Sickle cell anemia

Hemolytic anemia

Sickle cell anemia Hereditary HA Hb disorder (Hemoglobinopathy) Abnormal HbS is common in Africa, India and

among the Blacks in US Rare in Caucasian and Asian races The onset: early in infancy (HbS replace HbF)

death occurred during early adult life Improvements in management pts survive

longer Two phenotypes:1.Sickle cell trait – heterozygous (A/S) vs 2.Sickle cell ds. – homozygous (S/S)

Normal: HbA A single point mutation in

beta-chain Codon 6 (GAGGTG =

Glutamic acid to Valine) HbS

Tendency to polymerization, yielding semisolid crystalline structures TACTOIDs

TACTOIDs:1- Hb solubility 2- Change RBC shape3- Deformability of RBC

Pathology

Clinical features:① Chronic extravascular hemolysis② Severe anemia③ Growth retardation (common)④ Mild hemolytic jaundice – absent urinary

bilirubin & fecal & urinary urobilinogen⑤ Bone marrow: normoblastic hyperplasia –

leading to expansion of the marrow cavity in bones an causing bony deformities (tower skull and hair-on-end appearance on skull x-rays)

⑥ Chronic leg ulcers – unknown pathogenesis

Frontal BossingFrontal Bossing

X-ray: ‘Hair-on-end’ X-ray: ‘Hair-on-end’ skullskull

Chronic leg ulcerChronic leg ulcer

Diagnosis:

1.Peripheral blood smear – sickle cells

Normal RBC Sickle cells

2. Hb electrophoresis –

Identification & quantification of HbS (80% Hbs, absence of HbA; HbF & HbA2 variably increased)

3. Molecular techniques –

• Mutation detection in the gene causing SC condition (supplementary test)

• Single mutation in β-globin gene

• DNA probe - limited to prenatal diagnosis

Complications:1. Aplastic crisis – sudden failure of hematopoeisis in BM

2. Hemolytic crisis – unknown cause, characterized by a sudden hemolysis

3. Hemosiderosis & secondary hemosiderosis – common in long-term survivor, stimulation iron absorption in the intestine due to chronic erythroid hyperplasia & blood transfusions

4. Vaso-occlusive crisis – plugging of microcirculation (aggregates of sickle cells)

5. Splenic changes: Early childhood – slightly enlarged due to RE hyperplasia Adults – SC ds. shrunken & contain *Gamna-Gandy bodies,

systemic infection by encapsulated bacteria (Pneumococcal bacterimia & Salmonella osteomyelitis

- SC trait without symptom*Gamna Gandy nodules/ siderotic nodules/ fibrosiderotic nodules

An enlarged spleen due to splenic sequestration crisis in a patient with sickle anemia

Sickle cells are seen in splenic red pulp in a case of splenic sequestration crisis.

Kidney: Hemosidrin deposit

LIVER: HEMOSIDEROSIS

Hemosiderin deposits

Alloimmune/ Isoimmune:

1) Hemolytic Transfusion Reaction 2) Hemolytic Disease of the Newborn

Hemolytic anemia

RBCs are lysed as a result of the action of antibodies of another individual

Hemolytic Transfusion Anemia Transfusion if incompatible blood – ABO incompatibility, rarely due to other

blood gp.

Typically cause acute hemolytic reaction

Severe form – produce intravascular hemolysis, occurs within minutes to hours shock death

Less severe – produce extravascular hemolysis delayed hemolytic reaction

The transfused (donor) RBCs are destroyed by antibody present in the recipient’s plasma

ABO hemolytic transfusion reaction avoided by ABO grouping

Hemolytic Disease of the Newborn Clinically significant caused by Rh incompatibility, rarely due to ABO incimpatibility Rh system is complex – consists of 3 pairs of alleles (D, d, C, c, E, e), produces

variety of phenotypes Allele D is the strongest antigen, routinely tested Rh +ve or Rh –ve: to denote the presence or absence of D antigen Anti-Rh antibodies: Rh –ve doesn’t have natural anti-Rh antibodies, may develop immune anti-Rh

antibodies (IgG) if RBC with Rh+ve enter the circulation (blood transfusion or pregnancy)

Effect on fetus: Intrauterine death or hemolytic ds of newborn Prevention: Accurate Rh typing Administration of high dose of Rh antibody (Rogham) to an Rh-ve woman during

childbirth or abortion Avoid sensitizing Rh-ve women

Hemostatic

disorders

Normal vascular system1. Blood vessels – vasoconstriction2. Platelets – form hemostatic plug &

permanent thrombus3. Blood coagulation4. Fibrinolysis

Disturbance of any one of these mechanism may produce abN bleeding or abN thrombus

Clinical effects are similar regardless of the mechanism

Vascular defects The most common cause of bleeding

diathesis Certain vascular disorder: abN collagen

or elastin Henoch-Schönlein purpura Hereditary hemorrhagic telangiectasia

Henoch-Schönlein purpura

Poststreptococcal ds in childhood Occurs1-3 weeks after streptococcal

infection Mediated by deposition of cross-reaction

IgA or immune complexes + complement on the endothelial

Clinical features: Purpura, abdominal pain, arthralgia/ arthritis, glomerulonephritis, fever

Prognosis - based on renal lesion

Hereditary hemorrhagic telangiectasia

Hereditary: autosomal dominant trait Manifested by multiple capillary

microaneurysms in the skin & mucous membranes

Lesions – become more conspicious with age & fragile

Predisposing to episodes of acute severe bleeding & chronic blood loss from the intestinal tract

Results in Iron def. Anemia

Platelets Anuclated cytoplasmic fragments Derived from megakaryocytes Normal count = 150,000 – 400,000/μL Peripheral blood smear: small granular cytoplasmic

fragment, ¼RBC size Main function: HEMOSTASIS Abnormalities:1. Thrombocytopenia ()2. Thrombocytosis ()3. AbN platelet fx.

Idiopathic Thrombocytopenic Purpura (ITP)

Severe reduction of platelet no. Caused by immune destruction of platelets Pathology: Platelet survival is impaired Platelet count is markedly BM – increased megakaryocytes Spleen – major sites of destruction of antibody-coated

platelets Bleeding time is prolonged & capillary fragility Test of coagulations are N

Acute ITP: Mainly seen in children 50% of the cases assoc. with history of viral inf.

2-3 weeks before infection Immune complexes bind to the surface of

platelet Phagocytosis by splenic macrophages Spontaneous recovery in the majority of pts,

80% are normal after 6 months

Chronic ITP: Mainly in adults With a predilection for female (3:1) Frequent relapse occurrence during pregnancy Thrombocytopenia due to peripheral destruction of platelets IgG antiplatelet autoantibody on the platelet surfaces Multiple relapses & remissions Neonatal TP: Occurs in children born to mothers with chronic

ITP Transfer of the IgG antibodies across the

placenta

Clinical features & Treatment: Bleeding tendency Purpura Bleeding from mucosal surface – hematuria,

melena, menorrhagia & hemoptysis Treatment with dose corticosteroids –suppress

splenic phagocytic activity Splenectomy – removal of main site of platelet

destruction

Disorder of blood coagulation

Etiology: Def. of coagulation factors Presence of circulating anticoagulants Fibrinolytic activity

Clinical features: Tend to bleed excessively Severe cases: spontaneous bleeding Usual bleeding & persistent

Factor VIII Def. Factor VIII coagulant (VIII:c) – critical component

of intrinsic coagulation pathway aka as antihemophilic globulin def. Factor VIII:c – measured by bioassay or

immunoassay Hemophilia A Von Willebrand’s ds.

Hemophilia A Inherited as X-linked recessive trait Mainly in males Female: both abN gene on X-chromosome (homozygous) Pts has less than 1% factor VIII coagulant activity Spontaneous bleeding Partial Thromboplastin Time (PTT) test is prolonged Significant factors VIII activity Treatments: maintain plasma factor VIII activity,

cryopercipitate (lyophilized factor VIII concentrate pooled from plasma of large number of blood donors)

Von Willebrand’s Ds. Autosomal dominant Def. of entire circulating factor VIII complex Both factor VIII & Von Willebrand factor to the

same extent Clinically, pts show bleeding after minor trauma Onset symptoms is in childhood, but may with

age Common sites of bleeding: skin (easy bruising)

& mucous membrane (epistaxis) Dx: Prolonged PTT, factor VIII coagulant

activity, Von Willebrand factor, Prolonged bleeding time

Factor IX Def. Christmas ds; Hemophilia B Uncommon Results from def. of factor IX X-linked recessive Greater prevalence in males Clinical picture – identical to hemophilia A Dx is made when factor VIII activity is N Plasma factor IX assay – greatly Treatment: Fresh plasma or factor IX

concentrate