Hemolytic anemia is characterized by intravascular and extravascular destruction of erythrocytes. It manifests if the production of the erythrocytes in the bone marrow is slower than their degradation. A first good differentiation of the several forms of hemolytic anemia can be made between ‘hereditary’ and ‘acquired’. In this article, the most important forms of hereditary hemolytic anemia are presented, emphasizing on their etiology, clinic and therapy.
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hemolytic anemia

Image: “Hämolytische Anämien” by Ed Uthman, MD. License: Public Domain


Thalassemia

Definition

Thalassemia is a microcytic-hypochromic anemia. Its cause is a decreased synthesis of one or several globin chains. Since this globin synthesis is flawed, the disease is one of the so-called hemoglobinopathies. Depending on which globin chain is affected by the disorder, one speaks off ß- or α-thalassemia.

In another article, you can learn everything about alimentary anemia.

Epidemiology

Since thalassemia more frequently occurs in the Mediterranean area including Turkey, it is also referred to as ‘Mediterranean anemia’. However, it can be found worldwide. It is estimated that ca. 3% of the world population carry at least one ß-thalassemia-gene. In Germany, the most frequent form is heterozygous ß-thalassemia.

Etiology

Thalassemia is inherited autosomal-codominantly. At heterozygosity, a milder form of the disease develops (minor thalassemia). At homozygosity, the severe form (major thalassemia) can be observed. Also, the so-called intermediate thalassemia exists as an intermediate form. The primary causes are genetic defects, which form the pathogenetic basis of the decreased synthesis of one of several polypeptide chains of the globin molecule.

In turn, this results in a decreased hemoglobinization of the erythroblasts. In the blood count, this condition can be observed as hypochromasia of the erythrocytes. Additionally, the globin chains which continue being produced aggregate and make for increased apoptosis of precursor cells via different pathophysiological mechanisms. Also, the erythrocytes in the peripheral blood have a decreased lifespan.

Clinic

Depending on the genetic defect, thalassemia shows a variable clinical picture.

Minor thalassemia usually does not show severe symptoms. Slight hepatosplenomegaly and possibly a recurrent jaundice in a mild form can be present. Also, target cells can be observed in the blood count.

Target-Cells

Image: “Target-Cells” by Osaretin. License: CC BY-SA 4.0

In its more distinct form, that is major thalassemia, thalassemia can lead to bone deformations, and even fractures, due to the reactive expansion of erythropoiesis in the bone marrow. Because of the decreased and often pathological erythrocytes, hypoxia becomes clinically relevant, as growth disturbances and trophic skin changes in child age show.

Diagnosis

The blood count of minor thalassemia shows microcytic, hypochromic erythrocytes. Since this is also the case with iron deficiency and this condition is more frequent in practice, one should consider minor thalassemia when confronted with a non-confirmed iron deficiency anemia. A blood smear with target cells and poikilocytosis provides additional certainty.

At major thalassemia and intermediate thalassemia, hypochromasia and poikilocytosis are more distinct. Reticulocytes, LDH and bilirubin are increased; haptoglobin is decreased.

Further criteria confirming the suspicion are a positive family history, disturbed hemoglobinization in bone marrow aspirate, and genome analysis.

Therapy

The ideal therapy is allogenic stem cell transplantation. Since the minor form does usually not require treatment, this primarily applies to major thalassemia.

Course and prognosis

While minor thalassemia and intermediate thalassemia mostly progress without complications, major thalassemia leads to death at infant age without treatment. Another life-shortening factor is increased iron residue in the organism (hemosiderosis). This is why therapeutic iron substitution of any kind is contraindicated.

Note: Thalassemia is a microcytic-hypochromic anemia. Its cause is a genetically based decreased synthesis of one or several globin chains. One distinguishes 3 forms: minor thalassemia, major thalassemia and intermediate thalassemia. In blood smear, target cells can be seen. Concerning differential diagnoses, thalassemia must not be confused with iron deficiency anemia since iron substitution in the case of thalassemia falsely diagnosed as iron deficiency anemia leads to increased hemosiderosis.

Sickle-Cell Anemia

Definition

Sickle-cell anemia is a hereditary hemolytic anemia based on a point mutation. In the erythrocytes, sickle-cell hemoglobin (Hb-S) can be found instead of the normal hemoglobin.

Epidemiology

Sickle-cell anemia is almost exclusively present in black-skinned people.

Etiology and Pathogenesis

On the basis of a base replacement in the DNS-code (thymine instead of adenine), an exchange of an amino acid at position 6 of the ß-chain of the hemoglobin occurs. Genetically, this is a point mutation. The result is a crystallization of the altered hemoglobin in the erythrocytes. If the partial pressure of oxygen decreases, the erythrocytes assume a characteristic, sickle-shaped form. This leads to micro-embolisms and infarctions.

The severity of the disease depends on the rate of sickle-cell hemoglobin in the erythrocytes. This rate is determined by the hereditary disposition and the inheritance mode. While heterozygosity leads to Hb-S-values of less than 50%, the rate of Hb-S at homozygosity is ca. 70-99%.

Since crystallization of sickle-cell hemoglobin depends on the partial pressure of oxygen, the symptoms mainly manifest in situations leading to hypoxia or are accompanied by it. Greater physical exertion can already lead to hemolytic crises. The same goes for infections, stay in greater heights, increased cold exposition, surgeries and suchlike.

Clinic

Patients with sickle-cell anemia show the typical symptoms of a chronic hemolytic anemia. Besides this, the patients suffer from abdominal, colicky complaints; bone and joint pain is also possible. Due to the pathogenesis, infarctions, especially in the kidneys and in the spleen, are frequently observed. Also, infarctions in the lung, the liver, and in bone tissue are often. First clinical hints are conspicuous shortenings of individual extremities already in child age (hand-foot syndrome).

Therapy

The minor form usually does not need treatment. However, the major form often leads to death at child age if not treated. Thus, allogenic HLA-identical bone marrow transplantation should be attempted if there are siblings. Otherwise, therapy of the major form is symptomatic and is limited to avoiding situations of oxygen deficiency, the application of folate and the transfusion of erythrocyte concentrate.

Course and Prognosis

Due to Hb-S-values between 25 and 50%, the heterozygous form barely develops symptoms and, thus, practically is no disease. However, states of hypoxia – e.g. after severe exertion, or prior infectious diseases, can trigger hemolytic crises. Still, life expectancy is not decreased by the disease in any measurable way. Also, the patients exhibit a relative resistance against malaria tropica due to the point mutation and the resulting morphological changes of the erythrocytes.

Homozygous sickle-cell anemia patients are severely ill since their Hb-S value lies between 70 and 99%. Untreated, homozygous and double heterozygous patients die in child age.

Hereditary Spherocytosis

Definition

In most cases, hereditary spherocytosis is an autosomal-dominantly inherited disease of the red blood cell line, which presents itself in a morphological change of the erythrocytes to so-called spherocytes.

Epidemiology

With a prevalence of 1:3,000, hereditary spherocytosis is the most frequently inherited hemolytic anemia in Central Europe.

Etiology and Pathogenesis

Generally, spherocyte anemia is autosomal-dominantly inherited. The cause of the disease is a membrane defect. Due to the defect or a lack of certain structure proteins of the cytoskeleton (ankyrin, spektrin, or pallidin), cell stability is impaired in such a manner that the typical biconcave shape of the erythrocytes is lost, being replaced by a spherical shape instead. With its shape and morphology, this spherocyte has a negative influence on microcirculation and gets prematurely stuck in the spleen to be degraded there.

Spherocytes

Image: “Spherocytes” by Prof. Osaro Erhabor. License: Public Domain

Clinic

A person with jaundice from hepatic failure

Image: “A person with jaundice from hepatic failure” by James Heilman, MD. License: CC BY 3.0

Spherocyte anemia can clinically appear at every age. Like any other anemia, spherocytosis develops the typical signs of anemia. Another very distinct symptom is the recurrent jaundice. Also, an enlarged spleen can often be palpated (splenomegaly). Often, pigmented gallstones develop.

Pigment Gallstones

Image: “Pigment Gallstones” by Openi. License: CC BY 2.0

Diagnosis

A positive family history gives the first important hint. Also, microspherocytes with low diameter are visible in the blood smear. The proportion of reticulocytes in the blood count is usually 5-20%. For protection of the findings, osmotic resistance of the erythrocytes can be tested, which has a right-shifted spread at spherocytosis. To exclude auto-immunological events as a cause of hemolysis, the Coombs test should also be performed. Since there is no autoimmune mechanism at spherocytosis, it will be inconspicuous.

Therapy

First-resort therapy is splenectomy. After removal of the spleen, the hemoglobin level usually normalizes since the number of degraded erythrocytes markedly decreases. However, splenectomy should only be conducted if the state of the patients makes this necessary, as the removal of the organ increases the risk for infectious disease and sepsis.

It is absolutely advised against splenectomy on children under the age of 6 due to the risk for infections. Alternatively, ectomy can be performed subtotally. In any case, vaccination against pneumococci, meningococci, and haemophilus influenza should be performed before splenectomy!

Complications

Frequent complications of spherocytosis are gallstone colics due to pigmented gallstones. Also, hemolytic, vasoocclusive crises can occur, which can also lead to infarctions.

Glucose-6-Phosphate-Dehydrogenase-Deficiency (G6PF Deficiency)

Definition

Glucose-6-phosphate-dehydrogenase-deficiency is an enzymatic disorder of erythrocyte metabolism.

Epidemiology

Glucose-6-phosphate-dehydrogenase-deficiency is one of the most frequent congenital diseases and the most frequent enzymatic disease worldwide.

Etiology and Pathogenesis

The cause for the disease can be a point mutation or a deletion in the glucose-6-phosphate-dehydrogenase-gene. It is X-chromosomal-recessively inherited. Usually, this leads to women to be conductors, while men become diseased.

The absence or the lack of the enzyme in the erythrocytes leads to production disorders of NADPH. However, without sufficient NADPH, the erythrocytes lack protection for oxidation. As a consequence, they are prematurely degraded. Hemolysis occurs.

Clinic

The clinical picture is not clear and mainly depends on the degree of the enzymatic defect or deficiency. While some patients do not show any or only slight discomforts, others suffer from partially severe hemolytic crises with severe pain conditions in the abdominal and back area. Also, fever and shivers are possible.

If infants suffer from the enzyme deficiency, they often show neonatal jaundice due to the impaired liver function.

Neonatal jaundice

Image: “Newborn infant undergoing phototherapy to treat neonatal jaundice” by Martin Pot. License: CC BY 3.0

Since the erythrocyte only possesses decreased or no protection against oxidation at glucose-6-phosphate-dehydrogenase-deficiency, increased oxidative stress can quickly lead to hemolytic crises. The consumption of bell beans alone can break through the existing protective barrier against oxidatively effective substances, which is why the disease has the epithet favism. Further, oxidative stress triggering factors are acute infections, medicaments like sulfonamides, ASS, vitamin-k-analogs, but also analgesics and antibiotics.

Diagnosis

Since the blood count between the individual hemolytic crises can be inconspicuous, further tests for backup of the diagnosis can be made. The detection of decreased or absent glucose-6-phosphat-dehydrogenase-activity is evidence, preferably via a direct enzyme-assay. Since contracted and fragmented cells can be seen in the blood smear during a crisis (bite cells, vesicular cells), this can also be used for diagnostics. Finally, Heinz bodies in the erythrocytes can be seen in the blood smear with supravital stain out of oxidized, denatured hemoglobin.

Therapy

A possible, already existing medication should be checked for tolerance. If an acute infection is present, it has to be treated. In severe cases, blood transfusion can be performed. Infants with neonatal jaundice get phototherapy and exchange transfusions.

Pyruvate Kinase Defects

Definition and Etiology

The pyruvate kinase defect is an autosomal-recessively inherited disease. Due to a decreased production of ATP, the erythrocytes lose their physiological flexibility and become rigid.

Clinic and Diagnosis

Usually, the symptoms are less distinctly present; besides jaundice and gallstones, skeleton deformations can occur (frontal bumps). In the blood smear, poikilocytes can be seen.

A safe diagnosis is made via enzyme deficiency proof.

Therapy

Splenectomy can be considered, which often brings relief, but no cure.

 

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