Protein S Deficiency Clinical Presentation

Updated: Sep 20, 2018
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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Presentation

History

Signs and symptom s of protein S deficiency are those associated with deep venous thrombosis (DVT), thrombophlebitis, or pulmonary embolus. Some women may have fetal loss as their only manifestation of a thrombophilic disorder (eg, protein S deficiency).

With venous thrombosis of the lower limbs, lower limb swelling and discomfort are the usual symptoms. Occasionally, redness or discoloration also is present, with or without associated cellulitis.

A family history of thrombosis is an important finding, which suggests inherited thrombophilia. Thrombosis at an early age (eg, usually < 55 y) or recurrent thrombosis is also frequently indicative of an inherited thrombophilic state (eg, protein S deficiency).

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Physical

Direct the examination to identify signs of venous thrombosis or pulmonary embolism. The results of the physical examination are nonspecific and often misleadingly indicate the diagnosis of DVT. Unusual sites of thrombosis (eg, mesenteric vein, [15] cerebral sinuses) are rare (< 5%) but, when observed, characteristically suggest one of the inherited thrombophilias (eg, protein S deficiency)

Deep vein thrombosis

See the list below:

  • The most common manifestation is venous thrombosis of the lower extremities, whichaccounts for approximately 90% of all events

  • Superficial veins that are obviously thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain

  • Superficial thrombophlebitis can be observed in some cases, with or without DVT

  • Suspect DVT if identifying signs of venous obstruction and local inflammation are present on examination

  • The classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (ie, Homan sign). However, less than a third of DVT cases exhibit these three findings; physicians observe unilateral leg or calf swelling with mild or moderate pain more often, which suggests DVT; rarely, calf discomfort without swelling is the only sign of DVT

  • Differential diagnoses for DVT include muscle strains and tears, passive swelling of a paralyzed or immobilized limb, Baker cyst, cellulitis, knee trauma or derangement, lymphatic obstruction, and postphlebitic syndrome

  • In postphlebitic syndrome, chronic swelling and pain are present in the limb, and the occurrence of a new venous thrombosis is often impossible to assess without Doppler or venography.

Pulmonary embolism

See the list below:

  • Some patients may have associated or isolated pulmonary embolism and may experience dyspnea, chest pain, syncope, or cardiac palpitations; dyspnea is the most frequent symptom of pulmonary embolism, and tachypnea is the most frequent sign

  • Some patients with massive pulmonary embolism can present with syncope or cyanosis

  • Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement

  • Acute right-sided heart failure occurs rarely and is associated with massive embolus

  • Findings of right ventricular dysfunction include bulging neck veins, a left parasternal lift, and an accentuated pulmonic component of the second heart sound; these findings are not specific for pulmonary embolism

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Causes

Protein S deficiency may be hereditary or acquired.

Hereditary protein S deficiency

Researchers have identified 2 genes for human protein S; both are linked closely on chromosome 3p11.1-3q11.2. [16]  One gene is the active gene, PROS-b (ie, PROS1), and the other, PROS-a, is an evolutionarily duplicated nonfunctional gene, which is classified as a pseudogene because it contains multiple coding errors (eg, frameshifts, stop codons). [17]  The expressed (alpha) PROS1 gene is more than 80 kb long and contains 15 exons and 14 introns. The protein S pseudogene (beta) has 97% homology to the PROS-a gene. [18]  Molecular studies into the genetic causes of protein S deficiency are complicated by the presence of the pseudogene, PROS-b, and phenotypic variation.

A number of mutations in PROS1 have been identified as causes of protein S deficiency and thrombophilia. Most are point mutations, such as transversion mutations that generate a premature stop codon and thus result in a truncated protein S molecule. [19, 20, 21]  In addition, deletions of large portions of the PROS1 gene have been reported. [22]  Researchers located the first such deletion in the central portion of the gene. [23]  The second deletion described (5.3 kb) was a deletion of coding exon XIII, which resulted in a truncated protein product. [24]

Acquired protein S deficiency

Acquired conditions associated with decreased protein S levels include the following [25] :

  • Oral contraceptive use
  • Warfarin anticoagulant use
  • Vitamin K deficiency
  • Chronic liver disease
  • Certain viral infections (eg, HIV, varicella)
  • Systemic lupus erythematosus
  • Myeloproliferative disorders

In addition, protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range. These low levels of protein S in pregnancy do not cause thrombosis by themselves.

Another seldom recognized cause for acquired protein S deficiency is sickle cell anemia. However, this condition alone does not produce a thrombophilic state.

 

 

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