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Heme - Strom > Pathophysiology of Anemias II > Flashcards

Pathophysiology of Anemias II Flashcards

1
Q

T or F: multiple causes of Hemolysis may exist concurrently.

A

True, the most example is a GI bleed which causes blood loss and iron deficiency

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2
Q

What are the 2 common causes of hemolytic anemia?

A
  1. Intravascular Rupture
  2. Extravascular Hemolysis - Uptake of RBCs by phagocytes (such as those in the spleen or liver, aka Reticuloendothelial System)
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3
Q

What are 5 tests you can use to try to confirm Hemolytic Anemia in a patient?

A
  1. Free Hemoglobin
  2. LDH (lactose Dehydrogenase)
  3. Unconjugated Bilirubin
  4. Haptoglobin
  5. Peripheral Blood Smear
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4
Q

What is the pathophysiological basis for using Free Hemoglobin and LDH to detect hemolytic anemia?
- pitfalls?

A

Hemoglobin:
Red Tinge to Serum or Urine (aka Visible Hemolysis)
• Plasma Hgb detected in the urine when levels are severe in plasma or if Kidneys are Dysfunctional

Pitfalls
• Serum can appear red in traumatic blood draw
• Damage from kidney to Urethra can put blood cells into urine

LDH:
Tons of Lactose Dehydrogenase in Red Cells (b/c no aerobic respiration), if lots of them rupture then lots of LDH will end up in the plasma

Pitfalls
• Lymphoblast lysis in Acute Leukemias and lysis of other cells can elevate plasma LDH levels as well

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5
Q

What is the pathophysiological basis for using Unconjugated Bilirubin and Haptoglobin to detect hemolytic anemia?
- pitfalls?

A

Unconjugated Bilirubin:
End Product of Heme Catabolism gets dumped into serum faster than liver can metabolize and Serum turns YELLOW

Pitfalls:
• Liver Disease or Gilbert Syndrome may also cause it to be elevated

Haptoglobin:
Hemoglobin Recycling Transporter whose conc. gets REDUCED when lots of free Hgb is being cleared

Pitfalls:
• Its an acute phase reactant so its presence may be masked by the increase in haptoglobin in infectious/Inflammatory States

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6
Q

Where is the 1st place you should see evidence of hemolysis when you start investigating the condition?

A

Peripheral Blood Smear - you should see it here first because investigation of ANY hematologic disease begins with a Peripheral Blood Smear

• Reticulocytes will be Elevated

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7
Q

What is the difference between plasma and serum?

- limitations to using serum for lab enzyme assays.

A

Plasma - Liquid Portion of Blood
Serum - Liquid Left Over after letting a tube of blood clot

Serum Limitation - CANNOT be used to assess blood clotting abilities

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8
Q

What 5 aspects of RBC synthesis are most commonly defective genetic Hemolytic Anemias?

A
  1. Membrane (cable reinforced)
  2. Hgb
  3. Simplified ATP generating System (glycolysis)
  4. Anti-oxidant system (glutathione etc.)
  5. Surface Proteins that inhibit Complement Fixation
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9
Q

Defects in what proteins can lead to membrane Fragility of RBCs?

  • What is the job of each of these proteins?
  • What diagnostic Test is used?
A

Defects in anchors - Band 3, others
Defects in Cables - Spectrin
Defects in associated proteins - Ankyrin, others

Dx:
Osomotic Fragility Test - reduces osmolarity of environment to see how much expansion the RBC can handle

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10
Q

Clinical Terms that Refer to Cells with Membrane Abnormalities

  • Hereditary Spherocytosis
  • Hereditary Elliptocytosis
  • Pyropoikilocytosis
  • Stomatocytosis
A

Clinical Terms that Refer to Cells with Membrane Abnormalities

  • Hereditary Spherocytosis
  • Hereditary Elliptocytosis
  • Pyropoikilocytosis
  • Stomatocytosis
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11
Q

How can defects in hemoglobin lead to hemolytic disease?

  • what are some hemoglobinopathies known to cause hemolytic disease?
  • How to Dx?
A

Hemoglobin is packed as tight as it can be into RBCs, any sort of change in the amino acid sequence can cause the Hgb to precipitate into crystals causing damage to RBCs

Diseases: 
HEMOGLOBIN C Disease = Cytstals 
- Hgb S
- Hgb C
- Hgb SC
- Hgb E, and others

Dx:
- Hemoglobin Electrophoresis

**Note: these diseases have persisted because heterozygotes have some resistance to malaria

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12
Q

How does a ATP generating Deficiency manifest on a peripheral Blood Smear?

  • how do RBCs make ATP?
  • What Enzyme is Most Commonly Defective?
  • Dx?
A

ATP Deficiency:

  • POLYCHROMASIA (Red RBCs and Bluish RBCs will show up)
  • Increased Reticulocytes or

How:
PYRUVATE KINASE most commonly defective
(RBCs make ATP through glycolysis and rely heavily on this)

Dx:
- Enzyme Activity Test

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13
Q

Why does loss of an enzyme like Pyruvate Kinase lead to hemolysis?

A

ATP is needed to run the Na+/K+ pump

Na+/K+ pump is needed to maintain the osmotic gradient so that H2O doesn’t rush in due to all of the Hgb in the cell

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14
Q

What is the most common defect in the RBC antioxidant system?

  • why is this a problem?
  • Peripheral Smear, Stain used?
A
  • G6P deficiency is most common Defect

Why?
- G6P works in the PPP pathway to generate NADPH which is needed to reduce Glutathione sulfhydryl groups

  • Glutathione is needed to reduce oxidized protein and the ROS that oxidize these proteins

Smear:
- METHYLENE Blue stain will show HEINZ BODIES (oxidized Hgb crystals)

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15
Q

What populations are more likely to have G6P deficiency?

  • why?
  • what sorts of things can make their disease worse?
A

People from places where Malaria is Common are more likely to have this.
- Having RBCs that burst easily is an advantage against malaria because RBCs will burst before malaria can replicate in the cell

Exacerbation:

  • Fava Beans
  • Bactrim (sulfamethoxazole)
  • Anti-Malarials, others
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16
Q

What is Methemoglobinemia?

- what enzyme deficiencies are common causes of this?

A

Methemoglobinemia:
- Fe in heme gets oxidized to Fe+++ state and can’t bind oxygen in this state

Susceptible:

  • G6P deficient people can’t reduce back to Fe++
  • Cytochrome B5 Reductase (enzyme that Reduces Fe+++ back to Fe++)
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17
Q

What medications should you always avoid giving a G6P deficient patient?

A 
Dapsone
Methylthioninium Chloride (methylene blue) 
Nitrofurantoin 
Phenazopyridine 
Primaquine 
Rasburicase 
Tolonium Chloride (toluidine blue)
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18
Q

What defect leads to Paroxysmal Noctural Hemoglobinuria?

- what kind of mutation leads to this disease?

A

Hemolytic Disease resulting from a defect in DAF

Non-Malignant Acquired Colonal Proliferation:
- NOT inherited BUT occurs from SOMATIC acquisition of PIG-A enzyme defect in HEMATOPOIETIC Stem cells. PIG-A is needed to make the glycolipid that DAF needs in order to anchor onto the membrane

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19
Q

What are 4 bugs known to lyse RBCs?

A
  • Malaria
  • Babesia
  • Bartonella
  • C. Perfringes
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20
Q

What is typically the clinical context in which someone presents with malaria?
- vector?

A

Recent Travel to an Endemic Area (tropical, Subtropical)

Vector:
- Anopheles Mosquito

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21
Q

What are 3 general clinical features are common in people affected by malaria?
- what to look for in a smear?

A

3 general Clinical Features:

  • High Fever
  • Dark Urine
  • Jaundice

Smear:

  • Merozoites - early forms
  • Gametocytes - Late forms

***Look out for PLASMODIUM FALCIPARUM - the most deadly form of malaria

22
Q

What is Babesia

  • where is typically found/Clinical context?
  • Vector?
A

Babesia:
- Protozoal Intracellular Parasite with milder clinical course than Malaria

Vector:
- Transmitted by Ticks and Endemic in Northeastern US (MA, RI, NY)

23
Q

Bartonella Bacilliformis

  • acute vs. Chronic?
  • where is typically found/Clinical Context?
  • Vector?
A

Acute - SEVERE Anemia
Chronic - Peruvian Warts

Clinical Context:
- Recent travel to endemic area (Peru, Ecuador, Columbia)

Vector:
- Sand Flies

24
Q

Synonyms for disease caused by Bartonella Bacilliformis?

A
  • Carrion’s Disease

- Oroya Fever

25
Q

C. Perfringes

  • How does it cause hemolytic anemia?
  • other diseases caused?
  • Prognosis?
A

Clostridium Perfringes
- Part of the normal skin flora but can secrete ALPHA toxin that lyses RBCs

  • Can also cause Gas Gangrene

People with this type of anemia typically die

26
Q

In what clinical context might you see hemolytic anemia that results from C. Perfringes?

A

Septic Abortions
Cholecystitis (Rare Complication)
Various Cancers (Rare)

27
Q

What are the 2 possibilities of how antibodies can cause RBC destruction in warm autoimmune hemolytic anemia?
- is destruction partial or complete?

A
  1. Antibodies bind directly to the RBCs and they will be phagocytosed in the Reticuloendothelial System (RES)

Outcomes:

  • Bite Cells
  • Microspherocytes
  • Clearance (complete destruction)
  1. Antibodies bind to the RBC and fix complement leading to formation of the MAC.

Outcome:
- RBC lysis - aka INTRAVASCULAR HEMOLYSIS

28
Q

What are some key features to look for in a patient that you suspect might have Warm Autoimmune Hemolytic Anemia?

  • Lab Values?
  • Smear?
A

Lab:
- Indications of Hemolysis - elevated LDH, unconjugated Bilirubin, haptoglobin.

  • Direct or Indirect Antiglobulin Test (DAT) aka Coomb’s test
Smear: 
• Polychromasia 
• Basophilic Stippling
• Microspherocytes 
• Nucleated RBCs

**NO BLASTS OR MYELOCYTES

29
Q

Why might the Direct Coomb’s/ Direct Antiglobulin test not be accurate?

  • what similar test can be used in its place?
  • expected result?
A

RBCs with bound Ab. may lyse before you can ever perform the DAT (direct antiglobulin test)

  • Indirect Coomb’s/Antiglobulin Test can be used
  • this requires use of the pts. serum rather than their RBC’s, Abs. in their serum are expected to bind to the “Reagent” RBCs and cause agglutination when anti-human antibodies are added

Result:
• 3 different Reagent RBC preparations are used and and patients with WAIHA will be positive for them all.

30
Q

T or F: to Dx autoimmune hemolytic Anemia Coomb’s test findings must align with other lab results.

A

True, there is no single Dx. test, but a positive Coomb’s along with increased reticulocytes, hemolysis, increased LDH or haptoglobin is diagnostic

**Note: 8% of hospitalized pts. will have positive DAT

31
Q

What is the Difference between Warm and Cold Autoimmune Hemolytic Anemia?

A

Warm AIHA:

  • IgG mediated
  • Occurs at normal Body temp (37 ˚C)

Cold AIHA:

  • IgM mediated
  • Occrs at Temp. below and up to Body temp.
32
Q

What are cold agglutinins and what phenomenon do they cause?

A

IgM antibodies that bind to RBCs and cause agglutination

• In the periphery of the body they cause veno-occlusion = RAYNAUD’S PHENOMENON (they dissociate in the core where the RES is and so are not recongnized and removed)

**Note: most people have these but they don’t usually bind and agglutinate until the temperature gets down to 4˚

33
Q

Cold Agglutinins are only present between 4˚ and 30˚ and thus dissociate before encountering the RES (reticuloendothelial system) so how can hemolysis occur?

A

IgM can bind and Fix complement leading to MAC formation and clearance of RBCs.

34
Q

What are some Key Lab/clinical findings you look for in someone with Cold Autoimmune Hemolytic Anemia?

A
  1. RAYNAUD’S PHENOMENON
  2. Hemolysis by serum testing (elevated LDH, Unconjugated Bilirubin, and Haptoglobin)
  3. Red Cell Agglutination
  4. Polychromasia
  5. Nucleated Red Cells

**NO BLASTS OR MYELOCYTES

35
Q

How will Red cell lyses and agglutination affect the following lab values?

  • RBC count?
  • Hematocrit?
  • Hgb?
A
  • RBC count will be low because agglutinated cells will be counted as a single cell
  • Hematocrit will also be low because this is calculated from the red count and and the mean cell volume.
  • Hgb will be higher than expected given the hematocrit and RBC count because Hgb is existing outside of RBCs inside the body and is therefore useless, but the analyzer doesn’t know the difference
36
Q

What is you best option to get accurate data when you suspect that lab values have been obscured by cold agglutination?

A

Heat up the Specimen to get an accurate red count and Hematocrit

37
Q

T or F: like Warm autoimmune Hemolytic Anemia you need clinical as well as lab evidence to make a Dx on a patient.

A

True, there is no single lab test to tell you that you have either one of these diseases.

38
Q

Dx of Cold Autoimmune Hemolytic Anemia depends on…

A
  • Clinical Evidence of Hemolysis
  • Lab Evidence of Hemolysis (LDH, unconjugated Bili., Haptoglobin)
  • Lab Evidence of C3 on RBC’s (at 37˚)
39
Q

When doing antibody testing in someone who has cold autoimmune hemolytic anemia, what do you expect to see on the lab results?

A
  • DAT positive at Room temp for IgM (b/c its colder than body temp.)
  • Positive for C3 at 37˚
  • Ab. screening positive from room to 30˚
40
Q

What disease associations should you make with Warm and Cold Autoimmune Hemolytic Anemia?
- compare their prognosis.

A

Warm:
• Lymphoma, and other malignancies
• Drug associated

Cold:
• Viral Syndromes (pneumonia, mono)
• Mycoplasma Pneumonia

Both:

  • Lymphoma (can be with either but more strong association with warm)
  • SLE and RA
  • can just be idiopathic

Px:
Cold - Chronic, Seasonal (overall not that bad)
Warm - Poor

41
Q

What is the treatment for both warm and cold autoimmune hemolytic anemias?

A
  • Steriods

- Splenectomy if Steriods don’t work

42
Q

What disease should come to mind when you see Schistocytes on a slide?
- What causes this (proteins, process, etc.)?

A

Thrombotic Thrombocytopenic Purpura (TTP)
• Most Often results from Autoantibodies for AdamTS13 (the protein that normally cleaves vWF)

• vWF binds to collagen causing clot formation and fibrin deposition which slices RBCs in small and medium sized BVs.

43
Q

What are some general symptoms experienced by patients who suffer from Thrombotic Thrombocytopenia Purpura (TTP)?

  • Why is it essential that you catch this disease in the clinic?
  • treatment?
A
  • Clinically evident thrombosis in their Brains and Kidney’s (renal failure, fluctuating CNS symptoms) (w/o sepsis)
  • Low Platelet counts
  • Purpura resulting from subcutaneous hemorrhaging
  • Hemolytic Anemia
  • *Very Treatable and Deadly if you don’t catch it
    • Treamtent = Plasmaphoresis
44
Q

Who is typically affected by TTP resulting from an Autoantibody for AdamTS13?
- why is plasmaphoresis the treatment for this disease?

A
  • Young adults
  • Females affected more than males

Plasmaphoresis:

  • Removes Autoantibody
  • Replaces vWF
45
Q

What HUS?

- what defines this disease?

A

HUS = Hemolytic Uremic Syndrome

Definition:

  • Microangiopathic Hemolysis (MAHA)
  • thrombocytopenia
  • Renal Failure
46
Q

Differentiate between Typical HUS and Atypical HUS (aHUS).

  • Genetic or Environmental?
  • Principle Trigger?
  • Mechanism?
A

Typical HUS:
• Occurs most often in children under 5 after recent gastroenteritis resulting from E coli. O157, but other bugs that release Shiga Toxin can cause this as well.

  • Shiga Toxin (Stx) release causes excess complement fixation that cannot be treated with eculizumab.
  • This one is just environmentally induced

Atypical HUS:
• Occurs WITHOUT recent infection by Stx- secreting microbe, but there is still some sort of infectious trigger

• There must ALSO be a GENETIC predisposition for this disease so its both environmentally and genetically caused

47
Q

Why is important that you make a Dx differentiating between aHUS and HUS?
- how do you make a DDx here?

A
  • aHUS patients are responsive to Eculizumab (which inhibits complement fixation)
  • HUS patients are NOT (…weird)

**DDx depends on PCR-based evaluation to see if genetic components are involved

48
Q

**What is the standard progression of treatment when you encounter a patient that you suspect might have TPP, HUS, or aHUS?

A

1 you can’t wait to treat

1) order all necessary labs: ADAMTS13 level, HUS-associated mutation testing, Stool sample for PCR-based Stx-toxin assay
2) Treat for TTP (via therapeutic plasma exchange, TPE), keep doing if it works
3) if TPE isn’t effective AND pt. is STX positive, then treat with IV fluids and Dialysis as needed
4) if TPE isn’t effective AND pt. is positive for HUS genetic mutations then treat with Eculizumab OR plasma exchange.

49
Q

T or F: even if a blood transfusion is not mismatched patients can develope alloantibodies against foreign blood that can cause hemolysis.

A

True, if A, B and Rh are matched then it will be the second transfusion before we see rejection.

50
Q

A patient get jaundiced and weak about 1-7 days after a blood transfusion. What is likely the cause?

A

Delayed Hemolytic Transfusion reaction to proteins other than A/B/Rh

51
Q

Differentiate causes of delayed (days to a week) and acute hemolysis (instant to hours)?

A

Delayed:
Minor Antigens involved
(~350 of these) e.g. JK and RBC surface protein

Acute:
Major Antigens invoved
A, B, and Rh

Heme - Strom (13 decks)

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