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HU Hcmalology Toronto Notes 2023

Lymphopenia

Definition

• absolute lymphocyte count <1.0 x 1071-

Etiology

• older age

• idiopathicCD4+ lymphopenia

• iatrogenic (radiation, chemotherapy, immunosuppressive agents)

. H1V/A1DS, HBV, HCV

• malignancy

• malnutrition, alcoholism

• autoimmune disease (e.g.SLE)

Clinical Features

• opportunistic infections (see Infectious Diseases)

Investigations

• CBC and differential, lymphocyte subpopulations, immunoglobulin levels

Treatment

• treat underlying cause

• treat opportunistic infections aggressively and consider antimicrobial prophylaxis (see Infectious

Diseases, ID48)

Eosinophilia

Definition

• absolute eosinophil count >0.5 x 107L

Etiology 6 • primary: due to clonal BM disorder

if no primary etiology identified, classified as hypereosinophilic syndrome

6 mo of eosinophilia (count >1.5 x 107L) with end organ damage and no other detectable causes

can involve heart,BM, and CNS

Basophilia and/or Eosinophilia

Can be an indicator of CMl or other

MPNs. associated with pruritus due to

excessive histamine production

• secondary’

most common causes are parasitic (usually helminth) infections and allergic reactions

less common causes:

collagen vascular diseases (e.g. RA, polyarteritis nodosa,see Rheumatology, RH21)

respiratory causes (asthma, eosinophilic pneumonia, and eosinophilic granulomatosis with

polyangiitis (EGPA))

cholesterol emboli

hematologic malignancy, seeChronic Myeloid Leukemia,H42and Hodgkin Lymphoma,H47

adrenocortical insufficiency,see Endocrinology. E39

medications (penicillins)

atopic dermatitis

Investigations

• CBC and differential, peripheralsmear assessing eosinophil morphology

• end organ involvement:electrolytes,renal function tests,LET'

S, creatine kinase (CK), troponin, ECG,

pulmonary function tests (PETs),CXR, chest and abdominal CT, consider BM biopsy

Treatment

• treat underlying cause

• before initiating steroids, ensure strongyloidesserology is collected to rule out infection for patients at risk

Agranulocytosis

Definition

• ANC is <100/pL

Etiology

• associated with medications in 70% of cases: e.g. chemotherapy, clozapine, thionamides(antithyroid

drugs),sulfasalazine, and tidopidine

immune-mediated destruction of circulating granulocytes by drug-induced Abs or direct toxic effects

upon marrow granulocytic precursors

Clinical Features

• abrupt onset of fever, chills, weakness, and oropharyngeal ulcers

Prognosis

• high fatality without vigorous treatment

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H12 Hematology Toronto Notes 2023

Investigations/Treatment

• discontinue offending drug

• if patient is febrile, pan-culture and screen for infection (blood cultures x2, urine culture, and chest x-ray

as minimum, initiate broad-spectrum antibiotics)

• consider BM aspirate and biopsy If cause unclear

• consider G-CSF

Leukemoid Reaction

Definition

• leukocytosis >50 x 10’

/L

Etiology

• infection

• drugs

• asplenia

• intoxication

• malignancy

• hemorrhage

• acute hemolysis

Investigations/Treatment

• marked left shift (myelocytes, metamyelocytes, and bands in peripheral blood smear)

• rule out CML and chronic neutrophilic leukemia

• detect and treat underlying cause

Approach to Lymphadenopathy a

History

• constitutional/B-symptoms (seen in TB, lymphoma, other malignancies)

• growth pattern: acute vs. chronic

• exposures: cats (cat scratch - Bartonella henselae),ticks (Lyme disease - Borrelia burgdorferi ),and

high-risk behaviours (HIV)

• joint pain/swelling, rashes (connective tissue disorder)

• pruritus(seen in Hodgkin lymphoma)

• medications (can cause serum sickness -> lymphadenopathy)

ConstitutionaUB-Symptoms

• Unexplained temperature >38"C

• Unexplained weight loss(>10% of

body weight in 6 mo)

• Night sweats Clinical Features

• determine if lymphadenopathy is localized or generalized

• generalized:typically features ofsystemic diseases(HIV,TB, EBV,SLE, medications,sarcoidosis,

lymphoma)

• localized:typically reactive or neoplastic

cervical (bacterial/mycobacterial infections,ENT malignancies, and metastatic cancer)

• supraclavicular (highest malignancy risk)

right (mediastinal, bronchogenic, esophageal cancer)

left (gastric, gallbladder, pancreas, renal, and testicular/ovarian cancer)

axillary (cat scratch fever, breast cancer, and metastatic cancer)

• epitrochlear (infections,sarcoidosis, and lymphoma)

• check for splenomegaly, constitutional symptoms

Drugs that can Cause

Lymphadenopathy

• Allopurinol

• Atenolol

• Captopril

• Carbamazepine

• Cephalosporins

- Gold

• Hydralazine

• Penicillin

. Phenytoln

• Primidone

. Pyrimethamine

• Ouinidlne

• Sulfonamides

• Sulindac

Investigations

•

(.BC and differential, blood film

• if generalized, consider tuberculin test, HIV UNA, VDRL, MonospotVEBV serology, antinuclear

antibodies (ANA), and imaging

• if localized and no symptomssuggestive of malignancy, can observe 3-4 wk (if no resolution >

excisional biopsy to preserve lymph node architecture)

• in areas difficult to access (retroperitoneal, mediastinal/hilar), multiple core biopsies may be more

practical/feasible

• FNA should NOT be used for diagnostic purposes in lymphoproliferative disease (excisional biopsy is

the gold standard)

FNA is helpful for recurrence ofsolid tumour malignancy

Table 7. Inflammatory vs. Neoplastic Lymph Nodes n

L J

Feature Inflammatory Neoplastic

Consistency

Mobility

Tenderness

flucluanl/sofl

Mobile

Firm/hard

Matted/immobile

lender +

<1cm’

Non-lender

Size »1cm*

Note:these classifications are not absolute;lymphoma andCLL nodescan leel rubbery and are frequently mobile,non-lender

'Note:inguinal lympli nodescan be up to 2 cm in size and non-pathologic

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1113 Hematology Toronto Notes 2023

Table 8. Differential Diagnosis of Generalized Lymphadenopathy

Reactive Inflammatory Neoplastic

Bacterial (TB, Lyme, brucellosis,catscratch

disease, and syphilis)

Viral (EBV.CMV, HIV )

Parasitic (toxoplasmosis)

Fungal (histoplasmosis)

Collagen disease (DA.dermatomyositis.SLE, Lymphoproliterative disorder

vasculitis, and Sjogren's)

Drug hypersensitivity

Sarcoidosis, amyloidosis

Serum sickness

Metastatic cancer

Histiocytosis X

Approach to Splenomegaly

Table 9. Differential Diagnosis of Splenomegaly

Increased Demand for Splenic Function Congestive Infiltrative Causes of Splenomegaly

Hematological

Nutritional anemias

Hemoglobinopathies

Hemolysis

Spherocytosis

Sequestration crisis

Elliptocytosis

Infectious

Viral e.g.EBV, HIV/

AIDS.CMV

Bacterial

e.g.bacterial

endocarditis.TB

Parasilrc e.g.malaria,

histoplasmosis,

leishmaniasis

Fungal

Inflammatory Cirrhosis

Portal H1N

Portal vein obstruction

Hon -Malignant

Benign metaplasia

Cysts

Amyloidosis

Sarcoidosis

Splenic vein thrombosis Hamartomas

Vascular abnormalities

Lysosomal storage diseases

(Gaucher's, Niemann - Pickj

Glycogen storage diseases

Malignant

leukemia [CML.CUI

CHINA

Cirrhosis/Congestion (portal HTN)

Hematological

Infectious

Neoplasm

Autoimmune

SIE

Sarcoidosis

Felty syndrome

Still’s disease

(including right heart

failure)

lymphoptolileralive disease (Ctt, NHL.'HL)

MPHs (CMl. Mf )

Metastatic tumour

The underlined conditions cause massive splenomegaly (spleen crosses midline or reaches pelvis)

History

• constitutional/B symptoms, feeling of fullness in LUQ, and early satiety

• signs or symptoms of infection (e.g. mononucleosis) or malignancy

• history ofliver disease, hemolytic anemia, or high-risk exposures

Clinical Features

• jaundice, petechiae

• signs of chronic liver disease

• percussion (Castell'ssign, Traube’sspace, and Nixon'

s method) and palpation

• associated LAD or hepatomegaly

• signs of CHE

Investigations

• CBC and differential, blood film

• as indicated: liver enzymes (AST, ALT, ALP, and GGT) and/or LFTs (platelet, 1NR, albumin, and

bilirubin), reticulocyte count, MonospotVEBV, haptoglobin, LDH, infectious and autoimmune

workup, and BM biopsy/aspirate when malignancy suspected

• imaging

• ultrasound of abdomen/liver to assess for cirrhosis and portal vein thrombosis (if positive, refer

to hepatology)

echo for cardiac function

• CL to rule out lymphoma and assess splenic lesions

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HI I Hematology Toronto Notes 2023

Microcytic Anemia s . MCV <80 fL

• see Figure 2, H6

Table 10. Iron Indices and Blood Film in Microcytic Anemia Causes of Microcytic Anemia

lab Tests Blood Film TAILS

Thalassemia

Anemia of chronic disease

Iron deficiency

lead poisoning

Sideroblastic anemia

Ferritin Serum Iron TIBC % saturation RDW

Iron Deficiency Anemia

Anemia olChronic Disease N/e

Sideroblastic Anemia

1*15) Hypochromic,microcytic

Normocylic/microcylic

Dual population

Basophilic stippling

» » t a

« » N N

N/ t » H N/ t t

Thalassemia N/t H/t N N/ t N/t Hypochromic,microcytic

Basophilic stippling

Foikilocytosis

Iron Metabolism

Iron Intake (Dietary)

• average North American adult diet = 10-20 mg iron daily

• steady state absorption is 5-10% (0.5-2 mg/d);enhanced by citric acid and ascorbic acid (vitamin C);

reduced by polyphenols (e.g.in tea), phytate (e.g. in bran), dietary calcium, and soy protein

• males more likely to have positive iron balance; up to 20% of menstruating females have negative iron

balance

Iron Absorption and Transport

• dietary iron is absorbed in the duodenum (absorption impaired in IBD and celiac disease)

• in drculalion, the majority of non-heme iron is bound to transferrin which transfers iron from

enterocytes and storage pool sites (macrophages of the reticuloendothelial system and hepatocytcs) to

RBC precursors in the BM

Iron Levels

• hcpcidin is a hormone produced by hepatocytcs that regulatessystemic iron levels

• hinds to iron exporter ferroportin (on duodenal enterocytes and reticuloendothelial cells)

and induces its degradation, thereby inhibiting iron export into circulation (iron trapping in

reticuloendothelial system cells and diminished absorption of iron)

• hepcidin production is:

increased in states of iron overload (inhibiting additional iron absorption) and inflammation

(mediating anemia of chronic disease through iron trapping)

decreased in states where erythropoiesis is increased (e.g. hemolysis) or oxygen tension islow

Iron Storage

• ferritin

ferric iron (Fe 3+) complexed to a protein called apoferritin (liver,spleen, and BM are main ferritin

storage sites)

small quantities are present in plasma in equilibrium with intracellular ferritin

also an acute phase reactant- can be spuriously elevated despite low iron stores in response to a

stressor

• hemosiderin

aggregates or crystals of ferritin with the apoferritin partially removed

macrophage-monocyte system isthe main source of hemosiderin storage

Dietary Fe^inQI lumen LEGEND

Ferritin {

^

hamoudenn

QHepodin flLj? Transfer

h.

millv f i/ytfvopoiew

4 Oxygen c I Enterocyles

of proximal

duodenum

mg N M

I i

Ft

- G -

c"TAF«

J

- Ftf

ri

*

f 1 L J

Ntp : d

•

:

L;

/

i

Plasma 4 Body iron stores 0*2? f InflammatJOft/infection + i

RBC precursors

in bonB marrow

Iron Absorption and Transport Iran Homeostasis v

Figure 5.Iron metabolism

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H15 Hematology Toronto Notes 2023

Iron Indices

• BM aspirate:gold standard test for assessment of iron stores (rarely done)

• serum ferritin: most important blood test for iron stores

decreased in iron deficiency anemia

elevated in infection, inflammation, malignancy, liver disease, hyperthyroidism, and iron

overload

• serum iron: measure of all non-heme iron present in blood

variessignificantly daily

• TIBC:indirect measure of total amount of transferrin present in blood

normally,one third of TiBC issaturated with iron

increased TIBC has high specificity for decreased iron,low sensitivity

• transferrin saturation

serum iron divided by TIBC,expressed as a proportion or a percentage

• sTfR

reflects the availability of iron at the tissue level

transferrin receptor is expressed on the surface of erythroblasts and is responsible for iron uptake

- some are cleaved off and are present in circulation assTfR

in iron deficient states, more transferrin receptors are expressed on erythroblasts leading to an

increase in sTfR

sTfR also increased during extramedullary hematopoiesis (i.e.thalassemia syndromes)

low in reduced erythropoiesis and iron overload

useful in determining iron deficiency in the setting of chronic inflammatory disorders (see Iron

Deficiency Anemia )

Hi Iron Deficiency Anemia

•see Paediatrics. P51

•most common cause of anemia in North America

Etiology

•increased demand

increased physiological need for iron in the body (e.g. pregnancy)

•decreased supply: dietary deficiencies (rarely the only etiology in the developed world )

• cow'

s milk (infant diet), “tea and toast" diet (elderly), absorption Imbalances, post-gastrectomy,

malabsorption (IBD of duodenum, celiac disease, autoimmune atrophic gastritis, and H , pylori

infection)

•increased losses

hemorrhage

obvious causes: abnormal uterine bleeding,Gl bleed

occult:peptic ulcer disease,GI cancer

hemolysis

chronic intravascular hemolysis (e.g. PNH, cardiac valve RBC fragmentation)

Clinical Features

•iron deficiency may cause fatigue before clinical anemia develops

•signs/symptoms of anemia:see Anemia, H6

•brittle hair, nail changes (brittle,koilonychia)

•pica (appetite for non-food substances, e.g. ice, paint, and dirt)

•restlessleg syndrome

Investigations

•CBC, iron indices, including sTfR

• low ferritin (<30 pg/L) is diagnostic of iron deficiency

ferritin is an acute phase reactant and is elevated in the setting of inflammatory conditions

and liver disease;serum ferritin <100 pg/L in these settings is suggestive of iron deficiency,

necessitating further workup

•peripheral blood film

hypochromic microcytosis:RBCs have low Hb levels due to lack of iron

pencil forms, anisocytosis

• target cells

•BM aspirate (gold standard, but rarely done)

iron stain (Prussian blue) shows decreased iron in macrophages and in erythroid precursors

(sideroblasts)

intermediate and late erythroblasts show micronormoblastic maturation

Plummer-Vinson Syndrome

• Dysphagia (esophageal)

• Glossitis

• Iron deficiency anemia

• Stomatitis

Iron deficiency anemia is a common

“

esentation of chronic lower Gl

_ _eds(right-sided colorectal cancer.

—liodysplasia,etc.)

males and in post-menopausal

women, a Gl workup is always

warranted (gastroscopy, colonoscopy)

ble

ang

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H16 Hematology Toronto Notes 2023

Patient with microcytic anemia

t

Ferritin <45 glL

(likelihood ratio 3.12)

Ferritin 46-99R/L

(likelihood ratio 0.46)

Ferritin >100 g/L

(likeBhood’

ratioO.13)

i

Assess other iron indices

i I

TTIBC. 4 serum Fe

i saturation

4 TIBC. t serum Fe

t saturation

Any other result

Order sTIR 4

tsTfR 4 sTtR

Iron deficiency anemia NO iron deficiency anemia

oach to interpreting iron indices

am Physician 2007:75.-671-

Figure 6.Appn

Adapted from:AmF 678

Treatment

•treat underlying cause

•iron supplementation

oral (capsules,syrup)

ferrous sulphate 325 mg once daily (65 mg elemental iron ), ferrous gluconate 300 mg once

daily (35 mg elemental iron), or ferrous fumarate 300 mg once daily (100 mg elemental

iron), polysaccharide iron complex (150 mg elemental iron), heme iron polypeptide (11 mg

elemental iron)

supplement until anemia corrects, then continue for 3+ mo until serum ferritin returns to

normal

recentstudies demonstrate alternate day dosing may be superior to daily or more frequent

dosing, due to improved absorption, though thisisstill an area of investigation

IV iron can be considered if patient cannot tolerate or absorb oral iron, and/or if there is a need

for quick recovery (e.g.chronic bleeding not manageable with oral iron)

•monitoring response

reticulocyte count will begin to increase after one wk

Hb normalizes by 10 g/L per wk (if no blood loss)

Anemia of Chronic Disease

Etiology

• infection, malignancy, inflammatory, and rheumatologic disease

• chronic renal and liver disease

• endocrine disorders(e.g. diabetes mellitus, hypothyroidism, hypogonadism, and hypopituitarism)

Pathophysiology

• an anemia of underproduction due to impaired iron utilization (hepddin is a key regulatory peptide)

hepatic hepcidin production is increased in inflammatory processes, trapping iron in enterocytes

and macrophages (via ferroportin inhibition),see Figure 5, H 14

• reduced plasma iron levels make iron relatively unavailable for new Hb synthesis

marrow unresponsive to normal orslightly elevated EPO

• mild hemolytic component is often present i.e.RBC survival is modestly decreased

Investigations

• diagnosis of exclusion

• associated with elevation in acute phase reactants (ESR, CRP,fibrinogen, and platelets)

• peripheral blood

mild: usually normocytic and normochromic

moderate: may be microcytic and normochromic

• severe: may be microcytic and hypochromic

absolute reticulocyte count is frequently low,reflecting overall decrease in RBC production

• “classic" serum iron indices:see Table 10, H14

. BM

normal or increased iron stores

decreased or absent staining for iron in erythroid precursors

Treatment

• treat underlying disease;only treat in patients who would benefit from a higher Hb

• IV iron if no benefit from PO iron (overcomessequestration in enterocytes) or with use of ESAs in

CKD

• EPO indicated in chronic renal failure; not to be used if patient has concomitant curative solid tumour

malignancy; ensure Hb target <110 g/L

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H17 Hematology Toronto Notes 2023

Sideroblastic Anemia

•uncommon compared to iron deficiency anemia or anemia of chronic disease

Sideroblasts

•erythrocytes with iron-containing (basophilic) granules in the cytoplasm

•“normal”:granules are small and randomly spread in the cytoplasm

•

"ring": iron deposits in mitochondria,forming large, abnormal granules that surround the nucleus

hallmark of sideroblastic anemia

Etiology

•due to defectsin heme biosynthesis in erythroid precursors

•hereditary (rare):X-linked; median survival 10 yr

•idiopathic (acquired)

refractory anemia with ringed sideroblasts: a subtype of MDS (see Myelodysplastic Syndromes,

H U )

• may be a preleukemic phenomenon (1-2% transform to AML)

•reversible

drugs(isoniazid, chloramphenicol),alcohol,lead, copper deficiency, zinc toxicity, and

hypothyroidism

Clinical Features

•anemia symptoms (see Anemia, H6 )

•hepatospienomegaly

Investigations

•serum iron indices:see Table 10, H14

•CBC and blood film

• ring sideroblasts (diagnostic hallmark)

• RBCs are hypochromic; can be micro-, normo-, or macrocytic

anisocytosis, poikilocytosis, basophilic stippling

•BM biopsy

Treatment

•depends on etiology

• X-linked: high dose pyridoxine (vitamin Be) In some cases

• acquired: EPO and G-CSF

reversible:remove precipitating cause

•supportive transfusionsfor severe anemia

•monitor for iron overload driven by ineffective erythropoiesis and/or transfusion

Consider lead poisoning in any child with

microcytic anemia who lives in a house

built before1977

Lead Poisoning

Definition/Etiology

• blood lead levels >80 pg/dL, may be symptomatic at 50 pg/dL

• identify source: consider occupational history'

, exposures history'

, and utensil history

Clinical Features

• pallor, abdominal pain, constipation, irritability, and difficulty concentrating

Treatment

• chelation therapy: dimercaprol and EDTA are first line agents

§< 5

Features of Lead Poisoning

LEAD

Lead lines on gingivae and epiphyses

of long bones on x-ray

Encephalopathy and Erythrocyte

basophilic stippling

Abdominal colic and microcytic Anemia

(sideroblastic)

Normocytic Anemia Drops(wrist and foot drop)

• MCV 80-100 fL

• see Figure 2, H6

Causes

m

of Normocytic Anemia

Aplastic Anemia ABCD

Acute blood loss

BM failure

Chronic disease

Destruction (hemolysis)

Definition

• destruction of hematopoietic cells of the BM leading to pancytopenia and hypocellular BM n

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H18 Hematology Toronto Notes 2023

Etiology

Table 11. Etiology of Aplastic Anemia

Congenital Acquired

Ionizing Radiation

Post-Viral Infection

ParvovirusB19. EBV, HOV. HIV.HBV.

HHV6. HIV

Fanconi syndrome

Shweehmafl-Diamond syndrome

tclomeropalhics (dyskeratosis congenita)

Idiopathic

Olten T-cell mediated

Drugs

Dose-related (i.e.chemotherapeutics)

Idiosyncratic (chloramphenicol,antimalarials, Autoimmune (rare)

SLE, Gralt-versus-host disease

Others

Benzeneforganic solvents. DDT, insecticides PNH.pregnancy, anorexia nervosa,and

thymoma

and phenylbutazone)

Toxins

Clinical Features

• can present acutely or insidiously

• symptoms of anemia (see Anemia, H6 ),thrombocytopenia (see thrombocytopenia, H7),and/or

infection

• ± splenomegaly and lymphadenopathy (depending on the cause)

Investigations

• exclude other causes of pancytopenia (see Figure 4, H 9 ),including PNH (50% of aplastic anemia

patients have PNHt- stem cell clones)

. CBC

anemia, neutropenia, or thrombocytopenia (any combination including pancytopenia)

decreased reticulocytes(<1% of the total RBC count)

• blood film

decreased number of normal RBCs

• BM aspirate and biopsy

» aplasia or hypoplasia of cells with adipose tissue replacement

no evidence of infiltration with malignant cells or fibrosis

Treatment

• remove offending agents

• supportive care (RBC and platelet transfusions, antibiotics)

judicious use of blood products to decrease the risk of immune sensitization

iron chelation therapy for iron overload (accumulation of iron after multiple >20-unit RBC

transfusions)

• immunosuppressive therapy (for idiopathic aplastic anemia)

horse or rabbit anti

-thymocyte globulin:

‘

10-50% of patients respond

• cyclosporine (for improved response and survival)

• allogeneic BM transplant

• eltrombopag (TPO receptor agonist) shown to be effective;G-CS1-

'

and EPO not effective

Hemolytic Anemia ® 0

Definition

• anemia due to destruction and consequently shortened survival of circulating RBCs, usually defined

as <100 d

• uncommon cause for anemia (<5% of cases) with many etiologies (>200)

Classification

• hereditary

abnormal membrane (spherocytosis, elliptocytosis)

abnormal enzymes (pyruvate kinase deficiency, G6PD deficiency)

abnormal Hb synthesis (hemoglobinopathies)

• acquired

• immune

autoimmune:warm vs.cold A1HA,see Table 14, Classification o/

AIHA, H23

alloimmune: hemolytic disease of the fetus/newborn and post-transfusion

non-immune

TMA (includes MAHA): thrombus in blood vessel causes RBCs to be sheared - associated

with D1C, HUS, aH US,TTP, preedampsia/HELLP, vasculitis, and malignant hypertension

other causes: PNH, hypersplenism, march hemoglobinuria (exertional hemolysis), infection

(e.g. malaria),snake venoms, and mechanical heart valves

• also classified as intravascular or cxtravascular

• intravascular:TMA and PNH (complement mediated)

• extravascular:RBCs are coated with Abs (A1HA) or have an abnormal membrane structure/shape

or inclusions

infections can cause intravascular (Clostridium),extravascular,or both (malaria)

On blood film,schistocytcs reflect

an intravascular hemolysis while

spherocytes usually reflect an

extravascular hemolysis

Disruption of the heme biosynthetic

pathway causes porphyria

Porphyria

Inherited or acquired disorders of

defective heme synthesis leading to

accumulation of porphyrin precursors.

T ypically presents with non-specific

clinical findings (abdominal pain,

peripheral neuropathy, neuropsychiatric

changes, and/or cutaneous

photosensitivity)

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H19 Hematology Toronto Notes 2023

HEMOLYTIC ANEMIA

I

'

f

( INTRAVASCULAR HEMOLYSIS ] [ EXTRAVASCULAR HEMOLYSIS ]

Homo Broakdown I

f

'

Mechanical destruction 1

(e.g. mechanical heart valve,

aortic stenosis)

-» Schistocytes

Transfusion reaction

(e.g. ABO incompatibility,

Rh disease)

Paroxysmal nocturnal

hemoglobinuria

Infection (e.g. sepsis)

Microangiopathies (e.g. TTP, PIC)

Heme ( INTRINSIC DEFECT I c EXTRINSIC DEFECT Hijne oxygenase I T

Membrane defect

(e.g. hereditary spherocytosis)

Enzymopathy

(e g G6PD deficiency,

PK deficiency)

Hemoglobinopathy

(e.g. sickle cell disease)

Drugs/Toxins (e.g. lead)

Autoimmune (e.g. AIHA)

Infections (e.g.malaria)

Hypersplenism

Biliverdin

Bil^

erdin reductase

Bilirubin

Figure7. Hemolytic anemia

Clinical Features

• jaundice

• dark urine (hemoglobinuria, bilirubinuria)

• cholelithiasis (pigment stones)

• potential for an aplastic crisis(i.e. BM suppression in overwhelming infection)

• iron overload with extravascular hemolysis

• iron deficiency with intravascular hemolysis

Investigations

Haptoglobin is a circulating protein that

mops up free Hb,allowing its clearance

in the spleen;when free Hb is abundant,

haptoglobin levels decrease

Table 12. Investigations for Hemolytic Anemia

Screening Tests Tests Specific For Intravascular Hemolysis

Schistocytes on blood film (MAHA)

free Hb in scrum

Methemalbuminemia|heme •albumin)

Hemoglobinuria (immediate)

Hemosidennuria (delayed)

- most sensitive

IncreasedIDH

Decreased haptoglobin

Increased unconjugated bilirubin

Increased urobilinogen

Reliculocylosis

Tests Specific for Extravascular Hemolysis

Direct Antiglobulin Test (direct Coombs)

Detects IgG or complement on the surface of RBC

Add anti-IgG or anti-complement Ab lo pabent's RBCs:positive if aggInUnabon

Indications:hemolytic disease of newborn,AIHA.hemolytic transfusion reaction

Indirect Antiglobulin Test (indirect Coombs)

Detects Abs in serum that can recognize antigens on RBCs

Mix patient's serum+donor RBCs *

Coombs serum (anU-humanIgAb);positiveit agglutination

Indications:cross-matching donor RBCs.atypical blood group,blood group Ab in pregnant women,AIHA

Thalassemia

Definition

• defects in production of the a or (5 chains of Hb

• resulting imbalance in globin chains leads to ineffective erythropoiesis and hemolysis in the

spleen or BM

• clinical manifestations and treatment depend on specific gene and number of alleles affected

• common features

increasing severity with increasing number of alleles involved

• hypochromic microcytic anemia

• basophilic stippling, abnormally shaped RBCs on blood film

• CBC: low MCV, low Hb, high RBC count, ± high reticulocyte count

Pathophysiology

• defect may be in any of the Hb genes

• normally 4 a genes in total;2 on each copy of chromosome 16

• normally 2 (5 genes in total; 1 on each copy of chromosome 11

fetal Hb, Hbl;

(a’

yz),switches to adult forms HbA (a’P'

) and HbA2 (a262) at age 3-6 mo

HbA constitutes 97% of adult Hb

HbA2 constitutes 3% of adult Hb

Thalas"SEA"mia

p thalassemia •

*

more prevalent in

Mediterranean

o- thalassemia » more prevalent in

South East Asia (SEA) and Africa

(a - Asia.Africa)

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H20 Hematology Toronto Notes 2023

p-Thalassemia Minor (Thalassemia Trait)

Definition

• defect in single allele of (1gene (heterozygous for one normal p globin allele and one P globin

thalassemia allele)

• common in people of Mediterranean and Asian descent

Clinical Features

• usually asymptomatic; a palpable spleen is very rare

Investigations

• Hb (100-140 g/L), MCV (<70 fL),l-

'

e (normal), RBC count (normal/high)

• peripheral blood film - microcytosis, basophilic stippling

• Hb electrophoresis

specific: HbA2 increased to 3.5-5% (normal l.5-3.5%)

non-specific:50% have slight increase in HbT

Treatment

• no treatment required

• genetic counselling for patient and family

Microcytosis in p-Thalassemia Minor

Microcytosis is more profound and the

anemia is much milder than that of iron

deficiency

p-Thalassemia Major

Definition

• defect in both alleles of p gene ( homozygous, autosomal recessive)

Pathophysiology

• ineffective chain synthesis leading to decreased erythropoiesis,hemolysis of RBCs, and increase in

HbT

Clinical Features

• initial presentation at age 6-12 mo when HbA (a2/(

)2) normally replaces HbT (a i l y i )

• severe anemia, jaundice

• iron overload due to compensator)'gastrointestinal iron uptake progressing to hemochromatosis

secondary to repeated transfusions and ineffective erythropoiesis

leads to iron-induced organ damage

• stunted growth and development (due to hypogonadism)

• gross hepatosplenomegaly (due to extramedullary hematopoiesis)

• radiologic changes (due to expanded marrow cavity) and extramedullary hematopoietic masses

(erythroid tissue tumours)

• skull x-ray has “hair-on-end"

appearance

pathologic fractures common

• evidence of increased Hb catabolism (e.g. pigmented gallstones)

• death can result from:

• untreated anemia (should transfuse)

infection (should identify and treat early)

» iron overload (common):late complication

Investigations

•