8/6- Hemolytic Anemia Flashcards Preview

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Flashcards in 8/6- Hemolytic Anemia Deck (67):
1

What is hemolytic anemia (broad def)?

What is seen with marrow production? Reticulocyte count?

Anemia caused by a shortened RBC lifespan

- Marrow production is typically normal or increased

- Reticulocyte count is increased

2

What may cause proliferative anemia?

- Hemolysis

- Blood loss

- Sequestration (big spleen)

3

What is the normal lifespan of a RBC?

About 120 days

4

What is the response of bone marrow to accelerated red cell destruction?

Increased production (more than 6-8x)!

5

What is seen in compensated hemolysis in regards to hematocrit and reticulocytes?

Hematocrit; normal

Reticulocytes: elevated

6

When does hemolytic anemia occur/what characterizes it?

Hemolytic anemia ensues when RBC survival is shortened to < 30 days

7

What are the phases of normal RBC senescent destruction?

1. Reticuloendothelial Phase

2. Transport and Hepatic Phases

3. Intestinal Phase

8

What are processes/steps of normal RBC senescent destruction in the reticuloendothelial phase?

- Macrophages do what?

- What happens to protoporphyrin?

- What happens to CO?

- What happens to Fe?

- What happens to globin chains?

- Macrophages in spleen, liver and bone marrow ingest old RBC (the reticuloendothelial system)

- Protoporphyrin is converted to bilirubin

- Carbon monoxide is generated and expired in lungs

- Iron is stored in macrophages as ferritin and hemosiderin

- Globin chains are hydrolyzed to amino acids, which can be re-utilized

9

T/F: There is typically some amount of intravascular destruction of normal RBCs

False! There is typically no intravascular destruction of normal red blood cells

10

What are processes/steps of normal RBC senescent destruction in the transport and hepatic phases?

- Unconjugated bilirubin binds to albumin, is transported to liver (not soluble!)

- Taken up by hepatocytes and conjugated by glucuronyl transferase (soluble!)

11

What are processes/steps of normal RBC senescent destruction in the intestinal phase?

Conjugated bilirubin excreted into bile is converted by bacteria to stercobilinogen which can be resorbed and excreted in the urine as urobilinogen

12

Overview (picture) of extravascular hemolysis

Extravascular hemolysis is just an acceleration of the usual pathway for senescent red blood cells

- RBC gobbled up by macrophage

- Globin converted into amino acids

- Heme converted into CO, Fe, and biliverdin

---Iron binds to transferrin

- Biliverdin converted to bilirubin and sent to liver as unconjugated form

- Liver conjugates and sends bilirubin glucuronides to colon (excreted as stercobilinogen?)

- Stercobilinogen sent to kidney and excreted as urobilinogen 

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13

What is direct bilirubin a measure of? Soluble or insoluble?

Direct = conjugated (soluble)

14

Overview (picture) of intravascular hemolysis

- Hemoglobin breaks down into its dimer and binds haptoglobin and is reclaimed in the liver

- Hemoglobin can overwhelm haptoglobin and go to the kidney where it passes into the urine as hemoglobinuria

- Some of the hemoglobin is take up by tubular cells and these cells are eventually sloughed into the urine and can be stained with Perl’s Prussian blue: hemosiderinuria

- Free heme is also generated and this is bound to another protein hemopexin and cleared by the liver

- Intravascular hemolysis results in plasma hemoglobin, hemoglobinuria, hemosiderinuria (if chronic), decreased haptoglobin, and typically increased LDH. 

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15

What are the 2 main categories of hyperbilirubinemia?

- Indirect (unconjugated) hyperbilirubinemia (acholuric)

- Direct (conjugated) hyperbilirubinemia

16

What characterizes indirect (unconjugated) hyperbilirubinemia (acholuric)?

- Elevation of total bilirubin with low direct

- Elevation of total is modest (under 5%)

17

What are some causes of indirect (unconjugated) hyperbilirubinemia (acholuric)?

- Hemolytic anemia

- Ineffective erythropoiesis

- Resorption of hematomas

- Sometimes hepatocellular disease

- Hereditary (Gilbert’s disease)

18

What characterizes direct (conjugated) hyperbilirubinemia?

- Elevation of total bilirubin with 50% or more direct

- Can be quite high

19

What are some causes of direct (conjugated) hyperbilirubinemia?

- Biliary obstruction

- Cholestasis (drugs, sepsis)

- Hepatocellular disease

- Hereditary (Dubin-Johnson)

20

What is seen in Gilbert's disease?

- Pts have mild intermittent jaundice (sometimes brought on by stress or dieting)

- Characterized by 70-80% reduction in the glucuronididation activity or uridine diphosphate glucuronosyltransferase isoform 1A1 or UGTA1

21

Hemolysis causes (direct/indirect) bilirubinemia? Unless?

Hemolysis causes indirect bilirubinemia

- Unless there is co-morbid hepatobiliary disease

22

What are the 2 classes of hemolytic anemia?

Are they hereditary or acquired?

How are transfused RBCs affected in each?

Intrinsic abnormality

- Hereditary (except PNH- paroxysmal nocturnal hemoglboniuria, which is acquired)

- Transfused RBCs typically have normal lifespan

Extrinsic abnormality

- Acquired

- Includes autoimmunity

- Transfused RBCs have shortened lifespan

23

What is another method of classifying hemolytic anemia?

By where the RBCs are destroyed

- Intravascular: red cells perish in the bloodstream

- Extravascular: red cells perish in the RE system

Hemolytic anemias can be mostly one or the other or a combination of both

24

Basic approach to hemolytic anemia?

- Hx and physical

- Review peripheral blood smear

- Reticulocyte count

25

What is this? 

Q image thumb

Hereditary elliptocytosis

26

What is a reticulocyte? What is seen in staining?

Youngest normal circulating RBC

- When a nucleated RBC precursor extrudes the nucleus

- The RNA in residual ribosomes stains supravitally with crisyl violet of methylene blue 

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27

Normally RBCs leaving the bone marrow stain as reticulocytes for how long?

24 hours

28

What is the normal reticulocyte count?

1%

29

What is the corrected (absolute) reticulocyte count?

It corrects for degree of anemia

30

Causes of reticulocytosis?

1. Treatment or resolution of hypo-proliferative anemia

---Recovery after aplastic crisis

---“Recovery” from relative hypoproliferative state (moving from Houston to Denver!)

---Treatment of iron, folate or B12 deficiency

2. Bleeding (in iron replete patient)

3. Myelophthisis (marrow with fibrosis or tumor; marrow so disordered that reticulocytes don't stay there)

4. Hemolytic anemia

31

What are some routine tests for hemolysis?

Results of:

- Hgb/hct

- Reticulocyte count

- Indirect bilirubin levels

- CBC, especially hgb/hct (decreased)

- Including smear review!

- Reticulocyte count (increased)

- Indirect bilirubin (increased)

32

What are test results of intravascular hemolysis?

- LDH

- Haptoglobin

- What in the plasma?

- What in the urine?

- LDH: increased

- Haptoglobin: decreased

- Plasma hemoglobin

- Urine hemoglobin and hemosiderin (iron in tubular cells shed into the urine)

33

What are some congenital causes of hemolysis?

Membrane abnormalities

- Hereditary spherocytosis

- Hereditary elliptocytosis

- Others

Enzymopathies

- G6PD deficiency

- Pyruvate kinase deficiency

- Others

Hemoglobinopathies

- Sickle cell disease

- Thalassemias (also ineffective erythropoiesis)

- Unstable hemoglobins

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34

What is seen here?

Q image thumb

Spherocytosis

35

What is seen here?

Q image thumb

HbSS

36

What is seen here?

Q image thumb

Elliptocytosis

37

What is seen here?

Q image thumb

HbSC

38

What are some acquired causes of hemolysis?

Immunologic

- Warm antibody, cold agglutinin, allo-immune

Fragmentation

- TTP, HUS, DIC, valve hemolysis Infections

- Malaria, Clostridia, Babesiosis

Metabolic/osmotic/chemical or physical agents

- Hypophosphatemia, Wilson’s disease, fresh water near drowning, burns

Membrane abnormalities

- Paroxysmal nocturnal hemoglobinuria, spur cell anemia Hypersplenism

39

What are examples of intravascular hemolytic events?

- ABO incompatible transfusion

- Clostridial sepsis

- PNH crisis

40

Symptoms of acute anemia?

- Chills, fever

- Dark or red urine

- Back and/or abdominal pain

- If severe: shock, DIC, acute renal failure

- In children: listlessness, irritability, or sleepiness

41

Complications of chronic hemolytic anemias?

- Anemia,

- Cholelithiasis (pigment stones)

- Splenomegaly, hypersplenism

- Leg ulcers

- Folate deficiency (megaloblastic crisis)

- Worsened anemia with intercurrent illness

---Accelerated hemolysis

---Decreased red cell production (ACD)

- Iron deficiency (chronic intravascular)

- Growth retardation in children, pubertal delay

- Venous thromboembolic disease/pulmonary hypertension

- Aplastic Crises with Parvovirus

42

What is this? 

Q image thumb

Pt PBS in hemolytic anemia?

43

What is the most likely acquired cause of hemolytic anemia associated with this blood smear?

A. Hereditary spherocytosis

B. Cold Agglutinin disease

C. Warm autoimmune hemolytic anemia

D. Microangiopathic hemolytic anemia

E. March hemoglobinuria or foot strike hemolysis 

Q image thumb

?

44

What are some immune hemolytic anemias?

Characteristics/tests for them?

Warm-Antibody-induced

- Coombs’ positive AIHA

Cold Agglutinin disease

Allo-Immune Hemolytic Anemia

- Hemolytic transfusion reactions

- Hemolytic disease of the newborn

Paroxysmal Cold Hemoglobinuria

45

What is AIHA (warm-antibody) hemolytic anemia?

Cause? Severity? Symptoms? Lab findings?

Immune cause: pt prodcues an Ab that targets autologous red cells

- IgG and/or C3 attaches to RBC membrane

Severity: variable

Presenting symptoms:

- Those of anemia

- Jaundice in 1/3

- Splenomegaly in 1/3

Lab findings;

- Smear: spherocytes common (warm AB), agglutination (cold AB)

- Positive DAT (Coombs) in 97% of pts

- Sometimes indirect Coombs positive as well

46

What is the direct Coombs' test (or Direct Antiglobulin Test, DAT)?

What is a positive finding?

- Patient’s erythrocytes are washed in NS to remove nonspecifically adherent IgG

- The washed cells are incubated with anti globulin sera, and more specific anti-IgG and anti-C3d

- After incubation, the cells are gently centrifuged and then observed for agglutination—or aggregation in a column

- Positive: immunoglobulin or complement is attached to cell surface

47

What is the indirect Coomb's test (or Indirect Antiglobulin Test, IAT)?

What is a positive finding?

- Normal RBCs (typically a panel) in a dilute suspension are incubated for 15-30 minutes with patient’s serum, then washed thoroughly with NS to remove the serum and nonspecifically adherent antibodies

- Antiglobulin serum is added and mixture incubated again - Cells centrifuged and checked for agglutination

- Agglutination = cells have acquired antibodies, complement, or both from patient’s serum

48

Table of typical scenarios in regards to DAT and IAT? 

Q image thumb

- If DAT is positive, lab will then do an IgG Coombs and a C3 Coombs

- For warm autoimmune hemolytic anemia (IgG): DAT+++, IgG+++, C3 +/-

- For cold agglutinin disease (IgM): DAT+++, IgG-, C3++ 

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49

- Findings for warm autoimmune disease?

- Findings for cold agglutinin disease?

- For warm autoimmune hemolytic anemia (IgG): DAT+++, IgG+++, C3 +/-

- For cold agglutinin disease (IgM): DAT+++, IgG-, C3++

50

What are some underlying causes of AIHA?

- Idiopathic in 1/3; in children often triggered by viral infections

- Lymphoproliferative disorders in 1/3

---CLL

---Non Hodgkin’s and Hodgkins lymphomas

- Systemic lupus erythematosus in 1/3

- Other immune disorders (sarcoid, thyroid)

- Common variable hypogammaglobulinemia, ALPS

- Less common, solid tumors

- Drugs

---Haptene mechanism (penicillin)

---Immune complex (quinine)

---Immune dysregulation (Aldomet)

 

51

Treatment of AIHA (warm)?

Corticosteroids

- decrease RE cell function, Ab finding, etc.

- response rate only 60% in adults

Splenectomy

- effective in 2/3, rarely done in children

Immunosuppression or immunomodulation

- anti-CD20 monoclonal Ab (rituximab)

- Cyclophosphamide, azathioprine

- IVIg

- Cyclosporine; Danazol

RBC transfusion (some caution)

52

What is this? 

Q image thumb

**Will see this on test**

Agglutination

- IgM antibody that agglutinates red cells in the presence of cold

- Indicative of IgM cold agglutinin syndrome

53

A 19 year old college student presents with fever cough

- Has chest X ray showing a small infiltrate

- Treated as walking pneumonia

- Gets better, but a week or so later

- Becomes fatigued short of breath and

- Has a hemoglobin of 7 and this smear.

Which one of these is most likely:

A. EBV virus infection

B. Mycoplasma

C. Pneumocystis carinii

D. Pneumococcal pneumonia

E. Hemophilus influenzae B 

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Which one of these is most likely: 

A. EBV virus infection 

B. Mycoplasma???

C. Pneumocystis carinii 

D. Pneumococcal pneumonia

E. Hemophilus influenzae B 

54

What causes cold agglutinin hemolytic anemia?

Extravascular or intravascular?

- Due to IgM antibodies, usually directed against I (or i) antigens

- Bind best to RBC at cold temperature (20°C)

- Avidly fix complement

- Extravascular and intravascular hemolytic component

55

What are direct Coombs' results in cold agglutinin hemolytic anemia?

Direct Coombs’ test may be negative in half—requires cold agglutinin titer

- When the direct Coombs is positive, the IgG Coombs is negative but the C3 Coombs is positive. These patients may have hemoglobinuria.

56

In adition to signs/symptoms of anemia, what else may be observed in cold agglutinin hemolytic anemia

Ischemia of fingers, earlobes

57

Causes of Cold Agglutinin Disease?

Monoclonal, Chronic Forms

- Lymphoproliferative disorders

- Chronic, Idiopathic

Polyclonal forms

- Mycoplasma pneumonia (Anti I)

- Infectious mononucleosis (Anti i, so Cord blood interacts)

- Other infections

- Systemic lupus erythematosus

58

Treatment of Cold Agglutinin Disease?

Infectious types

- Often transient→support

- Keep warm, gloves, earmuffs, move to Houston!

Corticosteroids usually ineffective

Splenectomy usually ineffective

Immunomodulatory drugs

- anti-CD20

- cyclophosphamide

- IVIg

RBC Transfusions

- Use a blood warmer!

59

What is this? 

Q image thumb

Microangiopathic hemolytic anemia

- Also note that there are no platelets in this high power field

- Helmets, schizocytes, and spherocytes are seen

- Remember that the spherocyte can be the end stage cell in any hemolytic process—when they predominate we think of HS and AIHA

60

Causes of MAHA?

- TTP

- HUS

- DIC

- Disseminated Carcinomatosis

- Obstetric

---Eclampsia, pre-eclampsia

---HELLP

---DIC—retained dead fetus, placenta previa and septic abortions

- Vasculitis

---SLE

---Acute glomerulonephritis

---Wegener’s

- Vascular Malformations

---Kasabach-Merritt Syndrome

---Hemangioendothelioma of liver

- Increased Shear Stress (platelets are often normal)

---Valves

---LVADs Etc

---Intracardiac patch repair

---March hemoglobinuria

- Malignant Hypertension

---Scleroderma

61

What is PNH (Paroxysmal Nocturnal Hemoglobinuria)?

Rare acquired disorder characterized by episodic intravascular hemolysis

- Relationship to Aplastic Anemia (10%) and AML (5%)

62

What is the most serious morbidity and mortality in PNH?

Related to thromboembolic complications:

- Budd-Chiari

- VTE

- Strokes, MIs, etc.

63

What is the pathophysiology of PNH?

- Mutation in PIG-A gene

- Impaired ability to form phospho-inositol glycoprotein membrane bridges

- At least 20 GPI (glycosyl-phosphatidyl-inosityl)-linked proteins are missing from the surface of PNH hematopoietic cells

- CD55 and CD59 are complement inhibitors

- Red cells (and other cells) are abnormally sensitive to complement lysis, resulting in intravascular hemolysis

64

Diagnosis of PNH?

- Mostly historic: sucrose hemolysis test and Ham’s acidified serum test, decreased leukocyte alkaline phosphatase

- Flow cytometry now diagnostic method of choice

- Red cells are most frequently analyzed, using monoclonal antibodies to the GPI-anchored proteins CD55 and CD59

65

Treatment of PNH?

- RBCs during acute crises

- Corticosteroids

- Anabolic steroids, Danazol

- Bone Marrow Transplantation

- Anticoagulation of Patients with Budd-Chiari Syndrome

- Eculizumab (Anti-C5)

66

What can hypersplenism cause?

Can cause any cell line (RBC, WBC, platelets) to be low, or any combination

- Degree of cytopenias roughly proportional to spleen size

67

Causes of splenomegaly?

Portal Hypertension (cirrhosis)

Infectious disorders

- Viral (mononucleosis, CMV)

- Malaria

- Bacterial (typhoid, brucellosis)

- Mycobacterial, Etc.

Infiltrative disease

- Gaucher’s; amyloidosis…

Neoplastic disorders

- Leukemias, lymphomas, myeloproliferative disorders

Hemoglobinopathies

- SCD, thalassemia