Protein S deficiency


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Protein S deficiency

Hematological system


Iron deficiency anemia



Sideroblastic anemia

Anemia of chronic disease

Lead poisoning

Hemolytic disease of the newborn

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Autoimmune hemolytic anemia

Pyruvate kinase deficiency

Paroxysmal nocturnal hemoglobinuria

Sickle cell disease (NORD)

Hereditary spherocytosis

Anemia of chronic disease

Aplastic anemia

Fanconi anemia

Megaloblastic anemia

Folate (Vitamin B9) deficiency

Vitamin B12 deficiency

Fanconi anemia

Diamond-Blackfan anemia

Heme synthesis disorders

Acute intermittent porphyria

Porphyria cutanea tarda

Lead poisoning

Coagulation disorders


Vitamin K deficiency

Platelet disorders

Bernard-Soulier syndrome

Glanzmann's thrombasthenia

Hemolytic-uremic syndrome

Immune thrombocytopenic purpura

Thrombotic thrombocytopenic purpura

Mixed platelet and coagulation disorders

Von Willebrand disease

Disseminated intravascular coagulation

Heparin-induced thrombocytopenia

Thrombosis syndromes (hypercoagulability)

Antithrombin III deficiency

Factor V Leiden

Protein C deficiency

Protein S deficiency

Antiphospholipid syndrome


Hodgkin lymphoma

Non-Hodgkin lymphoma


Chronic leukemia

Acute leukemia

Leukemoid reaction

Leukemoid reaction

Dysplastic and proliferative disorders

Myelodysplastic syndromes

Polycythemia vera (NORD)

Myelofibrosis (NORD)

Essential thrombocythemia (NORD)

Langerhans cell histiocytosis

Mastocytosis (NORD)

Plasma cell dyscrasias

Multiple myeloma

Monoclonal gammopathy of undetermined significance

Waldenstrom macroglobulinemia

Hematological system pathology review

Microcytic anemia: Pathology review

Non-hemolytic normocytic anemia: Pathology review

Intrinsic hemolytic normocytic anemia: Pathology review

Extrinsic hemolytic normocytic anemia: Pathology review

Macrocytic anemia: Pathology review

Heme synthesis disorders: Pathology review

Coagulation disorders: Pathology review

Platelet disorders: Pathology review

Mixed platelet and coagulation disorders: Pathology review

Thrombosis syndromes (hypercoagulability): Pathology review

Lymphomas: Pathology review

Leukemias: Pathology review

Plasma cell disorders: Pathology review

Myeloproliferative disorders: Pathology review


Protein S deficiency


0 / 9 complete

USMLE® Step 1 questions

0 / 2 complete

High Yield Notes

6 pages


Protein S deficiency

of complete


USMLE® Step 1 style questions USMLE

of complete

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?  

External References

First Aid




Sean Watts, MD

Evan Debevec-McKenney

Robyn Hughes, MScBMC

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.


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.


  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  3. "Harrison's Principles of Internal Medicine" McGraw-Hill Medical Publishing (2005)
  4. "Protein C deficiency" Haemophilia (2008)
  5. "Protein C and protein S deficiency - practical diagnostic issues" Adv Clin Exp Med (2013)
  6. "Protein S deficiency: a clinical perspective" Haemophilia (2008)

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