Response to Low PS Inquiry on Diverse Health Hub

This question was posted on the Diverse Health Hub site (AKA Diagnostic Equity): “Can my birth control pills explain why my protein S level is low at 55%? OR…. should I be evaluated for an actual clotting disorder since low protein S runs in my family?”

This comprehensive response was provided by my colleague, LaShanta Brice, DCLS, MLS(ASCP)^CMSH^CM, Scientific Engagement & Clinical Education Scientist, Diagnostica Stago Inc., [email protected], and permission was given by Tamara Lobban-Jones, Diverse Health Hub Proprietor, [email protected]:

Yes, birth control pills can lower protein S levels, and this is one of the most common non-genetic reasons healthcare professionals see a “low” result. Estrogen-containing contraceptives naturally reduce free protein S activity in the blood, which can make results look abnormal even when there is no underlying clotting disorder. A protein S level of 55% could fall into this medication-related effect, depending on the reference range used.

Protein S activity and protein S free antigen tests measure the amount and function of protein S, a natural anticoagulant that helps prevent excessive clotting. Low levels can occur temporarily due to estrogen-containing birth control, pregnancy, acute illnesses, or certain medications. Still, they can also indicate a hereditary protein S deficiency that is passed down through families. Because low protein S may increase the risk of blood clots, results must be interpreted carefully and often require repeat testing to determine whether the decrease is temporary or truly genetic.

No single test can diagnose a clotting disorder, so your provider will interpret results alongside your family history, any current medications such as birth control, any past clots or related symptoms, and whether any abnormal results persist after repeat testing. Putting all of this information together helps determine whether your results reflect a temporary change or a true hereditary condition.

That said, your family history is also important. If low protein S “runs in your family,” it is reasonable to ask whether this could represent a hereditary protein S deficiency, a condition that can increase the risk of blood clots in some individuals.

When low protein S is likely due to birth control pills:

• You are currently taking estrogen-containing contraception
• You have no personal history of blood clots
• The level improves after stopping estrogen for at least 4–6 weeks, which is when retesting is typically done
• Other clotting tests are normal. When additional evaluation for a hereditary clotting disorder may be appropriate:
  • Strong family history of blood clots at a young age
  • Known family members with confirmed hereditary protein S deficiency
  • Your level remains low even after stopping estrogen and repeating the test
  • You have had a clot in the past (deep vein thrombosis, pulmonary embolism, or unusual-site clot)

Your clinician may recommend:

1. Repeating the protein S level after stopping estrogen for 4–6 weeks (if safe for you to do so).
2. Reviewing your family history in more detail, including who was affected, at what age, and what type of clot they had.
3. A referral to hematology if the repeat level is still low or if your family history raises concern.

Below are a few questions to ask your provider and/or healthcare team:

• Do you recommend repeating my protein S test, and what factors should be avoided before retesting so the result is accurate?
• Based on my family history, are there additional laboratory tests or panels that would help clarify whether this is hereditary or a temporary change?
• How should I interpret my protein S result, and which values are most important to monitor over time?

Additionally, below are some patient-friendly resources to review:

• ASH (American Society of Hematology): https://www.hematology.org/education/patients/blood-clots
• Testing.com (Protein C and Protein S): https://www.testing.com/tests/protein-c-and-protein-s/
• MedlinePlus (Protein S Deficiency): https://medlineplus.gov/genetics/condition/protein-s-deficiency/