CMPP: Hemolytic Anemia 1

Hemolytic anemia

disorders that are characterized by the premature destruction of RBCs

reticulocytosis

one should consider hemolysis in all anemic patients with...

cause of hemolysis

location of hemolysis

hemolytic anemias are characterized by...

Intracorpuscular

hemolytic anemia that is caused by something being wrong with the actual RBC; almost always HEREDITARY!

enzymopathy (G6PD)

hemoglobinopathy (sickle cell, alpha/beta thalassemia)

membranopathy (hereditary spherocytosis)

causes of intracorpuscular hemolytic anemia

hereditary

intracorpuscular hemolytic anemia is almost always...

Extracorpuscular

external force is acting upon the cell, causing hemolysis; ACQUIRED!

mechanical injury

infection

immunologic

medications

stasis

causes of extracorpuscular hemolytic anemia

Intravascular hemolysis

hemolysis within systemic circulation; RBC intracellular contents are released into plasma; excess intracellular components produce specific symptoms

Hemoglobinemia

free hemoglobin is released into the plasma and can cause significant tissue damage; the body works quickly to remove it; causes the plasma to be PINK!

Haptoglobin

removes free hemoglobin from the body

there is only a finite amount of Hp in the body, so it is not freely present in the blood because it is being consumed by the large amount of intravascular hemolysis

why are plasma haptoglobin levels decreased/absent in those with intravascular hemolysis?

renal filtration -- glomerulus filters small alpha-beta globulins

once haptoglobin is overwhelmed, how does Hgb get filtered out?

hemoglobinuria and kidney damage

renal filtration of hemoglobin results in...

after urine is centrifuged, if the supernatant is...

clear = hematuria

red/pink = hemoglobinuria

how can one tell the difference between hematuria and hemoglobinuria

elevated, high (these are byproducts of intravascular hemolysis)

in the lab work for someone going through intravascular hemolysis, unconjugated bili is ______, and LDH is _____

Reticuloendothelial system

extravascular hemolysis; hemolysis is taking place inside macrophages and monocytes; very little hemoglobin escapes into the plasma; Hp would be normal or slightly decreased

jaundice and splenomegaly

in extravascular hemolysis, since heme is broken down within macrophages in the spleen/liver, what symptoms would be more likely to be present?

CBC

reticulocytes

peripheral smear

CMP

unconjugated bili

LDH

haptoglobin

urinanalysis

what tests should be ordered in one with a suspected hemolytic anemia

presence/absence of antigens on the blood cell membrane (e.g. type B blood have B antigens on their surface)

blood type is designated by the...

Direct COOMBS

if hemolysis is supported by initial workup but its cause is unknown, start with...

Direct COOMBS

detects if antibodies (or complement) are bound to the RBC surface antigens; antibodies should NOT be bound to RBC surface, presence indicates the cause of hemolysis

draw blood

add coombs reagent

monitor for agglutination

how to perform a direct coombs test

antibodies/complement are causing hemolysis

if agglutination occurs in a direct coombs test, what does that mean?

effectively rules out autoimmune hemolytic anemia

if agglutination does not occur in a direct coombs test, what does that mean?

G6PD deficiency

what is the most common enzymatic disorder of RBCs?

G6PD deficiency

genetic defect that results in decreased enzyme glucose 6-phosphate dehydrogenase; indirectly allows for premature RBC hemolysis

both!

in G6PD deficiency, is hemolysis extra or intravascular?

X-linked recessive

--> males will be hemizygous (all RBCs affected)

--> females are often heterozygous (1/2 RBCs affected)

in G6PD deficiency, it is an ________ trait. How does this differ how this presents in men vs women?

malaria (thought to provide advantage against malaria infection)

G^PD deficiency is more prevalent in areas that ________ infections are prevalent

G6PD

enzyme found in all normal RBCs that protects them against free radicals; activity of this enzyme diminishes as RBCs age, and low levels of this enzyme makes RBCs more susceptible to oxidation injury and destruction

reticulocytes

what blood cells have the highest G6PD activity?

yes! they make some, just much less than normal

do patients with G6PD have any G6PD?

methemoglobin (Fe3+), insoluble masses, rigid, inflexible, prone to destruction

when exposed to oxidative stress, hemoglobin is oxidized and becomes ________, and this further denatures into _________ that attach to the red cell membrane. This makes the RBCS ______ and ______ and _________________.

Heinz bodies

round denatured hemoglobin inclusions that are bound to cell membrane; sign that RBC was exposed to oxidation

Bite cells

macrophages recognize that Heinz bodies are abnormal, so they "bite" the denatured Hb out of the cell; results in RBCs with semicircular portions removed

infection

medications

food exposure

chemical exposure

what causes oxidative stress?

infection

what is considered the most likely cause of hemolysis in G6PD-deficient individuals

fluoroquinolones

methylene blue

nalidixic acid

nitrofurantoin, nifuratel, nitrofurzone

phenazopyridine

primaquine and tafenoquine

rasburicase and pegloticase

sulfonylureas

what medications are indicated in precipitating hemolysis in G6PD deficient patients?

fava beans

henna compounds

naphthalene (mothballs, lavatory deodorant)

RUSH (isobutylene nitrate, amyl nitrate) -- sexual enhancement drug

what foods are indicated in precipitating hemolysis in G6PD deficient patients?

Favism

subset of G6PD deficiency that occurs following ingestion of fresh fava beans; occurs mostly in children; can cause acute intravascular hemolysis; not all patients with G6PD deficiency will have this

acute intravascular hemolysis

favism causes...

hemolyze, hemoglobin, reticulocytosis

after an oxidative stressor, G6PD deficiency cells _______ but cells with sufficient G6PD survive. This leads to a rapid drop in _________, and the body responds by producing new RBCs (____________).

8 days

acute hemolytic process lasts approx...

jaundice/icterus

pallor

dark urine

hyperbillirubinemia

abdomen/back pain

what is a common presentation of a G6PD deficiency pt within 24 hours of exposure to oxidative stressor?

abrupt drop in Hb

increased reticulocyte count

Bite cells/Heinz bodies on peripheral smear

what is seen in labs for those with G6PD deficiency?

education -- avoid foods, meds, chemicals known to cause oxidative stress

prophylactic folic acid supplement

treatment of G6PD deficiency

hydration, but not too much

blood transfusion if hemodynamically unstable

splenectomy is typically ineffective

how to treat acute anemia in G6PD deficiency

Hereditary spherocytosis

what is the most common cause of hemolytic anemia due to a red cell membrane defect?

Hereditary spherocytosis

autosomal dominant genetic defect that affects the proteins involved in the cytoskeleton and cell membrane of the RBC; results in spherocytosis and hemolysis

cytoskeleton and membrane of the RBCs

in HS, there is a mutation within the...

Cytoskeleton

the microscopic network of proteins inside living cells which gives it its shape and flexibility

flexible

Normal RBCs are ________ and are able to travel through capillaries and splenic sinusoids.

swell, shrink

Normal RBCs can change their shape in response to the tonicity of its environment. They _______ in response to a hypotonic environment, and _______ in response to a hypertonic environment.

Band 3

Ankyrin

Spectrin

HS results from gene mutations that code for...

weak

in HS, genetic mutations cause defects in the RBC membrane that causes it to become...

blebs to form on RBC surface

K+/H2O exit the cell

Cells become dehydrated

RBC changes shape (spherocyte)

a weak RBC membrane can cause...

Spherocyte

round RBC (NOT biconcave); no central pallor; decreased surface area and flexibility

RBC gets stuck in splenic sinusoids, and macrophages identify and phagocytize the spherocytes

what happens when extravascular hemolysis occurs in those with hereditary spherocytosis?

this process occurs because RBCs are less likely to survive in unfriendly environments -- spontaneously lyse/hemolyze

--> acidic stressors, oxidative stressors, metabolically unfavorable conditions

what happens when intravascular hemolysis occurs in those with hereditary spherocytosis?

repeated hemolysis gets rid of nutrients needed to produce effective RBCs

--> iron, folate, and B12 deficiencies

why does hereditary spherocytosis lead to nutritional deficiencies?

anemia can worsen as volume expansion occurs throughout pregnancy

why does hereditary spherocytosis become more complicated during pregnancy?

parvovirus B19

in hereditary spherocytosis, aplastic crisis can occur with infections. it is very common with what pathogens?

splenic pooling of RBCs and increased hemolysis

--> EBV, Hepatitis, cirrhosis

in one with hereditary spherocytosis, conditions that cause splenomegaly can cause...

splenomegaly (VERY COMMON)

jaundice

hyperbilirubinemia

hemoglobinuria

hemogloinemia

cholelithiasis

what are some common symptoms of hereditary spherocytosis?

Gallstones are PIGMENTED and radiopaque -- can be seen on XR

--> unconjugated bili from hemolysis combines with calcium

what is unique about the cholelithiasis that occurs in hereditary spherocytosis?

microcytic anemia

elevated MCHC (hyperchromic)

Elevated RDW

Pseudohyperkalemia

what are some unique lab values associated with hereditary spherocytosis?

there is membrane loss and red cell dehydration, so, since that membrane is lost, more cell is taken up by Hgb due to a smaller size

why is MCHC elevated in those with hereditary spherocytosis?

varied cells are being affected with bulging

why is RDW elevated in hereditary spherocytosis?

K+ leaking out of a faulty membrane

why is pseudohyperkalemia seen with hereditary spherocytosis?

round cells without central pallor

hyper chromic cells

--> these results alone are NOT diagnostic for hereditary spherocytosis

what is seen on peripheral smear in those with hereditary spherocytosis?

NEGATIVE, since antibodies are not responsible for the hemolysis

what are the direct coombs results in one with hereditary spherocytosis?

Eosin-5'-maleimide (EMA) binding test

confirmatory test of choice for hereditary spherocytosis; dye (EMA) binds RBC membrane proteins; flow cytometry is used to measure labeled RBCs

decreased -- as they lack the mabrane proteins/membrane isn't as strong

EMA labeled RBC levels will be ______ in patients with HS

Osmotic fragility test

test RBC ability to respond to tonicity; adds patient RBC to hypotonic solution and sees how it tolerates it; relatively low sensitivity/specificity

expand and swell, burst

in the osmotic fragility test, normal RBCS ______________, spherocytes will _____.

folic acid -- prophylactic supplementation due to increased use (hemolysis)

blood transfusion -- based on severity

EPO -- corrects anemia (but not cell shape)

splenectomy -- reserved for SEVERE cases, effective in improving anemia/hemolysis

treatment for hereditary spherocytosis

children, but discontinued as bone marrow picks up

EPO supplementation is primarily used in what age group?

age 6

a splenectomy to treat HS is delayed until a child is older than...

PCV20

H flu type B

Meningitis A/B

Flu

COVID

what vaccinations should be given prior to a splenectomy?

if gallstones are present

when would a cholecystectomy be performed in one with HS?

Paroxysmal nocturnal hemoglobinuria

acquired chronic hemolytic anemia; mutation (PIG-A) results in a defect of myeloid stem cells; defect leads to recurrent episodes of hemolysis that occurs mainly at night; occurs in 3rd-4th decade of life; associated with aplastic anemia, iron deficient anemia, myeloid leukemia/myelodysplasia

PIG-A, myeloid stem cells

Paroxysmal nocturnal hemoglobinuria results from a mutation in what gene that affects what types of stem cells?

hemolysis and concentration of urine is happening anyway (usually happens at night), so buildup is more noticeable in the morning

why does Paroxysmal nocturnal hemoglobinuria mainly occur at night?

PIG-A gene

gene essential for production anchor proteins (CD55/CD59) in the RBC membrane

deterring complement activation

CD55/CD59 are responsible for...

fatigue, dyspnea, hemoglobinuria

abdominal/muscular pain

thrombosis or peripheral AND ABDOMINAL/CEREBRAL VEINS

presentation of paroxysmal nocturnal hemoglobinuria

normocytic, normochromic, pancytopenia with reticulocytosis

also contains products indicative of hemolysis (LDH, absent haptoglobin, elevated unconjugated bili)

what are the findings on labs for one paroxysmal nocturnal hemoglobinuria

flow cytometry

what test is needed for diagnosis of paroxysmal nocturnal hemoglobinuria

RBCs lack CD55/CD59 anchored proteins

what does flow cytometry show in one with paroxysmal nocturnal hemoglobinuria

C5 complement inhibitors

treatment for paroxysmal nocturnal hemoglobinuria

eculizumab (Soliris)

ravulizumab (Ultomiris)

C5 complement inhibitor agents

anticoagulants if thrombosis is present

what should be given in conjunction to those with PNH on C5 complement inhibitors

N. meningitidis

treatment of PNH using C5 complement inhibitors increases the risk of what condition?

Meningococcal vaccines (both MenA/B)

Antibiotic prophylaxis (Pen V)

patients on C5 complement inhibitors should receive what to help decrease their risk of N. meningitidis