RED BLOOD CELL DISORDERS III

By: Dr Abiodun Mark Akanmode MD.

HEMOGLOBINOPATHIES

Genetically determined abnormal hemoglobin synthesis and function.

HbS most common in United States followed by HbC and HbE

SICKLE CELL ANEMIA

Most common familial hemolytic anemia in the world

In malaria endemic parts of Africa - 30% ( protective effect against Plasmodium falciparum)

In United States, 8% blacks are heterozygous for HbS, and 1 in 600 have sickle cell anemia

SICKLE CELL ANEMIA

Autosomal recessive disorder

Intrinsic defect with predominantly extravascular hemolysis, mild intravascular hemolysis

In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced

MOTHER & FATHER HAVE SICKLE CELL TRAIT

Normal child 25%

Sickle cell trait 50%

Sickle cell disease 25%

FACTORS AFFECTING SICKLING

Intracellular concentration of HbS >60% is the most important cause of sickling No sickling in heterozygotes with sickle cell trait (HbS

< 50%)

Presence of other hemoglobins: ↓ with HbA/HbF, ↑ with HbC

↑ concentration of deoxy Hb: Red cell dehydration, Acidosis, Hypoxemia

MORPHOLOGY IN HOMOZYGOUS SICKLE CELL DISEASE (HBSS)

In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells

CONSEQUENCES OF SICKLING IN HOMOZYGOUS SICKLE CELL DISEASE

Severe hemolytic anemia - life span of RBC only 20 days

Microvascular obstructions (Vaso-occlusive crises)

↑ transit time for red cells through the microvasculature (sluggish blood flow in spleen and bone marrow)

↑ expression of adhesion molecules on sickled cells

Inflammation increases adhesion of RBC/WBCs to endothelium

Repeated sickling damages RBC membrane, make them adhere to endothelium

FETAL HEMOGLOBIN (HBF)

↑ HbF at birth prevents sickling in HbSS till 5-6 months of age

Hydroxyurea increases synthesis of HbF

HbF has high affinity for oxygen, prevents sickling

HOMOZYGOUS SICKLE CELL DISEASE

Anemia and vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules

Compensatory hyperplasia of erythroid progenitors in marrow

Bone resorption and secondary new bone formation, resulting in prominent cheekbones and “crewcut” skull

Extramedullary hematopoiesis in liver and spleen

HOMOZYGOUS SICKLE CELL DISEASE In children - moderate splenomegaly, over time hypoxic

damage leads to auto-splenectomy by adulthood

“Autoinfarcted” splenic remnant in sickle cell disease

HOMOZYGOUS SICKLE CELL DISEASE Vascular congestion, thrombosis, and infarction in bones, liver,

kidney, retina, brain, lung, and skin Dactylitis (hand-foot syndrome): painful swelling due to

infarctions in metacarpal bones (aseptic necrosis), mostly infants

Renal papillary necrosis in kidney

HOMOZYGOUS SICKLE CELL DISEASE Hemosiderosis and Pigment Gallstones (calcium

bilirubinate)

Recurrent leg ulcers: commonly around malleoli

Avascular necrosis of femoral head

Proliferative retinopathy → blindness

End-stage renal failure after 40 years of age

Priapism: leading to penile fibrosis and erectile dysfunction

HOMOZYGOUS SICKLE CELL DISEASE

Acute Chest Syndrome Common cause of death in young adults Vaso-occlusion in pulmonary microcirculation Presents with chest pain, dyspnea and lung infiltrates Precipitated by pneumonia, bone infarct with fat embolism

Stroke Common cause of death in children (2-5 yrs) Recurrence rate 70%

HOMOZYGOUS SICKLE CELL DISEASE

Aplastic crisis (associated mostly with parvovirus; no reticulocytes in peripheral blood)

Sequestration crisis (Rapid splenic enlargement with entrapment of sickled RBCs and blood, Reticulocytosis present )

Prone to infections (S. pneumoniae)

Salmonella osteomyelitis

RENAL FINDINGS IN SICKLE CELL TRAIT

Sickling happens in peritubular capillaries in medulla Oxygen tension low enough to cause sickling even with trait

Microhematuria

Renal papillary necrosis

DIAGNOSIS

In homozygous sickle cell disease - irreversibly sickled red cells seen in routine peripheral blood smears

In sickle cell trait - sickling can be induced in vitro by exposing cells to marked hypoxia (Sodium metabisulphite)

TREATMENT Penicillin prophylaxis to prevent pneumococcal

infections

Pneumococcal vaccine, Folic Acid supplementation

Hydroxyurea reduces pain crises and lessens anemia (1) Increases red cell levels of HbF (2) Anti-inflammatory effect due to inhibition of WBC

production (3) Increases red cell size, lowers MCHC (4) Metabolizes to NO (potent vasodilator /inhibits platelet

aggregation)

Allogeneic bone marrow transplantation

APLASTIC ANEMIA. Aplastic anemia is characterized by chronic primary

hematopoietic failure and pancytopenia.

The causes of aplastic anemia includes the following:

-Idiopathic causes.-Chemical agents: carbamazepine, chloraphenicol, gold salts.-Physical agents: full body radiation.-Viral infections: EBV,CMV.-Inherited syndromes: fanconi anemia, telomerase defects.

PURE RED CELL APLASIA.

Pure red aplasia is another marrow disorder in which erythroid progenitors are suppressed.

Its associated with B19 infection.

Pure red aplasia may also seen in neoplastic conditions like thymomas.

IMMUNOHEMOLYTIC ANEMIAS(IHA)

Group of extrinsic hemolytic anemia's with extravascular or intravascular hemolysis.

Antibodies may arise spontaneously or be induced by exogenous agents (drugs/ chemicals)

CLASSIFICATION OF IMMUNOHEMOLYTIC ANEMIA'S

Autoimmune hemolytic anemia(AIHA):-Most common type of IHA.-W>M.-AIHA is either warm or cold type.

Drug induced IHA:penicillins,2/3rd generation cephalosporin's.

Alloimmune hemolytic anemia: ABO & Rh hemolytic disease of newborn.

AUTOIMMUNE HEMOLYTIC ANEMIA. Warm Antibody Type (70%)

Primary (idiopathic) Secondary:

B cell neoplasms (e.g., chronic lymphocytic leukemia),

Autoimmune disorders (e.g., systemic lupus erythematosus),

Drugs(e.g., α-methyldopa, penicillin, quinidine) Cold Antibody Type (30%)

Acute: Mycoplasma infection, infectious mononucleosis

Chronic: Idiopathic, B cell lymphoid neoplasms (e.g., lymphoplasmacytic lymphoma)

WARM ANTIBODY IMMUNOHEMOLYTIC ANEMIA'S

Most common immune hemolytic anemia, caused by immunoglobulin G (IgG) active at 37°C

> 60% cases are idiopathic

Opsonization of RBCs by autoantibodies leading to erythrophagocytosis in spleen and elsewhere (Extravascular)

WARM ANTIBODY IMMUNOHEMOLYTIC ANEMIAS

Incomplete consumption (“nibbling”) of antibody-coated red cells by macrophages leads to spherocytes

Positive Direct Coombs test / DAT ( Direct AntiGlobin Test)

COLD ANTIBODY IMMUNOHEMOLYTIC ANEMIA'S

Low-affinity IgM antibodies that bind to RBC membranes only at temperatures < 30°C

Mediated by antibodies to blood group antigen I or i anti – I antibodies seen in Mycoplasma pneumoniae anti – i antibodies are associated with EBV infection

RBCs are phagocytosed by macrophages, mainly in spleen and liver (extravascular hemolysis)

Sludging of blood in capillaries due to agglutination often produces Raynaud phenomenon

AUTOIMMUNE HEMOLYTIC ANEMIAS

HEMOLYTIC DISEASE OF THE NEWBORN(ERYTHROBLASTOSIS FETALIS)

Maternal antibodies cross the placenta and react with fetal red cells causing hemolysis of fetal RBCs

Rh Incompatibility: maternal allo-immunization to fetal red cell antigens (D antigen of Rh blood group)

No problems during first pregnancy, but anti-Rh antibodies may cause problems in subsequent pregnancies

ABO Incompatibility – mostly mother is group O and the fetus is either group A or B ( milder than Rh incompatibility)

HEMOLYTIC DISEASE OF THE NEWBORN(ERYTHROBLASTOSIS FETALIS)

Kernicterus: staining of basal ganglia and other CNS structures by unconjugated bilirubin

Still birth

Hydrops fetalis – fetal heart failure with massive generalized edema

HEMOLYTIC ANEMIA'S RESULTING FROM MECHANICAL TRAUMA TO RED CELLS

Macroangiopathic hemolytic anemiaMechanical hemolysis from Aortic Stenosis, Defective cardiac valve prostheses (“the blender effect”)

Microangiopathic hemolytic anemia DIC Malignant Hypertension Systemic Lupus Erythematosus Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome Disseminated Cancer

MICROANGIOPATHIC HEMOLYTIC ANEMIA

MALARIA Plasmodium falciparum, malariae, vivax and

ovale

Transmitted by the bite of female Anopheles mosquitoes

Humans are the only natural reservoir

The parasites destroy large numbers of infected red cells, thereby causing a hemolytic anemia

Massive splenomegaly and occasional hepatomegaly

CEREBRAL MALARIA

Infection of RBCs with P. falciparum induces positively charged surface knobs which bind to adhesion molecules on activated endothelium

Trapping of RBCs in post-capillary venules, especially cerebral vessels in children

Rapidly progressive; convulsions, coma, and death usually occur within days to weeks

BLACKWATER FEVER

Massive intravascular hemolysis

Hemoglobinemia

Hemoglobinuria

Jaundice