Which congenital thrombophilias should be included in the differential diagnoses of protein S deficiency?

Updated: Jan 03, 2021
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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Patients who develop VTE in the absence of acquired risk factors may have protein S deficiency or some other congenital thrombophilia, or may have more than one congenital risk factor for VTE. In a retrospective analysis of prospectively gathered data on 58 outpatients with VTE (approximate mean age 39 years) without major acquired risk factors, 45 had at least one hereditary risk factor for VTE. Diagnoses in these patients were as follows [30] :

  • Protein S deficiency - 17 patients
  • Protein C deficiency - 18 patients
  • Factor V Leiden mutation - 30 patients (25 heterozygous and five 5 homozygous)
  • Prothrombin gene mutation - 16 patients
  • Methylenetetrahydrofolate reductase C677T mutation - 24 patients (19 heterozygous, 5 homozygous)
  • Antithrombin III deficiency - 14 patients
  • Hyperhomocysteinemia - 13 patients

Of the 17 patients with protein S deficiency, 13 also had protein C deficiency, hyperhomocystinemia, antithrombin III deficiency, or some combination of those conditions.

These authors concluded that thrombophilia testing should be performed in younger VTE patients without known acquired risk factors. Testing for protein C, protein S, and prothrombin gene mutations should be followed by additional molecular assessment in patients with suspicious findings. [30]

Similarly, in a cohort of 367 unselected pediatric patients with VTE, Klostermeier et al found that 30 children (8.2%) from 27 families had protein S deficiency. After adjustment for family status, the prevalence of protein S deficiency was 7.4 %. Mean age at first onset of VTE was 14.5 years. Of the 30 children with protein S deficiency, 18 (60%) had a concomitant risk factor for VTE. The factor V mutation at rs6025 and the homozygous factor II susceptibility variant at rs1799963 were observed along with protein S deficiency in one patient each, and the Heerlen polymorphism was found in five children with milder protein S deficiency. These researchers concluded that thrombophilia testing and consideration of appropriate interventions are warranted in this high-risk group of patients. [31]

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