Protein S Deficiency Medication

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

Medication Summary

Heparin is used for patients with acute thrombotic events or for the prevention of thrombosis. Heparin treatment currently is available in two forms: unfractionated (standard) heparin or low molecular weight heparin (LMWH).

Unfractionated heparin for treatment of thrombosis is administered properly by a weight-based dosing protocol, with a target heparin therapeutic range as monitored by the activated partial thromboplastin time (aPTT) test and for a minimum of 5 days. A heparin dosing protocol includes the specified weight-dosing regimen, the target therapeutic aPTT range, the time for measuring aPTT tests after bolus or adjustment in dose (4-6 h), and a standard means of adjusting the unfractionated heparin infusion on the basis of the aPTT (eg, subtherapeutic, therapeutic, supratherapeutic).

A commonly used weight-adjusted unfractionated heparin regimen is termed 80/18, and consists of an 80 U/kg IV bolus followed by 18 U/kg continuous IV infusion. The target therapeutic heparin range is ideally individualized to the institution's laboratory aPTT test instrument and reagent.

To obtain an institutional heparin therapeutic range, employ a method such as that described by Brill-Edwards or any other similar comparison of in vitro and ex vivo heparin levels with aPTT test results in multiple individuals. In the absence of an established institutional therapeutic range, an aPTT ratio of 1.5-2.0 is commonly used; however, aPTT reagents and patient responses to unfractionated heparin vary, and the ratio can be 1.8-3.0 for some reagents.

The pharmacodynamics of LMWHs are different from the parent unfractionated heparin. LMWHs are administered subcutaneously. The aPTT test is not affected significantly by LMWH and is not used to monitor LMWH therapy. Several different LMWHs are available in the United States, but they have different pharmacodynamic properties and are not considered interchangeable. Weight-based dosing regimens for each LMWH and for treatment or prophylaxis indications are available from each manufacturer.

LMWHs are approved for treatment of deep venous thrombosis (DVT) with or without pulmonary embolism in the inpatient hospital setting. LMWHs are approved for treatment of DVT without pulmonary embolism in the outpatient setting.

Warfarin is used for long-term oral anticoagulant management of patients with protein S deficiency after first or subsequent thrombosis.

Investigational Anticoagulants

Agents in the following classes are under development:

  • Tissue factor pathway inhibitor (TFPI)  –  TFPIs act in two ways: by directly inhibiting factor Xa and by forming a complex together with factor Xa that inhibits tissue factorTF/factor VIIa. Currently the recombinant form is being tested.
  • Factor VIII inhibitor – With an approximate 3-week half-life, TB-402 is a human IgG4 monoclonal antibody with a partial inhibitor activity. TB-402 has been found to be effective for a 10 days equivalent of LMWH in a randomized phase II trial in patients who have undergone total knee replacement.
  • Factor IXa inhibitor  – REG1 has two components: RB006, which binds and inhibits factor IXa; and RB007, which neutralizes its anti-IXa activity. Trials are still underway to determine its effect when combined with anit-platelet therapy in patients with coronary artery disease.
  • Factor XI inhibitor  – FXI-ASO is a factor XI antisense oligonucleotide that potentially reduces factor XI.
  • Factor XIIa inhibitor  – rHA-Infestin-4 is a factor XIIa inhibitor that is being investigated in the management of acute ischemic cardiovascular and cerebrovascular events.
  • Polyphosphate inhibitors Platelets, when activated, release polyphosphate, which impacts coagulation via the intrinsic pathway. Compounds that inhibit polyphosphate are being investigated.
  • Thrombomodulin  ART-123 is the recombinant part of the extracellular domain of thrombomodulin. It has been approved in Japan for the treatment of disseminated intravascular coagulation. It has a plasma half-life of 2-3 days and can be administered subcutaneously every five to six days.




Class Summary

Unfractionated IV heparin and fractionated low molecular weight SC heparins are the 2 choices for initial anticoagulation therapy. Warfarin therapy may be initiated after 1-3 days of effective heparinization.


Usually administered as a continuous IV infusion for the treatment of acute thrombosis. For prevention of thrombosis, unfractionated heparin is administered subcutaneously.

Enoxaparin (Lovenox)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Dalteparin (Fragmin)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Tinzaparin (Innohep)

LMWH: Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Average duration of treatment is 7-14 d.

Warfarin (Coumadin)

Oral anticoagulant that antagonizes action of vitamin K in normal synthesis of clotting factors II, VII, IX, and X. Safe and effective for long-term oral management of thrombotic disorders. See articles on Deep Venous Thrombosis or Pulmonary Embolism (discussed in Treatment section) for additional details on dosing and monitoring of warfarin. Therapy is initiated without a loading dose at a dose range of 5-10 mg qd for 70-kg adult. Monitor PT/INR daily during initiation of therapy to measure anticoagulation effect. After initial 5-10 d and stabilization of warfarin dose, measure PT/INR 2-3 times qwk for 2-4 wk, then monthly thereafter.


Factor Xa Inhibitors

Class Summary

These agents bind to factor Xa and prevent it from cleaving prothrombin to thrombin.

Rivaroxaban (Xarelto)

Orally administered factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. 

Its anticoagulant action develops within 2-4 hours of ingestion and lasts for approximately 24 hours. It should be used if the creatinine clearance is < 15mL/min. 

Rivaroxaban does not require monitoring of PT and aPTT. However, its presence can be tested by the prothrombin time (PT) or anti–factor Xa activity.

Apixaban (Eliquis)

Factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It is metabolized in the liver via CYP3A4/5.

Used in patients with atrial fibrillation to prevent venous thromboembolism and stroke.

PT, aPTT and INR are prolonged but, routinely no monitoring is required. Anti-Xa assay can be used to rely upon if testing is necessary.

Edoxaban (Savaysa)

Orally active, with a half life of 6-11 hours. Undergoes hydrolysis, conjugation and oxidation by CYP3A4. Inhibits free Xa, prothrombinase activity and thrombin-induced platelet aggregation without requiring routine monitoring. 

Fondaparinux (Arixtra)

This compound is a novel pentasaccharide capable of inhibiting factor Xa via the action of antithrombin (AT) but devoid of anti-factor IIa (thrombin) activity. Interestingly, this compound does not appear to cross-react with HIT antibodies.

Approved for use in hip fracture surgery, knee replacement surgery, and hip replacement surgery. Only FDA-approved anticoagulant drug for hip fracture surgery. Also used and approved for extended prophylactic dosing for 21 d following hip fracture surgery.


Thrombin Inhibitors

Class Summary

Prevent thrombus development through direct, competitive inhibition of thrombin.

Dabigatran (Pradaxa)

Prevents thrombus development through direct, competitive inhibition of thrombin Plasma half- life is 12-14 hours and duration of action is 24 hours.

Dabigatran etexilate is a prodrug that is rapidly hydrolyzed to dabigatran (active form) in the liver by plasma and hepatic esterases. It undergoes hepatic glucuronidation to active acylglucuronide isomers. Routine monitoring is not required; however, the measurement of activated partial thromboplastin time (aPTT), ecarin clotting test (ECT) if available, or thrombin time may be useful to determine presence of dabigatran and level of coagulopathy. Also, reversal agent has