Authors: Kato G J and Goldwin M T – National Institute of Health (NIH), USA – Haematology Education: The Education Programme for the annual Congress of the Haematology Association - 2007
Summarised by Dr. Michael Angastiniotis, TIF Medical Advisor

Pulmonary hypertension is the “new” threat of which thalassaemia patients and doctors are becoming more aware. It occurs in adults, more often those with Thalassaemia Intermedia or Sickle Cell Disease (SCD). It causes failure of the right side of the heart, with fatigue, difficulty in breathing, enlargement of the liver and swelling of the jugular vein.

Scientists have been trying to understand this condition, its causes and pathophysiology, so that an effective treatment can be found.

Doctors G J Kato and M T Goldwin from the National Institute of Health (NIH) in the USA are two of the researchers who have been working on this condition. They recently presented a review of current knowledge at the European Haematology Association Congress in Vienna (June 2007).

They point out that in both SCD and thalassaemia, there is chronic anaemia due to the breakdown of red cells within the blood vessels (intravascular haemolysis). Chronic intravascular haemolysis influences the function of the cells lining the blood vessels, known as the endothelium.

Nitric Oxide: As the red cells break down, they release their contents, which consist mainly of the haemoglobin molecule. The free molecules are normally scavenged by the so-called haptoglobin-hemopexin system, but the massive breakdown of red cells associated with these conditions means that the system’s capacity is far exceeded. This results in the prolonged exposure of the blood vessel wall to high levels of free haemoglobin.

The cells of the inner lining of the vessels of the endothelium produce a gas molecule, Nitric Oxide (NO), which regulates the function of blood vessels and enhances blood flow by causing the smooth muscle of the vessels to relax and dilate, and prevents obstruction of the vessels. The free haemoglobin molecules inactivate the NO, so that the ability of the vessels to dilate is reduced.

Arginase: Intravascular haemolysis also releases red cell arginase into the plasma. This enzyme depletes blood plasma of the amino acid arginine, which is necessary for NO production. Reactive oxygen species (oxygen radicals) also deplete NO and further increase the endothelial dysfunction.

Pulmonary Hypertension: The reduced natural capacity for blood vessels to dilate due to the endothelial dysfunction result in a state of chronic pulmonary vasoconstriction. This condition may cause early and sometimes sudden death, especially in cases with SCD. The frequency of painful crises and acute chest syndrome episodes do not appear to contribute to this complication in SCD.

In untransfused thalassaemia, the prevalence of pulmonary hypertension may exceed 65%. Originally, before the elucidation of the effects on vascular constriction, these cases were thought to be due to recurrent pulmonary emboli.

Splenectomised patients are also more at risk for this complication. All patients should be monitored by echocardiography, as the condition is frequently underdiagnosed.

Leg Ulcers: This troublesome complication of SCD and Thalassaemia Intermedia, which was previously unexplained, is now also thought to be due to haemolysis-associated vascular dysfunction.

From these pathophysiological mechanisms, it is hoped that effective treatments to counteract chronic vasoconstriction will emerge. Already, encouraging pilot data indicate a potential role for Sildenafil.

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