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Nitric Oxide (NO) metabolism is essential for normal blood flow.  In addition to regulating vascular tone and inhibiting endothelial adhesion molecule expression, nitric oxide has potent anti-thrombotic effects. Several factors are involved to maintain normal nitric oxide levels. Nitric oxide synthase generates NO from  Arginine, a nutrient, which needs to be present at appropriate levels in plasma.


NO generation can be measured by its determination in exhaled air, or as the oxidized products nitrite and nitrate (NOx). In several diseases states, nitric oxide can be dysfunctional, in part due to the increased level of hemolysis, which leads to the release of arginase in the circulation. Hemolysis can be confirmed by the measurement of cell free hemoglobin and the presence of elevated levels of lactate dehydroginase (LDH). Increased hemolysis can in part be due to the rapid breakdown of phosphatidylserine (PS) exposing cells in the circulation, by inflammatory mediators such as secretory phospholipase A2 (sPLA2).

In addition to alterations in markers of endothelial activation such as soluble VCAM 1 (sVCAM-1), a dysregulation of hemostasis can be identified  activation of hemostatic pathways such as the prothombinase complex, and can be measured by altered levels of Fragment 1+2 (F1.2), D-dimer, or the thrombin-antithrombin complex (TAT).

The figure indicates the relations between hemolysis, hypercoagulability and dysregulation of NO metabolism (from Gladwin and Kato: Haematologica 2008 vol. 93 (1) pp. 1-3)

 

Hemolysis-Associated Hemostatic Activation.
Intravascular hemolysis releases hemoglobin into plasma which quenches NO and generates reactive oxygen species (directly via fenton chemistry or via induction of xanthine oxidase and NADP oxidase). In addition,  arginase I is released from the red blood cell during hemolysis and metabolizes arginine, the substrate for NO synthesis, further impairing NO homeostasis. The depletion of NO is associated with pathological platelet activation and tissue factor expression. Hemolysis and splenectomy are also associated with phosphatidylserine exposure on red cells which can activate tissue factor and form a platform for coagulation.

 

Exhaled Breath Nitric Oxide

Serum Nitric Oxide

Cell Free Hemoglobin

Lactate Dehydrogenase

Arginase Activity

Arginase Concentration