Pulmonary hypertension is a common and debilitating condition which is increasingly being recognized in haematological patients. This is particularly so in haemolytic diseases like thalassaemia and myeloproliferative conditions like idiopathic myelofibrosis. Recently, splenectomy, which may be required for some of these conditions, have been linked to this complication although the exact pathophysiology is still not established. The manuscript explains the role of the less recognized ‘lung megakaryocytes’ in the development of this complication.
Pulmonary hypertension (PHT) is an increasingly recognized complication observed in patients with haemolytic anaemia and myeloproliferative disorders.1 It is found in over 60% of the patients with thalassaemia and can be the leading cause of heart failure in these patients.2 Doppler-defined PHT has also been demonstrated in 32% of the sickle cell disease patients in a single-centre series.3 A Mayo clinic report of 26 patients with myeloproliferative disorders (mainly idiopathic myelofibrosis) with co-existing PHT far exceeds the expected incidence suggesting that plausible mechanisms linking the two may exist.4 There is also recent evidence for a higher risk for the development of PHT in patients undergoing splenectomy (8.6%) for thalassaemia and other haemolytic disorders like hereditary spherocytosis.5–7 The pathophysiological mechanisms for this complication are not fully understood although several theories have been proposed which include: (i) thromboembolic occlusion of the pulmonary vasculature; (ii) an increase in the production of reactive oxygen species; and (iii) the depletion of nitric oxide by free haemoglobin released by damaged red cells leading to pulmonary vasoconstriction.1,8 At the same time, the less recognized phenomenon of the presence of megakaryocytes in the lungs, can also be postulated to contribute to PHT in these disease states.
The presence of megakaryocyte in the lungs has been observed for many years and it is suggested that they originate in the bone marrow, circulate in the blood and get lodged in the capillary bed of the lung where they release platelets.9 These large-sized platelet precursors can contribute to in situ thrombosis leading to chronic pulmonary thromboembolic disease, where a definite history of venous thrombosis has not been demonstrated.7 This explains the observation that many patients with thromboembolic PHT are not suitable for thrombo-endarterectomy, because they may have distal thrombus from occlusion with the megakaryocytes.7,10
Another contributory factor for PHT can be the extramedullary haematopoiesis (EMH), which can occur with these conditions, especially in the setting of splenectomy, where once again the megakaryocytes can be a role player. Idiopathic myelofibrosis and Gaucher's disease are two haematological disorders commonly associated with PHT, the incidence of which can worsen with splenectomy.4,11 In these conditions, EMH can occur as a physiological compensatory phenomenon and commonly involves the liver and the spleen. However, with splenectomy, lungs become another site for EMH to continue the production of blood cells. Interestingly, pulmonary EMH has been observed in Gaucher's disease with the presence of both Gaucher cells and megakaryocytes in the lungs.12 Enzyme replacement therapy in Gaucher's disease does not improve the PHT associated with this condition, suggesting that the Gaucher cells themselves may not be causative for this complication.11
The presence of megakaryocytes in the pulmonary bed can contribute to PHT in Gaucher's disease in a manner similar to that in myelofibrosis. Histological bone marrow specimens in patients with myelofibrosis demonstrate fibrosis in the areas corresponding to the megakaryocytes, which usually reside adjacent to the marrow vessels (or sinusoids) for the easy release of platelets. These platelet precursors contribute to the pathogenesis of the fibrosis by a phenomenon called ‘pathological emperipolesis’, which leads to the release of fibrogenic mediators like vascular endothelial growth factor, platelet-derived growth factor and transforming growth factor-β.13 The areas of the lung vasculature, where the megakaryocytes may reside can similarly correspond with the areas of pulmonary fibrosis, leading to PHT. The argument for pulmonary megakaryocyte to behave in a manner similar to the bone marrow megakaryocytes is only a logical conclusion and does not imply causality. At the same time, the presence of megakaryocytes with its fibrogenic mediator reserve has been demonstrated to contribute to fibrotic changes in places other than the bone marrow. The disease processes which disrupt the normal pulmonary circulation (e.g. right to left shunt in cyanotic heart disease) would allow the whole of the lung megakaryocytes and their larger fragments to enter the systemic circulation reaching its most distal sites.14 When their large size causes them to become impacted in the fingertip circulation, they can release the fibrogenic mediators, which can increase vascular permeability, attract fibroblasts and result in clubbing.15 Also skin fibrosis in a patient with myelofibrosis was elegantly demonstrated by Kawakami and colleagues16 to be due to the transforming growth factor-β overexpression from extramedullary haematopoiesis.
Patients with thalassaemia and chronic haemolytic anaemia generally have EMH, which involves the liver and the spleen. However, after splenectomy, pulmonary EMH can commence and may evolve over a period explaining the gradual development of PHT in these situations.7 In sickle cell disease, autosplenectomy is known to occur commonly, which can also lead to EMH in the lungs and PHT. Nitric oxide depletion has been suggested to be causative in the development of PHT in these haemolytic conditions. Interestingly, this molecule has an inhibitory function on the megakaryocytes leading to their apoptosis.17 The current management of PHT includes vasodilators including phosphodiesterase-type 5 inhibitors (which increase nitric oxide levels, e.g. sildenafil), and prostacyclin analogues with a combination of these agents demonstrating better results.18 In this context, it is useful to note that even though in platelets, the actions of nitric oxide and prostacyclin are thought to be synergistic, they regulate opposite megakaryocyte survival responses through a delicate balance between intracellular cyclic nucleotide levels and caspase-3 activity control.19 These agents will also inhibit platelet aggregation and thus thrombus formation, another risk factor for PHT. In recent years, imatinib, a tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukaemia, has been found to be effective in the treatment of PHT.20 The rationale for using this drug is its ability to inhibit platelet-derived growth factor (PDGF), a critical player in the development of PHT.21 PDGF is also a fibrogenic mediator released by megakaryocytes, among other cells. In this context, it is also interesting to note that imatinib was shown in a single report to reverse myelofibrosis in a patient with megakaryoblastic crisis of chronic myeloid leukaemia.22 However, it is premature to consider the use of this agent in the treatment of PHT post-splenectomy and further studies are required.
There is increasing recent evidence that thrombus formation and thus thrombin, is important in the development of fibrosis in the liver.23 Functional thrombin receptors are expressed on cells of the megakaryocytic lineage with thrombin having important functions in the megakaryocytic release reaction and pro-platelet formation.24 The pulmonary thrombi which form as a precursor for pulmonary fibrosis in chronic pulmonary thromboembolic disease-related PHT can cause the release of fibrogenic mediators from the lung megakaryocytes and lead on to fibrosis. The unresolved issue of portal vein thrombosis and portal hypertension after splenectomy may also be related to the EMH and liver megakaryocytes in a similar manner.25,26
In summary, the role of megakaryocytes in the pathogenesis of PHT after splenectomy for haemolytic disorders should be considered and studied to improve our understanding and identifying new therapeutic agents to prevent this complication.