NORD gratefully acknowledges Kenneth A. Bauer, MD, Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, for assisted in the preparation of this report.
Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene. This variation is inherited in an autosomal dominant manner. Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off and travel to the lungs, which is termed pulmonary embolism. Affected individuals are deficient in protein S, which is a specialized blood protein. Specifically, protein S is involved in inhibiting coagulation. This means that it helps to prevent the blood from clotting too much. Affected individuals who inherit one abnormal protein S gene are at risk for developing blood clots. Although very rare, there is a severe form that is present at birth (congenital) due to the presence of 2 abnormal protein S genes that can potentially cause widespread small clots in the body and life-threatening complications in infancy. Occasionally protein S deficiency may be acquired as a result of acquired conditions such as kidney disease (i.e., nephrotic syndrome), pregnancy, or the use of oral contraceptives.
Individuals with protein S deficiency are at risk for developing blood clots, specifically blood clots that begin in veins (venous thromboembolisms). Veins are the blood vessels in the body that carry blood to the heart. The exact risk of a blood clot, the age of onset of the disease, the severity of the disease, and the number and frequency and location of blood clots will vary greatly among affected individuals. This is due, in part, to the amount of residual protein S activity there is in the body. Some individuals with protein S deficiency due to inheritance of a single abnormal protein S gene (termed heterozygous) may never develop a blood clot and others may not develop one until adulthood.
The two most common findings associated with protein S deficiency are deep vein thrombosis and pulmonary embolism. Deep vein thrombosis or DVT is a clot that forms in the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins or other areas.
Infants with the severe forms of protein S deficiency (homozygous or compound heterozygous forms due to inheritance of abnormal protein S genes from both parents) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal.
Protein S deficiency is caused by a variation in the PROS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Some individuals inherit a variation in one PROS1 gene. These individuals usually have the mild form of protein S deficiency. Far less often, individuals inherit a variation in both of their PROS1 genes. These individuals usually have the severe form of protein S deficiency.
Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
The risk to have a child to a parent who has one abnormal protein S gene is 50% with each pregnancy.
Sometimes, episodes of blood clots are “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization, trauma, hormonal contraception or replacement therapy, or inactivity.
Protein S deficiency is a rare disorder that affects both men and women. The exact prevalence the common form of protein S deficiency (the number of people who have the disorder in a given population) and incidence (new cases identified each year) of the disorder overall is unknown. Severe protein S deficiency is an extremely rare disorder and often goes undiagnosed or misdiagnosed making it difficult to determine its frequency in the general population.
A diagnosis of protein S deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Some indications of a possible protein S deficiency include blood clots that develop before the age of 50 without an obvious cause, recurrent blood clots, blood clots in a person in a family with history of blood clot formation, and blood clots that occur in sites that are not normally affected by blood clots including veins in the small bowel (mesenteric veins), veins of the liver (portal veins), and veins in the brain (cerebral veins).
A diagnosis of the genetic form of protein S deficiency can be challenging because there are many different conditions that can temporarily lower the levels of protein S in the blood (acquired protein S deficiency).
Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein S in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. The amount of protein S can vary based on several factors including age.
Molecular genetic testing can confirm a diagnosis of protein S deficiency in some people. Molecular genetic testing can detect a variation in the PROS1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
There is not a specific therapy for patients with protein S deficiency. The use of anticoagulant therapy however is highly effective in the treatment and prevention of blood clots in patients with the common type of protein S deficiency (due to inheritance of one abnormal protein S gene). Such therapies are generally effective regardless of the underlying risk factor or genetic abnormality predisposing a patient to developing a blood clot.
Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with a severe form of protein S deficiency may remain on this therapy for life. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis.
Some individuals with protein S deficiency who have never had a blood clot will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization or trauma. Some individuals with a strong family history of developing blood clots may receive preventative therapy (e.g. anticoagulant therapy).
Anticoagulant therapy is the use of drugs like heparin, warfarin or direct oral anticoagulants that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with protein S deficiency may remain on this therapy for life.
Genetic counseling may be of benefit for affected individuals and their families.
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