Evolving paradigm of sickle cell VOC
| Year . | Scientific observation . | Contribution . |
|---|---|---|
| 1910 | James Herrick: Description of the first patient with sickle-shaped RBCs on peripheral smear | Original description |
| 1930 | Shriver and Waugh: Venous circulation in a patient is enriched in sickle-shaped cells that regain normal shape upon reoxygenation | A disease of the RBC |
| 1949 | Linus Pauling demonstrates that the disease originates from a mutated hemoglobin molecule | A molecular disease of hemoglobin |
| 1974 | Hofrichter and Eaton: “delay time” for the initiation of rapid phase of deoxy-HbS polymerization | VOC is dependent on deoxy HbS concentration and transit time of the RBCs |
| 1979, 1980 | Hebbel and Hoover: Increased propensity of SS-RBCs to adhere to endothelium in vitro and correlation with disease severity | Widened the scope of scientific studies outside the RBC. Adhesive interactions of the RBCs and endothelium leads to VOC |
| 1978-1986 | Brugnara and others: increased KCl cotransport and Gardos channel activity in SS-RBCs | SS-RBC dehydration due to cation loss |
| 1989 | Kaul and Nagel: SS RBCs adhere in postcapillary venules SS reticulocytes are more adherent than older and denser RBCs | SS reticulocytes initiate VOC by adhering to endothelium, followed by trapping of dense cells, hypoxia, and retrograde extension of obstruction to neighboring vessels |
| 1984-2004 | Characterization of multiple discrete mechanisms of sickle RBC adhesion | Role of cell, matrix adhesion molecules and plasma factors in VOC |
| 1994 | Platt: Baseline WBC count >15 × 109/L is associated with increase morbidity and mortality | Leukocyte counts are a marker of SCD severity |
| 1997 | Pastzy and Narla/Ryan and Townes: Humanized murine models of SCD | Transgenic models expressing only human sickle hemoglobin |
| 2000 | Kaul and Hebbel: exaggerated inflammatory response in hypoxia followed by reoxygenation | Contribution of the ischemia-reperfusion injury to inflammation |
| 2002 | Turhan and Frenette: SS-RBC interactions with adherent leukocytes initiate VOC. P- and E-selectin deficiency protects against TNF-α induced VOC | First in vivo evidence in a sickle cell murine model for the role of leukocytes in initiating VOC. P and E-selectins are important in mediating this interaction |
| 2002 | Reiter and Gladwin: Cell-free hemoglobin limits nitric oxide bioavailability in SCD | Nitric oxide depletion in SCD and its contribution to vasculopathy |
| 2003 | Hines and Parise: Role for epinephrine in the regulation of BCAM/Lu dependant SS RBC adhesiveness | Role of physiologic stress as a trigger for VOC |
| 2004-2007 | Zennadi and Telen: Epinephrine-induced activation of LW-mediated sickle cell adhesion and VOC in a vivo mouse model is blocked by propranolol | Identifies β-adrenergic receptor antagonism as a potential therapeutic approach |
| 2009 | Wallace and Linden: Ischemia reperfusion injury is amplified by the activation of CD1d-restricted iNKT cells | Role of iNKT cells in triggering inflammation |
| 2009 | Hidalgo and Frenette: Role of secondary activation signals in neutrophils | Role of E-selectin as an activating signal, Src kinases and αMβ2 |
| 2009 | Belcher and Vercellotti: Heme oxygenase-1 inhibits vascular stasis in a murine model of SCD | Importance of heme in inflammation and VOC |
| Year . | Scientific observation . | Contribution . |
|---|---|---|
| 1910 | James Herrick: Description of the first patient with sickle-shaped RBCs on peripheral smear | Original description |
| 1930 | Shriver and Waugh: Venous circulation in a patient is enriched in sickle-shaped cells that regain normal shape upon reoxygenation | A disease of the RBC |
| 1949 | Linus Pauling demonstrates that the disease originates from a mutated hemoglobin molecule | A molecular disease of hemoglobin |
| 1974 | Hofrichter and Eaton: “delay time” for the initiation of rapid phase of deoxy-HbS polymerization | VOC is dependent on deoxy HbS concentration and transit time of the RBCs |
| 1979, 1980 | Hebbel and Hoover: Increased propensity of SS-RBCs to adhere to endothelium in vitro and correlation with disease severity | Widened the scope of scientific studies outside the RBC. Adhesive interactions of the RBCs and endothelium leads to VOC |
| 1978-1986 | Brugnara and others: increased KCl cotransport and Gardos channel activity in SS-RBCs | SS-RBC dehydration due to cation loss |
| 1989 | Kaul and Nagel: SS RBCs adhere in postcapillary venules SS reticulocytes are more adherent than older and denser RBCs | SS reticulocytes initiate VOC by adhering to endothelium, followed by trapping of dense cells, hypoxia, and retrograde extension of obstruction to neighboring vessels |
| 1984-2004 | Characterization of multiple discrete mechanisms of sickle RBC adhesion | Role of cell, matrix adhesion molecules and plasma factors in VOC |
| 1994 | Platt: Baseline WBC count >15 × 109/L is associated with increase morbidity and mortality | Leukocyte counts are a marker of SCD severity |
| 1997 | Pastzy and Narla/Ryan and Townes: Humanized murine models of SCD | Transgenic models expressing only human sickle hemoglobin |
| 2000 | Kaul and Hebbel: exaggerated inflammatory response in hypoxia followed by reoxygenation | Contribution of the ischemia-reperfusion injury to inflammation |
| 2002 | Turhan and Frenette: SS-RBC interactions with adherent leukocytes initiate VOC. P- and E-selectin deficiency protects against TNF-α induced VOC | First in vivo evidence in a sickle cell murine model for the role of leukocytes in initiating VOC. P and E-selectins are important in mediating this interaction |
| 2002 | Reiter and Gladwin: Cell-free hemoglobin limits nitric oxide bioavailability in SCD | Nitric oxide depletion in SCD and its contribution to vasculopathy |
| 2003 | Hines and Parise: Role for epinephrine in the regulation of BCAM/Lu dependant SS RBC adhesiveness | Role of physiologic stress as a trigger for VOC |
| 2004-2007 | Zennadi and Telen: Epinephrine-induced activation of LW-mediated sickle cell adhesion and VOC in a vivo mouse model is blocked by propranolol | Identifies β-adrenergic receptor antagonism as a potential therapeutic approach |
| 2009 | Wallace and Linden: Ischemia reperfusion injury is amplified by the activation of CD1d-restricted iNKT cells | Role of iNKT cells in triggering inflammation |
| 2009 | Hidalgo and Frenette: Role of secondary activation signals in neutrophils | Role of E-selectin as an activating signal, Src kinases and αMβ2 |
| 2009 | Belcher and Vercellotti: Heme oxygenase-1 inhibits vascular stasis in a murine model of SCD | Importance of heme in inflammation and VOC |