In the end, if the plasma concentration of the "free met-hemoglobin" and/or "free hemoglobin" is still too high for proximal tubule to absorb back into the body, then hemoglobinuria occurs, indicating an extensive intravascular hemolysis. These remaining free hemoglobin entities also begin to consume nitric oxide, which is critical regulators of vascular homeostasis and basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. The reduction of nitric oxide deeply disturbs the bodys mechanism to maintain the stability of the hemodynamics. Additionally, free hemoglobin manifests direct cytotoxic, inflammatory, and pro-oxidant effects that in turn negatively impact endothelial function. At the meantime, free heme exerts its multiple pro-inflammatory and pro-oxidant effects to the tissues it goes through.It is important to note that although hemosiderins are also included in the urine in the setting of intravascular hemolytic hemoglobinuria, it will be detected only several days after the onset of the extensive intravascular hemolysis and will remain detectable several days after termination of intravascular hemolysis. The phenomenon tells that the detection of hemosiderin in urine is indicative of either ongoing or recent intravascular hemolysis characterized by excessive hemoglobin and/or met-hemoglobin filtered through the renal glomerulus as well as the loss of hemosiderin-laden necrotic tubular cells. See also
Extravascular hemolysis

Note


== References ==
Pai syndrome, also known as Median cleft of the upper lip-corpus callosum lipoma-midline facial cutaneous polyps syndrome, is a very rare genetic disorder which is characterized by nervous system, cutaneous, ocular, nasal and bucal anomalies with facial dysmorphisms. Signs and symptoms
List of common symptoms:
Depressed nasal bridge
Median cleft lip
Central nervous system lipomas. Nasal polyposis
Presence of skin tags
Subcutaneous noduleList of not-so-common symptoms:[2]

Oral frenulum abnormalities
Bifid uvula
Hypertelorism
TelecanthusList of uncommon symptoms:[2]

Missing/underdeveloped corpus callosum
Down-slanting parpebral fissures
Encephalocele
Coloboma
Nose defects
Frontal bossing
High palate

Causes
A specific, shared genetic cause hasnt been found. The closest thing to it was a case reported by Masuno et al. of a Japanese girl with symptoms of the disorder plus short stature and intellectual disabilities with a spontaneous reciprocal translocation. This translocation involved chromosome Xq28 and chromosome 16q11.2 (more specifically, 46,X,t(X;16)(q28;q11.2). Epidemiology
According to OMIM, 18 cases have been described in medical literature, but according to ORPHAnet, 67 cases have been described. == References ==