What Is Protein S Deficiency?

  • Jasmine Abdy Bachelor of Science - BSc, Medical Microbiology with a Year in Industry, University of Bristol, UK

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Protein S deficiency is a rare disorder that is defined by the reduced activity of Protein S in the blood1. This deficiency can be inherited from your parents or developed over the course of your life. Protein S is responsible for the control of clotting throughout the body and does so by acting on other important clotting proteins throughout the body, such as Protein C. Therefore, patients with Protein S deficiency are unable to control blood clotting effectively.1 This can result in excessive clotting of the blood (thrombophilia) which can lead to conditions such as deep-vein thromboembolism (DVT) and pulmonary embolism (PE).1 Protein S deficiency is equally common amongst both genders, with some patients never developing symptoms. In this article, we discuss the crucial things to know about Protein S deficiency, including its symptoms, diagnosis and treatment. 

Understanding protein S1

As discussed, Protein S and Protein C work closely alongside one another in controlling coagulation. To understand the role of Protein S, we will look at how it would normally function in injury-causing bleeding. In these instances, Protein C and S are relatively inactive, allowing for proteins known as ‘factors’ to be activated and to form the blood clot necessary to prevent further bleeding. Once the clot has formed and bleeding has been adequately stopped, Protein C and S are then required to prevent further clotting. To do so, Protein C is first activated Protein S acts alongside Protein C to inactivate what are known as ‘factors’ in the blood. Factors are responsible for forming the components of a blood clot. By preventing their action, Protein S then prevents excessive clotting. We can therefore see how, in its absence, excess clotting can occur. It is helpful to think of Protein S as the ‘regulator’ of blood clotting. 

Causes of protein S deficiency 

Protein S Deficiency can be inherited from your parents or acquired throughout life. In cases where it is inherited, this is associated with mutations to the PROS1 gene.1 This defective gene can be inherited from both parents or only one. Importantly, Protein S deficiency is reported to have an ‘autosomal dominant’ inheritance pattern.1 This means that if you are to inherit one copy of the defective gene from your parents, then you will have Protein S deficiency. However, if you inherit only one copy of the defective gene, then you will only experience mild symptoms.1 If the defective gene is inherited from both parents, then you will have a severe form of Protein S deficiency.1 

There are three main types of Protein S deficiency that can occur:3

  1. Type I: the decrease in the activity of Protein S is directly related to the decrease in the levels of Protein S found in your blood
  2. Type II: the levels of Protein S in the blood are normal, but it does not function properly due to the genetic defect
  3. Type III: there is a normal level of ‘total’ Protein S in the blood but the level of ‘free’ Protein S available to work throughout the body is low

Acquired Protein S deficiency can be caused by several factors listed below:1

Symptoms of protein S deficiency

  • Pregnancy 
  • Older age 
  • Oral contraceptive pill use
  • Recent surgery 
  • Long periods of immobilization or inactivity (such as during long-haul flights)

Diagnosing protein S deficiency 

Identification of Protein S deficiency can sometimes be challenging, especially if symptoms are mild. Your healthcare provider will take into consideration the number of DVTs and/or PEs experienced. For those assigned female at birth (AFAB), the only symptom may be recurrent miscarriages.1 Understanding your family history is also important in forming a diagnosis of Protein S Deficiency. Your healthcare provider will often ask if any members of your family had experienced thrombotic events before the age of 50, as this is indicative of Protein S deficiency.1 To summarize, you may be asked the following questions: 

  • Have you experienced any blood clots recently? 
  • Has any of your family experienced a blood clot before they were 50? 
  • Have you been miscarrying frequently? 

If suspicion is high regarding the presence of Protein S deficiency, your healthcare provider may then want to conduct a physical examination to assess for the presence of any obvious blood clots. They will then order laboratory tests which will look at certain levels of enzymes in the blood. This is known as an Enzyme-Linked ImmunoSorbent Assay (ELISA) and will assess the following:1 

  1. Protein S Antigen 
  2. Functional Protein S

Using the results from this test, your healthcare provider will then be able to distinguish between the different types of Protein S deficiency. Types I and III are the most common, with Type II being quite rare.1 Your healthcare provider may also suggest genetic testing to assess for deficiencies in the PROS1 gene. This will allow for a definitive diagnosis of Protein S deficiency. 

Treating protein S deficiency 

Protein S deficiency is often treated in the presence of a DVT. In these cases, your healthcare provider will use anticoagulation medications to thin the blood. These include the use of low molecular weight heparin, Vitamin K antagonists such as Warfarin or DOACs such as Enoxaparin.1 If you have been diagnosed with Protein S deficiency but remain asymptomatic, these medications may be used to prevent the occurrence of blood clots. 

If you have Protein S deficiency and develop either a PE or DVT, you may be on one of these medications for longer than expected. For example, if you start on Warfarin, you can expect to continue this treatment for at least 3-6 months.1 This is to ensure that coagulation activity returns to normal so that these adverse events do not reoccur.1 If you develop a DVT or PE and it is life-threatening, then your healthcare provider will consider placing you on anticoagulation for the remainder of your life. Remember that symptoms can vary amongst individuals with the deficiency and so treatment will differ amongst cases. 

If your DVT or PE was precipitated by an identifiable factor (such as surgery) then life-long anticoagulation is not advised.1 Treatment may also be advised when there is an increased risk of clots developing, such as during long-haul travel, pregnancy and surgery.1 


Protein S is a rare disorder that causes your blood to clot excessively. Protein S can be considered the ‘regulator’ of blood clotting and so its deficiency results in unregulated clotting. Protein S deficiency can either be inherited or acquired throughout life due to issues with your liver, surgery or chronic infections. It is associated with defects in the PROS1 gene. The severity of symptoms associated with Protein S deficiency is highly dependent on the inheritance pattern related to the defective gene. If it is inherited from both parents, symptoms will be more severe. These symptoms typically present as recurring DVTs or PEs. Diagnosis can be challenging due to the variability in symptoms associated with the deficiency. Your healthcare provider will take an elaborate medical history before conducting a physical examination and ordering laboratory tests. This will enable them to distinguish between the different subtypes of Protein S deficiency. Treatment can either be life-long or for 3-6 months following the event of a DVT or PE. This will centre around the use of anticoagulants such as low molecular weight heparin, Warfarin or DOACs. 


How long will I have Protein S deficiency for? 

If inherited, Protein S deficiency is life-long. Unfortunately, there are no current cures for Protein S deficiency. Despite this, it can be managed effectively with treatments administered by your healthcare provider. In some instances, you may not notice that you have a Protein S deficiency as it can be asymptomatic. 

What precautions should I take to look after myself? 

It is important to be aware of the risk factors associated with the development of a PE or DVT. Understanding these will allow you to make the appropriate arrangements with your healthcare provider to prevent them from occurring. Some small lifestyle changes can also be beneficial. For example, Protein S deficiency can cause bleeding of the gums when brushing your teeth. In this instance, consider switching to a toothbrush with softer bristles or perhaps consider the use of an electric toothbrush. 

It is also important to be aware of the symptoms of DVT and PE. Make use of the links within this article to become aware of these. Through doing this, you will be able to rapidly identify them and report to your healthcare provider without delay. 


  1. Gupta A, Tun AM, Gupta K, Tuma F. Protein S Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Nov 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK544344/.
  2. Padda IS, Patel P, Citla Sridhar D. Protein C and S. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Nov 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557814/.
  3. Protein S (PS) Deficiency | Thrombosis and Clotting [Internet]. [cited 2023 Nov 17]. Available from: https://www.ihtc.org/protein-s-deficiency.
  4. Mukhtar B, Garg R, Ibrahim G, Batra J. Investigating protein C and S levels in pregnant women with recurrent early pregnancy loss versus normal pregnancy. J Med Life [Internet]. 2023 [cited 2023 Nov 17]; 16(1):160–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979182/

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Morgan Keogh

MBBS, Medicine, King's College London, UK

I am a fourth year Medical Student at Kings College London, currently intercalating in a BSc in Cardiovascular Medicine. I have a strong interest in Cardiology, Acute Internal Medicine and Critical Care. I have also undertaken a research project within the field of Cardiology whereby I explored the efficacy of a novel therapeutic test at detecting correlations between established clinical characteristics and salt-sensitive hypertension. I have broad experience with both the clinical and theoretical aspects of medicine, having engaged with a wide array of medical specialities throughout my training. I am currently acting as a radiology representative within the Breast Medicine Society and have experience with tutoring at both GCSE and A-level. I am also working closely alongside medical education platforms to ensure the delivery of content applicable to the learning of future doctors.

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