Anaemia, haemolytic D58.9

Worlledge et al. are considered the first describers of hemolytic anemia (HA), having first described cases of HA in 1966 (Arnold 1970).

Hemolytic anemia (HA) is a group of disorders of varying clinical and molecular heterogeneity characterized by a decreased level of circulating erythrocytes in the blood (Jamwal 2020).

This results in a shortened erythrocyte survival time (< 100 d) due to increased erythrocyte degradation. Hemolysis can occur intravascularly or extravascularly. If the Hb content in the blood remains normal, it is referred to as compensated hemolysis, otherwise as hemolytic anemia (Herold 2023).

Hemolytic anemias may be acute or chronic, result from intravascular or extravascular hemolysis, and be due to intra- or extracorpuscular causes (Kasper 2015).

Hemolytic anemias are differentiated into the following forms:

• I. corpuscular hemolytic anemias.
  • 1. congenital enzyme defects of erythrocytes, also called "enzymopenic hemolytic anemias" (Herold 2023) These include defects:
    • 1. a. in the hexose monophosphate cycle such as occur in glucose 6- phosphate dehydrogenase deficiency.
    • 1. b. of glycolysis as found in pyruvate kinase def iciency (Herold 2023)
  • 2. congenital disorders of hemoglobin synthesis, also known as "hemoglobinopathy" (PNH). These include:
    • 2. a. abnormal hemoglobins, these are e.g. variants with abnormal Hb- structure.
    • 2. b. Thalassemias, which are variants in which the formation of normal Hb polypeptide chains is reduced (Herold 2023).
  • 3. congenital membrane defects of erythrocytes, so-called enzymopenic hemolytic anemias.
    • 3. a. Examples include elliptocytosis and spherocytosis (Herold 2023).
  • 4. acquired membrane defects.
    • This includes, for example, paroxysmal nocturnal hemoglobinuria (Herold 2023).

• II. extracorpuscular hemolytic anemias
  • 1. immunologically induced hemolysis: these are subdivided into.
    • 1.a. alloimmune hemolytic anemias due to alloantibodies such as in Rh incompatibility in the newborn.
    • 1.b. antibody-mediated transfusion reactions (Herold 2023)
  • 2. microangiopathic hemolytic anemia (MHA): This occurs in:
    • 2. a. metastatic carcinoma
    • 2. b. Hemolytic-uremic syndrome (HUS or Gasser syndrome)
    • 2. c. Drug-induced MHA, e.g. due to the use of mitomycin C.
    • 2. d. atypical hemolytic-uremic syndrome (aHUS)
    • 2. e. thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome) (Herold 2023)
  • 3. hemolysis in infectious diseases
    • 3. a. e.g. in the context of malaria disease (Herold 2022)
  • 4. hemolytic anemia due to physical and chemical damage
    • 4. a. chemical noxae by e.g. arsenic, lead, copper, snake venom
    • 4. b. mechanical hemolysis with fragmentocytes in e.g. march hemolysis, heart valve replacement
    • 4. c. thermal damage of erythrocytes in e.g. burns (Herold 2022)
  • 5. autoimmune hemolytic anemias (AIHA) In this form of extracorpuscular anemia, autoantibodies cause erythrocyte breakdown. The two most common AIHAs include:
    • 5. a. Heat antibody type (wAIHA).
    • 5. b. Cold antibody type (cAIHA) (Ehrlich 2022).
  • 6. other causes
    • 6. a. These include Zieve syndrome and hypersplenism (Herold 2022).

Hemolytic anemias can be both hereditary and acquired (Kasper 2015).

The clinical picture of HA depends very much on whether it is acute or chronic. Primarily, patients with hemolytic anemia present with signs and symptoms that are directly attributable to hemolysis (Kasper 2015).

Hemolysis can be compensated, as so-called "compensated hemolysis," or anemic, as "hemolytic anemia." In the compensated form, there are signs of hemolysis but no anemia, as erythropoiesis can increase up to 10 times normal (Herold 2023). In contrast, in hemolytic anemia, hemolysis exceeds compensatory mechanisms and hemolysis signs with anemia occur (Herold 2023)

The main symptoms of hemolysis are hemoglobinuria and icterus (Aulbert 2008).

In acute hemolysis, there may be:

- Tachycardia

- palpitations

- exertional dyspnea (Berger 2010).

In chronic hemolysis, there are usually hardly any symptoms. Even hemoglobin levels up to 6 - 8 mg / dl are tolerated. Otherwise, there may be:

- splenomegaly (but not in sickle cell disease)

- tendency to thrombosis (Herold 2023)

- low grade icterus

- often bilirubin gallstones (Berger 2010)

Hemolytic crisis

Hemolytic crisis is always an emergency situation. It can occur as an exacerbation of chronic hemolysis or spontaneously due to, for example, a transfusion incident.

The following symptoms are present

- chills

- fever

- Pain in the back, abdomen, head (Berger 2010)

- collapse

- Hemoglobinuria, which can lead to acute renal failure (Herold 2023)

In addition to physical examination and anamnesis, laboratory chemistry tests are of particular diagnostic importance.

Physical examination

- Splenomegaly

- Enlargement of the liver possible

- Skeletal changes in congenital forms (Kasper 2015)

Bone marrow puncture

Bone marrow aspiration is usually not necessary. If it is performed, erythroid hyperplasia will be seen (Kasper 2015).

Sanger sequencing

Together with conventional tests, this is the most efficient method for diagnosing HA of genetic origin (Jamwal 2020).

The destruction of the erythrocytes releases hemoglobin and other cell components such as LDH, GOT, potassium. Hemoglobin is bound to haptoglobin, so that free haptoglobin decreases (Müller 2023).

Typical laboratory changes in hemolysis are therefore:

There is a decrease in:

- Haptoglobin (most sensitive parameter).

- AP

- gamma- GT

- hemoglobin

- hematocrit

- erythrocytes

- Survival time of erythrocytes (Berger 2010)

and to an increase of:

- Total bilirubin (especially unconjugated bilirubin [Kasper 2015]).

- GPT

- Serum iron

- Free Hb

- hemopexin

- LDH (Berger 2010)

- AST (aspartate aminotransferase)

- Urobilinogen in stool and urine

- Reticulocytes (the most important sign of an erythropoietic reaction of the bone marrow with an increase in MCV [Kasper 2015]).

It should be noted that hemolysis in a blood sample causes the following values to increase artificially:

- LDH

- AST (GOT)

- ALT (GPT)

- Potassium (Herold 2022)

Differentiation intravascular / extravascular hemolysis

In intravascular hemolysis, there is an increase in serum free Hb, hemoglobinuria, hemosiderinuria, and a decrease in haptoglobin (Herold 2023).

In contrast, in extravascular hemolysis, serum haptoglobin and free Hb are normal, and hemoglobinuria and hemosiderinuria do not occur. The only exception is hemolytic crisis in extravascular hemolysis. In this case, there is decreased haptoglobin and hemoglobinuria (Herold 2023).

Peripheral blood smear

A peripheral blood smear should always be examined in the presence of HA to determine any abnormal red cell morphology that may be present (Phillips 2018).

This may include:

- Agglutination of erythrocytes: This is found, for example, in autoimmune hemolytic anemia of the cold antibody type.

- Acanthocytes: They occur, for example, in pyruvate kinase deficiency.

- Fragmentocytes (schistocytes): Found in microangiopathic hemolytic anemia, erythrocyte damage caused mechanically (e.g., by a heart valve).

- Heinz inner corpuscles: These represent hemoglobin precipitates in erythrocytes and are found in e.g. glucose 6- phosphate dehydrogenase deficiency, Met Hb and Hb abnormalities.

- Intraerythrocytic parasites: Occur in malaria.

- Globular cells (spherocytes): These are typical of hereditary spherocytosis and autoimmune hemolysis due to heat antibodies.

- Shooting target cells (target cells): These show hypochromic erythrocytes with central compaction. They are typical for thalassemia.

- Sickle cells (Drepanocytes): The erythrocytes take on a sickle shape and are typical of sickle cell anemia (Herold 2023).

Direct antiglobulin test (Coombs test).

This test can distinguish immunological causes from non-immunological causes (Phillips 2018).

- Normocytic anemias of other genesis

- Macrocytic anemias of other etiology (Phillips 2018).

Anemia with elevated serum iron is found in addition to HA, for example, in:

- Aplastic anemia

- Megaloblastic anemia

- Myelodysplastic syndrome (Herold 2023).

Differentiation of the cause of icterus

- Hemolysis: Indirect bilirubin markedly elevated, direct bilirubin normal, urine markedly elevated levels of urobilinogen. Stool color is normal in color (Herold 2023).

- Occlusive icterus: Indirect bilirubin slightly elevated, direct bilirubin markedly elevated, bilirubin clearly detectable in urine, stool is discolored (Herold 2023).

- Parenchymicterus: In this case, indirect and direct bilirubin are elevated, bilirubin and urobilinogen are found in the urine, the stool may be normal to light in color (Herold 2023)

The therapy depends on the cause of the HA.

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