University of Illinois - Urbana/Champaign

Carle Cancer Center

Hematology Resource Page

Mechanism of Action of Protein S Deficiency:
A detailed description of the clotting process is found on the clotting information web page. The function of protein S is to inactivate factor Va and factor VIIIa (the 'a' denotes the active form). This function is carried out directly by protein C, and protein S serves as a cofactor (an assistant). The first step in this process is the activation of thrombomodulin by thrombin. Subsequently, protein C combines with thrombomodulin in order to produce activated Protein C (see Figure 1). Activated protein C then combines with protein S on the surface of a platelet (platelets are the clotting cells that circulate in the blood and provide phospholipids to support that clotting process). Activated protein C can then degrade factor Va and factor VIIIa (see Figure 2).

Protein S exists in the body in two primary forms. One form is free and the other is bound to an additional protein. Only the free form of protein S is able to interact with protein C in the manner described above.

There are three classifications of protein S deficiency: type I, type II and type III. Type I protein S deficiency results from an inadequate amount of protein S present (see Figure 3) in both the free and bound forms. The protein S that is present functions normally, but the amount of protein S present is insufficient to control the coagulation cascade. Type II protein S deficiency is characterized by defective protein S molecules (see Figure 4). The amount of protein S present is normal, but it is unable to interact normally with the other molecules involved in coagulation to perform its function. A type III protein S deficiency is characterized by a low amount of free protein S, but an overall normal amount of total protein S (see Figure 3).

Epidemiology of Protein S Deficiency:
The incidence in the general population is not known. In the Caucasian population, protein S deficiency has been found in between 1 to 5% of persons who have a venous thrombotic event.

Risks of Protein S Deficiency:
The overall estimated incidence (annual occurrence) of deep venous thrombosis is 1 episode for every 1000 persons. This figure does not separate patients who had predisposing conditions from those who do not.

In patients that are born with two abnormal copies of the protein S gene (called homozygous), a severe form of thrombosis called purpura fulminans can result. Purpura fulminans involves severe clotting throughout much of the body, ultimately causing death to the tissues. This is a life-threatening condition.

There are studies that suggest an association between arterial thrombosis (stroke, heart attack) in patients with protein S deficiency. At this time, the exact role protein S deficiency plays and its relative importance in arterial disease is still being explored by physicians and scientists.

The role of protein S deficiency and venous thromboembolic disease is shown in the table below. The table shows the increase in risk compared with a patient without a known thrombophilic state. Relative risk is a numerical representation of the effects of a condition or treatment on an individual. If a condition or treatment has a relative risk of 1, patients with the condition have no additional risk or benefit from those without the condition. In the studies used below, a relative risk greater than 1 shows an increased risk. For the table below, a relative risk of 4 means that individuals with that condition are 4 times as likely as similar individuals without the same condition, to develop a venous thrombotic event. Despite the increased risk, it is important to remember that the relative risk is a statistical tool to help guide clinicians and scientists and that individual persons can have increased or decreased risks. Even with a very high relative risk, there is no guarantee that a venous thrombotic event will occur.

Treatment of Protein S Deficiency:
Treatment of a patient with protein S deficiency depends upon the individual patient's risk of thromboembolic disease. When a patient has a venous clot, regardless of what thrombophilic state(s) they may have, they will receive anticoagulation. This is accomplished by several different medications: 1) heparin, 2) warfarin and 3) low-molecular-weight heparins. These medications are generally continued for 3-6 months.

Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (for example, multiple deficiencies) may be considered for long-term oral anticoagulation (warfarin). Because studies have demonstrated an increased risk of recurrent venous thromboembolic disease in patients with protein S deficiency, long-term oral anticoagulation) is recommended. Long-term anticoagulation has risks associated with it (approximately a 3% chance per year of having a major hemorrhage, of which approximately 1/5 are fatal). Beginning long-term anticoagulation is influenced by the patient's overall risk of recurrent thrombosis balanced against the risks associated with long-term anticoagulation on an individual basis.

Use of fresh frozen plasma (FFP) can be helpful in life-threatening thrombosis from protein S deficiency. In contrast to protein C and antithrombin, there is no purified form of protein S available for clinical use.

Further Information:
For further information on the other thrombophilic states, please refer to their respective pages. Brief information on the various medications that are discussed above and are regularly used to treat clotting disorders is discussed on the medication pages. A selection of the references used to compile this information is listed on the references page.