Natural history of PNH
Diagnosis of paroxysmal nocturnal haemoglobinuria (PNH) can take from 1 to >10 years and median survival from the time of diagnosis is 10–15 years1-3; 35% of PNH patients die within 5 years of diagnosis.2
Study description: Researchers followed 80 consecutive patients with PNH referred to Hammersmith Hospital in London, United Kingdom.2 The patients were treated with supportive measures such as oral anticoagulant therapy after established thromboses and transfusions.
Although PNH is a chronic disease of continuous haemolysis, the course of the disease can be marked by exacerbations of haemolysis (paroxysms) of varying severity. Chronic or repeated acute intravascular haemolysis or subsequent venous/arterial thrombosis can lead to progressive end-organ damage and mortality.4-6
Who is affected by PNH?
PNH patients are mainly young adults with a median age of 33 years (range 6–82 years) at the time of diagnosis.3 The disease affects both men and women and no link has been established between ethnicity and PNH.4
A retrospective study in women showed that in 25% of cases the diagnosis of PNH was made during pregnancy.7 The incidence of clinical venous thromboembolism during pregnancy in women with PNH is ~10% and this is associated with an increased mortality rate.7
PNH can be particularly severe in children but is often underdiagnosed. The clinical picture is that of haemolysis, marrow insufficiency and thromboembolic events. Haemoglobinuria seems to occur less frequently than in adults.8
Patients with bone marrow insufficiency
One-third (33%) of patients screened for bone marrow insufficiency have a PNH clone. This is most evident in patients with aplastic anaemia, where almost half (45%) have a PNH clone.9 In patients with aplastic anaemia, the bone marrow environment can promote expansion of a PNH clone.
Patients with acute leukaemia
PNH is only rarely associated with acute myeloid leukaemia. Marrow aplasia predisposes to PNH and to acute myeloid leukaemia. However, the occurrence of PNH does not increase the risk of developing acute leukaemia; rather, it is likely that the underlying bone marrow failure predisposes to the leukaemic transformation. In most leukaemia patients with PNH who have been studied, the leukaemic clone is derived from the PNH clone.2
Clinical manifestations of PNH
Chronic haemolysis – and resulting free haemoglobin – is the underlying cause of progressive morbidities and mortality in PNH.10
Clinical manifestations of PNH11
Thrombosis is the leading cause of death in PNH.2,3,5,12 Even patients with a relatively small PNH clone (as low as 10%) are at markedly increased risk of thrombosis when compared to the normal population.12
Initial thromboembolism increases relative risk of death in PNH 5- to 10-fold.13
- 40–67% of deaths are due to venous or arterial thrombosis.13
- Patients with PNH with thrombosis at presentation have only a 40% survival rate at 4 years.3
- First thrombotic event can be fatal.12,14
- Thromboembolism in PNH is complex and may occur at any site, including intra-abdominal and cerebral veins.12
- 35% of patients with thromboembolisms had multiple events.15
- 31% of thromboembolisms occurred at arterial sites, including cerebral and coronary arteries.15
- Thrombophilia in PNH is multifactorial.12,16
- PNH is associated with a highly increased risk of thrombosis.2,3,5,17-20
- D-dimers, an indicator of thromboembolism, were increased in 61–82% of patients with PNH.18,20
- Patients with PNH frequently experience new thrombotic episodes despite anticoagulation.13,15,21
- Anticoagulation does not address the underlying disease process of chronic, complement-mediated haemolysis.12,13,21-23
- In a recent study, 50% of thromboembolisms occurred while patients were on anticoagulants.24
Chronic kidney disease
64% of patients with PNH have chronic kidney disease (CKD), which, in advanced stages, is associated with early mortality.5,25,26
- End-stage renal disease accounts for approximately 8–18% of patient deaths in PNH.5
- Patients with renal impairment have an increased risk of mortality (odds ratio 2.953; 95% confidence interval 1.116–7.818; P=0.029)26 and an increased prevalence of thromboembolism (38%; P<0.001).27
- Clinical symptoms such as haemoglobinuria (P<0.0001) and abdominal pain (P<0.0001) are predictive of renal impairment.27
Nearly 50% of patients with PNH have evidence of pulmonary hypertension (PHT).28
- PHT is a result of haemolysis-induced nitric oxide (NO) depletion.28,29
- NO depletion impairs regulation of smooth muscle tone, resulting in vascular constriction, PHT and dyspnoea.
- Dyspnoea may be a common indicator of PHT4,15 and is associated with increased risk of thromboembolism (P=0.003).15
- 60% of patients with PNH show evidence suggesting previous subclinical pulmonary thrombosis.30
Bone marrow failure
Approximately 45% of patients with aplastic anaemia may have a PNH clone.9
- Bone marrow aplasia may be diagnosed before identification of the PNH clone or may be found concomitantly with the diagnosis of classical PNH.31
Most patients with PNH will have symptomatic anaemia due to haemolysis.32
- Chronic haemolysis may lead to iron deficiency, which further contributes to the anaemia and chronic fatigue experienced by the patient.32
- In some patients, chronic haemolysis is associated with haemoglobinuria, often in the morning.32
Smooth muscle dystonias resulting from haemolysis-induced NO depletion are a key clinical feature of PNH.11,29,33
- Erectile dysfunction, dysphagia and gastrointestinal contractions have a significant impact on the quality of life of PNH patients.11,29,33
- A multinational epidemiological study of PNH patients reported incidence rates of 47%, 41% and 59% for erectile dysfunction, dysphagia and abdominal pain, respectively.34
Smooth muscle dystonias associated with PNH have a significant impact on quality of life29,33,34
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