Rare Anaemias

2. Hereditary Haemolytic Anaemias (HHA)

Red blood cell enzymopathies

A group of hereditary anaemias in which enzymes, active in red cell metabolism, are deficient; this disturbs the function and so reduces the life span of the cells, hence causes haemolysis (destruction of red blood cells). Diagnosis is mainly by enzyme assay. There are many enzymes which are affected, and most are extremely rare. The most common types of red blood cell enzymopathies are:

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) is by far the most common enzyme deficiency, caused by various mutations. In some populations the prevalence is very high (e.g. in Cyprus 10% of the male population is deficient). The inheritance is in most cases x-linked and so males are affected, with only rare female homozygotes having symptoms. In the majority of patients, haemolysis occurs under conditions of oxidative stress; this means that an individual is well unless he is in contact with a substance that causes oxidation, in which case an acute haemolytic episode is triggered. The best known substance is found in the fava bean (favism) but there also various medications which have such an effect. In populations where other mutations cause the deficiency, a chronic haemolytic anaemia is the most usual manifestation. Most patients with chronic anaemia do not require treatment but in an acute haemolytic crisis blood transfusion is usually necessary.

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Pyruvate kinase deficiency (PK Deficiency or PKD) is another rare genetic disorder (exact prevalence is unknown) involving the premature destruction of red blood cells. It is caused by mutations to the pklr gene, which leads to a reduction in the amount of the enzyme pyruvate kinase. This enzyme is involved in converting sugar molecules into energy for the body. Insufficient energy provided to red blood cells leads to their premature death and destruction (haemolysis). The severity of the disease is highly variable between patients, with some patients experiencing little to no symptoms, while others experience quite severe illness. Due to very mild cases that may be undiagnosed, the true prevalence may be higher than the known cases. Diagnosis is made by determining the red cell enzyme activity and molecular characterisation of the defect. Treatment: Possible splenectomy, folic acid, transfusion. Mitapivat (currently approved in the USA and UK, and pending approval in the EU is a substance which activates the enzyme and is given orally twice daily). Other new enzyme activators under investigation.

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Red blood cell membranopathies

This is a group of hereditary haemolytic anaemias, which are caused by an inherited defect defect in the structure of the membrane covering the red cell (erythrocyte). The main conditions in this group are:

• Hereditary Spherocytosis – this is the commonest, encountered in 1:2000 individuals, present in all racial groups
• Hereditary Elliptocytosis – more common in patients of African and Mediterranean descent in whom 1:1000-4000 may be affected. A rare form is pyropoikilocytosis (1-2 families in Cyprus for our information)
• Hereditary Stomatocytosis – very rare. Has two forms, the dehydrated type (xerocytosis) found in 1:50000 people, and the overhydrated type found in less than 1:million.
• Southeast Asian Ovalocytosis, very common only in SE Asian populations, where it may reach 5-25% of the population

Most cases have an autosomal dominant mode of inheritance (a carrier may have symptoms).

In Spherocytosis, a protein that is part of the cell membrane is mutated (deficient or dysfunctional), resulting in a dysfunctional red cell membrane, which progressively loses its surface area, making the red cell more spherical, and with reduced deformability, making it difficult to pass through the capillary circulation and shortening the life span of each cell (haemolysis). Moreover, the spleen traps these abnormal cells contributing in this way to the degree of anaemia. The resulting anaemia varies in severity, so that in some patients the anaemia along with jaundice becomes obvious in infancy, while in others there is compensation and the condition becomes manifest in later life. The diagnosis can be made by red cell morphology (appearance of red cells under the microscope), and confirmed by osmotic fragility and osmotic gradient ektacytometry. A special electrophoresis allows the identification of the defective protein. Treatment is by splenectomy. For more information click here.

In Elliptocytosis, defects in the cell membrane proteins result in a decreased membrane stability, with an increased red cell destruction, and loss of cell surface area. The result may be mild asymptomatic or moderately severe haemolytic anaemia. Splenectomy is again the only treatment option according to the severity of the anaemia. Diagnosis includes red cell morphology and osmotic gradient ektacytometry. For more information click here.

Stomatocytosis, is due to abnormal red cell permeability, meaning that there is abnormal concentration of salts (sodium and potassium) in the cell. In one form this increases the water content of the cell and in another form the cell is dehydrated (xerocytosis). Both forms cause a mild to moderate haemolytic anaemia which rarely leads to splenectomy.  Osmotic gradient ektacytometry is again diagnostic.

More information: Dehydrated hereditary stomatocytosis, Overhydrated hereditary stomatocytosis

In Southeast Asian Ovalocytosis, the altered membrane proteins cause a marked membrane rigidity, which does not allow deformability of the red cells as they pass from small blood vessels. Diagnosis and Treatment are similar to the other membranopathies.

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4. Dyserythropoietic Anaemias

This is a group of hereditary and acquired anaemias characterised by ineffective erythropoiesis.

Congenital dyserythropoietic anaemias (CDA)

Different mutations result in subtypes of Congenital dyserythropoietic anaemias (CDA) which share some common features but also differ in clinical manifestations, and require different treatment approaches. The subtypes are classified as I-III plus variant types. With the exception of type II the rest are very rare. The pattern of inheritance is autosomal recessive (both parents must be carriers). CDA Type I is a rare anaemia with increased size of red cells (macrocytosis), and usually not transfusion dependent. CDA Type II (HEMPAS) is an anaemia with a distinct pattern of red cells under the microscope; the cell are of mostly normal size but varying shapes and contain characteristic spots (basophilic stpling). In the bone marrow the developing red cells (erythroblasts) are increased in number,but may have two or more nuclei. Apart from morphological changes in peripheral blood and bone marrow, there are changes in the cell membrane and mutations which confirm the diagnosis. Prevalence varies in various populations and may be as high as 3 per million in some regions. Splenomegaly and gallstones are common and iron overload increases over time. In CDA Type II patients may benefit from splenectomy. Haematopoietic Stem Cell Transplantation (HSCT) has also been curative to severe cases.

Click on the links for more information about Congenital dyserythropoietic anemia type I, type II, type III, and type IV.

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a varied (heterogeneous) group of malignant hematopoietic (blood forming) stem cell (HSC) disorders in the bone marrow. They are characterized by ineffective maturation and production of blood cells, resulting in low counts of all or some blood cells (red cells, white cells and platelets) in the peripheral blood, and an increased risk of transformation to acute myeloid leukemia (AML). MDS arise when some of the stem cells (progenitor cells) suffer changes, which include mutations and chromosome abnormalities. These aberrant cells form clones within the blood forming tissues and trigger activation of the immune system which affects the survival of these cells.  Patient disease course, progression, and survival rates are highly variable, and the disease is divided into Low, Intermediate and High-risk categories; the higher-risk subtypes are associated with higher aberrant progenitor cell counts, increased risk of leukaemic transformation, and shorter median overall survival. Even though MDS affect children, frequency increases with age and so MDS is the most frequent hematological disease in the elderly. The only curative treatment is by HSCT, which is not possible in all patients, especially the elderly with co-morbidities which do not allow the necessary immunosuppression. Alternative treatments are often required. Most available are cytotoxic agents however, half of the patients do not respond to these treatments and many eventually acquire resistance leading to relapse. Combining therapies (e.g. venetoclax and azacitidine combination) is a promising strategy to overcome or avoid the problem of acquired resistances. New approaches are currently in various stages of development (including luspatercept). Supportive therapy with blood transfusions, with or without oral iron chelators, may also be necessary.

References:

• Hatzimichael E, Timotheatou D, Koumpis E, Benetatos L, Makis A. Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis. Diseases. 2022 Oct 9;10(4):85. doi: 10.3390/diseases10040085. PMID: 36278584
• Sekeres MA, Taylor J. Diagnosis and Treatment of Myelodysplastic Syndromes: A Review. JAMA. 2022;328(9):872–880. doi:10.1001/jama.2022.14578

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6. Non-sideroblastic anaemias due to iron metabolism defects

This is a group of disorders in which there is mild to severe anaemia, but without ring sideroblasts, and there is a disturbed regulation of iron metabolism.

Disorders of this group are extremely rare, with perhaps Iron-refractory Iron-deficiency anaemia (IRIDA) being the least rare. In IRIDA there is an increased amount of the hormone hepcidin, which inhibits the absorption of iron and so leads to iron deficiency. In other members of this group there is iron overload.

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8. Paroxysmal nocturnal haemoglobinuria (PNH)

This disease is characterised by destruction (haemolysis) of red cells in the circulation (intravascular haemolysis) and bone marrow failure, causing anaemia and organ dysfunction (renal failure, pulmonary hypertension and others) due to a propensity to thrombosis (thrombophilia). PNH is caused by somatic mutations in PIG-A gene in one or more blood forming stem cell clones. This gene codes for a protein which is important for stem cell development and deficiency of the protein defines the severity of the disease. PNH erythrocytes are susceptible to haemolysis, which can lead to thrombosis. Diagnosis is by a test called Flow cytometry. Treatment is by bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective in reducing complications.

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10. Anaemias of unknown origin (AUO)

More information coming soon.