HEMOLYTIC ANEMIASHEMOLYTIC ANEMIAS

INCREASE RED CELL DESTRUCTION INCREASE RED CELL DESTRUCTION = REDUCED RED-CELL LIFE SPAN= REDUCED RED-CELL LIFE SPAN

HEMOLYTIC ANEMIASHEMOLYTIC ANEMIAS

A red blood cell survives 90 to 120 days in the circulation; about 1% of human red blood cells break down each day

The spleen is the main organ which removes old and damaged RBCs from the circulation

MECHANISMS OF HEMOLYSISMECHANISMS OF HEMOLYSIS

Extravascular Extravascular red cells destruction occurs in red cells destruction occurs in

reticuloendothelial systemreticuloendothelial system

Intravascular Intravascular red cells destruction occurs in red cells destruction occurs in

vascular space vascular space

SIGNS OF HEMOLYTIC ANEMIAS

Symptoms of anemia – pallor, fatique, rapid pulse

Jaundice Splenomegaly

DIAGNOSIS OF HEMOLYTIC DIAGNOSIS OF HEMOLYTIC ANEMIASANEMIAS AnemiaAnemia

ReticulocytosisReticulocytosis

Indirect hyperbilirubinemiaIndirect hyperbilirubinemia

Increased level of Increased level of lactate dehydrogenase (LDH) lactate dehydrogenase (LDH) Absence or reduced of free serum haptoglobinAbsence or reduced of free serum haptoglobin

INTRAVASCULAR INTRAVASCULAR HEMOLYSISHEMOLYSIS

• laboratory signs of intravascular hemolysis: - tests for hemolysis

and aditionally: - hemoglobinemia - hemoglobinuria - hemosiderynuria

HEMOLYTIC ANEMIASHEMOLYTIC ANEMIAS

Compensated hemolysis – increase erythropoesis compensates increase destruction of erythrocytes

Decompensated hemolysis - erythropoesis can not compensates increae destruction – patient needs therapy

COMPLICATIONS OF INCREASED, CHRONIC HEMOLYSIS

Folinic acid deficiency Gallstones Thrombosis Hemolytic crisis

- rapid destruction of large numbers of red blood cells

CLASSIFICATION OF HEMOLYTIC CLASSIFICATION OF HEMOLYTIC ANEMIASANEMIAS

1.1.Hereditary Hereditary a)a) Membrane defect (spherocytosis, elliptocytosis)Membrane defect (spherocytosis, elliptocytosis)

b)b) Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) (G6PD) deficiency, Pyruvate kinase (PK)

deficiency)deficiency)

c)c) Hemoglobinopathies (thalassemias, sickle cell anemia )Hemoglobinopathies (thalassemias, sickle cell anemia )

2.2.AcquiredAcquireda)a) Immune hemolytic anemiasImmune hemolytic anemias

b)b) Nonimmune hemolytic anemiasNonimmune hemolytic anemias

Hereditary Hereditary membrane defectsmembrane defects1.1. SpherocytosisSpherocytosis

• The most common defect of red cell membrane protein (1/2000 birth)The most common defect of red cell membrane protein (1/2000 birth)• Inheritance - autosomal dominantInheritance - autosomal dominant• Deficient of membrane protein causes change of shape (round, no Deficient of membrane protein causes change of shape (round, no

central pallor)central pallor)• Clinical features: jaundice, gallstones, splenomegaly, constitutional

skeleton changes (ie tower cranium, gothic palate)• Laboratory features: anemia, hiperbilirubinemia, retikulocytosis, LDH

- blood smear - microspherocytes - abnormal osmotic fragility test

• Treatment - splenectomy

SPHEROCYTES

Hereditary Hereditary membrane defectsmembrane defects

2.2. ElliptocytosisElliptocytosis

Hereditary metabolic defectHereditary metabolic defect

Glucoze-6-Phosphate-Dehydrogenaze (G6PD) Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency deficiency Hemolysis is induce by infections, drugsHemolysis is induce by infections, drugs Hemolysis is intravascularHemolysis is intravascular

Pyruvate kinase (PK) deficiencyPyruvate kinase (PK) deficiency

HEREDITARYHEREDITARY HEMOGLOBINOPATHIES HEMOGLOBINOPATHIES

ThalassemiasThalassemias Alfa thalassemia Beta thalasemia: major, minor (trait),

intermedia Delta/Beta thalassemia Hereditary persistentce of fetal hemoglobin

Sickle cell anemiaSickle cell anemia

SICKLE CELL ANEMIA

DEFINITION: CHRONIC HEMOLYTIC ANEMIA CHARACTERIZED BY SICKLE-SHAPED RED CELLS CAUSED BY HOMOZYGOUS INHERITANCE OF HEMOGLOBIN S

SICKLE CELL ANEMIA - INCIDENCE

- Occurs mainly in people of African, Caribbean, Mediterranean descent

- Homozygous - about 0,3% of Arficans Americans in the USA (have sickle cell anemia)

- Hetezygotes-8-13% of Africans Americans (are not anemic, but the sickling trait = sicklemia can be demonstrated in vitro)

SICKLE CELL ANEMIA-PATHOGENESIS

- Hemolysis - because sickle RBCs are too fragile to withstand the mechanical trauma of circulation

- Occlusion in microvascular circulation caused by distorted, inflexible RBCs adhering to vascular endothelium

SICKLE CELL ANEMIA - CLINICAL FEATURES

IN HOMOZYGOTES Onset in the first or second year of live Period episodes of acute vascular occlussion (painful crisis) Consequences of vaso-occlusion of the microcirculations

(tissue ischemia and infarction) - infarction of spleen, brain, marrow, kidney, lung, aseptic necrosis, central nervous system and ophtalmic vascular lesionsEvents which impair tissue oxygenation can precipitate crisis (f.e. pneumonia)

SICKLE CELL ANEMIA-THERAPY

Preventive measures:

prevention or remedy of: infections (penicillin prophylaxis and pneumococcal vaccination), fever, dehydratation,acidosis, hypoxemia, cold exposure

Blood transfusions for very severe anemia

New approaches to therapy;

1. Activation of Hb F synthesis - 5-azacytidine

2. Antisickling agents acting on hemoglobin or membrane

3. Bone marrow transplantation

2. ACQUIRED2. ACQUIRED

A. Immune hemolytic anemias A. Immune hemolytic anemias

1. 1. Autoimmune hemolytic Autoimmune hemolytic anemia anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. Alloimmune hemolytic anemia (transfusion of 2. Alloimmune hemolytic anemia (transfusion of incompatible incompatible blood)blood)

B. Nonimmune hemolytic anemias B. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria) 2. Bacterial infections, parasitic infections (malaria) 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma (e.g. microangiopathic hemolytic anemia) (e.g. microangiopathic hemolytic anemia)

4. Hypersplenism4. Hypersplenism

5. Paroxysmal nocturnal hemoglobinuria (PNH) 5. Paroxysmal nocturnal hemoglobinuria (PNH)

AUTOIMMUNE HEMOLYTIC ANEMIA - AUTOIMMUNE HEMOLYTIC ANEMIA - AIHAAIHA

caused by warm-reactive antibodies (70%)caused by warm-reactive antibodies (70%)

- infections, connective tissue disorders, drugs- infections, connective tissue disorders, drugs

caused by cold-reactive antibodies (30%) caused by cold-reactive antibodies (30%)

– – in temp. < 37 (4in temp. < 37 (4°°))

- infections, CLL, NHL- infections, CLL, NHL

Laboratory findings: Laboratory findings: direct Coombs testdirect Coombs test (direct (direct antiglobulin test)antiglobulin test)

Treatment: underlying disease, steroids, Treatment: underlying disease, steroids, immunosupresive immunosupresive

Avoid RBC transfusionsAvoid RBC transfusions

2. ACQUIRED2. ACQUIRED

A.A. Immune hemolytic anemias Immune hemolytic anemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies

2. 2. Alloimmune hemolytic anemiaAlloimmune hemolytic anemia

B. Nonimmune hemolytic anemias B. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria) 2. Bacterial infections, parasitic infections (malaria) 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma (e.g. microangiopathic hemolytic anemia) (e.g. microangiopathic hemolytic anemia) 4. Hypersplenism 4. Hypersplenism

5. Paroxysmal nocturnal hemoglobinuria (PNH) 5. Paroxysmal nocturnal hemoglobinuria (PNH)

ALLOIMMUNE HEMOLYTIC ALLOIMMUNE HEMOLYTIC ANEMIAANEMIA

Transfusion of incompatible bloodTransfusion of incompatible blood

Serologic incompatibilitySerologic incompatibility

After transplantation of bone marrow or organsAfter transplantation of bone marrow or organs

2. ACQUIRED2. ACQUIRED

A.A. Immune hemolytic anemias Immune hemolytic anemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. 2. Alloimmune hemolytic anemiaAlloimmune hemolytic anemia

B. Nonimmune hemolytic anemias B. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria) 2. Bacterial infections, parasitic infections (malaria) 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma

- microangiopathic hemolytic - microangiopathic hemolytic anemia anemia 4. Hypersplenism 4. Hypersplenism

5. Paroxysmal nocturnal hemoglobinuria (PNH) 5. Paroxysmal nocturnal hemoglobinuria (PNH)

CLASSIFICATION OF CLASSIFICATION OF MICROANGIOPATHIC HEMOLYTIC MICROANGIOPATHIC HEMOLYTIC ANEMIAANEMIA

Thrombotic thrombocytopenic Thrombotic thrombocytopenic purpura (TTP)purpura (TTP)

Hemolytic uremic syndrome Hemolytic uremic syndrome (HUS)(HUS)

MICROANGIOPATHIC HEMOLYTIC MICROANGIOPATHIC HEMOLYTIC ANEMIAANEMIA

Intravascular hemolysis caused by fragmentation of normal red cells passing through abnormal arterioles

Arterioles are changed by deposition of platelets and fibrin

Microvascular lesion cause organ demage (kidney, CNS)

MICROANGIOPATHIC MICROANGIOPATHIC HEMOLYTIC ANAEMIAHEMOLYTIC ANAEMIA

Underlying diseaseInvasive carcinomaComplication of pregnancySerious infectionDrugs

MICROANGIOPATHIC HEMOLYTIC MICROANGIOPATHIC HEMOLYTIC ANAEMIAANAEMIA

Symptoms: Related to the primary disease Related to organs demage

Laboratory findings

Blood film: schistocytes

2. ACQUIRED2. ACQUIRED

A.A. Immune hemolytic anemias Immune hemolytic anemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood 2. Transfusion of incompatible blood

B. Nonimmune hemolytic anemias B. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria) 2. Bacterial infections, parasitic infections (malaria) 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves - prosthetic heart valves

4. 4. HypersplenismHypersplenism 5. Paroxysmal nocturnal hemoglobinuria (PNH) 5. Paroxysmal nocturnal hemoglobinuria (PNH)

HYPERSPLENISM

State of hyperactivity of the spleen Causes of hypersplenism

Infection – bacterial, viruses, fungi Inflammatory diseases - Neoplasm Storage disorders (Gaucher disease) Other – amyloidosis, sarcoidosis

2. ACQUIRED2. ACQUIRED

A.A. Immune hemolytic anemias Immune hemolytic anemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood 2. Transfusion of incompatible blood

B. Nonimmune hemolytic anemias B. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria) 2. Bacterial infections, parasitic infections (malaria) 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves - prosthetic heart valves 4. 4. HypersplenismHypersplenism

5. 5. Paroxysmal nocturnal Paroxysmal nocturnal hemoglobinuria hemoglobinuria (PNH) (PNH)

PATHOGENESISPATHOGENESIS

- AN ACQUIRED CLONAL DISEASE, ARISING FROM A SOMATIC - AN ACQUIRED CLONAL DISEASE, ARISING FROM A SOMATIC MUTATION IN A SINGLE ABNORMAL STEM CELLMUTATION IN A SINGLE ABNORMAL STEM CELL - DEFICIENCY OF THE GPI (GLYCOSYL-PHOSPHATIDYL-- DEFICIENCY OF THE GPI (GLYCOSYL-PHOSPHATIDYL-INOSITOL) ANCHOR ON THE SURFACE OF HEMATOPOIETIC INOSITOL) ANCHOR ON THE SURFACE OF HEMATOPOIETIC CELLSCELLS

- RED CELLS ARE MORE SENSITIVE TO THE LYTIC EFFECT OF - RED CELLS ARE MORE SENSITIVE TO THE LYTIC EFFECT OF COMPLEMENT COMPLEMENT

- INTRAVASCULAR HEMOLYSIS - INTRAVASCULAR HEMOLYSIS

Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH)(PNH)

PAROXYSMAL NOCTURNAL PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)HEMOGLOBINURIA (PNH)

SymptomsSymptoms Irregularly hemoglobinuria occurs with dark Irregularly hemoglobinuria occurs with dark

brown urine in the morningbrown urine in the morning Hemolysis is released by infection, surgery or Hemolysis is released by infection, surgery or

other eventsother events

Increased risk of thrombosisIncreased risk of thrombosis Renal failureRenal failure Neurologic manifestation - headachesNeurologic manifestation - headaches

LABORATORY FEATURESLABORATORY FEATURES - HEMOGLOBINURIA- HEMOGLOBINURIA - HEMOSIDERINURIA - HEMOSIDERINURIA - PANCYTOPENIA - PANCYTOPENIA - CHRONIC URINARY IRON LOSS - CHRONIC URINARY IRON LOSS - SERUM IRON CONCENTRATION DECREASED - SERUM IRON CONCENTRATION DECREASED - POSITIVE HAM’S TEST (ACID HEMOLYSIS TEST) - POSITIVE HAM’S TEST (ACID HEMOLYSIS TEST) - SPECIFIC IMMUNOPHENOTYPE OF ERYTROCYTES - SPECIFIC IMMUNOPHENOTYPE OF ERYTROCYTES (CD59, (CD59, CD55)CD55)

Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH)(PNH)

TREATMENTTREATMENT

- WASHED RBC TRANSFUSION- WASHED RBC TRANSFUSION - IRON THERAPY - IRON THERAPY - ALLOGENIC BONE MARROW TRANSPLANTATION - ALLOGENIC BONE MARROW TRANSPLANTATION

MONOCLONAL ANTIBODY MONOCLONAL ANTIBODY ECULIZUMAB (TRADE NAME SOLIRIS)

Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH)(PNH)

WHAT DO YOU HAVE TO REMEMBER

Anemia +

1.Retikulocytosis

2. bilirubin (unconjugated), LDH

3. haptoglobin

4.Haemoglobin and haemosiderin in urine