Normocytic anemia Flashcards
When a Pt presents with early concurrent B12 or folate deficiency and iron deficiency, what type of anemia is found?
Normocytic anemia
Microcytic anemia will present as time goes on
Rapid decline in the Hb/hematocrit w/o hyperbilirubinemia
Blood loss
Anemia may not show until expansion of blood volume w/ plasma/IV fluid
Blood loss into an extravascular space can masquerade as ______
Hemolysis, because breakdown of the extravascular blood collection will lead to an increase in indirect bilirubin.
This would be a very characteristic scenario for an elderly person who presents with a broken hip, a drop in hematocrit/hemoglobin, and elevated bilirubin.
Lab findings in hemolysis
Hyperbilirubinemia (indirect)
Elevated lactacte DH (LDH)
Decreased haptoglobin
Anemia associated w/ congenital RBC enzyme deficiency
Intravascular hemolytic anemia
G6PD deficiency
Pyruvate kinase deficiency
Hexokinase deficiency
Non-immune intravascular hemolysis caused by infections
- Clostridium septicum
- Malaria
- Leishmaniasis
- Babesiosis
Types of non-immune hemolysis
Mechanical hemolysis
Microangiopathic hemolysis
Specific infections
Causes of extravascular hemolysis
RBC membrane disorders: hereditary spherocytosis; hereditary ovalocytosis
Autoimmune hemolytic anemia - most types (“warm” AIHA)
Hemoglobinuria is indicative of what type of anemia?
W/o hematuria
Intravascular hemolytic anemia
Plasma hemoglobinemia is specific to?
Intravascular hemolysis
Urine hemosiderin
is a specific marker of?
Chronic intravascular hemolysis
Sickle Hb polymerization leads to what pathophysiological trait of sickle cell anemia?
Vasoocclusion
Perfusion/repurfusion leads to what pathophysiological trait of sickle cell anemia?
Inflammatory cytokine activation
Intravascular hemolysis leads to what pathophysiological trait of sickle cell anemia?
Free Hb that binds to NO - creating vasodilation and pulmonary hypertension
Increased expression of RBC adhesion molecules in sickle cell anemia leads to?
Vasoocclusion
Virtually all Pt’s w/ SS disease undergo?
Auto-infarction and atrophy of the spleen early in childhood - increases susceptibility to infection by encapsulated organisms
Transient aplastic crisis
An acute severe (but self-limited) drop in hemoglobin with reticulocytopenia due to acute parvovirus B19 infection of Pt w/ sickle cell anemia
Splenic sequestration (“hyperhemolytic crisis”) crisis
Associated with delayed hemolytic transfusion reactions.
- Acute splenomegaly
- massive drop in hemoglobin concentration
- extremely high reticulocyte counts
Seen in sickle cell anemia
Cholestatic crisis
1.Severe abdominal pain
2.Bilirubin > 50 mg/dL (normal ~1.3 mg.dL)
3.Hepatocellular damage
Seen in sickle cell anemia
The optimal hemoglobin concentration in an SS patient
9-10 mg/dL
Nearly all Pt’s w/ hereditary membrane defects will eventually require _____
Cholecystectomy
Inheritance pattern of heriditary spherocytosis (HS)
Autosomal dominant
Most common RBC membrane defect resulting in hemolytic anemia
Hereditary spherocytosis
Eosin-5-maletimide binds to what on RBCs?
Provides definitive confirmation for what Dx?
EMA binds to AEP/band3 on RBCs
Dx: Hereditary spherocytosis
Hereditary stomatocytosis
What is “absolutely contraindicated” in hereditary stomatocytosis?
Splenectomy - extremely high incidence of post-splenectomy intra-abdominal venous thrombosis
LOF mutation in PIGA leads to?
Paroxysmal nocturnal hemoglobinuria (PNH)
PIGA gene regulates the anchoring proteins to the RBC cell membrane by glycosylphosphatidylinositol - one of the proteins is decay accelerating factor (DAF)
An acquired clonal disorder where patients have hemolytic anemia, frequently with leukopenia and often thrombocytopenia and a hypocellular bone marrow.
Paroxysmal nocturnal hemoglobinuria (PNH)
Also increased risk of venous thromboembolic events
Decay accelerating factor (DAF)
Turns off complement on the cell surface
PIGA LOF mutation in PNH - RBCs are excessively susceptible to complement-mediated lysis
How is paroxysmal nocturnal hemoglobinuria dx’d?
Demonstrating decreased expression of the glycosylphosphatidylinositol-anchored proteins CD55 and CD59 on RBC and granulocyte surfaces
Tx of paroxysmal nocturnal hemoglobinuria
PNH Pt’s are Tx’d w/ anti-C5a agents - eculizumab - significantly reduces hemolysis and improves QOL
require vaccination against significant organisms whose clearance is dependent on complement, especially Neisseria meningitidis and Haemophilus influenzae
Spur cell anemia
Acquired membrane defect due to dyslipidemia in end stage liver disease
As opposed to the usual target cells of liver disease, these patients develop acanthocytes
Spur cell anemia with 5% acanthocytes
predictor of short survival and is a reason for liver transplantation
McLeod syndrome
Congenital abetalipoprotinemia
X-linked abnormality of the Kell minor blood group associated w/ hemolysis, cardiomyopathy, and both peripheral and central neurologic abnormalities
G6PD A variants
commonly seen in Black individuals
These variants have significantly low levels of G6PD, primarily in older RBCs
-after the initial drop in hemoglobin/hematocrit, they will begin to recover from anemia even if the offending agent continues
-they will replete the hemolyzed cells with new younger cells
(although they will not fully recover from the anemia until the oxidative insult is removed).
G6PD B variants
characteristic variant of Mediterranean ancestry
significantly low levels in all
but reticulocytes and the very youngest RBCs, so they have more severe and sustained anemia.
CNSHA variants
Chronic nonspherocytic
hemolytic anemia
Very low baseline G6PD activity
typically present with neonatal jaundice - mildly anemic (~9-10 g/dL) all the time
develop gallstones like other patients with chronic congenital hemolysis.
If exposed to an oxidative drug, their anemia becomes much worse.
Inheritance pattern of G6PD deficiency
X-linked recessive
Pyruvate kinase deficiency inheritance pattern
Autosomal recessive
PK deficiency sxs
Congenital chronic hemolytic anemia
Often beginning w/ neonatal jaundice
Develop gallstones and splenomegaly
May have extremely brisk reticulocytosis (mitigates PK deficiency - able to generate ATP from oxidative phosphorylation)
PK deficiency exhibits both intravascular and extravascular hemolysis
Mitapivat
Activator of pyruvate kinase - can improve hemoglobin concentration in pyruvate kinase deficiency
Differences between PK and hexokinase deficiencies
RBC 2,3- BPG levels are decreased in hexokinase deficiency.
This means that hemoglobin holds on to oxygen rather than releasing it to peripheral tissue and anemia symptomatology is more severe than would be
predicted from the hemoglobin/hematocrit.
Causes of mechanical hemolysis
aka “macroangiopathic anemia”
Disseminated intravascular coagulation (DIC)
coagulation is inappropriately activated by some concurrent illness – sepsis typically, but sometimes-metastatic cancer.
Platelets and soluble coagulation factors are consumed - results in prolonged clotting times and thrombocytopenia
Hemolytic anemia is not a major feature
Microangiopathic hemolytic anemia
Cause of thrombotic thrombocytopenic purpura (TTP)
ADAMSTS-13 deficiency - acquired autoimmune deficiency mediated by antibodies.
Platelets are excessively activated and form disseminated small clots in the microvasculature
ADAMSTS-13 is a matrix metalloproteinase that cleaves very high molecular weight multimers of vWF
Sxs of thrombotic thrombocytopenic purpura (TTP)
Hemolysis (small microvascular platelet thrombi damage passing RBCs)
Thrombocytopenia
Neurologic and renal issues
Clotting times are normal
Hemolytic uremic syndrome (HUS)
Results from the activities of bacterial toxins:
-particularly Shiga toxin and the toxins from E. coli 0157 or other enterotoxigenic E. coli
Atypical HUS (aHUS)
Resembles hemolytic uremic syndrome (HUS) but is caused by excessive complement activation - Tx’d w/ anticomplement agents (same as PNH)
aHus/Hus in pregnancy
pregnancy-related HELLP syndrome
similar complement mediated syndrome as seen in aHUS
H - hemolysis
E - elevated
L - liver tests
L - low
P - platelets
What infections can cause intravascular non-immune hemolysis?
Plasmodium falciparum (“blackwater fever) malaria
Clostridium perfringens
African trypanosomiasis (not American - Chaga’s disease)
Babesiosis
Bartonelosis
Visceral leishmaniasis
Clostridial sepsis can cause extremely rapid onset of massive hemolysis.
Infection associated with hemophagocytosis by circulating macrophages/monocytes
Leishmaniasis
First line treatment for IgG-mediated AIHA
Corticosteroids (prednisone) with or without rituximab (anti-CD20 mAbs)
Splenectomy = third line Tx
First line treatment for C3-mediated AIHA
Rituximab (anti-CD20 mAbs)
Pt’s do not respond well to prednisone or splenectomy
Direct Ab test (DAT - aka direct Coomb’s test) for neoantigen/immune complex
Only positive for C3
Positive DAT (direct Coomb’s test) without anemia
Nonspecific and clinically irrelevant binding of antibodies to RBCs resulting in a positive DAT
Nonspecific finding
Screening for alloimmunization for blood transfusion
Indirect antiglobulin test (aka indirect Coomb’s test)
ABO blood group incompatibility
Massive hemolytic rx’n
Hemoglobinuria
Flank pain
Kidney damage
Systemic collapse and possibly death
Pt is managed w/ hydration, dialysis, and aggressive support
Delayed hemolytic transfusion reaction (DHTR)
At time of transfusion - IAT was negatigve
Approx. 5-7 days later - sudden drop in Hb/Hct with signs of hemolysis (IAT is not positive)
Pt was exposed to Ag on transfused blood from a prior pregnancy/transfusion
The DAT is negative because
the only RBCs to which the antibody would bind would be the transfused RBCs and those had been hemolyzed.
The “hyperhemolytic crisis” seen in sickle-cell patients is an unusually severe variant of DHTR.
Pure red cell aplasia (PRCA)
Marrow failure state
Presents as an isolated normocytic anemia w/ extreme reticulocytopneia (uncorrected reticulocyte count frequently < 0.1%; absolute reticulocyte count typically <10,000/µL).
PRCA is usually a primary autoimmune disorder mediated by an IgG antibody against some erythroid progenitor antigen that has not yet been defined.
It can also be secondary to other disorders, most significantly chronic lymphocytic leukemia; systemic lupus erythematosus; thymoma; or B19 parvovirus infection in an immunocompromised patient, particular organ transplant patients or patients with HIV infection.
Anemia of chronic kidney disease
Anemia is almost invariable in significant renal insufficiency, beginning when the estimated glomerular filtration rate (eGFR) falls below 45 mL/min/1.73 m2 body surface area.
Anemia is a less frequent
complication of polycystic kidney disease, due to secretion of erythropoietin (EPO) from the cysts.
Tx of anemia of uremia
Anemia of uremia aka anemia of CKD
Tx w/ recombinant EPO or an EPO analog
Fe supplementation when Tf/TIBC saturation is less than 30% or serrum ferritin concentration is less than 500 ng/mL
Which of the following drugs inhibits sickle RBC adhesion to the vascular endothelium?
A. Hydroxyurea
B. Crizanlizumab
C. L-glutamine
B. Crizanlizumab
L-glutamine reduces inflammation
Hydroxyurea increases HbF conc.
In which of the following syndromes is the etiology of hemolysis extrinsic to the RBC?
A. Spur cell anemia
B. Delayed hemolytic transfusion rx’n
C. Methylene blue exposure in a Pt w/ G6PD deficiency
D. Paroxysmal nocturnal hemoglobinuria
B. Delayed hemolytic transfusion reaction
Hereditary spherocytosis most commonly results from mutations in the genes for which RBC proteins?
Both anykrin and spectrin
Band 7 defect gives you hereditary stomatocytosis
Which of the following would be most likely to be associated with sickle cell trait (AS genotype)?
A. Painful vasoocclusive
B. Auto-infarction of the spleen in childhood
C. Dilute urine specific gravity gravity despite fluid fluid retention
D. Splenomegaly
C. Dilute urine specific gravity despite fluid restriction
Sickle trait Pt’s do not get painful vasoocclusive crises
This, episodic hematuria (due to papillary necrosis), and increased risk of a rare kidney cancer are the only sxs of Pt w/ sickle trait
A 48 year old man has received repeated RBC transfusions for myelodysplastic syndrome. Five days after his most recent transfusion he has a sudden drop in hemoglobin and hematocrit with increased in serum bilirubin. There is no evidence of bleeding.
Immunohematologic evaluation of this patient is most likely to have which of the following results for direct/indirect antiglobulin tests (Coomb’s test)?
Negative direct antiglobulin test
Positive indirect antiglobulin test
Hemolysis in which of the following disorders is predominantly intravascular?
A. Clostridium sepsis
B. Hereditary spherocytosis
C. IgG “warm” autoimmune hemolytic anemia
D. Spur cell anemia
A. Clostridium sepsis
Which of the following is most consistent with Gilbert syndrome?
A. Elevated direct bilirubin
B. Elevated indirect bilirubin
C. Decreased haptoglobin
B. Elevated indirect bilirubin
D. GI blood loss
A. Folate supplementation
B. Aortic valve repair
C. Splenectomy
D. Supplemental oxygen
A. Folate supplementation
Direct vs. indirect antiglobulin test (Coomb’s)
What type of sickle cell anemia is implicated when a Pt presents w/ chronic splenomegaly
Not an acute crisis
Sickle C or sickle-thalassemia
A. Serum iron, transferrin/TIBC, ferritin
C. Decreased serum haptoglobin
D. Increased urine hemoglobin
Urine hemosiderin = chronic intravascular hemolysis (heme deposited in renal tubule
C. PK deficiency
C. L-glutamine
Hydroxyurea - increased HbF
Crizanlizumab - prevents cell adhesion to endothelium
SS vs. AS in sickle cell anemia
Splenic seqestration in Pt w/ sickle cell anemia
Typically due to delayed transufsion reaction
C. Hereditary stomatocytosis
Hereditary stomatocytosis is resulting from defect in band 7 (acquired)
Pt’s w/ hereditary stomatocytosis that receive splenectomy get abdominal thromboses
Hereditary spherocytosis
Eculizumab
Anticomplement mAb used in Tx of paroxysmal nocturnal hemoglobinuria
Have to be vaccinated against pertient encapsulated organisms
A. Increased RBC 2,3-BPG levels
Blister cells and bite cells (denatured hemoglobin that does not take up stain)
Blister would stain w/ Heinz body stains
Unstable hemoglobin - resulting from defect in metabolism in RBC
C. Antibodies against ADAMSTS13
E. coli O157 toxin - HUS
D - AHUS
Schistocytes
Tx for thrombotic thrombocytopenic purpura
Plasma exchange = #1
Caplacizumab (anti-vWF)
A. Rhesus (Rh) Ag complex
I/i Ag complex - cold autoimmune hemolytic anemia
Duffy complex - receptor that takes up malaria
Genotypes of ABO blood types
B. Anemia of CKD
Masked megaloblastic anemia
Concurrent B12 and Fe deficient - presents initially as normocytic the progresses to microcytic
Why are Pt’s w/ polycystic kidney disease rarely EPO deficient?
Renal cysts contain EPO that can diffuse into systemic circulation
Physiologic anemia of pregancy
During pregnancy - RBC mass goes up, but slower than plasma volume
Pure RBC aplastic anemia
Infection of pronormoblast should make you think
Parvovirus
Tx’d w/ IVIG
Thymoma can be associated w/?
Two pathologies
Pure red cell aplasia
Myasthenia gravis
