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1

RBC lacks

Nucleus and organelles

2

RBC source of energy

Glucose → 90% used in glycolysis, 10% used in HMP shunt

3

Compare anisocytosis and poikilocytosis

Anisocytosis → varying sizes

Poikilocytosis → varying shapes

4

Granules stored in platelets

Dense granules → ADP, Ca2+

Alpha granules → vWF, fibrinogen, fibronectin

5

Granulocytes

Neutrophils, eosinophils, basophils

6

Mononuclear cells

Monocytes, lymphocytes

7

Granules stored in neutrophils

Specific granules → leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, lactoferrin

Azurophilic granules → lysosomes, proteinases, acid phosphatase, myeloperoxidase, β-glucuronidase

8

Neutrophilic chemotactic agents

- C5a
- IL-8
- LTB4
- Kallikrein
- Platelet-activating factor

9

Macrophages are an important component in the formation of what

Granulomas

10

Lipid A from bacterial LPS binds what to initiate septic shock

CD14 on macrophages

11

Causes of eosinophilia

- Neoplasia
- Asthma
- Allergic processes
- Chronic adrenal insufficiency
- Parasites (invasive)

"NAACP"

12

Eosinophils produce

- Histaminase
- Major basic protein (a helminthotoxin)

13

Granules in basophils contain

- Heparin (anticoagulant)
- Histamine (vasodilatory)

- Leukotrienes are synthesized and released on demand

14

Degranulation of mast cells leads to release of

- Histamine
- Heparin
- Tryptase
- Eosinophil chemotactic factors

Mast cells contain basophilic granules, just like basophils

15

What cells originate from the same precursor as basophils

Mast cells

16

Where are plasma cells found

Found in bone marrow and normally do not circulate in peripheral blood

17

Where does fetal erythropoiesis occur

- Yolk sac (3-8 weeks)
- Liver (6 weeks - birth)
- Spleen (10-28 weeks)
- Bone marrow (18 weeks to adult)

"Young Liver Synthesizes Blood"

18

Migration pattern for hemoglobin

Furthest from cathode (-)

Normal adult (AA) → Normal newborn (AF) → Sickle cell trait (AS) → Sickle cell disease (SS) → HbC train (AC) → Hb C disease (CC) → Hb SC disease (SC)

"A Fat Santa Claus"

19

Anticoagulant with greatest efficacy against factors Xa and IIa

Factor Xa → LMWH

Factor IIa (thrombin) → heparin

20

Enzyme responsible for reducing vitamin K

Epoxide reductase

21

vWF protects and carries which factor

VIII

22

Antithrombin inhibits activated forms of which factors

II, VII, IX, X, XI, XII

23

What are the principal targets of antithrombin

Thrombin and factor Xa

24

How do protein C and S work as anticoagulants

Protein C → Activated Protein C
- via Thrombin-thrombomodulin complex in endothelial cells

Activated Protein C + Protein S → Cleaves and inactivates Va, VIIIa

25

Describe primary hemostasis

INJURY→ endothelial damage → transient vasoconstriction via neural stimulation reflex and endothelin (released from damaged cell)

EXPOSURE → vWF binds to exposed collagen; vWF is from Weibel-Palade bodies of endothelial cells and α - granules of platelets

ADHESION → platelets bind vWF via GpIb receptor at the site of injury only (specific) → platelets undergo conformational changes → platelets release ADP and Ca2+ (necessary for coagulation cascade) and TXA2 → ADP helps platelets adhere to endothelium

ACTIVATION → ADP binding to receptor induces GpIIb/IIIa expression at platelet surface

AGGREGATION → fibrinogen binds GpIIb/IIIa receptors and links platelets

26

Pro-aggregation factors

- TXA2 (released by platelets)
- ↓ blood flow
- ↑ platelet aggregation

27

Anti-aggregation factors

- PGI2 and NO (released by endothelial cells)
- ↑ blood flow
- ↓ platelet aggregation

28

Mechanism of ristocetin

- Activates vWF to bind GpIb
- Failure of agglutination with ristocetin assay occurs in von Willebrand disease and Bernard-Soulier syndrome

29

Acanthocyte

- Liver disease
- Abetalipoproteinemia (states of cholesterol dysregulation)

30

Basophilic stipiling

- Lead poisoning
- Sideroblastic anemias
- Myelodysplastic syndromes

31

Dacrocyte

Bone marrow infiltration (eg myelofibrosis, osteopetrosis)

32

Degmacyte

G6PD deficiency

33

Echinocyte

- End-stage renal disease
- Liver disease
- Pyruvate kinase deficiency

Different from acanthocyte; its projections are more uniform and smaller

34

Elliptocyte

- Hereditary elliptocytosis (usually asymptomatic)
- Caused by mutation in genes encoding RBC membrane proteins (eg spectrin)

35

Macro-ovalocyte

- Megaloblastic anemia (also, hypersegmented PMNs)
- Marrow failure

36

Ringed sideroblast

- Sideroblastic anemia
- Excess iron in mitochondria

37

Schistocyte

- DIC
- TTP/HUS
- Mechanical hemolysis (eg heart valve prosthesis)

Examples include "helmet cells"

38

Sickle cell

Sickle cell anemia

Sickling occurs with dehydration, deoxygenation and at high altitude

39

Spherocyte

- Hereditary spherocytosis
- Drug and infection induced hemolytic anemia

40

Target cell

- HbC
- Asplenia
- Liver disease
- Thalassemia

"HALT"

41

Heinz bodies

G6PD deficiency

Oxidation of Hb-SH groups to -S-S- → Hb precipitation (Heinz bodies) with subsequent phagocytic damage to RBC membrane → degmacyte ("bite cell")

42

Howell-Jolly bodies

- Seen in patients with functional hyposplenia or asplenia
- Basophlic nuclear remnants found in RBCs
- Howell-Jolly bodies are normally removed from RBCs by splenic macrophages

43

How does lead poisoning cause basophilic stippling

Inhibits rRNA degradation → RBCs retain aggregates of rRNA (basophilic stippling)

44

Symptoms of lead poisoning

- Lead Lines on gingivae (Burton lines) and on metaphyses of long bones on x-ray
- Encephalopathy and Erythrocyte basophilic stippling
- Abdominal colic and sideroblastic Anemia
- Drops - wrist and foot drop

"LEAD"

45

Treatment of lead poisoning

- Dimercaprol and EDTA are 1st line of treatment
- Succimer used for chelation for kids ("it SUCks to be a kid who eats lead")

46

Causes of sideroblastic anemia

- Defect in heme synthesis due to X linked defect in ALA synthase gene
- CAUSES: genetic, acquired (myelodysplastic syndromes), and reversible (alcohol is most common, also lead, B6 deficiency, copper deficiency, isoniazid)

47

Treatment of sideroblastic anemia

Pyridoxine (B6, cofactor for ALA synthase)

48

Orotic aciduria

- Inability to convert orotic acid → UMP (de novo pyrimidine synthesis pathyway) because of defect in UMP synthase
- AR
- Present in children as failure to thrive, developmental delay and megaloblastic anemia refractory to folate and B12
- NO hyperammonemia (vs ornithine transcarbamylase deficiency → ↑ orotic acid with hyperammonemia)
- Orotic acid found in urine
- TREATMENT: UMP to bypass mutated enzyme

49

Diamond-Blackfan anemia

- Rapid-onset anemia within 1st year of life due to intrinsic defect in erythroid progenitor cells
- ↑ % HbF (but ↓ total Hb)
- Presents with short stature, craniofacial abnormalities, and upper extremity malformations (triphalangeal thumbs)

50

Nonmegaloblastic macrocytic anemia

- Macrocytic anemia in which DNA synthesis is unimpaired
- RBC macrocytosis without hypersegmented neutrophils
- Causes include alcoholism and liver disease

51

Intravascular hemolysis findings

- ↓ haptoglobin
- ↑ LDH
- Schistocytes and ↑ reticulocytes on blood smear
- Characteristic hemoglobinuria, hemosiderinuria, and urobilinogen in urine
- May also seen ↑ unconjugated bilirubin
- Causes include mechanical hemolysis (eg prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias

52

Extravascular hemolysis findings

- Macrophages in sleep clear RBCs
- Spherocytes in peripheral smear
- ↑ LDH
- NO hemoglobinuria/hemosiderinuria
- ↑ unconjugated bilirubin (can cause jaundice)
- Can present with urobilinogen in urine

53

Pathogenesis of anemia of chronic disease

Inflammation → ↑ hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron tranport) → ↓ release of iron from macrophages and ↓ iron absorption from gut

54

Treatment of anemia of chronic disease in the case of chronic kidney disease

Erythropoietin

55

Causes of aplastic anemia

Caused by failure or destruction of myeloid stem cells due to:
- Radiation and drugs → benzene, chloramphenicol, alkylating agents, antimetabolites
- Viral agents → parvovirus B19, EBV, HIV, hepatitis viruses
- Fanconi anemia → DNA repair defect with NHEJ causing bone marrow failure as well as short stature, ↑ incidence of tumors/leukemias, cafe-au-lait spots, thumb/radial defects
- Idiopathic (immune mediated, primary stem cell defect), may follow acute hepatitis

56

Presentation of hereditary spherocytosis

- Splenomegaly
- Aplastic crisis (parvovirus B19 infection)

57

Hereditary spherocytosis - intravascular or extravascular hemolysis

Extravascular hemolysis

58

Presentation of G6PD deficiency

- Back pain
- Hemoglobinuria a few days after oxidant stress

59

Inheritance pattern of G6PD deficiency

X linked recessive

60

G6PD deficiency - intavascular or extravascular hemolysis

Both

61

Pyruvate kinase deficiency

- AR
- Defect in pyruvate kinase → ↓ ATP → rigid RBCs → extravascular hemolysis
- Hemolytic anemia in a newborn

62

Hb C disease - intravascular or extravascular hemolysis

Extravascular

63

What does the blood smear show for Hb C disease homozygotes

Blood smear shows hemoglobin crystals inside RBCs and target cells

64

Triad of paroxysmal nocturnal hemoglobinuria

- Coombs (-) hemolytic anemia
- Pancytopenia
- Venous thrombosis

65

Cause of paroxysmal nocturnal hemoglobinuria

Acquired mutation in a hematopoietic stem cell. ↑ incidence of acute leukemias.

66

Paroxysmal nocturnal hemoglobinuria - intravascular or extravascular hemolysis

Intravascular

67

Treatment of paroxysmal nocturnal hemoglobinuria

Eculizumab → terminal complement inhibitor

68

Sickle cell anemia - intravascular or extravascular hemolysis

Both

69

Treatment of sickle cell anemia

Hydroxyurea and hydration

70

Compare microangiopathic and macroangiopathic anemia

Microangiopathic → RBCs are damaged when passing through obstructed or narrowed vessel lumina; seen in DIC, TTP/HUS, SLE, and malignant hypertension

Macroangiopathic → prosthetic heart valves and aortic stenosis may also cause hemolytic anemia secondary to mechanical destruction of RBCs

Schistocytes are seen on peripheral blood smear for both

71

Iron deficiency anemia lab values

- ↓ serum iron (primary)
- ↑ TIBC
- ↓ ferritin
- ↓ % transferrin saturation

72

Chronic disease lab values

- ↓ serum iron
- ↓ TIBC
- ↑ ferritin (primary)

73

Hemochromatosis lab values

- ↑ serum iron (primary)
- ↓ TIBC
- ↑ ferritin
- ↑↑ % transferrin saturation

74

Pregnancy/OCP use

- ↑ TIBC (primary)
- ↓ % transferrin saturaiton

75

Why do corticosteroids cause neutrophilia despite causing eosinopenia and lymphopenia

Corticosteroids ↓ activation of neutrophil adhesion molecules, impairing migration out of the vasculature to sites of inflammation. In contrast, corticosteroids sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes

76

Causes of neutropenia

- Sepsis/post-infection
- Drugs (including chemotherapy)
- Aplastic anemia
- SLE
- Radiation

77

Causes of lymphopenia

- HIV
- DiGeorge syndrome
- SCID
- SLE
- Corticosteroids
- Radiation
- Sepsis
- Postoperative

78

Causes of eosinopenia

- Cushing syndrome
- Corticosteroids

79

Left shift

- ↑ neutrophil precursors, such as band cells and metamyelocytes, in peripheral blood
- Usually seen with neutrophilia in the acute response to infection or inflammation
- Called LEUKOERYTHROBLASTIC REACTION when left shift is seen with immature RBCs → occurs with severe anemia (physiologic response) or marrow response (eg fibrosis, tumor taking up space in marrow)

80

Lead poisoning

- Affected enzymes → ferrochelatase, ALA dehydratase
- Accumulated substrates → protoporphyrin, ALA (blood)

Presentation:
- Microcytic anemia (basophilic stippling), GI, kidney disease
- Children → exposure to lead paint → mental deterioration
- Adults → environmental exposure (eg batteries, ammunition) → headache, memory loss, demyelination

81

Acute intermittent porphyria

- Affected enzyme → porphobilinogen deaminase
- Accumulated substrates → porphobilinogen, ALA, corphobilinogen (urine)

Presentation (5 Ps):
- Painful abdomen
- Port wine-colored urine
- Polyneuropathy
- Psychological disturbances
- Precipitated by drugs (eg cytochrome P450 inducers), alcohol, starvation

Treatment → glucose and heme, which inhibit ALA synthase

82

Porphyria cutanea tarda

- Affected enzyme → uroporphyrinogen decarboxylase
- Accumulated substrate → uroporphyrin (tea-colored urine)

Presentation:
- Blistering cutaneous photosensitivity
- Most common porphyria

83

Iron poisoning

- Cell death due to peroxidation of membrane lipids
- Symptoms → N/V, gastric bleeding, lethargy, scarring leading to GI obstruction
- Treatment → chelation and dialysis → IV deferoxamine, oral deferasirox

84

PT tests function of what

- Common and extrinsic pathway
- Factors I, II, V, VII, and X

85

PTT tests function of what

- Common and intrinsic pathway
- All factors except VII and XIII

86

PT and PTT in vitamin K deficiency

↑ PT, ↑ PTT

87

Bernard-Soulier syndrome

- -/↓ platelet count
- ↑ BT
- Defect in platelet plug formation
- ↓ GpIb → defect in platelet-to-vWF adhesion
- Large platelets

88

Glanzmann thrombasthenia

- - platelet count
- ↑ BT
- Defect in platelet plug formation
- ↓ GpIIb/IIIa → defect in platelet-to-platelet aggregation
- Labs: blood smear shows no platelet clumping

89

Hemolytic-uremic syndrome

- ↓ platelet count
- ↑ BT
- Characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure
- Typical HUS seen in children, accompanied by diarrhea and commonly caused by Shiga-toxin producing E coli (STEC)
- HUS in adults does NOT present with diarrhea, STEC infection is NOT required
- Same spectrum as TTP, with a similar clinical presentation and same initial treatment of plasmapheresis

90

Immune thrombocytopenia

- ↓ platelet count
- ↑ BT
- Anti-GpIIb/IIIa antibodies → splenic macrophage consumption of platelet-antibody complex
- Commonly due to viral illness
- Labs: ↑ megakaryocytes on bone marrow biopsy
- Treatment: steroids, IVIG, splenectomy for refractory ITP

91

Thrombotic thombocytopenic purpura

- ↓ platelet count
- ↑ BT
- Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease) → ↓ degradation of vWF multimers
- Pathogenesis: ↑ large vWF multimers → ↑ platelet adehesion → ↑ platelet aggregation and thrombosis
- Labs: schistocytes, ↑ LDH
- Symptoms: pentad of neurologic and renal symptoms, fever, thrombocytopenia, and microangiopathic hemolytic anemia
- Treatment: plasmapheresis, steroids

92

von Willebrand disease

- - platelet count
- ↑ BT
- - PT
- -/↑ PTT
- Intrinsic pathway coagulation defect: ↓ vWF → ↑ PTT (vWF acts to carry/ protect factor VIII)
- Defect in platelet plug formation: ↓ vWF → defect in platelet-to-vWF adhesion
- AD
- Mild but most common inherited bleeding disorder
- No platelet aggregation with ristocetin cofactor assay
- Treatment: desmopressin (releases vWF stored in endothelium)

93

Disseminated intravascular coagulation

- ↓ platelet count
- ↑ BT
- ↑ PT
- ↑ PTT
- Widespread activation of clotting → deficiency in clotting factors → bleeding state
- Causes: Sepsis (gram -), Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion ("STOP Making New Thrombi")
- Labs: schistocytes, ↑ fibrin degradation products (D dimers), ↓ fibrinogen, ↓ factors V and VIII

94

Antithrombin deficiency

- Inherited deficiency of antithrombin → has no direct effect on the PT, PTT or thrombin time but diminitshes the increase in PTT following heparin administration
- Can also be acquired: renal failure/ nephrotic syndrome → antithrombin loss in urine → ↓ inhibition of factors IIa and Xa

95

Factor V Leiden

- Production of mutant factor V (G → A DNA point mutation → Arg506Gln mutation near the cleavage site) that is resistant to degradation by activated protein C
- Most common cause of inherited hypercoagulability in Caucasians
- Complications include DVT, cerebral vein thromboses, recurrent pregnancy loss

96

Protein C or S deficiency

- ↓ ability to inactivate factor Va and VIIIa
- ↑ risk of thrombotic skin necrosis with hemorrhage after administration of warfarin
- If this occurs, think protein C deficiency
- "Together protein C Cancels and protein S Stops Coagulation"

97

Prothrombin gene mutation

Mutation in 3' untranslated region → ↑ production of prothrombin → ↑ plasma levels and venous clots

98

Packed RBCs

- ↑ Hb and O2 carrying capacity
- Clinical use → acute blood loss, severe anemia

99

Platelets

- ↑ platelet count (↑ by approximately 5000/mm3/unit)
- Clinical use → stop significant bleeding (thrombocytopenia, qualitative platelet defects)

100

Fresh frozen plasma

- ↑ coagulation factor levels
- Clinical use → DIC, cirrhosis, immediate warfarin reversal

101

Cryoprecipitate

- Contains fibrinogen, factor VIII, factor XIII, vWF, and fibronectin
- Clinical use → coagulation factor deficiencies involving fibrinogen and factor VIII

102

Risks of blood transfusions

- Infection transmission (low)
- Transfusion reactions
- Iron overload (may lead to secondary hemochromatosis)
- Hypocalcemia (citrate is a Ca2+ chelator)
- Hyperkalemia (RBCs may lyse in old blood units)

103

Compare Hodgkin and Non-Hodgkin lymphomas

Hodgkin:
- Localized, single group of nodes
- Contiguous spread (stage is strongest predictor of prognosis)
- Many patients have a relatively good prognosis
- Characterized by Reed-Sternberg cells
- Bimodal distribution → young adulthood and >55 years; more common in men except for nodular sclerosing type
- Associated with EBV
- Constitutional ("B") signs/symptoms": low grade fever, night sweats, weight loss

Non-Hodgkin:
- Multiple lymph nodes involved
- Extranodal involvement common
- Noncontiguous spread
- Majority involve B cells; a few are of T cell lineage
- Can occur in children and adults
- May be associated with HIV and autoimmune diseases
- May present with constitutional signs/symptoms

104

Primary central nervous system lymphoma

- Non-Hodgkin lymphoma
- Neoplasm of mature B cells
- Occurs in adults
- Most commonly associated with HIV/AIDS
- Considered an AIDS-defining illness
- Variable presentation: confusion, memory loss, seizures
- Mass lesion(s) on MRI, needs to be distinguished from toxoplasmosis via CSF analysis or other lab tests

105

Waldenstrom macroglobulinemia

- M spike = IgM
- Hyperviscosity syndrome (eg blurred vision, Raynaud phenomenon)
- No CRAB findings

106

Monoclonal gammopathy of undetermined significance (MGUS)

- Monoclonal expansion of plasma cells
- Asymptomatic
- May lead to multiple myeloma
- No CRAB findings
- Patients with MGUS develop multiple myeloma at a rate of 1-2% per year

107

Myelodysplastic syndromes

- Stem-cell disorders involving ineffective hematopoiesis → defects in cell maturation of all nonlymphoid lineages
- Caused by de novo mutation or environmental exposures (eg radiation, benzene, chemotherapy)
- Risk of transformation to AML

108

Pseudo-Pelger-Huet anomaly

- Neutrophils with bilobed nuclei
- Typically seen after chemotherapy
- Myelodysplastic syndrome

109

Lukemia cutis

Lukemic cell infiltration of skin

110

Rare leukemias present with

Normal/ ↓ WBCs

111

Lymphoid neoplasm associated with autoimmune hemolytic anemia

Chronic lymphocytic leukemia/ small lymphocytic lymphoma

112

Richter transformation

SLL/CLL transformation into an aggressive lymphoma, most commonly diffuse large B cell lymphoma

113

Patients with hairy cell leukemia generally present with

Massive splenomegaly

114

Treatment of hairy cell leukemia

- Cladribine
- Pentostatin

115

Are dendritic/Langerhans cells of Langerhans cell histiocytosis functional

Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentation

116

Presentation of polycythemia vera

- Erythromelalgia → severe, burning pain and red-blue coloration due to episodic blood clots in vessels of the extremities
- Itching after hot shower
- These symptoms respond to aspirin

117

Relative polycythemia

- ↓ plasma volume
- - RBC mass
- - O2 saturation
- - EPO
- Associated with dehydration and burns

118

Appropriate absolute polycythemia

- - plasma volume
- ↑ RBC mass
- ↓ O2 saturation
- ↑ EPO levels
- Associated with lung disease, congenital heat disease, and high altitude

119

Inappropriate absolute polycythemia

- - plasma volume
- ↑ RBC mass
- - O2 saturation
- ↑ EPO
- Associated with malignancy (eg renal cell carcinoma, hepatocellular carcinoma), hydronephrosis
- Due to ectopic EPO secretion

120

Polycythemia vera

- ↑ plasma volume
- ↑↑ RBC mass
- - O2 saturation
- ↓ EPO (due to negative feedback)