Description

Protein S is an anticoagulation protein, naturally found in the human body, that interacts with a variety of other proteins in the coagulation cascade to prevent over-coagulation during secondary hemostasis. In other words, it keeps the body's coagulation pathways in check by preventing internal blood clots from becoming too large. Normally, during the clotting process, thrombomodulin and thrombin proteins form a complex in the endothelial cells that line blood vessels. Protein S joins the complex and activates the proteolytic site of protein C, which inactivates several clotting factors and inhibits the coagulation pathways, decreasing fibrin production so that coagulation slows down.

Protein S Deficiency and Related Disorders

When there is a deficiency of protein S in the body, there is a risk of over-coagulation and formation of large blood clots, particularly venous thromboembolism (VTE), a disorder that includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

A DVT occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis. This blood clot can get dislodged, travel through the bloodstream, and stop in the lung capillaries, causing a PE. This critical condition causes sudden shortness of breath, coughing up blood, discomfort around the chest, wheezing, and even death. PEs are the third most common cardiovascular cause of death. They are often caused by old age, blunt trauma, fractures, infectious material, or tumor emboli. Despite major strides made in the development of diagnostic tools to detect PE, many cases go untreated.

Blood thinners (anticoagulants) and clot dissolvers (thrombolytics) are commonly used to treat PE. They are not necessarily expensive, but can have dangerous side-effects, especially when administered life-long, which is usually the case in people with protein S deficiency and other coagulation disorders. Some of these side effects include hemorrhages, birth defects, severe bleeding, hematuria, hematochezia, dyspepsia, swelling, coughing blood, dizziness, vision change, and increasing vulnerability to concussions and contusions. Furthermore, blood thinners such as Warfarin cause placental bleeding and may not always be safely administered during pregnancy.

For individuals with protein S deficiency, the chances of developing a DVT increase by 50% before the age of 45. In severe cases, newborns have a high chance of experiencing purpura fulminans, an often fatal condition characterized by an increase of abnormal blood clots in the infant’s blood vessels and necrosis of their tissues.

Inherited or Acquired Protein S Deficiency

Protein S deficiency is a genetic disorder that increases the risk of blood coagulation, and the formation of serious and fatal blood clots. It is caused by various different mutations in the PROS1 gene. These variations are inherited in an autosomal dominant manner. Protein S deficiency can also be acquired; this means that an affected individual does not need to have a variation of the PROS1 gene. Acquired protein S deficiency can occur as a result of other underlying conditions such as liver disease, traumatic brain injury, nephrotic syndrome, certain infections, the use of oral contraceptives, vitamin K deficiency, surgery, chemotherapy treatment, and even COVID-19.

When caused by mutations, protein S deficiency is an autosomal dominant genetic disease. In Type 1 of Protein S deficiency, there is insufficient amount of protein S in the body, and in Type 2, there is enough protein S but it is non-functional. The disease may be asymptomatic; however, if an abnormal blood clot forms, it can be fatal.

1 in 500 individuals in the United States suffer from an inherited or acquired mild protein S deficiency. Furthermore, African American and Indigenous populations suffer disproportionately from protein S deficiency, DVT, and PE. Administration of protein S to treat these disorders can provide an effective therapeutic which lessens the severity of these disorders, and is significantly more accessible.

PROS: Our Solution

Major advances have been made in the technology used to detect diseases such as VTE. However, the mortality rates for the disorder are significantly high, and continue to rise. Countless studies support that PE prevention and diagnosis is significantly under-prioritized in the modern American healthcare system. The Stony Brook University iGEM Team of 2022 is focused on creating a novel alternative treatment to the modern drugs currently used in the conservative treatment of PE, as well as improving diagnostic methods for related disorders.

The administration of protein S to patients can also help treat disorders such as traumatic brain injury and severe COVID-19 in addition to Protein S Deficiency. There is currently no therapy to administer solely protein S directly into the bloodstream.

This is why our project, PROS, proposes an injectable delivery of a recombinant human protein S therapy.

There are multiple steps to our project:

Through our project, we hope to address current gaps in treatment and existing health disparities. If properly implemented, our research will help establish an improved therapy for a significant number of patients suffering from protein S deficiency and related disorders.

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