Protein S deficiency
AssessmentsProtein S deficiency
Protein S deficiency
USMLE® Step 1 style questions USMLE
A 52-year-old woman, para 4 gravida 2 aborta 2, comes to the clinic for a follow-up appointment after a hospitalization. Two weeks ago, she had an incident of acute, severe abdominal pain and bloody stools. She was diagnosed with portal vein thrombosis. She denies similar episodes in the past. Medical history is notable for Legg-Calvé-Perthes disease as a child. She does not smoke, drink excessive alcohol, or use illicit drugs. She had 2 spontaneous abortions in the first trimester, following 2 successful pregnancies. Family history is remarkable for DVT in her maternal uncle and colon cancer in her father. The physician suspects an inherited condition. Which of the following will prompt further evaluation in this patient?
Protein S deficiency exam links
Content Reviewers:Rishi Desai, MD, MPH, Yifan Xiao, MD, Viviana Popa, MD
Contributors:Robyn Hughes, MScBMC, Evan Debevec-McKenney, Sean Watts, MD
Protein C and S are two anticoagulation proteins that inactivate coagulation factors Va and VIIIa in the coagulation cascade. This means, they act like brakes on coagulation, limiting clot formation and preventing clots from growing too big. So, when either of these proteins is deficient, it leads to a hypercoagulable state, meaning a person is at increased risk of developing a clot that could block blood flow. The most common places for such clots to develop are in the deep veins of the legs and in the vessels that carry de-oxygenated blood through the lungs.
Normally, protein C and protein S are 2 of many proteins or enzymes that regulate the complex process called hemostasis. This is where a solid clot forms in the flowing, liquid blood to plug the defect in a damaged blood vessel. It has two steps; Primary hemostasis involves the formation of a platelet plug at the site of injury, and secondary hemostasis involves coagulation, where several clotting factors come into play to form a fibrin mesh over the platelet plug to reinforce it, and form the blood clot. The main role of protein C and protein S is to prevent excess coagulation, or fibrin formation, during secondary hemostasis.
Protein C and S prevent excess coagulation by interacting with several other proteins involved in a complex system of checks and balances. So, it starts with a protein called thrombomodulin, which is on endothelial cells that line our blood vessels, and together with thrombin, they form a complex that also includes protein C and protein S.
When protein S joins this complex, it activates the proteolytic site of protein C, which cleaves and inactivates active factor V, a cofactor for factor X in the common pathway, and factor VIII, a cofactor for factor IX in the intrinsic pathway. The factor V degradation product also binds to this complex and further enhances its ability to cleave more active factor V and active factor VIII. By inhibiting both the intrinsic and common pathway, less fibrin is produced and coagulation slows down dramatically.
So, in people with protein C and S deficiency, the thrombin-thrombomodulin complex can’t cleave and inactivate factors V and VIII. This increases circulating factor V and factor VIII levels, and “tips the scale” toward coagulation, putting them at increased risk for thrombosis, or developing blood clots. This usually occurs in the deep veins of the legs or in the pulmonary arteries that carry deoxygenated blood from the heart to the lungs.
There are two types of familial, or congenital, protein C and S deficiency; both are inherited in an autosomal dominant manner. Type I disease is when there’s not enough protein C or S, so there’s a quantitative defect. Type II disease, however, is a qualitative defect, because enough protein C or S are made, but the proteins don’t function properly. There are also acquired forms of protein C or S deficiency, like impaired production as seen in patients with liver disease or in patients taking warfarin, also called coumadin. Another cause is excessive urinary loss of these proteins which can happen in people with nephrotic syndrome.
Protein C or S deficiency is commonly asymptomatic, but symptoms arise when a venous thromboembolism develops. That’s when a clot forms, usually in the deep veins of the leg, and then parts of the clot can break off and travel to other parts of the body. Symptoms of venous thromboembolism include pain similar to a muscle cramp, and swelling in the affected leg.
Protein S deficiency is a disorder associated with an increased risk of venous thrombosis. Protein S, a vitamin K-dependent natural anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the proteolytic degradation of factor Va and factor VIIIa. Decreased levels or impaired function of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased risk of blood clots, which can cause complications like deep vein thrombosis (DVT) and pulmonary embolism (PE). Treatment includes anticoagulant medications and avoiding drugs that predispose to hypercoagulability, such as oral contraceptives.
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