Semiotics

Extract from the VADE-MECUM by Professor Gérard Socié  

Chronic intravascular haemolysis

Chronic intravascular haemolysis is clinically manifested by anaemia, observed in 35% of patients at diagnosis. This anaemia is later observed in 90% of patients. It is responsible to varying degrees for signs of fatigue, paleness and dyspnoea on exertion1, 4, 6.

Haemolysis is also reflected clinically by fluctuating haemoglobinuria (dark urine). Therefore, while 26% of patients have haemoglobinuria at the time of diagnosis, most of them will have at least one episode of haemoglobinuria during the disease1, 10.
 

Significant intravascular haemolysis may manifest as jaundice: 9% of patients have jaundice when diagnosed1.

The haemolysis also causes chronic and sometimes disabling fatigue. The severity of the fatigue is not necessarily correlated to anaemia4, 15.

The chronic intravascular haemolysis is the primary cause of high morbidity and mortality in patients with PNH4.

Consequences of chronic haemolysis4 4

 

TIA: Transient ischemic attack
CVA: Cerebrovascular accident (stroke)
PE: Pulmonary embolism
PAH: Pulmonary arterial hypertension
MI: Myocardial infarction
DVT: Deep vein thrombosis

Atypical thromboses  

Thrombosis is the primary complication of PNH. It is responsible for 40% to 67% of deaths, making thrombosis the leading cause of death in patients with PNH8. The thrombo-embolic risk in PNH is associated with a mortality rate 15 times that of the general population5.Uncontrolled complement activation is one of the underlying causes leading to the formation of thrombosis8, 10.

40% of PNH patients experience a thrombotic event, 85% of which are venous events and 15% arterial events8. The thromboses are characterised by their recurrence and their often unusual sites4, 16:

A study conducted by the SFH5 analysed separately the natural history of the different categories of patients with PNH: patients with ordinary PNH (113 patients), patients with PNH in association with bone marrow failure (PNH-BMF) (224 patients) and intermediate patients not belonging to either of the first two groups (93 patients).In this study, thromboembolic events (TEEs) were observed in 38% of the patients with ordinary PNH and in almost 30% of patients with PNH-BMF (incidence accumulated over 10 years). The two most common sites are the hepatic veins (Budd-Chiari) and the central nervous system. It would also appear that the incidence of thromboembolic events does not decrease over time in any PNH patient category.

changes in thrombotic risk in PNH patients5
 

Thromboembolic events can occur rapidly in patients with PNH. The median time between diagnosis and the first thromboembolic event is around 2 years5. This first event can be fatal17.

There is a risk of thrombosis regardless of:

• . clone size17:
  - TEEs have been observed with a PNH clone size of around 10%18,
  - a 10% increase in the size of the clone on the neutrophils/monocytes increases 1.64 times the risk of a TEE8;
• . haemolysis intensity17;
• . transfusion history17;
• . anticoagulant treatments17.

In PNH patients, anticoagulation alone is not always sufficient and there is a risk of bleeding in thrombocytopenic PNH patients5, 8.

Deterioration in quality of life

PNH patients have a lower quality of life than the general population. This is because, as the disease progresses, it is accompanied by dysphagia, dyspnoea, abdominal pain, erectile dysfunction, along with chronic fatigue1, 4.

This chronic fatigue is very often debilitating, creating a considerable handicap for patients in their professional and personal life. Its intensity is correlated to the degree of haemolysis, whatever the extent of anaemia19.

Abdominal pain is often very intense, especially during paroxysms. It would appear that this is due to venous thrombosis and smooth muscle dystonia10.

This pain is accompanied by dyspnoea and dysphagia. Dysphagia appears to be caused by a nitric oxide deficiency which plays a major part in relaxing the smooth muscles10.

In addition, this NO deficiency is also thought to be the cause of erectile dysfunction affecting 35% of men10, 20.

Patients with chronic haemolysis complain of different symptoms1: apathy, malaise, myalgia, the loss of well-being, significantly reducing their quality of life.

Myelosuppression

PNH clones readily develop in a context of myelosuppression2. 40 to 50% of patients with bone marrow failure21 and 18% of patients with myelodysplastic syndrome with refractory anaemia22 have PNH clones.

There is a close relationship between PNH and myelosuppression. When the patient has myelosuppression, it seems that PNH clones have an advantage in terms of growth or survival compared to normal residual stem cells. However, in the absence of myelosuppression, mutated cells have a limited growth potential23.

PNH presents itself in a number of forms. It can take on an essentially haemolytic or aplastic form. Most often, these two forms coexist to varying extents.

Renal impairment

Renal failure (RF) is responsible for 8-18% of deaths in PNH patients24. This is a common complication in PNH patients25. RF is due to intravascular haemolysis, which is thought to be responsible locally for microthromboses8, inflammation26 and renal tissue fibrosis4.

Furthermore, the deposit in the proximal renal tubules of hemosiderin produced from free haemoglobin contributes to RF in these patients4. NO deficiency results in RF by increased renal arteriolar resistance and a reduction in renal plasma flow and glomerular filtration rate (GFR)8.

Assumption of renal impairment in PNH

 

Prevalence of signs and symptoms at diagnosis

Prevalence1
• Anaemia 35%
• Haemoglobinuria 26%
• Bleeding 18%
• Bone marrow failure 13%
• Gastrointestinal symptoms 10%
• Jaundice 9%
• Iron deficiency anaemia 6%
• Thromboembolic events 6%
• Infections 5%
• Neurological signs 4%

PNH in pregnancy1. . In women with PNH, pregnancy puts them at increased risk of venous thrombosis and infections. They therefore have a higher morbidity and mortality. A retrospective study has shown that in 25% of cases, PNH is diagnosed during pregnancy.The incidence of clinical venous thromboembolic events during pregnancy in women with PNH is 10%. These events are associated with a high mortality rate.

Summary

• . PNH is characterised by chronic intravascular haemolysis associated to varying degrees with myelosuppression.
• . Signs commonly associated with it are: abdominal pain, dyspnoea, dysphagia, erectile dysfunction and chronic fatigue.
• . PNH increases the risk of thrombosis in unusual sites (hepatic, cerebral, mesenteric), that are recurrent and potentially fatal.