There are 3 types of PS deficiency identified based on the deficit in total and free PS antigen levels and the functional activity of these proteins (Table 1).3,4 Normal PS values are shown in Table 2.4

Table 1. Protein S Deficiency Types3,4

SubtypeCharacteristicsRelative FrequencyTotal Protein S AntigenFree Protein S AntigenProtein S Activity
Type ILow levels of total and free PS antigen and reduced functional activity Total PS <50% of normal Free PS <15% of normal  67%DDD
Type IIReduced PS functional activity alone with normal free and total PS antigen levels This isolated qualitative defect is a rare anomalyRareNND
Type IIIReduced free PS antigen level and functional activity with normal total PS antigen level33%NDD
D, decreased; N, normal range
Table adapted from Simon et al.4  

Table 2. Normal PS Values

MeasureReference Range
Protein S antigen, total65%-135%
Protein S antigen, free65%-150%
Protein S activity65%-150%
Table adapted from Simon et al.4  

The quantitative and qualitative evaluation of PS demands expertise in interpretation of both the bound and free states, as well as the many other cofactor activity issues. Therefore, primary care clinicians should collaborate with a hematologist.                                                       

Differential Diagnosis of Protein S Deficiency

The differential diagnosis of VTE includes other inherited thrombophilias and acquired thrombophilia. Individuals with other inherited thrombophilias will have laboratory evidence of a specific defect and normal PS levels, and patients with acquired thrombophilia will have risk factors evident from patient history and physical examination. The full workup for hypercoagulability syndromes should include tests for prothrombin gene mutation and Lupus anticoagulant, among other tests. antithrombin III and protein C and S deficiency, PCR for factor V Leiden mutation and prothrombin G2021A mutation, testing for antiphospholipid antibodies and homocysteine level.20


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Management

The immediate focus of thrombosis management, regardless of the etiology, is to restore hemostasis by reestablishing perfusion using pharmacological agents. An unprovoked VTE is an event with no identifiable provocation such as postpartum, postsurgical, immobilization, or oral contraceptive use. There is no specific protocol for management of PS deficiency and VTE guidelines are followed. Length of anticoagulation therapy is determined based on a number of factors including history of thrombosis, whether VTE was provoked or unprovoked, underlying malignancy, upper vs lower extremity thrombosis, older age (fall risk).4,21-23

Initial management of acute VTE in patients with inherited PS deficiency or without an inherited thrombophilia is anticoagulation for at least 3 to 6 months.21 For a patient with a family history of VTE but no personal history, prophylactic anticoagulation is given only postoperatively and during pregnancy and the postpartum period.2,24 Common anticoagulants and their usage in treating and preventing thrombosis associated with PS deficiency are described below.

Heparin

Anticoagulation by unfractionated heparin (UFH) or LMWH (eg, enoxaparin, dalteparin) is the conventional treatment to reestablish blood flow. Heparin is available in injectable form only (subcutaneous or intravenous) and is linked to bleeding complications, heparin-induced thrombocytopenia (HIT), and osteoporosis.25 LMWH is administered subcutaneously and has a relatively low incidence of bleeding and secondary thrombocytopenia, less bone loss, and a long half-life.24

If UFH is indicated by urgency of the clinical situation, either weight-based or fixed rate protocol is used. Heparin infusion can be initiated followed by a bolus dose or without one. One weight-based protocol is 80 unit/kg body weight with a maximum of 10,000 units, followed by an infusion rate of 18 units/kg/hour with a maximum of 2000 units per hour.26 The goal is to reach and maintain a therapeutic range of a partial thromboplastin time (PTT) of 70 to 110 seconds or antifactor Xa activity of 0.3 to 0.7 IU/mL. A nonweight-based protocol starts with a bolus of 5000 units followed by an infusion of 1680 units per hour. However, each health care facility typically follows its own protocol or nomogram.

Testing for heparin-induced thrombocytopenia (HIT) antibody may be warranted in patients with a recurrent or breakthrough event.21 In patients with HIT, nonheparin anticoagulants argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) are recommended.27

Warfarin

Vitamin K antagonists such as warfarin should be initiated simultaneously with UFH or LMWH until the goal international normalized ratio (INR) is reached. Warfarin works by inhibiting vitamin-K dependent procoagulants such as II, VII, IX, and X.28 While working to impede these procoagulant factors warfarin hinders the vitamin K-dependent anticoagulants PS and PC.28 Therefore, warfarin may further aggravate clotting or generate new clots in certain cases.28 PS activities can be decreased even after 2 weeks of warfarin therapy leading to hypercoagulation; thus, PS levels should be measured again at 2 weeks after warfarin discontinuation.28 In addition, PS deficiency can cause warfarin-induced skin necrosis during warfarin therapy.29 Direct oral anticoagulants can effectively treat warfarin-refractory cases.25

The INR goal for warfarin therapy is 2 to 3 times the control and is typically monitored daily in hospital or every third day.30 The suggested duration of anticoagulation ranges from 3 to 6 months.31

Direct Oral Anticoagulants (DOACs)

Direct oral anticoagulants (DOACs; also known as new oral anticoagulants [NOACs]) can effectively treat warfarin-refractory cases.28 These agents act by suppressing thrombin (eg, dabigatran etexilate), or factor Xa (eg, apixaban, edoxaban, rivaroxaban). DOACs do not reduce PS and PC levels and they have fewer drug-to-drug and drug-to-food interactions compared with warfarin.28 However, false PS elevation may occur during riveroxaban therapy.32

The decision to choose between warfarin and a DOAC is dependent upon various factors such as patient preference, compliance, and drug and dietary interactions. Renal insufficiency and weight are also important considerations as DOACs vary in the proportion of the drug that is cleared by the kidneys and because DOACs are not recommended in patients with a BMI >40 or weight >120 kg.21,33 As emphasized above, diagnosis of the specific thrombophilia should take place after initial restoration of perfusion, and DOACs can affect functional assays for PS. PS and PC deficiency are complicated clinical conditions necessitating specialty care by a hematologist, and primary care clinicians should refer patients as soon as they suspect a heritable thrombophilia-related coagulation. 

This article originally appeared on Clinical Advisor