Pathogenesis of Paroxysmal Nocturnal Haemoglobinuria - Literature review Example

?THE IMPACT OF ADVANCES IN PERCEPTION OF THE PATHOGENESIS OF PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA TO ITS DIAGNOSIS, TREATMENT AND PROGNOSIS: A PERCEPTIVE ANALYSIS Introduction Paroxysmal nocturnal hemoglobinuria or PNH as defined by Kawaguchi and Nakakuma (2007) is caused by the clonal expansion of hematopoietic stem cells with mutations of the phosphatidylinositol glycan-class A gene or PIGA. PNH clones then fail to generate glycosylphosphatidylinositol (GPI) or to express a series of GPI-linked membrane proteins including complement-regulatory proteins, resulting in complement-mediated intravascular hemolysis and thrombosis (Kawaguchi & Nakakuma 2007). The clinical hallmark of paroxysmal nocturnal hemoglobinuria or PNH is chronic intravascular hemolysis that is a consequence of unregulated activation of the alternative pathway of complement or APC (Lindorfer et al 2010). Intravascular hemolysis can be inhibited in patients by treatment with eculizumab, a monoclonal antibody that binds complement C5 thereby preventing formation of the cytolytic membrane attack complex of complement (Lindorfer et al 2010). Many studies have been conducted to identify the effect of the advances in understanding the pathogenesis of paroxysmal nocturnal hemoglobinuria or PNH to its diagnosis, treatment and prognosis. Likewise, a variety of articles also analyzed the aforementioned subject matter. This paper endeavors to tackle the definition and etiology of Paroxysmal Nocturnal Hemoglobinuria or PNH; in particular, this paper will focus on the developments made in gaining perception of the pathogenesis of paroxysmal nocturnal hemoglobinuria and its impact to the diagnosis, treatment and prognosis of this condition employing the use of several journal articles as theoretical basis. Literature Review The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology (Rother et al 2007). Such case is evident in a rare hemolytic disease known as Paroxysmal Nocturnal Hemoglobinuria or PNH. Young et al (2006) described Paroxysmal Nocturnal Hemoglobinuria or PNH as an uncommon form of hemolytic anemia, results from the clonal expansion of hematopoietic stem cells that have somatic mutations in the X-linked gene PIG-A. This gene encodes a protein that is crucial for the fusion of glycosylphosphatidylinositol or GPI, a lipid moiety that is implanted in the plasma membrane, where it functions to attach an extensive strain of proteins to the cell surface (Hillmen et al 2004). Likewise, Risitano et al (2011) depicted Paroxysmal Nocturnal Hemoglobinuria or PNH as a hematological disorder characterized by complement mediated hemolytic anemia, thrombophilia and bone marrow failure. This occurs when PIG-A mutations trigger an untimely obstruction in the creation of glycosylphosphatidylinositol or GPI anchors, which bind many proteins to the cell surface. As a result, the blood cells in patients with PNH have a partial deficiency or type II or a complete deficiency or type III of GPI-linked proteins (Young et al 2006). According to Hillmen et al (2004), the major clinical signs of paroxysmal nocturnal hemoglobinuria or PNH are intravascular hemolysis, venous thrombosis, and hemoglobinuria. Intravascular hemolysis is the prominent feature of PNH and is the consequence of the absence of the GPI-linked complement regulatory protein CD59 as highlighted by Young et al (2006). Young et al (2006) cited that CD59 hinders the development of the terminal complement complex, also called the membrane-attack complex on the cell surface, thereby averting erythrocyte lysis and in vitro platelet instigation. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery; hence, deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of Paroxysmal Nocturnal Hemoglobinuria or PNH (Rother et al 2007). The clinical features of PNH result from the lack of one or more GPI-linked proteins that protect cells from complement-mediated attack as discussed by Hillmen et al (2004). Hillmen et al (2004) further elaborated that two such proteins—CD55 and CD59—are absent from PNH type III erythrocytes, platelets, and other blood cells. Furthermore, Hillmen et al (2004) pointed out that CD55 regulates early complement activation by inhibiting C3 convertases, whereas CD59 inhibits the assembly of the membrane-attack complex C5b–C9 by interacting with C8 and C9. Thus, the lack of CD59 is most likely accountable for the increased sensitivity of PNH erythrocytes and platelets to complement (Hillmen et al 2004). Risitano et al (2011) gave emphasis that intravascular hemolysis compels the major clinical features of PNH, such as anemia, hemoglobinuria, fatigue and other hemolysis-related disabling symptoms, such as painful abdominal crises, dysphagia and erectile dysfunction. Moreover, Risitano et al (2011) mentioned that an atypical thromboembolic probability has been correlated with the hemolysis in Paroxysmal Nocturnal Hemoglobinuria or PNH, but its pathophysiologic etiology remains uncertain. In the journal article by Lindorfer et al (2010) entitled, A Novel Approach to Preventing the Hemolysis of Paroxysmal Nocturnal Hemoglobinuria: Both Complement-mediated Cytolysis and C3 Deposition are blocked by a Monoclonal Antibody Specific for the Alternative Pathway of Complement, the authors mentioned that eculizumab can impede intravascular hemolysis in patients suffering from the condition, Paroxysmal Nocturnal Hemoglobinuria or PNH. Eculizumab as explained by Hillmen et al (2004) is a recombinant humanized monoclonal antibody that was intended to prevent the initiation of terminal complement elements. It attaches particularly to the terminal complement protein C5, impeding its cleavage into C5a and C5b, thereby thwarting the release of the inflammatory mediator C5a and the development of the cytolytic-pore C5b–C9 (Hillmen et al 2004). Obstruction of the complement cascade at C5 safeguards the early components of complement that are vital for the opsonization of microorganisms and clearance of immune complexes (Hillmen et al 2004).  Lindorfer et al (2010) highlighted in their article that they observed that in essentially all patients treated with eculizumab, persistent anemia, reticulocytosis, and biochemical evidence of hemolysis are observed; and in a significant proportion, their PNH erythrocytes become opsonized with complement C3.Moreover, according to Lindorfer et al (2010), these findings suggest that PNH patients treated with eculizumab are left with clinically significant immune-mediated hemolytic anemia because the antibody does not block APC activation.  With the aim of enhancing PNH therapy, Lindorfer et al (2010) illustrated the activity of anti-C3b/iC3b monoclonal antibody 3E7 in an in-vitro model of APC-mediated hemolysis. Furthermore, Lindorfer et al (2010) presented that 3E7 and its chimeric-deimmunized derivative H17 block both hemolysis and C3 deposition on PNH erythrocytes; the antibody is specific for the APC C3/C5 convertase because classical pathway–mediated hemolysis is unaffected by 3E7/H17. Thus, Lindorfer et al (2010) construed that these findings suggest an approach to PNH treatment in which both intravascular and extravascular hemolysis can be prevented while preserving significant immune functions of the classical pathway of complement. In another trial conducted by Hillmen et al (2004), they investigated whether eculizumab could lessen the incidence of intravascular hemolysis, hemoglobinuria, and transfusion requirements in patients with PNH. Hillmen et al (2004) uncovered that the defect in the membrane-bound inhibitor of terminal complement components in PNH was ameliorated by the administration of eculizumab. Their study also revealed that eculizumab treatment notably decreased transfusion requirements, even though the levels of hemoglobin did not vary considerably. However, the hemoglobin level in an individual patient prior to study entry was artificially preserved as an effect of the transfusion of normal red cells (Hillmen et al 2004). In summary, eculizumab appears to enhance the survival of type III PNH erythrocytes, improving the quality of life and reducing the extent of hemolysis, hemoglobinuria (the clinical hallmark of PNH), and the need for blood transfusions in patients with PNH (Hillmen et al 2004). Likewise, this study confirms that terminal complement activation is the key mediator of erythrocyte destruction in PNH (Hillmen et al 2004). Conversely, Luzzato and Gianfaldoni (2006) pointed out that the diagnosis of PNH is grounded on the demonstration that a substantial proportion of red cells and granulocytes have the PNH phenotype. Diagnosis is currently best performed by flow cytometry analysis, most appropriately by using anti-CD59 and anti-CD55 antibodies (Luzzato & Gianfaldoni 2006). Luzzato and Gianfaldoni (2006) added that flow cytometry can also quantify the said cells and monitor their numbers as a function of time, thereby aiding clinical management. They also stressed that eculizumab is the most important advance in treatment of PNH. On the other hand, the results of the randomized, double-blind, controlled study of Young et al (2006) revealed that the terminal complement inhibition with eculizumab reduces intravascular hemolysis, reduces or eliminates the need for transfusion, and improves anemia, fatigue, and the quality of life in patients with PNH. Furthermore, the data provided support for the central role of intravascular hemolysis in the pathogenesis of the disease and indicate that eculizumab is an effective treatment in patients with PNH (Young et al 2006). Conclusion The impact of the recent advances in understanding the pathogenesis of PNH to its, diagnosis, treatment and prognosis were proven valuable as presented by the discussed articles of study. All the studies utilized agreed that the discovery of the eculizumab is the most important advancement in the management of PNH. However, differences in the purposes and effect were also cited in each article. The study of Lindorfer et al (2010) deemed that there can still be an improvement in PNH Therapy aimed towards better prognosis for the patient. Conversely, Hillmen et al (2004) emphasized that such advance in PNH Therapy increased the chance of survival of individuals suffering from PNH. On the contrary, Luzzato and Gianfaldoni (2006) focused on the diagnostic method linked with PNH. Lastly, Young et al (2006) revealed in detail the effects of eculizumab. All in all, the articles aimed at discovering the influence of the advances in managing PNH; but still, each article was unique from each other, in the sense that they were able to divulge a variety of important points that can be taken into consideration in treating PNH. References Hillmen, P., Hall, C., Marsh, J.C.W., Elebute, M., Bombara, M.P., Petro, B.E., Cullen, M.J., Richards, S.J., Rollins, S.A., Mojcik, C.F. and Rother, R.P. (2004) Effect of Eculizumab on Hemolysis and Transfusion Requirements in Patients with Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine, 350, p. 552-559. Kawaguchi, T. and Nakakuma, H. (2007) New Insights in Molecular Pathogenesis of Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria. International Journal of Hematology, 86 (1), p. 27-32. Lindorfer, M.A., Pawluczkowycz, A.W., Peek, E.M., Hickman, K., Taylor, R.P., and Parker, C.J. (2010) A Novel Approach to Preventing the Hemolysis of Paroxysmal Nocturnal Hemoglobinuria: Both Complement-mediated Cytolysis and C3 Deposition are blocked by a Monoclonal Antibody Specific for the Alternative Pathway of Complement. Blood, 115 (11), p. 2283-2291. Luzzato, L. and Gianfaldoni, G. (2006). Recent Advances in Biological and Clinical Aspects of Paroxysmal Nocturnal Hemoglobinuria. International Journal of Hematology, 84 (2), p. 104-112. Risitano, M.A., Perna, F. and Selleri, C. (2011) Achievements and Limitations of Complement Inhibition by Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: The Role of Complement Component 3. Mini Reviews in Medicinal Chemistry, 11 (6), p. 528-535. Rother, R.P., Rollins, S.A., Mojcik, C.F., Brodsky, R.A. and Bell, L. (2007) Discovery and Development of the Complement Inhibitor Eculizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Nature Biotechnology, 25, p. 1256-1264. Young, N.S., Hillmen, P., Schubert, J., Brodsky, R.A., Socie, G., Muus, P., Roth, A., Szer, J., Elebute, M.O., Nakamura, R., Browne, P., Risitano, A.M., Hill, A., Schrezenmeier, H., Fu, C.L., Maciejewski, J., Rollins, S.A., Mojcik, C.F., Rother, R.P. and Luzzatto, L. (2006) The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine, 355, p. 1233-1243. Read More