Hypoxia downregulates protein S expression

Abstract

siblings were predicted to carry 2 mutant TMPRSS6 alleles. Thus, in many cases, it is highly likely that clinically affected individuals with 1 TMPRSS6 pathogenic variant possess a second occult mutant allele. While this manuscript was in preparation, another group of investigators also studied the utility of normalizing plasma hepcidin to the TfSat in patients with IRIDA. 6 In particular, they compared the TfSat:hepcidin ratio in TMPRSS6-mutated patients who had 1 or 2 mutated alleles and found that, in general, those individuals with a single detectable allele had a milder biochemical phenotype than those with 2 mutated alleles. We suggest that most patients with a severe clinical phenotype likely have biallelic TMPRSS6 mutations and that, in some cases, the second allele is genetically occult. One goal of this study was to elaborate a biochemical method that might predict which patients in a group of individuals with cID/A were most likely to have biallelic TMPRSS6 mutations. The study group included only those who were poorly responsive to oral iron and had a TfSat #15%, that is to say, those who had a higher pretest probability of having IRIDA as a result of TMPRSS6 mutations than an unselected group with ID/A and TfSat #15%. Application of these tests in a broader iron-deficient population would likely result in a lower specificity. Nonetheless, one might argue that, regardless of whether or not an individual with cID/A has TMPRSS6 mutations, a relative hepcidin excess, as indicated by the normalized hepcidin or ferritin ratios or multivariable model would indicate that they would benefit from early initiation of parenteral iron therapy.

COVID-19: The crucial role of blood coagulation and fibrinolysis

“…Hypoxia, obviously present in the COVID19 disease, is "per se" an important thrombogenic factor: examples of this pro-thrombotic effect are, for instance, sickle cell anemia, and high-altitude thrombosis. A reduced synthesis and release of the physiologic anticoagulant Protein S in hypoxic status, has been described as a possible cause of thrombosis [19].…”

COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy

“…Our past studies [ 9 – 13 ] with the natural anticoagulant Protein S illuminated our understanding about the significance of Protein S -Factor IXa interaction in hemostasis. Further, we identified a critical role of Protein S in regulating hypoxia and associated thrombotic complications [ 9 ].…”

“…An overlooked aspect of hypoxia and the IL6-induced cytokine storm is that both factors downregulate a key anticoagulant, Protein S [ 9 , 32 ] ( Figure 1 ). For example, in a population of stroke patients, IL6 was upregulated, and it caused downregulation of Protein S that resulted in venous thrombosis [ 37 ].…”

Venous thrombosis at altitude presents with distinct biochemical profiles: a comparative study from the Himalayas to the plains

“…46 In the present study, relative deficiencies in protein C, protein S, and AT were also observed in HAPs and SLPs, which, again is in accordance with earlier reports suggesting a higher prevalence of protein S deficiency in Asian populations compared with other risk factors, such as protein C and AT. [47][48][49][50] However, our study demonstrated greater protein S deficiency in HAPs compared with SLPs. This was in accordance with a report of protein S deficiency in an animal model resulting from hypoxia exposure.…”

“…This was in accordance with a report of protein S deficiency in an animal model resulting from hypoxia exposure. 50 Furthermore, AT deficiency leads to inhibition of prostacyclin release from endothelial cells, leading to platelet activation and aggregation and neutrophil tethering to blood vessels, and it increases the production of various cytokines and chemokines from endothelial cells. 51 Our study also revealed enhanced platelet and endothelial cell activation at HA.…”