Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 16)

PNH has about the same frequency in men and women, and it is encountered in all populations throughout the world, but it is a rare disease: its prevalence is 1–5 per million (it may be somewhat less rare in Southeast Asia and in the Far East). There is no evidence of inherited susceptibility. PNH has never been reported as a congenital disease, but it can present in small children or in people in their seventies, although most patients are young adults.Clinical FeaturesThe patient may seek medical attention because one morning she or he has passed "blood instead of urine."...
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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 16) Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 16) PNH has about the same frequency in men and women, and it isencountered in all populations throughout the world, but it is a rare disease: itsprevalence is 1–5 per million (it may be somewhat less rare in Southeast Asia andin the Far East). There is no evidence of inherited susceptibility. PNH has neverbeen reported as a congenital disease, but it can present in small children or inpeople in their seventies, although most patients are young adults. Clinical Features The patient may seek medical attention because one morning she or he haspassed blood instead of urine. This distressing event may be regarded as theclassical presentation; however, more frequently this symptom is not noticed or issuppressed. Indeed, the patient often presents simply as a problem in thedifferential diagnosis of anemia, whether symptomatic or discovered incidentally.Sometimes the anemia is associated from the outset with neutropenia orthrombocytopenia, or both. Some patients may present with recurrent attacks ofsevere abdominal pain, defying a specific diagnosis and eventually found to becaused by thrombosis. When thrombosis affects the hepatic veins, it may produceacute hepatomegaly and ascites, i.e., a full-fledged Budd-Chiari syndrome, which,in the absence of liver disease, ought to raise the suspicion of PNH. The natural history of PNH can extend over decades. Without treatment,the median survival is ~8–10 years; in the past the commonest cause of death hasbeen venous thrombosis followed by infection secondary to severe neutropeniaand hemorrhage secondary to severe thrombocytopenia. PNH may evolve intoaplastic anemia (AA), and PNH may manifest itself in patients who previously hadAA. Rarely (estimated 1–2% of all cases), PNH may terminate in acute myeloidleukemia. On the other hand, full spontaneous recovery from PNH has been welldocumented, albeit rarely. Laboratory Investigations and Diagnosis The most consistent blood finding is anemia, which may range from mild tomoderate to very severe. The anemia is usually normo-macrocytic, withunremarkable red cell morphology; if the MCV is high, it is usually largelyaccounted for by reticulocytosis, which may be quite marked (up to 20%, or up to400,000/µL). The anemia may become microcytic if the patient is allowed tobecome iron-deficient as a result of chronic urinary blood loss throughhemoglobinuria. Neutropenia and/or thrombocytopenia may or may not be presentfrom the outset or may develop subsequently. Unconjugated bilirubin is mildly ormoderately elevated, LDH is typically markedly elevated (values in the thousandsare common), and haptoglobin is usually undetectable. All these findings make thediagnosis of HA compelling. Hemoglobinuria may be overt in a random urinesample; if it is not, it may be helpful to obtain serial urine samples, sincehemoglobinuria can vary dramatically from day to day, and even from hour tohour (Fig. 101-8). The bone marrow is usually cellular with marked to massiveerythroid hyperplasia, often with mild to moderate dyserythropoietic features(these do not justify confusing PNH with MDS). At some stage of the disease themarrow may become hypocellular or even frankly aplastic (see below). The definitive diagnosis of PNH must be based on the demonstration that asubstantial proportion of the patients red cells have an increased susceptibility tocomplement (C), due to the deficiency on their surface of proteins (particularlyCD59 and CD55) that normally protect the red cells from activated C. The sucrosehemolysis test is unreliable, and the acidified serum (Ham) test is carried out infew labs. The gold standard today is flow cytometry, which can be carried out ongranulocytes as well as on red cells. A bimodal distribution of cells, with a discretepopulation that is CD59–, CD55–, is diagnostic of PNH. Usually this population isat least 5% of the total in the case of red cells and at least 20% of the total in thecase of granulocytes. Pathophysiology Hemolysis in PNH is due to an intrinsic abnormality of the red cell, whichmakes it exquisitely sensitive to activated C, whether it is activated through thealternative pathway or through an antigen-antibody reaction. The formermechanism is mainly responsible for intravascular hemolysis in PNH. The lattermechanism explains why the hemolysis can be dramatically exacerbated in thecourse of a viral or bacterial infection. Hypersusceptibility to C is due todeficiency of several protective membrane proteins, of which CD59 is the mostimportant because it hinders the insertion of C9 p ...