Protein S Deficiency Treatment & Management

Updated: Jan 03, 2021
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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Medical Care

Management of protein S deficiency takes place in the event of acute venous thromboembolism (VTE). Prophylaxis may be used in selected patients with asymptomatic carrier states without a thrombotic event.

Following an acute thrombosis, inital management is the same as for all acute VTE episodes, based on the severity of disease, co-morbidities, and hemodynamic stability. Main agents in the acute period include intravenous unfractionated heparin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (DOAC).

The choice between a DOAC and a vitamin K antagonist (VKA) depends on factors such as patient preference, cost, and convenience. Historically, VKAs were the mainstay of treatment for VTE, including those caused by inherited thrombophilias. With the advent of DOACs, with their comparable efficacy as well as their safety profile, they are now increasingly used for VTE, including in patients with hereditary thrombophilias. 

In a prospective cohort study of patients with acute VTE diagnosed with inherited thrombophilias, DOACs had the same efficacy as heparin/VKAs and were shown to significantly reduce the 2-year VTE recurrence after anticoagulant discontinuation. DOACs did show an increased risk of clinically relevant non-major bleeding, while VKAs showed a slight increase in major bleeding. [35] A systematic review and meta-analysis conducted by Elsebaie et al also reported a low VTE recurrence and comparable rates of bleeding events between DOAC and VKA. [36]  These studies support the use of DOACs for acute VTE in the setting of inherited thrombophilias, including protein S deficiency.  

The question of whether to continue lifelong anticoagulation in patients with diagnosed protein S deficiency after their first thrombotic event is controversial. If the first thrombotic event was life threatening or occurred in multiple or unusual sites (eg, cerebral veins, mesenteric veins), most experts recommend lifelong therapy initially. If precipitated by a strong event (eg, trauma, surgery) and the thrombosis was not life threatening or involved multiple or unusual sites, some experts argue that these patients may have a lower risk of recurrence and deserve a trial without anticoagulation after 9 months.


Heparin is administered as follows:

  • Initial heparin treatment may be with intravenous unfractionated heparin or subcutaneous low molecular weight heparin (LMWH)
  • Heparin should be given for a minimum of 5 days
  • Manage heparin with standard protocols; see Deep Venous Thrombosis or Pulmonary Embolism for additional details


Warfarin administration can start on day 1 or 2 of heparin therapy. After two consecutive clotting tests showing a therapeutic International Normalized Ratio (INR) and a minimum of 5 days of heparin therapy, the patient can continue on warfarin alone. In most patients, specialists recommend 6-9 months of initial treatment with warfarin.

Direct Factor Xa Inhibitors

These agents bind to factor Xa and prevent it from cleaving prothrombin to thrombin. These drugs are widely used in multiple hypercoagulable states, including protein S deficiency, with evidence of comparable efficacy versus VKAs. Currently the oral agents that are available are rivaroxaban, apixaban, and edoxaban. [37, 38, 39]

Direct Thrombin Inhibitors

Dabigatran  is another option for treatment of hypercoagulable states. In a post hoc analysis of data from the RECOVER, RE-COVER II, and RE-MEDY trials, Goldhaber et al reported no significant differences in rates of symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. [40]

Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lacking, but idarucizumab, an antibody fragment, is available for reversing the anticoagulant effects of dabigatran.


In patients who are asymptomatic carriers of protein S deficiency, the goal of therapy is prevention of the first thrombosis. In such patients, avoid drugs that predispose to thrombosis, including oral contraceptives. In these patients, if surgery is performed or orthopedic injury occurs, prophylaxis with heparin is mandatory.

Protein S deficiency is considered a high-risk thrombophilia during pregnancy, with absolute risks of pregnancy-associated VTE being 0.9% antepartum and 4.2% postpartum. [41] Experts recommend prophylaxis with LMWH. The timing is controversial, but most experts would treat from the second trimester through 4-6 weeks postpartum.

The patient's bleeding risks must be assessed on an individual basis for any of these prophylactic recommendations. No single prescription fits all cases.


Diet and Activity

Dietary issues relate to patients with protein S deficiency who are on oral anticoagulation with warfarin. Maintain the same amount of vitamin K in the diet.

Restrictions apply to activity shortly after acute venous thrombosis (ie, DVT, pulmonary embolism). See Deep Venous Thrombosis or Pulmonary Embolism for additional details concerning such restrictions. While on anticoagulation therapy, patients should avoid vigorous contact activities.