Main syndromes

A compilation of the main syndromes in medical practice.
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José Luis Fedele

Hemolytic anemias are characterized by an accelerated destruction of red blood cells in the general circulation, due to a shortening of their normal survival of 120 days.

Hemolytic processes are usually counteracted with an increase in erythropoiesis, which is proportional to the intensity of the erythrocyte destruction, and which in some cases, if it is not very intense, can compensate and prevent the appearance of anemia.

The pathophysiological mechanism consists, most of the time, in an accelerated elimination by physiological mechanisms (macrophages), which is called extravascular hemolysis. This process is usually chronic and is accompanied by splenomegaly.

Other times, at least, the destruction mechanism is intravascular, it is usually more acute and it is accompanied by hemoglobinuria.

The diagnosis of hemolytic anemia is often difficult, given the large number of pathologies that can trigger these conditions, and requires advanced clinical skills and knowledge of pathophysiology.

In general, hemolytic processes present a particular clinical and biological behavior, which, regardless of their etiology, is similar in all cases.

It should be noted that the laboratory data obtained for the study of hemolytic anemia should be guided by a careful anamnesis and detailed physical examination, since there are situations that can be confused with a hemolytic syndrome.

The only laboratory procedure that allows confirming the existence of hemolytic anemia without doubt is the determination of the erythrocyte half-life.

The problem with this technique is that it is extremely cumbersome, annoying for the patient and not available in most centers.

The most widely used method for determining the erythrocyte half-life is the marking of erythrocytes with radioactive chromium (51Cr). After marking, they are reinjected into the patient and serial extractions are performed every 3 to 4 days for no less than 20 to 25 days, measuring the residual radioactivity each time. The erythrocyte half-life corresponds to the time when the radioactivity falls by half.

In a normal individual, the half-life is 25 to 32 days, which does not correspond to the real one for technical reasons.

For their study, hemolytic anemias are divided into two large groups:

  • CONGENITAL HEMOLITHIC ANEMIAS
    1. Membranopatías
      • Hereditary Spherocytosis
      • Congenital Eliptositosis
      • Ion permeability disorders
      • Abetalipoproteinemia (Congenital Acanthocytosis)
      • Rh0 syndrome
      • Leach syndrome
    2. Enzymopathies
      • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
      • Lacking Piruvatoquinasa (PK)
      • Other enzyme diseases (PFK, PGI, TPI, etc.)
    3. Hemoglobinopathies
      • Structural hemoglobinopathies
      • Talasemias
      • Thalassemic Hemoglobinopathies
  • HEMOLYTIC ANEMIAS ACQUIRED
    1. Immune Hemolytic Anemias
      • Aloinmune hemolytic anemias (alloantibodies)
      • Transfusion Incompatibility
      • Hemolytic disease of the newborn
      • Autoimmune hemolytic anemias
      • Warm antibodies
      • Cold antibodies
      • Paroxística a cold hemoglobinuria
      • Immune-medicinal anemia
    2. Mechanical Hemolytic Anemias
      • Microangiopáticas
      • Hemolytic uremic syndrome
      • Thrombotic Thrombocytopenic Purpura
      • Heart valve prostheses
      • Traumatic (gait hemoglobinuria)
    3. Infectious Hemolytic Anemia
      • By parasites (Malaria, Toxoplasmosis, Leishmanias)
      • By bacteria (Bartonela, Clostridium W, Cholera)
    4. Hemolytic anemias by physicochemical agents
      • Oxidizing agents
      • Chemical substances
      • Hemodialysis
      • Poisons
    5. Hemolytic anemias secondary to other diseases
      • Hypophosphatemia
      • Liver disease (Zieve syndrome)
      • Chronic Kidney Failure (uremia)
    6. Paroxysmal Nocturnal Hemoglobinuria

Symptoms and signs

The clinical manifestations of a Hemolytic Syndrome depend on the speed of installation of the picture (Acute or Chronic), and on its intensity.

Since both depend on the cause that originates it, the picture can vary from an asymptomatic presentation to a severe anemia requiring transfusion.

Acute Hemolytic Anemia

They are pictures that appear abruptly in subjects, in general, previously healthy.

They are characterized by very flowery symptoms: fever, marked paleness, intense fatigue, palpitations, dyspnea at moderate or small efforts and eventually emission of dark urine.

Dark urine is due, in these cases, to the elimination of free hemoglobin (hemoglobinuria), the product of intravascular hemolysis, and not to the elimination of bile pigments.

If the anemia is of sufficient intensity, disorders of consciousness may appear, up to loss of consciousness, kidney failure and severe hypovolemic shock with risk to the life of the patient.

If it is a young person with a history of recent drug intake, one might think of G6PD deficiency or unstable hemoglobins.

In an adult patient, it is most likely an acquired phenomenon of an immune nature.

Chronic Hemolytic Anemia

It is slow and progressive in installation and can lead to the appearance of compensatory phenomena. For this reason, the clinical expression is usually less evident than the acute form and can vary from asymptomatic forms to moderate to severe anemias.

The physical examination shows moderate pallor and jaundice, and splenomegaly is common, if the time of evolution allows it.

The appearance of jaundice in these cases is due to an increase in the "indirect" or "unconjugated" form, so it is NEVER accompanied by coluria (acholuric jaundice) and pruritus, except when it coexists with a hepato-biliary disease.

As in the acute forms, when it occurs in children or young people, it is most likely of congenital origin, so it is important to inquire about family history. In adult subjects, one must first think of an acquired process.

Given the chronic nature of these anemias, the symptoms tend to be more the consequence of complications than of the hemolytic syndrome itself.

Complications due to chronic hypoxia are especially evident in very severe anemias with early onset in life (Thalassemia Major and Sickle Cell Disease); and consist of delayed bone development and body growth, delayed gonadal development, ankle ulcers.

These types of complications are usually accompanied by the effects of chronically increased erythropoiesis, which determines bone deformations of the skeleton due to expansion of the hemopoietic tissue. These deformations are especially evident in the skull and face (turricephaly, mongoloid facie, anomalous implantation of the teeth, etc.). Sometimes the excessive expansion of the hematopoietic tissue can produce true tumors that can cause compression of the medullary canal.

Other complications of excessive erythropoiesis can be alterations in iron and folate metabolism. The intestine increases iron absorption as a consequence of increased signals from the marrow. This can cause the calving of Hemochromatosis in genetically predisposed individuals.

On the other hand, folate reserves can easily be depleted by hyperconsumption.

In the context of chronic hemolytic anemia, a “megaloblastic crisis” can develop as a consequence of a folate deficiency, which can significantly aggravate the clinical picture.

The megaloblastic crisis should not be confused with a much more acute “aplastic crisis” or “erythroblastopenia”.

The latter is characterized by a sharp drop in hemoglobin, accompanied by intense reticulocytopenia. In bone marrow, a near disappearance of erythroid precursors can be seen, with the presence of isolated giant erythroblasts (giant proerythroblasts), which speaks of a maturation arrest from very early stages.

The erythroblastopenia crisis is associated with infection by Parvovirus B19, which causes a childhood rash and a polyarthrology in adults.

The effect of the virus is attributed to an inhibition of the more mature erythroid precursors with less action on the more immature ones.

Complications may appear as a consequence of hemoglobin hypercatabolism such as gallstones, which in the case of congenital anemias is observed in young people.

Finally, a state of hypersplenism may appear, which conditions plaquetopenia, leukopenia or worsening of the underlying anemia.

Study methodology

The laboratory, as in all hematology, is of vital importance in the determination of hemolytic anemias, but it should always be guided by a detailed clinical history.

Analyzes that determine the magnitude of anemia are combined, showing signs of cell destruction and increased erythropoiesis

From the general point of view, the complete blood count, of course, with the measurement of the erythrocyte indices, is of great importance. Hemolytic anemia is usually macrocytic due to the presence of reticulocytosis (MCV> 95).

MCHC acquires importance in Hereditary Spherocytosis, where it is characteristically increased and is an important diagnostic index.

As mentioned before, the measurement of the erythrocyte half-life is the only analysis that confirms the presence of hemolysis, but as it is not very viable in clinical practice, other methods are used.

Indirect hyperbilirubinemia is a characteristic feature of hemolysis.

Hyperbilirubinemia is associated with increased fecal stercobilinogen

The increase in serum LDH is due to a release of fraction-2 (isoenzyme-2) from the destroyed erythrocytes. In megaloblastic anemia with ineffective erythropoiesis, LDH also increases but in its fraction-1.

A decrease in haptoglobin is a very sensitive sign of peripheral red blood cell destruction. Unfortunately it is not specific since it can also descend in megaloblastic anemia (ineffective erythropoiesis).

Haptoglobin is a B-2-glycoprotein, which binds to free hemoglobin in plasma.

The Haptoglobin-hemoglobin complex is degraded in the liver, and constitutes a mechanism to slow the elimination of free hemoglobin by the kidney.

The determination of glycosylated hemoglobin has some value, since it is frequently decreased in hemolysis.

Measurement of free hemoglobin in plasma can be used to confirm the presence of intravascular hemolysis. When the hemoglobin level exceeds a renal threshold value, hemoglobin appears in the urine (hemoglobinuria).

If the hemolytic process is chronic, the elimination of small amounts of hemoglobin can be partly reabsorbed by the renal tubules.

Iron accumulates in the tubular cells in the form of hemosiderin and this can then be measured in urinalysis with the Perls stain (hemosiderinuria).

The increase in erythropoiesis is primarily measured by reticulocytes. The reticulocyte count serves not only as a diagnostic tool, but also as a follow-up for hemolytic anemia. Thus, the response to treatment is followed by a decrease in the reticulocyte count, and a relapse is preceded by an elevation of the same. The difference and importance of the lack of a reticulocyte rise characteristic of acute erythroblastopenia secondary to Parvovirus B19 infection has already been mentioned.

It is vital, given the various causes of hemolytic anemia, to perform a complete anamnesis and detailed physical examination.

According to the aforementioned table, the reasoning must begin with the premise of initially dividing hemolytic anemias into congenital and acquired.

The acute or chronic division also serves to guide the diagnosis.

In adults, those acquired should be discarded in the first instance. Once these are discarded, studies will be started to search for congenital pathologies.

The following table sets out the guidelines for the etiological diagnosis of hemolytic anemias.

GUIDELINES FOR THE DIAGNOSIS OF HEMOLYTIC ANEMIAS

  1. Family studies
    • Congenital hemolytic anemias
  2. Thorough examination of erythrocyte morphology
    • Hereditary spherocytosis
    • Congenital elliptocytosis
    • Sickle cell anemia
    • Anemias microangiopáticas
    • Malaria
  3. Reticulocyte count
    • Anemias regenerativas
  4. Direct Antiglobulin Tests (Coombs)
    • Autoimmune hemolytic anemia
    • Drug (immune) hemolytic anemia
  5. Erythrocyte osmotic resistance
    • Hereditary spherocytosis
    • Congenital stomatocytosis
    • Congenital xerocytosis
    • Talasemias
  6. Hemoglobin electrophoresis
    • Structural hemoglobinopathies
    • Talasemias
  7. Molecular stability tests of hemoglobins
    • Unstable hemoglobinopathies
  8. Determination Erythrocyte enzymes
    • Drug hemolysis
    • PK deficit and others
  9. Hemolysis test in acid medium (HAM test)
    • Paroxysmal Nocturnal Hemoglobinuria