Sickle cell disease
The earliest description of this haemolytic anaemia and its characteristic red cell morphology was published almost exactly 100 years ago (Herrick, 1910). Over the next century, this haemoglobinopathy became best known for the intraerythrocytic polymerization of its mutant haemoglobin in the first molecularly defined human disease. The polymer burden reduces the red cell compliance, resulting in rigid erythrocytes that slow or even halt blood flow in the microvasculature and cause tissue ischemia. This poor blood flow may be compounded by adhesion of activated blood cells to activated endothelium, especially in the post-capillary venules. Excessive blood viscosity, tissue ischemia and infarction are clearly part of the vaso-occlusive pain crisis, osteonecrosis and the acute chest syndrome, an acute lung injury that most commonly results from embolization of infarcted bone marrow to lung (Gladwin & Vichinsky, 2008). Pulmonary hypertension (PH), stroke, priapism and leg ulcers were all initially assumed also to be due to sludging of blood flow in the respective organs, but more recent epidemiological data more closely implicate the degree of haemolysis, rather than the degree of blood viscosity, in their development. In fact, sickling is not required for their development, as indicated by their association with other forms of haemolytic anaemia below, although it is likely that sickling also contributes.
Cor pulmonale was long known to be one of the occasional causes of death in patients with SCD (Yater & Hansmann, 1936). As lifespan improved dramatically for patients with SCD over the last 50 years, the diagnosis of symptomatic PH became more common. It is a grave prognostic factor, conferring as low as 50% 2-year survival (Castro et al, 2003). In more recent prospective screening studies in the Unites States using the tricuspid regurgitant velocity (TRV) measured on Doppler echocardiography, one-third of adults with sickle cell disease have a TRV at least two standard deviations above the mean (≥2·5 m/s), and 9% have a TRV approximately three standard deviations above the mean (≥3 m/s), a figure that more closely approximates the degree of pulmonary artery pressure elevation on right heart catheterization procedures classically accepted as proof of PH (Ataga et al, 2004, 2006; Gladwin et al, 2004; Lee et al, 2007; Nelson et al, 2007; Voskaridou et al, 2007; Aliyu et al, 2008; De Castro et al, 2008; Hagar et al, 2008; Onyekwere et al, 2008; Pashankar et al, 2008; Liem et al, 2009; Minniti et al, 2009; Sedrak et al, 2009). Regardless of the choice of semantics, adult SCD patients with a TRV ≥2·5 m/s have an approximately 10-fold relative risk for early mortality, making elevated TRV the strongest risk factor for sickle cell mortality in a proportional hazard model. Although proof is lacking that the patients actually die of PH, sudden death is common, similar to that seen in other forms of PH (Haque et al, 2002). SCD PH patients become symptomatic and die at less elevated pulmonary pressures than non-SCD PH patients, probably explained by the very low oxygen carrying capacity in the very anaemic SCD patients, frequent co-morbid conditions, and episodes of acute chest syndrome, which are associated with very high mortality in the patients with the highest pulmonary pressures.
There is possibly no other genetic disorder that has a higher and earlier risk of stroke than SCD. Median age of first stoke is 7 years of age (Ohene-Frempong et al, 1998). Although microvascular sludging due to sickling is thought to play a role, this might be more likely linked to the more patchy microvascular strokes that are considered silent infarcts of the brain. In the more clinically dramatic strokes, the cerebral infarcts occur as dense, vascular territory lesions associated with proliferative large vessel arterial lesions highly reminiscent histologically of atherosclerosis lesions without atheromatous plaque. The intimal and medial hyperplasia are often associated with irregular, activated and adhesive endothelium with superimposed in situ thrombosis, features that were emphasized many years ago in the definitive histopathology autopsy series of ischemic stroke in SCD (Rothman et al, 1986). These proliferative vasculopathy lesions in large arteries bear many histological, pathobiological and epidemiological similarities to those of PH and to atherosclerosis (Hebbel et al, 2004; Kato et al, 2006; Kato & Gladwin, 2008). The Cooperative Study of Sickle Cell Disease (CSSCD), a large natural history study, identified low haemoglobin values as an independent risk factor for the development of ischemic stroke, the first hint that severity of haemolysis might be associated with stroke (Ohene-Frempong et al, 1998). This was corroborated by additional studies from that group and others indicating that a known genetic modifier of haemolysis (Embury et al, 1982; De Ceulaer et al, 1983), alpha-thalassaemia trait, is protective against abnormal transcranial Doppler blood flow velocity and strokes (Adams et al, 1994; Neonato et al, 2000; Hsu et al, 2003; Bernaudin et al, 2008).
Priapism and leg ulceration in patients with SCD draw less attention than many other complications of SCD. However, they contribute to recurrent and prolonged misery in these patients. They originally were both envisioned to be due to sludging or adhesion of sickled erythrocytes in their respective circulations. However, they both epidemiologically are linked to severity of haemolysis, rather than blood viscosity. Once again, the alpha-thalassaemia trait reduces the severity of haemolysis and is protective against the development of both leg ulcers (Higgs et al, 1982; Steinberg et al, 1984; Koshy et al, 1989) and priapism (Nolan et al, 2005a). They both occur in non-sickling haemolytic anaemia patients, as detailed below, demonstrating that sickling is not required for their development. Finally, the report of priapism occurring in mice genetically deficient in nitric oxide (NO) production implicates vascular dysregulation due to NO deficiency as an important cause (Champion et al, 2005).
This second prevalent and well characterized disease of haemoglobin is usually classified as a disorder of ineffective erythropoiesis, meaning that there is a deficiency of formed erythrocytes released from the bone marrow. Although this concept is useful for modelling certain aspects of its pathophysiology, it may also be useful to understand that the unbalanced globin chain synthesis that defines the disorder results in highly unstable haemoglobin homotetramers that cause lysis of the developing erythroid cells even before they have a chance to exit the bone marrow medulla. From an alternative perspective, then, thalassaemia is a form of intramedullary haemolysis. Beta thalassaemia major patients are commonly treated with scheduled transfusion every 2–4 weeks, keeping their red cell mass relatively normal and intentionally suppressing the intramedullary erythropoiesis that otherwise becomes massive and distorts bone architecture, thereby also reducing the severity of intramedullary haemolysis. However, thalassaemia intermedia patients are only moderately anaemic and usually receive only intermittent transfusions which do not suppress their erythropoiesis, making them more strongly subject to the potential complications of chronic haemolytic anaemia.
Elevated pulmonary pressure by echocardiogram is reported in up to 75% of patients with thalassaemia major and intermedia (Grisaru et al, 1990; Du et al, 1997; Aessopos et al, 2001). Pulmonary thromboses have been reported several times in the literature, reportedly leading to PH (Taher et al, 2002), although it may be difficult clinically to distinguish this diagnosis from patients with initially clinically unsuspected PH who go on to develop in situ pulmonary thrombosis, a frequent scenario in all forms of PH. Patients with thalassaemia have a higher rate of all forms of thromboembolic disease than the general population (Eldor & Rachmilewitz, 2002). Leg ulcers and priapism have also been reported (Stevens et al, 1977; Jackson et al, 1986). Patients with thalassaemia frequently undergo surgical splenectomy to reduce red cell transfusion requirements, and post-splenectomy patients have a higher frequency of all of the above complications.
Hereditary spherocytosis, ovalocytosis and elliptocytosis
These inherited disorders of the red cell cytoskeleton lead to variable degrees of severity of haemolytic anaemia. Patients with these membranopathies have been reported to develop pulmonary thromboemboli (Hayag-Barin et al, 1998), PH, and leg ulcers (Vanscheidt et al, 1990). It has been suggested that these complications are more frequent among patients that have undergone splenectomy (Schilling et al, 2008). As therapeutic splenectomy to reduce red cell destruction is more common in the patients with the most severe haemolytic anaemia, history of splenectomy may simply be a surrogate marker of severity of underlying disease. However, haemolytic anaemia and loss of splenic function are a recurrent combination in the vascular complications being reviewed here.
Unstable haemoglobin disorders
Although SCD and thalassaemia could be, in a manner of speaking, considered unstable haemoglobin disorders, this label is usually reserved for other mutations of the globin subunits that produce no other readily observed feature than haemolytic anaemia. PH has been reported in patients with several unstable haemoglobinopathies (Honig et al, 1989; Krishnan et al, 1994; Lode et al, 2007). The same is true for priapism (Thuret et al, 1996; Gyan et al, 2001; Andrieu et al, 2003). Thromboembolic disease has been seen in patients with unstable haemoglobin (Pavlovic et al, 2004; Kim et al, 2005).
Paroxysmal nocturnal haemoglobinuria (PNH)
A chronic haemolytic anaemia due to an acquired somatic mutation in the hematopoietic stem cell, PNH manifests very severe intravascular haemolysis due to a loss of protection from complement-mediated membrane permeabilization of the red cell. Patients have variable degrees of chronic intravascular haemolysis and can develop acute exacerbations of this haemolysis. Well-known for catastrophic thromboembolic complications, this disease has recently been shown to have a high prevalence of elevated pulmonary pressures (Heller et al, 1992; Hill et al, in press). This is all the more remarkable because the haemolytic anaemia often develops only late in life, so that the patients do not have the same lifelong duration of haemolysis as seen in all the congenital haemolytic anaemia patients discussed above. Presumably, the severity of their intravascular haemolysis integrated with the shorter duration results in an equivalent ‘area under the curve’ of risk for haemolysis-associated complications. Priapism has also been reported in males with PNH (Montalban et al, 1986).
One of the most potent forces of evolutionary pressure in Africa and southern Asia, Plasmodium falciparum malaria produces the most explosive intravascular haemolysis known in clinical haematology. Although the malaria research literature has focused largely on the postulated toxicity of very high levels of inducible NO synthase activity during acute malaria, more recent findings suggest a haemolysis-linked defect in vascular reactivity in humans with malaria (Yeo et al, 2007). Like SCD and thalassaemia, acute haemolysis in malaria can release red cell arginase into plasma and deplete levels of the NO synthase substrate arginine (Lopansri et al, 2003). Furthermore, NO supplementation ameliorates the fatality of cerebral malaria in a mouse model (Gramaglia et al, 2006), and NO synthase polymorphisms that increase NO production appear to be protective in humans (Hobbs et al, 2002). In contrast to the vasculopathic consequences of chronic haemolysis discussed above, these malaria data suggest that acute, very severe haemolysis can have more immediate consequences.