Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

Bone Marrow of Contention: A Rare Case of Recurrent Acute Hepatitis.

Hepatitis-associated aplastic anemia is a well-recognized clinical syndrome in which marrow failure follows the development of hepatitis. Although aplastic anemia is intimately related to paroxysmal nocturnal hemoglobinuria, until now, no cases of PNH-associated hepatitis have been described. We report a case of recurrent acute hepatitis preceding the clinical onset of PNH. Treatment of PNH with the complement inhibitor eculizumab (Soliris®) prevented both recurrences of episodes of intravascular hemolysis and liver enzyme alteration. This is the first known published case of PNH-associated hepatitis.

The Role of Whole-Body Magnetic Resonance Imaging (WB-MRI) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

In PNH thromboembolic events (TEs) represent the leading cause of morbidity and mortality. Between Dec 2013 and Jan 2016 37 PNH patients (pts) (23 PNH, 14 AA/PNH; 51% (19/37) females; median age 44 years, median D-dimer levels 0.22 mg/l) were examined with a whole-body magnetic resonance imaging (WB-MRI) scan at 1.5 T to detect TEs. Pts were treated according to German PNH guidelines, including eculizumab therapy. 64% (24/37) of the pts had no documented TEs prior to observation. Two pts had suspected TEs in their clinical history. 29% of the pts (11/37) had a known history of venous thromboses (deep venous thrombosis (DVT) (5/11), portal venous thrombosis (PVT) (4/11), vena caval thrombosis (VCT) (2/11). A myocardial infarction was reported in one pt, and two had a cerebral venous sinus thrombosis (CVST) or a thalamic infarction. Six pts (16%) had at least two prior TEs. In pts with prior TEs no progression of the existing TEs was observed. In pts on eculizumab and prior TEs as well as treatment-naïve pts silent bone and renal infarctions were detected. Furthermore, a clinically non-critical arterial occlusion was identified. WB-MRI scans present a novel, non-invasive method to assess the complete vascular status of PNH pts and allow the detection of previously undiagnosed vascular complications, affecting treatment indications and regimens.

Resonancia magnética renal en un paciente con hemoglobinuria paroxística nocturna / Renal magnetic resonance in a patient with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease causing hematopoietic cell alteration, caused by a mutation in the PIG-A gene; which does not allow certain important proteins to bind to the cells. A 58-year-old patient presented with headache, a history of malaria, and occasionally dark urine. Magnetic resonance imaging proved to be an effective diagnostic method for detecting renal cortical hemosiderosis, thanks to its high spatial resolution capacity.

La hemoglobinuria paroxística nocturna (HPN) es una enfermedad clonal adquirida ocasionando la alteración de células hematopoyética, causada por una mutación en el gen GPI-A; lo cual no permite que ciertas proteínas importantes se fijen a las células. Se presenta un paciente de 58 años que acude con cefalea, antecedente de malaria y en ocasiones orinas oscuras. La resonancia magnética demostró ser un método diagnóstico eficaz para detectar la hemosiderosis renal cortical, gracias a su elevada capacidad de resolución espacial.

Diffuse renal parenchyma uptake with bone scintigraphy in a patient with paroxysmal nocturnal hemoglobinuria and normal kidney function.

A 41-year-old woman with a Harrington spondylodesis presented with lower back pain. Bone scintigraphy showed diffusely increased parenchymal uptake in both kidneys. She reported 2 previous periods of dark, almost black, urine. Additional flow cytometric analysis confirmed the diagnosis of paroxysmal nocturnal hemoglobinuria. The increased renal parenchyma uptake is very probably due to paroxysmal nocturnal hemoglobinuria-related renal hemosiderosis. Remarkably, the patient did not develop any abnormality of renal function.

Clinicoradiologic subtypes of Marchiafava-Bignami disease.

The clinical diagnosis of Marchiafava-Bignami disease (MBD) has considerably changed during recent decades with brain MRI providing the opportunity of a reliable in-vivo diagnosis. However, semiologic and neuroimaging characteristics of the currently known spectrum of MBD have not been investigated systematically, and knowledge of clinicoradiologic associations is sketchy. We report an illustrative case with limited callosal involvement on MRI and a favorable outcome and have reviewed literature on clinical and radiologic features in 50 cases of MBD diagnosed in vivo since 1985. Our reviewed data suggest the differentiation of two clinicoradiologic subtypes: Type A is characterized by major impairment of consciousness, T2-hyperintense swelling of the entire corpus callosum on early MRI and poor outcome. Type B shows at most slight impairment of consciousness, partial callosal lesions on MRI and a favorable outcome. Differentiation of these clinicoradiologic subtypes may help resolve inconsistencies of the established clinical classification resulting from new insights into the clinical course and prognosis of MBD by structural neuroimaging.

Paroxysmal nocturnal hemoglobinuria. Case report of MR imaging and CT findings.

A case of paroxysmal nocturnal hemoglobinuria (PNH) is presented in which MR imaging and CT findings were characteristic. The signal intensity of renal cortex was lower than that of medulla on both T1- and T2-weighted imaging. On CT without contrast enhancement the attenuation of renal cortex was higher than that of renal medulla. These findings at MR imaging and CT were the results of a deposition of hemosiderin in the cells of proximal convoluted tubules, and were helpful for diagnosis of PNH.

Acute coronary artery thrombosis in paroxysmal nocturnal hemoglobinuria.

We have reported a case of coronary artery thrombosis in a 36-year-old man with paroxysmal nocturnal hemoglobinuria (PNH), a potentially lethal thrombotic complication not previously documented in this unique patient population. Although the etiology of PNH remains unknown, the pathogenesis appears to be related to the deficiency of a specific membrane complement-regulatory protein, decay accelerating factor. Coronary artery thrombosis must now be added to the list of potential life-threatening thrombotic complications.

Renal and hepatic scintigraphy in paroxysmal nocturnal hemoglobinuria (PNH).

Scintigraphic findings in paroxysmal nocturnal hemoglobinuria (PNH) have been presented. To summarize, a focal hot spot on liver imaging was better seen on the IDA scan, showing resolution following a satisfactory portacaval anastomosis. PNH is another cause of hot kidneys on bone imaging.

The kidneys in paroxysmal nocturnal hemoglobinuria.

Long-term study of 21 PNH patients revealed an unexpectedly high incidence of functional and anatomic renal abnormalities. Most patients demonstrated varying degrees of hematuria and proteinuria distinct from hemoglobinuria. Evaluation of renal function revealed hyposthenuria, abnormal tubular function, and declining creatinine clearance. Radiologically these patients had enlarged kidneys, cortical infarcts, cortical thinning, and papillary necrosis which were confirmed by autopsy studies. Hypertension developed in eight patients. Urinary tract infection was uncommon. The renal findings bear striking similarity to those of sickle cell anemia. Contrary to the usual opinion, out studies clearly showed evidence of widespread renal pathology in PNH most likely due to repeated microvascular thrombosis similar to the venous thrombosis involving other organs in this disorder.

Paroxysmal nocturnal hemoglobinuria: small bowel findings.

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic hemolytic anemia of unknown etiology associated with morning hemoglobinuria, variable acholuric jaundice, and striking hemosiderinuria, all signs of hemolysis. Paroxysmal nocturnal hemoglobinuria with infarction and hemorrhage of the gut leading to emergency surgery has been reported [1]; a history of thrombosis may be found before PNH is diagnosed [2]. We describe the radiographic findings in the small bowel of a patient with paroxysmal nocturnal hemoglobinuria during an episode of moderately severe abdominal symptoms. Ours is the second reported case using barium study.

Urologic manifestations of paroxysmal nocturnal hemoglobinuria.

A long-term study of 17 patients with paroxysmal nocturnal hemoglobinuria revealed an unexpectedly high incidence of functional and anatomic renal abormalities. All patients demonstrated varying degrees of hematuria and proteinuria distinct from hemoglobinuria. All patients also had granular casts in multiple urinalyses. Evaluation of renal function revealed hyposthenuria, abnormal tubular function and declining creatinine clearance. Radiologically, one or more of these demonstrated enlarged kidneys, renal cortical infarcts and thinning, papillary necrosis, acute renal atrophy, retroperitoneal hematoma and ureteral infarction, which were confirmed by autopsy studies. Hypertension developed in 7 patients. Urinary tract infection was uncommon and no patient had a clinical history compatible with chronic or acute pyelonephritis. Contrary to usual opinion our compatible clearly showed evidence of frequent and widespread renal pathology in paroxysmal nocturnal hemoglobinuria most likely due to repeated microvascular thromboses similar to the venous trombosis involving other organs in this disorder. Since most of these patients present initially to urologists knowledge of this entity is mandatory.