Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH)는 phosphatidylinositol glycan ( PIG-A ) gene의 acquired somatic mutation으로 인해 RBCs 표면에 정상적으로 표현되는 complement regulatory proteins CD55와 CD59를 포함한 glycosylphosphatidylinositol (GPI) anchors와 GPI-anchored proteins이 결핍된 질환입니다. 따라서 PNH RBC는 발열, 산증, 저산소증의 경우에 표면의 보체 활성화와 membrane attack complex (MAC) 형성에 취약합니다. 이로 인한 chronic intravascular hemolysis는 이 질환의 전형적인 용혈의 특징이며 free hemoglobin은 임상 발현 (dysphagia, recurrent abdominal pain, erectile dysfunction)을 일으킵니다.

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PNH는

1. acquired chronic HA

2. persistent intravascular hemolysis

3. occasional or frequent recurrent exacerbations이며

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(triad)

1. hemolysis뿐만 아니라

2. pancytopenia가 있을 수 있고

3. venous thrombosis 경향을 보입니다.

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PNH affects males and females nearly equally. Even though the vast majority of cases are associated with mutation of PIGA (a gene on the X chromosome), PNH results from an acquired mutation in a somatic cell rather than a germline cell; somatic cells, including hematopoietic stem cells, only use one X chromosome (the other X chromosome being "lyonized")

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PNH 혈액검사는 hemolytic anemia의 전형적인 소견과 GPI-anchored proteins의 소실, hemolysis 또는 thrombosis로 인한 organ damage와 관련된 소견을 나타냅니다.

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Non-antibody-mediated (Coombs-negative) intravascular hemolysis 소견들은 다음과 같습니다.

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Anemia

Increased reticulocyte count

Increased lactate dehydrogenase (LDH) and bilirubin

Decreased haptoglobin

Free serum hemoglobin with pink/red serum

Hemoglobinuria with pink/red urine, positive dipstick for heme, and negative sediment for red blood cells

Negative direct antiglobulin (Coombs) test (DAT)

Hypocellular, normocellular or hypercellular bone marrow, often with erythroid hyperplasia; erythroid dysplasia is not uncommon

Findings of iron deficiency may be seen in some patients due to excessive iron loss from hemoglobinuria and hemosiderinuria (eg, low iron, low ferritin, increased transferrin, absent bone marrow iron)

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Flow cytometry는 말초혈액세포에서 감소된 GPI-anchored proteins을 나타낼 것입니다. 따라서 일단 Coombs-negative intravascular hemolysis가 확인이 되면 PNH의 선호되는 진단적 검사는 flow cytometry입니다.

The diagnosis of PNH (PIGA and PIGT) is made by demonstrating that peripheral blood cells are deficient in GPI-linked proteins, in the appropriate clinical setting (eg, Coombs-negative hemolytic anemia)

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치료는?

Intravascular hemolysis는 있으나 다른 골수 기능 이상이 없는 경우를 classic PNH라고 하며

allogeneic hematopoietic cell transplantation (HCT) 와 complement inhibition eculizumab이 유일한 확립된 치료입니다. Disabling fatigue, transfusion dependence, frequent pain paroxysms, thrombosis, worsening renal insufficiency, other end-organ complications을 포함한 hemolysis 때문에 의미 있는 질환 발현이 있는 환자에서는 eculizumab을 권고합니다.

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Thrombosis 증상이 있는 환자들은 바로 치료적 항응고치료와 eculizumab으로 치료합니다. 일차 혈전증 예방을 위해 예방적 항응고치료를 제안하지 않습니다.

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On eculizumab, PNH erythrocytes are protected from hemolysis from the inhibition of C5 cleavage; however, upstream complement activation may lead to C3 opsonization and possible extravascular hemolysis

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Eculizumab, a humanized monoclonal antibody against C5, reduces the signs of intravascular hemolysis, the requirement for transfusions, and the incidence of thrombosis in PNH

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A major advance has been the introduction in 2007 of a humanized monoclonal antibody, eculizumab, which binds to the complement component C5 near the site that, when cleaved, will trigger the distal part of the complement cascade leading to formation of the MAC. With C5 blocked, the patient is relieved of intravascular hemolysis and of its attendant consequences, including hemoglobinuria.

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! PNH

1. Non-antibody-mediated (Coombs-negative) intravascular hemolysis 소견

2. 치료 : eculizumab