not life-threatening or evolved in multiple or unusual sites, lifelong anticoagulation might not be required. However, preventive treatment should be administered to patients with protein S deficiency when they are exposed to risk factors for thrombosis, like during a long flight, surgery, long periods of immobility, or while being pregnant.
During pregnancy, special attention is needed. Women during the first trimester or after 36 weeks of pregnancy should be given a low-molecular-weight type of heparin instead of warfarin (a type of VKA) to minimize the risk of bleeding for both the mother and baby.
What else can Protein S Deficiency be?
People with a blood clotting disorder (thrombophilia) who do not have other risk factors could be battling a deficiency in ‘protein S’. There can be other reasons behind their clotting disorder. It could be due to inherent abnormalities with blood-clotting, or because protein S deficiency is being coupled with other risk factors of Venous Thromboembolism (VTE). It’s possible for protein S deficiency to develop over time (acquired) rather than being present since birth (congenital). Some conditions that might lead to an acquired protein S deficiency are pregnancy, lack of vitamin K, use of birth control pills, serious liver dysfunction, and long-standing infections.
The doctor must also consider several other potential diagnoses when a patient suffers from protein S deficiency. This list of conditions includes:
- Antiphospholipid syndrome: a disorder causing blood clots
- Antithrombin deficiency: lack of a protein that prevents blood from clotting too much
- Factor 5 Leiden mutation: a mutation causing a higher risk of blood clotting
- Protein C deficiency: lack of a protein that prevents excessive blood clotting
- Malignancy: presence of cancerous cells
- Prothrombin gene mutation: A mutation causing overproduction of a protein that helps the blood to clot
- Paroxysmal nocturnal hemoglobinuria: a rare blood disease causing the body to destroy its red blood cells too early
What to expect with Protein S Deficiency
People with a mild deficiency in protein S, a natural substance that prevents blood clots, tend to have more repeated instances of blood clot conditions such as venous thromboembolism (VTE), which includes deep vein thrombosis (DVT), a condition where blood clots form in deep veins, typically in the legs. This can lead to serious illness and even death, which makes VTE a major concern. However, current evidence doesn’t suggest that protein S deficiency worsens the outlook for those with VTE.
Recurring blood clot events can worsen the health condition of people who are prone to blood clots. Additionally, long-term use of a common blood thinner called warfarin to treat these clots can increase the risk of bleeding.
Babies diagnosed with severe protein S deficiency have a high risk of poor health outcomes. Severe protein S deficiency needs frequent plasma infusions, which can lead to complications such as fluid overload, contributing to a high infant death rate. There is currently limited information about the long-term health outlook for patients with this severe, inherited form of protein S deficiency.
Possible Complications When Diagnosed with Protein S Deficiency
The complications related to protein S deficiency, a condition that affects your blood’s ability to clot, are divided into two categories. The first group is associated directly with protein S deficiency itself, and the second group is linked to the treatment to prevent blood clots, known as anticoagulation therapy.
Complications from protein S deficiency include:
- Inflammation of blood vessels known as post-thrombotic phlebitis
- Recurrent blood clots in the lungs, known as pulmonary embolism, which can damage the right side of the heart
- The possibility of losing a pregnancy early on
- A severe skin symptom called Purpura Fulminans
Complications from anticoagulation treatments, (drugs used to prevent blood clots), vary between adolescents and adults:
- Long-term use of anticoagulation therapy can increase the risk of severe bleeding
- Skin necrosis, a condition where skin cells die, is a risk when using the anticoagulant drug warfarin, but this can be managed with short-term usage of another drug called heparin
Preventing Protein S Deficiency
Home monitoring using a simple blood test known as the international normalized ratio (INR), can make managing protein S deficiency easier for individuals. Protein S deficiency is a condition that increases risk of blood clots. This monitoring, paired with temporary blood-thinning treatment, can help patients take charge of their own care to prevent repeat incidents of blood clot events that could require hospital stays. Wearing compression stockings can also be very helpful in preventing blood clots in veins, also known as venous thromboembolism (VTE).
