AssessmentsProtein S deficiency
Protein S deficiency
USMLE® Step 1 style questions USMLE
A 43-year-old woman comes to the emergency department because of sudden-onset dyspnea. Her medical history is relevant for varicose veins in lower extremities, controlled diabetes mellitus, and 30 pack-year smoking history. The patient currently takes metformin and pioglitazone. Upon further questioning, the patient mentions that her sister died at 35 because of a pulmonary embolism. Physical exam shows clammy skin and diaphoresis, S3 gallop, erythema over varicose veins in her left leg. Her temperature is 37.8°C (100.04°F), pulse is 111/min, respirations are 18/min, blood pressure is 130/60 mmHg. She is heparinized to treat the suspected pulmonary embolism and started on a long-term prophylactic agent. Shortly after, the patient's clinical condition deteriorates (see image below).
Which of the following abnormalities is the most likely cause of these findings?
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, this activates the proteolytic site of protein C, which cleaves and inactivates active factor V, a cofactor for factor X in the common pathway, and 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 that’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.