Hemolytic Anemias Flashcards
Primary building blocks of the RBC membrane
α-spectrin and β-spectrin, which bind to each other to form long, stable dimers
protein 4.1 facilitates their association with actin
band 3, ankyrin, and protein 4.2 help the skeleton stay connected to the membrane.
Red cell membrane cross section
Defects in horizontal red cell membrane interactions cause ___.
hereditary elliptocytosis or its severe variant, hereditary pyropoikilocytosis
Defects in vertical red cell membrane interactions cause ___.
hereditary spherocytosis
Osmotic fragility test
Lab test that provides an assessment of the surface area to volume ratio of red cells. Basically dilute the concentration of salt until the cells pop, which you can detect by measuring hemoglobin release.
Cells with a low vs high surface area to volume ratio
Spherocytes have a low SA:V, and so they will pop quickly in an osmotic fragility test
Target cells have a high SA:V ratio, so they will take longer than healthy red cells to pop
Mutations that cause hereditary spherocytosis
Ankyrin
band 3
β-spectrin
protein 4.2 (this one causes a mild spherocytosis)
Many individuals with uncomplicated hereditary spherocytosis are asymptomatic. Why is this?
They can compensate with constantly elevated erythrocyte production. This is “compensated” hemolytic anemia.
Of course, if they are to be, say, infected with parvovirus B19, they will have a much worse disease than an individual with normal erythrocytes.
Clinical features of hereditary spherocytosis
- Splenomegaly
- Increased retics
- Markers of intravascular hemolysis + associated (icterus, gall stones, etc)
*
While spherocytes on blood smear certainly put hereditary spherocytosis on the differential, . . .
. . . multiple things can cause spherocytosis. Immune hemolytic anemia also produces spherocytosis. It takes an osmotic fragility test or genetic test to confirm the diagnosis.
What is the likely diagnosis?
Hereditary spherocytosis
___ is recommended in all patients with severe hereditary spherocytosis.
Splenectomy is recommended in all patients with severe hereditary spherocytosis.
However, you may want to wait until patients are at least >3 years old for immune system development, and for all necessary vaccinations.
Partial splenectomy is currently gaining favor.
Hereditary elliptocytosis mutations
α-spectrin
β-spectrin
protein 4.1
Hereditary elliptocytosis
Defect in the horizontal interactions prevents stable hexagonal αβ-spectrin arrangement, resulting in elliptical red cells.
Often results in only a modest anemia or no anemia at all. However, a small portion of these individuals have severe anemia (poikilocytosis) from birth. This will typically evolve into a mild anemia within a year.
Fewer still (often compound heterozygotes) have hereditary pyropoikilocytosis, a severe congenital anemia that does not improve and is transfusion dependent.
What is the likely diagnosis?
Hereditary elliptocytosis
Hereditary xerocytosis
Red cells are severely dehydrated due to defects in the control of red cell cation content that result in potassium efflux.
Osmotic fragility test shows high SA:V ratio, more like targetoid cells than spherocytes. Target cells may sometimes be seen, but overall morphology on smear is normal. However, cells are rigid and rapidly cleared by the spleen.
High risk for thromboembolism after splenectomy.
Hereditary stomatocytosis
Red cells are overhydrated owing to excess influx of sodium and water.
Stomatocytes have a mouth-like slit rather than a circular area of central pallor.
High risk for thromboembolism after splenectomy.
Why is splenectomy avoided in hereditary xerocytosis and stomatocytosis?
Because it results in a high risk of thromboembolism, possible due to accumulation of damaged erythrocytes that may serve as thrombus nucleation sites.
What is the likely diagnosis?
Hereditary stomatocytosis
What’s wrong with these red cells?
Their hemoglobin has precipitated out of solution to form Heinz bodies. This is the result of oxidative stress that is uncompensated for by red cell redox buffers, like glutathione.
Glucose-6-phosphate dehydrogenase deficiency
The enzyme that is necessary to commit glucose to the pentose phosphate pathway. Without it, red cells cannot produce NADPH to recharge their glutathione stores and are prone to oxidative stress.
G6PDH is on the X chromosome, so the deficiency is X-linked.
With the exception of the rare disorder paroxysmal nocturnal hemoglobinuria, all of the acquired hemolytic anemias are ___
With the exception of the rare disorder paroxysmal nocturnal hemoglobinuria, all of the acquired hemolytic anemias are extracorpuscular
This means that red cells from a compatible donor are hemolyzed as readily as the patient’s own red cells.
Warm autoantibodies
Bind avidly to the patient’s red cells at body temperature. They are immunoglobulin G (IgG) antibodies with specificity for Rh group antigens found on red cells of nearly all individuals.
How spherocytes form due to immune reactions against blood cells.
IgG binds Rh factor on an erythrocyte. A macrophage binds via an Fc gamma receptor. Often, erythrocytes are completely eaten, but sometimes they are able to get away after being ‘nibbled on’ by the macrophage. This results in a loss of extra surface area, and thus the cell takes on the morphology of a spherocyte.
What is the likely diagnosis?
Warm antibody autoimmune hemolytic anemia
Cold autoantibodies
Cold autoantibodies bind to the patient’s red cells with much higher affinity at low temperature than at body temperature. As a result, binding of cold autoantibodies to red cells is restricted to cool areas of the body, such as the extremities and the ear lobes
In the vast majority of cases, they are IgM macroglobulins that have specificity for the I antigen, which (like the Rh complex) is found on nearly all adult red cells.
New-onset autoimmune hemolysis is worrying for the possibility of underlying ___.
New-onset autoimmune hemolysis is worrying for the possibility of underlying lymphoproliferative disorder
Coomb’s test
Treating autoimmune hemoltyic anemias
- Immunosuppression
- Splenectomy
- Rituximab
Traumatic hemolysis
Extreme turbulence or other mechanical stresses can cause red cells to fracture into small fragments called schistocytes or become irreversibly deformed into shapes resembling a triangle or a helmet
Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome can contribute to pathology
What is the likely diagnosis?
Traumatic hemolysis or more broadly schistocytosis
What is the likely diagnosis?
Malaria
What is the likely diagnosis?
Babesiosis
What is the likely diagnosis?
Spur cell anemia
Spur cell anemia
Due to biliary obstruction, alcoholic fatty liver disease, or similar liver pathology.
Blood smear shows blotchy target cells, with increased SA:V ratio due to assive accumulation of extra cholesterol and phospholipid in the lipid bilayer of the red cell membrane. These target cells have a relatively normal lifespan.
An occasional patient, usually severe alcoholic liver disease, will develop more marked increases of lipid on red cell membranes, resulting in spikes and thorny projections on the cell surface. Spur cells are rigid and are rapidly destroyed in the circulation.
What happens if you transfuse a spur cell patient?
The cells you transfer in will spur!
Remember, this is an extracorpuscular disease.
Paroxysmal nocturnal hemoglobinuria
Previously healthy patients develop severe anemia accompanied by passage of red-brown urine (due to free Hb) following bed rest. High risk of developing thromboembolism.
Caused by clonality of hematopoietic stem cells with a somatic mutation in PIG-A (a glycosyl phosphatidyl inositol transferase) that is responsible for stabilizing certain proteins on the membrane. This includes CD55 and CD59, proteins that play a key role in down-regulating activated complement.
CD55 and CD59 flow cytometry for healthy individuals and PNH patients
How does one treat PNH?
With a monoclonal antibody that blocks the terminal step of the complement cascade.
But, this does not come without a price. Complement is very imporant for Neisseria meningitidis defense, and so these individuals are at high risk for meningococcemia.
What is the likely diagnosis?
Thrombotic thrombocytopenic purpura
Notice that there is 1) an abesnce of platelets, and 2) evidence of traumatic hemolysis
Thrombotic thrombocytopenic purpura presentation
Patients present with acute hemolytic anemia and thrombocytopenia, sometimes preceded by viral-infection-like symptoms of fatigue, malaise, and fever. Some patients have CNS manifestations, such as seizures, coma, hemiplegia, and dementia.
- Thrombocytopenia
- Microangiopathic hemolysis
- Neurologic dysfunction
- Renal functional impairment
- Fever
Thrombotic thrombocytopenic purpura pathology
Small platelet thrombi studding the endothelium of arterioles and capillaries, rich in vWF, but with little fibrin. vWF clumps act like glue tethering platelets to the endothelial surface.
In the herediray form, ADAMTS13, which cleaves extra-large vWF into normal size multimers, is deficient. In the acquired form, there are inhibitory autoantibodies against ADAMTS13.
Paradoxically, ___ is preserved in TTP patients.
Paradoxically, coagulation profile, assessed by partial thromboplastin time and prothrombin times, is preserved in TTP patients.
Hemoltyic uremic syndrome
Acute microangiopathic hemolysis and thrombocytopenia accompanied by oliguria, proteinuria, and uremia, usually in children. Often follows diarrheal illness. Associated with severe renal impairment.
About 50% of cases are caused by an enteropathic strain of Escherichia coli (O157:H7), which releases a Shiga-like toxin. Supportive care is the mainstay of therapy.
In adults, there is a continuous spectrum between ___ and ___.
In adults, there is a continuous spectrum between thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
The Sepsis Spectrum
Fava beans and anemia
An important acute trigger of G6PD-deficiency anemia. Many people with G6PD don’t know they have it until they encounter an acute oxidant, like fava beans, primaquine, dapsone, etc. This can precipitate an acute hemolysis.
Why is it not helpful to measure oxidant resistance for G6PD diagnosis after an acute event that you believe was triggered by primaquine or another oxidant?
All of their cells that would have lysed did!!! The only ones surviving are the resistant ones now. You have to wait until they have been off the oxidant for a while before you can do a diagnostic test.
G6PD activity and red cell age
Pyruvate Kinase deficiency
Decreased ATP production in erythrocytes leads to insufficient ATP to power ion pumps. Thus, cells get dehydrated, and then trapped in the spleen! Retics are unaffected, as they retain their mitochondria to maintain ATP production.
Lifelong hemolysis. Relatively normal smear. Some spiculated cells, especially after splenectomy.
Will have elevated 2,3-DPG due to lack of PK activity.
Bite cells and blister cells indicate. . .
. . . oxidative damage to erythrocytes
