Chapter 14: Anemias Flashcards
1
Q
In general, what are macrocytic vs. microcytic anemias each caused by?
A
- Macrocytic = abnormalities that impair maturation of erythroid precursors in the bone marrow
- Microcytic = disorders of hemoglobin synthesis (most often iron deficiency)
2
Q
Which mean cell volume (fL) is indicative of micro- vs. macrocytic anemia?
A
- MCV <80 = microcytic
- MCV >100 = macrocytic
3
Q
What does an elevated Red Cell Distribution Width (RDW) tell us?
A
- That marrow is pumping out reticulocytes (larger cells)
- Elevated RDW is a reactive phenomenon observed in states of anemia with a functioning marrow
4
Q
Which changes are seen in red cells, white cells, and platelets with acute blood loss?
A
- Leukocytosis
- Reticulocytosis
- Thrombocytosis
5
Q
A male or post-menopausal female presenting with iron-deficiency anemia is indicative of what until proven otherwise?
A
GI tract lesion
6
Q
Hemolytic anemias share what 3 red cell related features?
A
- A shortened red cell life span below typical 120 days
- ↑ EPO levels and compensatory ↑ in erythropoiesis
- Accumulation of hemoglobin degradation products as part of red cell hemolysis
7
Q
What ar the 3 principal clinical features of extravascular hemolysis?
A
- Anemia
- Splenomegaly
- Jaundice
8
Q
Patients with extravascular hemolysis often benefit from what?
A
Splenectomy due to much of the pathologic destruction of RBC’s occurring in the spleen
9
Q
What are the 5 main manifestations of intravascular hemolysis?
A
- Anemia
- Hemoglobin-emia
- Hemoglobin-uria
- Hemosiderin-uria
- Jaundice
10
Q
In all types of uncomplicated hemolytic anemias, the excess serum bilirubin is of what type?
A
Unconjugated
11
Q
What happens to the levels of serum haptoglobin with extra- and intravascular hemolysis?
A
- Extravascular = variably decreased as some Hgb escapes phagocytes
- Intravascular = becomes markedly reduced–> freeHgboxidizes tomethemoglobin
12
Q
Regardless of the cause of type of hemolytic anemia what morphological changes are seen in the peripheral blood and BM?
A
- ↑ numbers of erythroid precursors (normoblasts) in the marrow
- Prominent reticulocytosis in the peripheral blood
13
Q
With chronic hemolysis, elevated biliary excretion of bilirubin promotes what?
A
Formation of pigment gallstones (cholelithiasis)
14
Q
Hereditary spherocytosis is an inherited disorder caused by intrinsic defects in what?
A
Red cell membrane skeleton –> cells are spheroid, less deformable, and vulnerable to splenic sequestration
15
Q
What is the inheritance pattern of hereditary spherocytosis; prevalence is highest where?
A
Autosomal Dominant (75% of cases); highest in Northern Europe
16
Q
What is the characteristic morphology of the red cells seen on smears in pt with hereditary spherocytosis?
A
Small, dark-staining (hyperchromic) red cell lacking central zone of pallor
17
Q
Characteristc morphology of the spleen in hereditary spherocytosis?
A
Moderate splenomegaly (500-1000 gm)
18
Q
Red cells of hereditary spherocytosis are abnormally sensitive to what; what is the MCHC finding?
A
- Osmotic lysis when incubated w/ hypotonic salt solution
- HS red cells also have ↑ MCHC, due to dehydration caused by loss of K+ and H2O
19
Q
Characteristic clinical findings of hereditary spherocytosis are what; some may be asymptomatic but most will have what type of anemia?
A
- Splenomegaly + jaundice + anemia +/- gallstones
- CHRONIC hemolytic anemia of mild to moderate severity
20
Q
Aplastic crises occurring in the setting of hereditary spherocytosis is often triggered by what?
A
Parvovirus B19 infection (ssDNA virus)
21
Q
How is the anemia and its complications in hereditary spherocytosis treated?
A
Splenectomy
22
Q
What are the most common triggers responsible for the episodic hemolysis seen with G6PD deficiency?
A
- Infections: viral hepatitis, pneumonia, and typhoid fever
- Drugs: ASA, diphenhydramine, antimalarials, sulfonamides, and nitrofurantoins
- Foods: including simple CHO’s, tonic water, sulfites (wine and dried fruit), and fava beans** (endemic in Mediterranean, ME, and Africa)
23
Q
The acute intravascular hemolysis is greater in pt’s with which variant of G6PD deficiency?
A
Mediterranean variant
24
Q
What is seen 2-3 days following exposure of G6PD-deficienct pt’s to oxidants?
A
Acute intravascular hemolysis marked by anemia, hemoglobinemia, andhemoglobinuria
25
Sickle cell disease is due to a point mutation at which codon of β-globin; causes the replacement of which AA's?
**6th codon** of **β-globin** causing replacement of **glutamate ---\> valine**
26
Why do patients with hereditary persistence of HbF experience less severe sickle cell disease?
**HbF** inhibits polymerization of **HbS** even more than **HbA**
27
Why do individuals who are homozygous for HbS but also have co-existent α-thalassemia have decreased severity of disease?
- α-thalassemia **reduces Hgb synthesis** which **↓ MCHC**
- ↑ MCHC levels facilitate **sickling**
28
What factor is responsible for the vascular occlusion seen most prominently in the spleen, bone marrow, and inflammed tissues in a pt with sickle cell disease?
- **BM/Spleen** = **sluggish blood flow** through **microvascular beds**
- **Inflammed** = slowed blood due to **adhesion** of **leukocytes** to **activated endothelial cells** and **transudation** of fluid thru **leaky vessels**
29
Which AA's are swapped in the HbC variant?
Glutamic acid ---\> **lysine** ("ly**C**ine") in 6th AA of β-globin
30
How does the release of free hemoglobin from lysed sickle red cells contribute to vasoconstriction, ↑ platelet aggregation, stasis, sickling, and thrombosis?
Free Hbg can **bind** and **inactivate NO**, which is a potent vaso**dilator** and inhibitor of **platelet aggregation**
31
Which crises due to vaso-occlusion is extremely common in children w/ sickle cell disease; how does it manifest?
- **Painful bone** crises and often **difficult** to distinguish from **osteomyelitis**
- Most frequently manifest as **hand-foot syndrome** or **dactylitis** of the bones of the **hands** or **feet**, or **both**
32
Up to 45% of males with sickle cell disease are affected by what after puberty?
**Priapism** --\> may lead to **hypoxic damage** and **ED**
33
How does acute chest syndrome as a complication of sickle cell disease present?
**Fever** + **cough** + **chest pain** + **pulmonary infiltrates**
34
Sequestration crises occur in which pt's with sickle cell disease and how does it manifest?
- **Children** w/ **intact spleens**
- **Massive** entrapment of sickle red cells leads to **rapid splenic enlargement** + **hypovolemia**, and sometimes **shock**
- May be **fatal**
35
A sudden worsening in the anemia of a patient with sickle cell disease should prompt you to consider what underlying cause?
**Aplastic crises** due to **Parvovirus B19**
36
Chronic hypoxia in children with sickle cell disease is responsible for impairment in what?
**Growth** and **development**, as well as **organ damage** affecting **spleen, heart, kidney**, and **lungs**
37
Sickling provoked by hypertonicity in the renal medulla causes damage and eventually leads to what?
**Hyposthenuria** (inability to concentrate urine) --\> ↑ propensity for **dehydration**
38
What is the most common cause of death in adults vs. children w/ sickle cell disease?
- **Adults** = Acute Chest Syndrome
- **Children** = *Haemophilus influenzae*
39
How does the morphology of the spleen change from childhood to early adulthood in pt with sickle cell disease?
- **Children** have **splenomegaly** due to **red pulp congestion** caused by trapping of sickled cells in the **cords** and **sinus**
- **Early adulthood** will have **autosplenectomy** as chronic erythrostasis leads to **splenic infarction**, **fibrosis**, and progressive **shrinkage**
40
Leg ulcers are a common finding in which patients with sickle cell disease?
Adults
41
Which is more common and serious, Hgb C or Hgb SC disease?
**Hgb SC** is **more common** and **severe**
42
What is the distinctive morphology of Hgb C which may be seen on routine peripheral blood smear?
**Crystalline form**
43
The defects in globin synthesis that underlie thalassemia disorders cause anemia through what 2 mechanism?
- ↓ red cell production
- ↓ red cell life-span
\***NOT** primarily **hemolysis**\*
44
How is β-globin synthesis affected in β0 mutations vs. β+ mutations; what is the most common underlying mutation for each?
- **β0** mutation: **absent** β-globin **synthesis**; most commonly due to **chain terminator mutation**
- **β+** mutation: **reduced** (but detectable) β-globin synthesis; most commonly due to **splicing mutations**
45
Impaired β-globin synthesis in β-thalassemia causes a deficit in HbA synthesis producing what type of red cells?
"**Underhemoglobinized"** hypochromic, microcytic red cells
46
What occurs to the unpaired α-chains seen in β-thalassemia; what is the proximal cause of most red cell pathology?
- **Precipitate** within red cell precursors, forming **insoluble inclusions**
- Prox. cause of red cell pathology is **membrane damage** caused by these inclusions; also undergo **apoptosis**
47
What are some of the complications due to ineffective erythropoiesis seen in severe β-thalassemia?
- **Massive erythroid hyperplasia** in marrow and extensive extramedullary hematopoiesis ---\> **erosion** of **bony cortex** + **hepatosplenomegaly**
- Metabolically **active** erythroid progenitors **steal** nutrients from already hypoxic tissues causing **severe cachexia** in untreated pt's
- **Suppresses hepcidin** = ↑ iron absorption on top of **repeat transfusions** can lead to **seconary hemochromatosis**
48
β-thalassemia major is most common where?
**Mediterranean** countries, parts of **Africa**, and **SE Asia**
49
How soon after birth does the anemia of β-thalassemia major present?
**6-9 months** after birth as Hgb synthesis switches from **HbF** --\> **HbA**
50
What are the major manifestations of bone seen in pt with untreated β-thalassemia major?
- **Hypoxia --\> ↑ EPO** --\> **Expansion** of **marrow** erodes **existing** cortical bone and induces new bone formation of the **skull** and **face**
- Giving rise to **"crewcut" appearance** on **X-ray**
51
Blood transfusions may improve the anemia and suppress complications related to excessive erythropoiesis in β-thalassemia, but may lead to what complications?
**Cardiac disease** and **2' hemochromatosis** from **excessive iron overload** = **important** cause of **death**
52
What is survival like in pt's with β-thalassemia major who receive transfusions and iron chelation; what is the only therapy offering a cure?
- **Transfusions + chelators** = survival into the **3rd decade**
- **Hematopoietic stem cell transplantation** = only **cure**
53
What are the levels of HbF and HbA2 like in β-thalassemia minor?
- ↑ levels of **HbA2**
- **HbF** levels are **normal** or sometimes slightly ↑ (will be **↑**↑**↑** in **major**)
54
Recognition of β-thalassemia minor (trait) is important for what 2 reasons?
- Superficially **resembles** the **hypochromic microcytic anemia** of **iron deficiency**
- Has **implications** for **genetic counseling**
55
Which value is diagnostically useful in women of childbearing age who are at risk for both β-thalassemia trait and iron deficiency?
**HbA2** --\> ↑ in β-thalassemia minor (trait)
56
Basophilic stippling seen on smears of β-thalassemia major are indicative of what?
**Toxic injury** to **RBC's**
57
α-thalassemias are caused by what?
Inherited **_DELETIONS_** that result in **reduced** or **asbent** synthesis of **α-globins** (compared to β-thalassemias which are due to **mutations**)
58
How do the tetramers formed in infants with α-thalassemia differ from that of older children/adults?
- **Infants** form **γ4** tetramers known as **hemoglobin barts**
- **Older children/adults** form **β4** tetramers known as **HbH**
59
α-thalassemia trait is caused by deletion of how many α-globin genes and what 2 ways can this occur; which populations more affected?
- Deletion of **2** α-globin genes
- From **single chromosome** = **α/α -/-** = **Asians**
- From **two chromosomes** = α/- α/- = **African**, **Asian**
60
Clinically significant α-thalassemia is more common in children born to a parent with what type of halotype?
At least one parent with **-/- halotype**; more often seen in **Asians**
61
What is the clinical picture like in someone with α-thalassemia trait?
- **Small red cells** (**microcytosis**) **+ minimal** or **no anemia**
- **No abnormal physical signs**
- **HbA2 levels** are **normal** or **low**
\*Resembles β-thalassemia minor\*
62
Hemoglobin H Disease (HbH) is caused by deletion of how many α-globin genes and is most common in which population?
- Deletion of **3** α-globin genes
- Most common in **Asian populations**
63
Why is there tissue hypoxia disproportionate to the level of hemoglobin in patients with HbH disease?
**HbH** has **extremely** ↑ affinity for **O2**
64
What is the anemia like in HbH disease and it resembles that of which β-thalassemia?
- **Moderately severe anemia**
- Resembles that of β-thalassemia **intermedia**
65
What is the most severe form of α-thalassemia called and is due to what?
- **Hydrops fetalis**
- Due to **deletion** of **all 4 α**-**globin** genes
- Excess **γ-globin** chains form **hemoglobin barts** that have such a **high affinity** for O2 that they deliver little to tissues
66
When does hydrops fetalis become evident and what must be done for survival of the infant?
- **Fetal distress** becomes evident during **3rd trimester**
- **Require intrauterine transfusions**
- There will be **lifelong dependence** on **blood transfusions** for survival w/ the assoc. risk of **iron overload**
67
What is the only hemolytic anemia caused by an acquired genetic defect?
Paroxysmal Nocturnal Hemoglobinuria **(PNH)**
68
What is the inheritance pattern and dysfunctional enzyme in Paroxysmal Nocturnal Hemoglobinuria (PNH)?
- **X-linked** and subject to **lysonization** (random inactivationof one X chromosome in cells of females)
- Mutation of **PIGA** which encodes **enzyme** essential for **GPI**-linked proteins that regulate **complement** activity
69
In Paroxysmal Nocturnal Hemoglobinuria (PNH) blood cells are deficient in which 3 GPI-linked proteins that regulate complement; which is most important?
- **Decay-accelerating factor** (CD**55**)
- **Membrane inhibitor** of **reactive lysis** (CD**59**) = **most important**; potent inhibitor of **C3 convertase**, prevents spontaneous activation of **alternative complement path**
- **C8 binding protein**
70
What is the leading cause of death in pt's with Paroxysmal Nocturnal Hemoglobinuria (PNH)?
**Venous Thrombosis**, often involving **hepatic**, **portal**, or **cerebral** veins
71
5-10% of patients w/ Paroxysmal Nocturnal Hemoglobinuria (PNH) are at risk for developing which hematopoietic disorders?
**AML** or **a myelodysplastic syndrome**
72
Which monoclonal antibody can be used in PNH to prevent conversion of C5 to C5a and reduce risk of venous thrombosis by 90%?
**Eculizumab**
73
How is the diagnosis of Paroxysmal Nocturnal Hemoglobinuria (PNH) made?
**Flow cytometry** to detect red cells deficient in GPI-linked proteins such as CD59
74
What are the secondary causes of the warm antibody type of immunohemolytic anemia?
- **Autoimmune** disorders
- **Drugs**
- **Lymphoid neoplasms**
75
Most of the causative antibodies of the warm antibody type of immunohemolytic anemia are of what class?
**IgG**
76
What occurs in the pathophysiology of warm antibody types of immunohemolytic anemias?
- **IgG**-coated **red cells** bind **Fc** receptors on **phagocytes**, which remove the red cell membrane via **"partial" phagocytosis**
- Loss of membrane creates **spherocytes** which are sequestered and destroyed in the **spleen** ---\> **moderate splenomegaly**
77
Explain how antigenic drugs can cause warm antibody type of immunohemoltyic anemias and what are 2 drugs this is commonly seen with?
- **1-2 weeks** after initiating therapy w/ **large IV doses** of drugs such as **penicillin** or **cephalosporin**
- Drugs bind red cell membrane and antibodies can act as **opsonins** that promote **extravascular hemolysis**
78
What is the prototypical tolerance breaking drug responsible for warm antibody type of immunohemoltyic anemias; how does this occur?
- **α-methyldopa**
- Induces production of antibodies againt red cells antigens, particularly the **Rh antigen**
79
What are some conditions associated with microangiopathic hemolytic anemia?
- **DIC** = **most common**
- **Thrombocytopenic purpura (TTP****)**
- **Hemolytic-uremic syndrome (HUS)**
- **Malignant HTN**
- **SLE**
- **Disseminated cancer**
80
What is the morphology of both red cells and neutrophils seen on a blood smear in megaloblastic anemia?
- **Red cells** = macrocytic and oval (**macro-ovalocytes**) w/ variation in size (**anisocytosis**) and shape (**poikilocytosis**)
- **Neutrophils** = larger than normal (**macropolymorphonuclear**) and show **nuclear hypersegmentation**, having **5+ nuclear lobes**
81
Why is there pancytopenia in megaloblastic anemia if there are increased hematopoietic precursors being produced in the marrow?
**Abnormal DNA synthesis** causes most precursors to undergo **apoptosis** in the marrow
82
Pernicious anemia is a specific form of megaloblastic anemia caused by what?
**Autoimmune gastritis** impairiring production of **IF** needed for **Vit B12 uptake**
83
What is the proximate cause of anemia in vitamin B12 deficiency?
Lack of **folate**
84
What is thought to initiate the gastric mucosal injury underlying autoimmune gastritis and pernicious anemia?
**Autoreactive T-cell** response **initiates** the injury and triggers formation of **autoantibodies**
85
What are the characteristic morphological changes seen in the stomach of pt w/ autoimmune gastritis (pernicious anemia)?
- **Fundic gland atrophy**
- **Intestinalization** --\> glandular epithelium undergoes **metaplasia** to mucus-secreting goblet cells that resemble the lining of the large intestine
86
Long-standing pernicious anemia causes what finding of the tongue?
**Atrophic glossitis** = **beefy red tongue**
87
Which sx's of B12 deficiency respond to folic acid administration and which do not?
- **Hematologic** sx's (**anemia**) may **improve**
- **Neuro** sx's will **NOT** and may even **worsen**
88
Diagnosis of pernicious anemia is based on what 4 findings?
- Moderate to severe **megaloblastic anemia**
- **Leukopenia** w/ **hypersegmented granulocytes**
- **Low serum B12**
- ↑ levels of **homocysteine** and **methylmalonic acid**
89
Diagnosis of pernicious is **confirmed** how?
**Parenteral B12** causes an outpouring of **reticulocytes** and a rise in **hematocrit levels** around **5 days** after beginning administration
90
Elevated homocysteine levels as seen in vitamin B12 deficiency are a risk factor for what?
**Atherosclerosis** and **thrombosis**
91
Porphyria accumulation in the liver is associated with what conditions?
- **Liver damage** w/ **hepatic insufficiency**
and
- ↑ risk for **hepatocellular carcinoma**
92
What are the clinical signs/sx's associated with chronic porphyrias?
- **Skin** = very sensitive to sunlight --\> blistering, abnormal hair growth
- **Teeth** = staining
93
What are the clinical signs/sx's associated with acute porphyrias?
- **Referred pain** from the **thorax** and **abdomen**
- **Seizures**, **hallucinations**, and **general psychosis**
94
Which lab values and clinical signs/sx's distinguish a true folate deficiency from that of Vit B12 as a cause of megaloblastic anemia?
- Serum **homocysteine** levels are ↑, but **[methylmalonate]** = **normal**
- **Neurological changes** do **NOT** occur w/ **pure folate deficiency**
95
What is the effect of diseases with ineffective erythropoiesis leading to 2' hemochromatosis (i.e., β-thalassemia) on hepcidin levels?
**Suppresses** hepatic **hepcidin** production, even when **iron levels are high**
96
What are the HCT, Hgb, serum iron, ferritin, TIBC, and hepcidin levels like with iron deficiency anemia?
- **HCT, Hgb** **=** ↓
- **Serum iron =** ↓
- **Serum ferritin =** ↓
- **TIBC** = ↑
- **Serum hepcidin** = ↓
97
What is a diagnostically significant finding in the bone marrow with iron deficiency anemia?
**Dissapearance** of **stainable** **iron** from **macrophages**; best assessed with **Prussian blue stain** on smear of **aspirated marrow**
98
What is seen morphologically on peripheral blood smear of iron deficiency anemia?
Red cells are **hypochromic microcytic** w/ modest **poikilocytosis**
99
The chronic illnesses associated w/ anemia of chronic disease can be grouped into what 3 categories?
- **Chronic microbial infections**, such as **osteomyelitis**, bacterial **endocarditis**, and **lung abscess**
- **Chronic immune disorders**, such as **RA** and regional **enteritis**
- **Neoplasms**, such as **carcinomas** of the **lung** and **breast**, and **Hodgkin lymphoma**
100
Which inflammatory mediator associated with anemia of chronic disease is responsible for the increased production of hepcidin?
**IL-6**
101
Which 2 lab values distinguish anemia of chronic disease from iron deficiency anemia?
**High** **ferritin** and **low** **TIBC**
102
Aplastic anemia is a syndrome characterized by what?
**Chronic primary hematopoietic failure** + attendant **pancytopenia** (anemia, neutropenia, and thrombocytopenia)
103
What is the inheritance of Fanconi anemia and the dominant clinical features?
- **AR** caused by defects in **multiprotein complex** required for **DNA repair**
- **Marrow HYPO**function **early** in life, often other **congenital anomalies**, such as **hypoplasia** of **kidney** and **spleen**
- **Bone anomalies**, most commonly of **thumbs** or **radii**
104
List 6 physical agents/infections which may cause aplastic anemia?
- Whole-body **irradiation**
- **Viral infections**
- **Hepatitis** (non-A,B,C, or G type)
- **CMV**
- **EBV**
- **Herpes zoster** (**varicella zoster**)
105
What are 2 types of mutations which are associated with adult-onset aplastic anemia?
- Inherited defects in **telomerase**
- Abnormally **short telomeres**
106
What are the 2 major etiologies which have been proposed for the pathogenesis of aplastic anemia?
- **Extrinsic**, immune-mediate suppression of amrrow progenitors thru **activated TH1 cells** producing **IFN-y** and **TNF**
- **Intrinsic**, abnormality of **stem cells**; may be antigenically altered via exposure to drugs, infectious agents, etc.
107
How is the diagnosis of aplastic anemia made and what are you looking for?
- **Examination** of the **bone marrow** via **biopsy**
- Markedly **HYPOcellular** BM largely devoid of hematopoietic cells; only **fat cells**, **fibrous stroma**, and scattered **lymphocytes** + **plasma cells**
108
What are the presenting signs/sx's that may be seen with aplastic anemia?
- **Anemia** ---\> weakness, pallor, and dyspnea
- **Thrombocytopenia** --\> petechiae and ecchymoses
- **Neutropenia** --\> frequent/persistent minor infections or sudden onset chills, fever, and prostration
109
What is the morphology of the red cells in aplastic anemia; what is the rule?
- Slightly **macrocytic** and **normochromic**
- **Reticulocytopenia** is the rule
110
What is the treatment of choice for aplastic anemia; prognosis?
**Bone marrow transplant**; 5-year survival of **75%**
111
Pure red cell aplasia may occur in association with what conditions?
- **Thymoma**
- **Large, granular lymphocytic leukemia**
- **Drug exposures**
- **Autoimmune disorders**
- **Parvovirus B19**
112
With the exception of parvovirus, most pure red cell aplasias have what type of basis?
Autoimmune
113
How does the pure red cell aplasia associated with Parvovirus differ in a healthy pt vs. pt with moderate/severe hemolytic anemia?
- **Normal** = the aplasia is **transient** and infection cleared **1-2 weeks**
- Pt w/ **moderate** to **severe hemolytic anemia**, even a brief cessation of erythropoiesis results in **rapid worsening** of the **anemia** --\> **aplastic crisis**
114
What is Myelophthisic anemia and the most common cause?
- **Marrow failure** due to **space-occupying lesions** replacing normal marrow elements
- **Most commonly** due to **metastatic cancer**, often **carcinoma** of the **breast, lung**, and **prostate**
115
Myelophthisic anemia is also a feature of which phase of myeloproliferative disorders?
Spent phase
116
What is the seen in both the marrow and peripheral blood with Myelophthisic anemia?
- **Marrow** distortion and **fibrosis**
- Abnormal release of **erythroid precursors** and **immature granulocytic** forms (**leukoerythroblastosis**)
- Appearance of **tear-drop shaped red cells**
117
How does chronic renal failure lead to anemia and what is the severity of the anemia proportional to?
- Due to **diminished** synthesis of **EPO** by the **kidney**
- **Anemia** tends to be **proportional** to the **severity** of the **anemia**
