Chapter 17 hematology

TYPES OF MEMBRANE DEFECTS

DEFECTS DUE TO ABNORMALITIES IN MEMBRANE PROTEINS OR LIPIDS

• DEFECTS ALTER MEMBRANE’S STABILITY, SHAPE, DEFORMABILITY AND

PERMEABILITY

SKELETAL PROTEIN ABNORMALITIES (ERYTHROCYTE SKELETON)

◦ VERTICAL

SEPARATING OF LIPID BILAYER FROM SKELETAL LATTICE

 RESULT IN DECREASE IN SURFACE AREA-TO-VOLUME RATIO.. SPHEROCYTE

SKELETAL PROTEIN ABNORMALITIES (ERYTHROCYTE SKELETON)

HORIZONTAL

DISRUPTION OF SKELETAL LATTICE

 MEMBRANE DESTABILIZES

 CELL FRAGMENTATION.. POIKILOCYTOSIS

LIPID COMPOSITION ABNORMALITIES

EXCESS CHOLESTEROL ACCUMULATES IN THE OUTER BILAYER OF THE RBC

◦ ACANTHOCYTE

CONDITIONS ASSOCIATED WITH MEMBRANE

DEFECTS

HEREDITARY SPHEROCYTOSIS

◦ HEREDITARY ELLIPTOCYTOCYTOSIS

◦ HEREDITARY PYROPOIKILOCYTOSIS

◦ OVERHYDRATED AND DEHYDRATED HEREDITARY STOMATOCYTOSIS

◦ MEMBRANE LIPID DISORDERS

◦ PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Hereditary spherocytosis (HS)

Defect in ankyrin & spectrin

◦ Results in the formation of fragile spherocytic red

cells.

◦ Spherocyte becomes less flexible and more

permeable to Na+

◦ Tends to affect Northern Europeans

◦ Inherited

HEREDITARY SPHEROCYTOSIS

CLINICAL FINDINGS

VARIES IN SEVERITY

• COMPENSATED HEMOLYTIC DISEASE

• ANEMIA- VARIES WITH SEVERITY

• INTERMITTENT JAUNDICE

• SPLENOMEGALY

• CHOLELITHIASIS: PIGMENT BILE STONES FROM INCREASED BILIRUBIN

BREAKDOWN

HEREDITARY SPHEROCYTOSIS

LAB FEATURES

• CBC

MILD ANEMIA

• MCV IS USUALLY NORMAL (77-87FL)

• MCH NORMAL

• MCHC IS >36% (THIS IS THE ONLY CONDITION IN WHICH AN MCHC CAN BE TRULY

INCREASED.)

• RDW INCREASED

HEREDITARY SPHEROCYTOSIS

LAB FEATURES

Rbc morphology

SPHEROCYTE

• VARYING DEGREES OF POLYCHROMASIA, ANISOCYTOSIS AND POIKILOCYTOSIS

HEREDITARY SPHEROCYTOSIS

LAB FEATURES

 BONE MARROW

NORMOBLASTIC ERYTHROID HYPERPLASIA

 INCREASED IRON STORAGE

HEREDITARY SPHEROCYTOSIS

LAB FEATURES

chemistry and immunahematology

CHEMISTRY

 INCREASED

 BILIRUBIN

 FECAL UROBILINOGEN

 LD/LDH

 DECREASED

 HAPTOGLOBIN

 IMMUNOHEMATOLOGY

 DAT NEGATIVE

DIAGNOSTIC TESTS FOR HS

OSMOTIC FRAGILITY - INCREASED

• CELLS ARE INCUBATED IN DECREASING CONCENTRATIONS OF NACL.

SPHEROCYTES LYSE SOONER THAN NORMAL RED CELLS.

• AUTOHEMOLYSIS TEST

• RED CELLS ARE INCUBATED AT 37̊ C FOR 48 HOURS. DEGREE OF

HEMOLYSIS IS INCREASED WHEN SPHEROCYTES ARE PRESENT.

• RED CELL MEMBRANE STUDIES

• MEMBRANE PROTEINS ARE ANALYZED USING GEL ELECTROPHORESIS.

TREATMENT OF HS

SPLENECTOMY

• CAN CORRECTS FOR THE ANEMIA, BUT THE

MEMBRANE DEFECT REMAINS

• HELPS BY KEEPING THE SPHEROCYTES IN

CIRCULATION LONGER AND THE DEFECTS FROM THE

MEMBRANES FROM BEING REMOVED CREATING THE

SPHEROCYTES IN THE FIRST PLACE

HEREDITARY ELLIPTOCYTOSIS

A DEFECT OF ONE OF THE SKELETAL PROTEINS

• RESULTS IN THE FORMATION OF FRAGILE

ELLIPTOCYTIC RED CELLS THAT ARE SENSITIVE TO

MECHANICAL STRESS.

• MORE PERMEABLE TO NA+

• INCREASED SENSITIVITY TO HEAT

• FOUND COMMONLY IN AFRICA AND THE

MEDITERRANEAN

HEREDITARY ELLIPTOCYTOSIS

CLINICAL FINDINGS

HEMOLYSIS NOT EVIDENT

• ANEMIA NOT CHARACTERISTIC

• USUALLY IDENTIFIED BY THE PRESENCE OF LARGE NUMBERS OF

ELLIPTOCYTES IN THE PERIPHERAL BLOOD SMEAR.

HEREDITARY ELLIPTOCYTOSIS

LAB FEATURES

CBC

Mild anemia

Hgb level increased

RBC morphology

Elliptocytes or ovalocytes

TREATMENT OF HE

TREATMENT IS USUALLY NOT NECESSARY, BUT IF PATIENTS HAVE

HEMOLYSIS, SPLENECTOMY IS BENEFICIAL.

• CONDITION IS NOT FATAL

• MILD DISEASE

HEREDITARY PYROPOIKILOCYTOSIS (HPP)

SEVERE SUBTYPE OF HE

• DEFICIENCY OF Α-SPECTRIN AND A MUTANT

SPECTRIN LEADS TO DISRUPTION OF SKELETAL

LATTICE AND CELL DESTABILIZATION

• CELLS FRAGMENT WHEN HEATED

• TENDS TO AFFECT PATIENTS OF AFRICAN DECENT

• PRESENTS IN INFANCY OR EARLY CHILDHOOD

HEREDITARY PYROPOIKILOCYTOSIS

CLINICAL FINDINGS

HYPERBILIRUBINEMIA

HEREDITARY PYROPOIKILOCYTOSIS

LAB FEATURES

CBC

• MCV DECREASED (25-55 FL)

• RBC MORPHOLOGY

• EXTREME ERYTHROCYTE MORPHOLOGIES

• FRAGMENTS, ELLIPTOCYTES,

TRIANGULOCYTES ETC

TREATMENT OF HPP

SPLENECTOMY

• PATIENTS SHOW IMPROVEMENT AFTER SPLENECTOMY

• MEMBRANE DEFECTS STILL REMAIN AND ELLIPTOCYTES ARE STILL PRESENT IN THE

PERIPHERAL BLOOD

HEREDITARY STOMATOCYTOSIS SYNDROMES

OVERHYDRATED HEREDITARY STOMATOCYTOSIS (OHS)

• PERMEABLE TO NA+ AND K+, CELL TAKES ON WATER

• CELLS RESEMBLE STOMATOCYTES

• DEHYDRATED HEREDITARY STOMATOCYTOSIS (DHS)

• WATER CONTENT DECREASED CAUSING CELL DEHYDRATION

SO CELLS LOOK LIKE TARGETS

• NO TREATMENT REQUIRED

HEREDITARY STOMATOCYTOSIS SYNDROMES lab features

ANEMIA IS MILD TO MODERATE

• INCREASED BILIRUBIN

• MCV INCREASED

• STOMATOCYTES: OHS (OVERHYDRATED HEREDITARY STOMATOCYTOSIS)

• TARGET CELLS: DHS (DEHYDRATED HEREDITARY STOMATOCYTOSIS)

MEMBRANE LIPID DISORDERS

RBCS CAN ACQUIRE LIPIDS WHEN PLASMA LIPID

INCREASE

 RESULTS IN EXPANSION OF MEMBRANE AND FORMATION

OF ABNORMAL SHAPES

 ACANTHOCYTOSIS

 SPUR CELL ANEMIA

 ABETALIPOPROTEINEMIA

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

ACQUIRED INTRAVASCULAR HEMOLYTIC ANEMIA

CHARACTERIZED BY INTERMITTENT (PAROXYSMAL) SLEEP-

ASSOCIATED (NOCTURNAL) BLOOD IN THE URINE

(HEMOGLOBINUREA).

• ONSET IS GRADUAL OCCURRING MOSTLY IN YOUNG

ADULTHOOD OF EITHER GENDER.

• STRONGLY ASSOCIATED WITH APLASTIC ANEMIA

PNH

CLINICAL FEATURES

Hemoglobinurea in first morning specimen

Hemosidinurea

Chronic anemia

Infections

Thrombosis

5-10% of cases will convert to acute myelogenous

leukemia; 25% will convert to aplastic anemia.

LAB FEATURES: PNH

HAPTOGLOBIN: DECREASED

• HGB: 8-10 G/DL

• LEUKOPENIA

• THROMBOCYTOPENIA

• PERIPHERAL BLOOD

• NORMOCYTIC OR MACROCYTIC

• IF IDA DEVELOPS: HYPOCHROMIC, MICROCYTIC

• NRBCS

DIAGNOSTIC LABORATORY TESTS

SCREENING TEST: SUGAR WATER TEST

CONFIRMATION TEST: HAM’S TEST (ACIDIFIED SERUM LYSIS TEST

flow cytometry

SCREENING TEST: SUGAR WATER TEST

BLOOD IS INCUBATED IN A SOLUTION OF SUGAR WATER. THE LOW IONIC STRENGTH OF THE

SOLUTION ACTIVATES COMPLEMENT AND PNH CELLS ARE LYSED.

CONFIRMATION TEST: HAM’S TEST (ACIDIFIED SERUM LYSIS TEST)

PNH CELLS INCUBATED IN ACIDIFIED SERUM WILL LYSE WHEREAS NORMAL CELLS WILL NOT LYSE.

IN ORDER TO BE CALLED POSITIVE, TWO CONDITIONS MUST BE MET: 1) HEMOLYSIS OCCURS WITH

THE PATIENT’S CELLS AND NOT WITH NORMAL CELLS, 2) HEMOLYSIS IS ENHANCED BY ACIDIFIED

SERUM AND DOES NOT OCCUR WITH HEAT ACTIVATED SERUM IN WHICH COMPLEMENT HAS BEEN

DESTROYED.

FLOW CYTOMETRY

MORE SENSITIVE AND SPECIFIC THAN ABOVE TESTS

• IMMUNOPHENOTYPE OF RBC

anemia therapy

IRON THERAPY OR TRANSFUSION IF SEVERE ENOUGH

HEMOLYTIC EPISODES therapy

CORTICOSTEROID THERAPY TO STIMULATE

ERYTHROPOIESIS

THROMBOSES therapy

ANTICOAGULANT THERAPY

BONE MARROW TRANSPLANT IF

APLASIA EXISTS

• PATIENT YOUNGER THAN 50