Two most important pathogenesis of SCD patients are acute hemolytic anemia and vaso occlusive crisis. Hemolytic anemia is due to hemolysis of sickle cells. As polymerized hemoglobin S attached to each other forming straight rods of 6 to 14 stranded structure. Cell gets deformed and most of the free heme is transoported to the in inner membrane of the red cell. This heme may be toxic to the membrane and that may lead to lysis of cell membrane.
Wherease, pain episodes is the final consequence of vaso occlusive crisis. Vaso occlusive crisis is mainly due to clogging of the venules which in turn resulting from inflammation pathways i.e. due to modified membrane of blood cells, which includes cytoadhesion of RBC, WBC and platelets to endothelial cells.
My query is how these two pathways, (hemolysis and vasoocclusion) are related ? Or they are independent ? Based on that drugs can be developed.
Dear Devendra,
Most of the recent literature on SCD tends to distinguish two overlapping subphenotypes: i. the hemolytic and ii. the viscosity-vaso-occlusive phenotypes. Both have different pathophysiological bases, hemolysis and reduced nitric oxide bioavailability for the first one, and RBC sickling resulting from deoxyHbS polymerization for the second one. Although very much intertwined, hemolysis (chronic by the way) is more related to pulmonary hypertension, leg ulcers and priapism, and RBC sickling to vasoocclusive events such as painful crises, acute chest syndrome and osteonecrosis.
For more details, read the excellent review by Kato et al., Blood Rev. 2007 Jan;21(1):37-47.
From our experience with HYDROXYUREA in SCD, the two phenomenon are distinct. While haemolysis is a constant feature of SCD patients and hydroxyurea showed slight effect in decreasing haemolysis, vaso-occlusive crisis showed significant response to HU treatment. That is justifiable, because the pathophysiology of vasoocclusion involves the role of stress reticulocytes and neutrophils + lymphicytes. Whereas, haemolysis is due to intra and extra vascular mechanisms.
Mazin, I do fully agree with you concerning hydroxycarbamide action in SCD. However, every aspects of SCD pathophysiology are overlapping and intertwined. You are perfectly right to outline the role of stress reticulocytes and neutrophils in targeting vasoocclusion. But with no haemolysis and the resulting anaemia, no stress reticulocytes! Also, haemolysis releases free heme, a major component of inflammation and neutrophil activation.
Yes, that's true more hemolysis triggers more reticulocyte production. That's why rate of hemolysis is correlated with retic count. Except B19 virus pathogenesis, which specifically target retic and retic is zero, all the time SCD patients has high retic count.
Hi Devendra,
I believe that you cannot extricate the role of hemolysis from vascular occusion in SCD. Clearly, ongoing hemolysis increases inflammation which further induces sickling and vascular occlusion. Additionally, hemolysis results in NO reduction which also increases the risk for vascular occlusion. However, the rate/degree of hemolysis does not appear to directly impact the frequency of VOC and there are many patients with significant hemolysis with minimal VOC. I hope that helps.
- Badges
- Science topic
- Similar topics
- Chemistry
- Pharmacology
- Medical Pharmacology
- Clinical Pharmacology