What are the implications of Protein S deficiency (Protein S) and Factor V (Coagulation Factor V)?

From the Guidelines

Protein S deficiency is a condition that increases the risk of abnormal blood clotting and should be managed with anticoagulation therapy, with the choice and duration of treatment depending on the clinical situation, and low molecular weight heparin is preferred during pregnancy due to warfarin's potential teratogenic effects. Protein S deficiency is an inherited or acquired condition that occurs when there is a shortage of protein S, a natural anticoagulant that helps prevent excessive blood clot formation. This deficiency can lead to deep vein thrombosis, pulmonary embolism, and other thrombotic events. According to the American Society of Hematology 2018 guidelines for management of venous thromboembolism, for women who are heterozygous for the factor V Leiden or prothrombin mutation and in those who have protein C or protein S deficiency, regardless of family history of VTE, the ASH guideline panel suggests against using antepartum antithrombotic prophylaxis to prevent a first venous thromboembolic event 1.

The duration of treatment depends on the clinical situation - lifelong anticoagulation may be necessary for those with recurrent clots or severe deficiency, while those with a first unprovoked event might receive 3-6 months of therapy. Factor V (sometimes called Factor F) is a different clotting protein, and Factor V Leiden is a common genetic mutation that also increases clotting risk. Protein S deficiency diagnosis requires specialized blood tests, and levels can be temporarily decreased during pregnancy, acute illness, or while taking certain medications, so testing should be done when these conditions are not present for accurate results. The guidelines on diagnosis and management of acute pulmonary embolism from the European Society of Cardiology also highlight the importance of considering protein S deficiency as a risk factor for venous thromboembolism 1.

Some key points to consider in the management of protein S deficiency include:

• The use of anticoagulation therapy to prevent recurrent thrombotic events
• The choice of anticoagulant, with low molecular weight heparin preferred during pregnancy
• The duration of treatment, which depends on the clinical situation
• The importance of specialized blood tests for diagnosis, and the potential for temporary decreases in protein S levels during pregnancy, acute illness, or while taking certain medications. As noted in the guidelines for the primary prevention of stroke, protein S deficiency is one of the inherited hypercoagulable states associated with stroke, although the majority of case-control studies have not found an association between protein S deficiency and arterial stroke 1.

From the FDA Drug Label

Known or suspected deficiency in protein C mediated anticoagulant response Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

• Protein S deficiency is a condition that may increase the risk of tissue necrosis when taking warfarin.
• The decision to administer anticoagulants in patients with protein S deficiency must be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the benefits.
• Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal) are also conditions that may require special consideration when taking warfarin. It is recommended to use warfarin with caution in patients with protein S deficiency and to consider the risks and benefits of anticoagulant therapy on an individual basis 2.

From the Research

Protein S Deficiency

• Protein S deficiency is a major contributor to acquired hypercoagulability, which can cause myocardial infarction, stroke, and deep vein thrombosis 3.
• It is an inherited thrombophilia associated with an increased risk of venous thromboembolism (VTE) 4, 5.
• Protein S (PS) is an essential natural anticoagulant that acts as a cofactor for Activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI) 3.

Clinical Perspectives

• Protein S deficiency can be caused by genetic mutations, and its prevalence has been estimated to be less than 0.5% in the general European population 4.
• The diagnosis of protein S deficiency is challenging, and many preanalytical and analytical factors may affect the PS levels 4.
• Patients with low PS levels and known mutations within the PROS1 gene combined with other genetic or environmental thrombosis factors are at increased risk of recurrent thromboembolic events and require lifelong oral anticoagulation 4.

Treatment Options

• Anticoagulant therapy with warfarin or direct oral anticoagulants (DOACs) may be used to treat patients with protein S deficiency 6, 5.
• However, warfarin-induced skin necrosis can occur in patients with severe protein S deficiency, and switching to rivaroxaban, a direct inhibitor of activated factor X, may be a valid alternative 6.
• High-dose apixaban therapy may also be effective in treating recurrent venous thrombosis in patients with protein S deficiency 5.

Factor F (Factor IXa)

• Protein S has been shown to directly inhibit Factor IXa (FIXa), an activity that had been previously overlooked 3.
• This direct inhibition of FIXa by PS suggests that PS, particularly a small derivative of PS, could be used to treat individuals with PS deficiencies or abnormalities that cause thrombotic complications 3.