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1

Derivation of vWF during primary hemostasis

- Weibel-Palade bodies of endothelial cells
- Alpha granules of platelets

2

Derivation of ADP during primary hemostasis

Dense granules of platelets

3

Cause of platelet microthrombi in HUS

Typically due to damage done to endothelial cells by E coli verotoxin

4

Renal insufficiency - HUS or TTP?

More common in HUS

5

CNS abnormalities - HUS or TTP?

More common in TTP

6

Bernard-Soulier syndrome

- GpIb deficiency
- Platelet ADHESION is impaired
- Blood smear shows mild thrombocytopenia with enlarged platelets

7

Glanzmann thrombasthenia

- GpIIb/IIIa deficiency
- Platelet AGGREGATION impaired

8

Uremia induced qualitative platelet disorder

- Disrupts platelet function
- Both adhesion and aggregation are impaired

9

Coagulation factor inhibitor

- Acquired antibody against a coagulation factor resulting in impaired factor function
- Anti-FVIII is most common
- Clinical and lab findings are similar to hemophilia A
- PTT does NOT correct upon mizing normal plasma with patient's plasma (mixing study) due to inhibitor [PTT does correct in hemophilia A]

10

Increased, decreased or normal PTT in von Willebrand disease?

- Increased PTT, normal PT
- Decreased FVIII half-life (vWF normally stabilizes FVIII); however, deep tissue, joint and postsurgical bleeding are usually not seen

11

von Willebrand disease ristocetin test results

- Abnormal RISTOCETIN TEST - ristocetin induces platelet agglutination by causing vWF to bind platelet GpIb; lack o vWF leads to impaired agglutination which leads to an abnormal test

12

Best screening test for DIC

Elevated D-dimer

13

Fibrinolytic disorder - increased, decreased or normal levels D-dimer

- Increased fibrinogen split products without D-dimers
- Serum fibrinogen is lysed
- D-dimers are not formed because fibrin thrombi are absent

14

Role of heparin-like molecules secreted by endothelial cells

Augment antithrombin III (ATIII) which inctivates thrombin and coagulation factors

15

Role of thrombomodulin secreted by endothelial cells

Redirects thrombin to activate protein C, which inactivates factors V and VIII

16

Causes of endothelial damage include

- Atherosclerosis
- Vasculitis
- High levels of homocyteine

17

Causes of high levels of homocysteine

- Vitamin B12 and folate deficiency
- Cystathione beta synthase (CBS) deficiency

18

Cystathione beta synthase (CBS) deficiency

- Results in high homocysteine levels with homocysteinuria
- CBS convers homocystein to cystathione
- Enzyme deficiency leads to homocysteine buildup
- Characteried by vessel thrombosis, mental retardation, lens dislocation, and longer slender fingers (these people have kyphosis and Marfanoid habitus)

19

Protein C or S deficiency

- Hypercoagulable state
- AD
- Decreases negative feedback on the coagulation cascade
- Proteins C and S normally inactivate factors V and VIII
- Increased risk for warfarin skin necrosis
- Initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX and X
- In preexisting C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing the risk for thrombosis, especially in the skin

20

Factor V Leiden

- Hypercoaguable state
- Mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S
- Most common inherited cause of hypercoaguable state

21

Prothrombin 20210A

- Hypercoaguable state
- Inherited point mutation in prothrombin that results in increased gene expression
- Increased prothrombin results in increased thrombin, promoting thrombus formation

22

ATIII deficiency

- Hypercoaguable state
- Decreased the protective effect of heparin-like molecules produced by endothelium, increasing the risk for thrombus
- Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors
- In ATIII deficiency, PTT does not rise with standard heparin dosing
- Pharmacologic heparin works by binding and activating ATIII
- High doses of heparin activate limited ATIII
- Coumadin is then given to maintain an anticoagulated state

23

How do oral contraceptives cause a hypercoaguable state?

Estrogen enhances increased production of coagulation factors, thereby increasing the risk for thrombosis

24

Caisson disease

- Chronic form of decompression sickness
- Characterized by multifocal ischemic necrosis of bone

25

Amniotic fluid embous

- Enters maternal circulation during labor or delivery
- Presents with shortness of breath, neurologic symptoms, and DIC (due to thrombogenic nature of amniotic fluid)
- Characterized by squamous cells and keratin debris (from fetal skin) in the embolus

26

Microcytosis is due to

An "extra" division which occurs to maintain hemoglobin concentration

27

Congenital cause of sideroblastic anemia

Most commonly involves ALA synthetase (rate-limiting enzyme that converts succinyl CoA to aminolevullinic acid (ALA) using vitamin B6 as a cofactor)

28

Acquired causes of sideroblastic anemia

- ALCOHOLISM: mitochondrial poison
- LEAD POISONING: inhibits ALA dehydratase (converts ALA to porphobilinogen) and ferrochelatase (attaches protoporphyrin to iron to make heme)
- VITAMIN B6 DEFICIENCY: required cofactor for ALA synthetase; most commonly seen as a side effect of isoniazid treatment

29

α thalassemias is usually due to gene (mutation or deletion) whereas βthalassemias is usually due to gene (mutation or deletion)

- α thalassemias → gene deletion
- β thalassemias → gene mutation

30

Megaloblastic change is seen in which cells

- Impaired division and enlargement of RBC precursors leads to megaloblastic anemia
- impaired division of granulocyte precursors leads to hypersegmented neutrophils
- Megaloblastic change is also seen in rapidly dividing (eg intestinal) epithelial cells

31

Dietary B12 absorption

- Salivary gland enzymes (eg amylase) liberate vitamin B12, which is then bound by R-binder (also from the salivary gland) and carried through the stomach
- Pancreatic proteases in the duodenum detach vitamin B12 from R-binder
- Vitamin B12 binds intrinsic factor (made by gastric parietal cells) in the small bowel; the intrinsic factor-B12 complex is absorbed in the ileum

32

Describe subacute combined degeneration of the spinal cord

- Seen in vitamin B12 deficiency
- Increased levels of methylmalonic acid (cannot be converted to succinyl CoA, an important step of fatty acid metabolism)
- Increased levels of methylmalonic acid impair spinal cord myelinization
- Damage results in poor propioception and vibratory sensation (posterior columns) and spastic paresis (lateral corticospinal tract)

33

Examples of vaso-occlusion due to extensive sickling

- Dactylitis (common presenting sign in infants)
- Autosplenectomy (can lead to infection, most common cause of death in children)
- Acute chest syndrome (most common cause of death in adults)
- Pain crisis
- Renal papillary necrosis

34

Sickle cell trait RBCs sickle in what location

Sickle cell trait is generally asymptomatic with no anemia as RBCs with

35

Are sickle cells and target cells seen on blood smear of sickle cell trait

No

36

Metabisulfite screen

Causes cells with any amount of HbS to sickle, therefore positive in both sickle cell disease and trait

37

Describe the blood smear of HbC

HbC crystals + target cells

38

What is the role of decay accelerating factor (DAF)

Inhibits C3 convertase

39

What cells are lysed in paroxysmal nocturnal hemoglobinuria

RBCs, WBCs, and platelets are lysed via intravascular hemolysis

40

Main cause of death in paroxysmal nocturnal hemoglobinuria

Thrombosis of hepatic, portal or cerebral vines

41

Complications of paroxysmal nocturnal hemoglobinuria

- Iron deficiency anemia (due to chronic loss of hemoglobin in the urine)
- Acute myeloid leukemia (AML) [develops in 10% of patients]

42

G6PD deficiency is due to

Reduced half-life of G6PD, not a deletion

43

Myelophthisic process

Pathologic process (eg metastatic cancer) that replaces bone marrow and impairs hematopoiesis, resulting in pancytopenia.

44

High cortisol state and white cells

- Causes lymphopenia (induces apoptosis of lymphocytes)
- Cause neutrophilic leukocytosis (impairs leukocyte adhesion, leading to release of marginated pool of neutrophils)

45

Characterize a left shift

Release of immature forms of leukocytes, which are characterized by decreased Fc receptors (CD16)

CD16 is generally found on NK cells and binds the Fc region of IgG

46

Bordatella pertussis infection

Bacteria produce lymphocytosis promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node

47

Definitive diagnosis of infectious mononucleosis

Serologic testing for EBV viral capsid antigen

48

Complications associated with infectious mononucleosis

Dormancy of irus in B cells leads to increased risk for both recurrence and B cell lymphoma, especially if cases of immunodeficiency develops

49

Describe blasts on blood smear

Large immature cells often with punched out nucleoli

50

Marker for acute lymphoblastic leukemia (ALL)

- TdT, a DNA polymerase
- Absent in myeloid blasts and mature lymphocytes

51

Demographic of acute lymphoblastic leukemia (ALL)

- Children
- Associated with Down syndrome (usually arises after the age of 5)
- Subclassified into B-ALL and T-ALL

52

Markers for B-ALL

- TdT +
- CD10, CD19, CD20

53

Cytogenetics for B-ALL

- t(12,21) → children → good prognosis
- t(9,22) → adults → poor prognosis

54

Markers for T-ALL

- TdT +
- CD2-CD8

55

Marker for acute myeloid leukemia (AML)

- MPO, myeloperoxidase
- May be seen as Auer rods

56

Demographic of acute myeloid leukemia (AML)

Older adults

57

Subtypes of acute myeloid leukemia (AML)

ACUTE PROMYELOCYTIC LEUKEMIA (APL)
- t(15,17)
- Translocation of the retinoic acid receptor
- Contain numerous primary granules that increase risk for DIC

ACUTE MONOCYTIC LEUKEMIA
- Lack MPO
- Characteristically infiltrate gums

ACUTE MEGAKARYOBLASTIC LEUKEMIA
- Proliferation of megakaryoblasts
- Lack MPO
- Associated with Down syndrome (usually arises before the age of 5)

58

Markers of chronic lymphocytic leukemia (CLL)

Neoplastic proliferation of naive B cells that co-express CD5 and CD20

59

Involvement of chronic lymphocytic leukemia (CLL) with lymph nodes

Leads to generalized lymphadenopathy and is called small lymphocytic lymphoma

60

Complications of chronic lymphocytic leukemia (CLL)

- Hypogammaglobulinemia (infection is the most common cause of death)
- Autoimmune hemolytic anemia
- Transformation to diffuse large B-cell lymphoma (Richter transformation) - marked clinically by an enlarging lymph node or spleen

61

Marker of hairy cell leukemia

Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes and are positive for tartrate-resistant acid phosphatase (TRAP)

62

Clinical features of hairy cell leukemia

- Splenomegaly (accumulation of hairy cells in red pulp)
- Dry tap on bone marrow aspiration (due to marrow fibrosis)
- Lymphadenopathy is ABSENT

63

Clinical features of adult T-cell leukemia/lymphoma

- Neoplastic proliferation of mature CD4+ T cells
- Rash (skin infiltration)
- Generalized lymphadenopathy with hepatosplenomegaly and lytic (punched out) bone lesions with hypercalcemia

64

Clinical features of mycosis fungoides

- Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin
- Localized skin rash, plaques and nodules
- Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses

65

Cytogenetics of chronic myeloid leukemia (CML)

- t(9,22)
- BCR-ABL fusion
- Mutation is in a pluripotent stem cell

66

Enlargening spleen in chronic myeloid leukemia (CML)

- Suggests progression to accelerated phase of disease
- Transformation to acute leukemia usually follows shorty therafter
- Can transform to AML (2/3 of cases) or ALL (1/3 of cases) since mutation is in pluripotent stem cell

67

Cytogenetics of polycythemia vera

Associated with JAK2 kinase mutation

68

Cytogenetics of essential thrombocythemia

Associated with JAK2 kinase mutation

69

Cytogenetics of myelofibrosis

Associated with JAK2 kinase mutation in 50% of cases

70

Cause of marrow fibrosis in myelofibrosis

Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis

71

Types of small B cell non-Hodgkin lymphoma

- Follicular lymphoma
- Mantle cell lymphoma
- Marginal lymphoma
- Small lymphocytic lymphoma (CLL that involves tissues_

72

Type of intermediated sized B cell non-Hodgkin lymphoma

Burkitt lymphoma

73

Type of large B cell non-Hodgkin lymphoma

Diffuse large-B cell lymphoma

74

In which cancer does a leukemic phase occur - Hodgkin or non-Hodgkin lyphoma?

Leukemic phase only occurs in non-Hodgkin lymphoma

75

Cytogenetics of follicular lymphoma

- t(14,18)
- BCL2 on chromosome 18 translocates to Ig heavy chain locus on chromosome 14
- Results in overexpression of Bcl2, which inhibits apoptosis

76

Complication of follicular lymphoma

Progression to diffuse large B cell lymphoma (presents as an enlarging lymph node)

77

Cytogenetics of mantle cell lymphoma

- t(11,14)
- Cyclin D1 on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
- Overexpression of cyclin D1 promotes G1/S transition in the cell cycle, facilitating neoplastic proliferation

78

Marginal zone lymphomas are associated with

- Chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome and H pylori gastritis
- Keep in mind that the marginal zone is formed by post-germinal center B cells

79

MALToma

- A marginal zone lymphoma located in mucosal sites
- Gastric MALToma may regress with treatment of H pylori, unless patient has Trisomy 3

80

Cytogenetics of Burkitt lymphoma

- t(8,14)
- Most common translocation of c-myc on chromosome 8 to Ig heavy chain locus on chromosome 14
- Overexpression of c-myc oncogene promotes cell growth

81

Type of lymphoma associated with "B symptoms"

- Hodgkin lymphoma
- Fever, chills, weight loss, and night sweats

82

Subtypes of Hodgkin lymphoma

NODULAR SCLEROSIS
- Most common subtype
- Occurs in young adult females
- Lymph node is divided by bands of sclerosis and RS cells are present in lake-like spaces (lacunar cells)

LYMPHOCYTE-RICH
- Best prognosis

MIXED CELLULARITY
- Abundant eosinophils (RS cells produce IL-5)

LYMPHOCYTE-DEPLETED
- Most aggressive
- Usually seen in the elderly and HIV+ individuals

83

Marker for non-Hodgkin lymphoma

CD20+

84

Markers for Hodgkin lymphoma

CD15+ and CD30+

85

Cause of lytic bone lesions and hypercalcemia in multiple myeloma

Neoplastic plasma cells activate the RANK receptor on osteoclasts, leading to bone destruction

86

Presentation of monoclonal gammopathy of undetermined significance (MGUS)

- Increased serum protein with M spike on SPEP
- ABSENCE of lytic bone lesions, hypercalcemia, AL amyloid or Bence Jones proteinuria)

87

Markers of Langerhans cell histiocytosis

CD1a+ and S100+

S100 also seen in melanoma and schwannoma

88

Clinical presentation of Langerhans cells histiocytosis

LETTERER-SIWE DISEASE
- Malignant
- Skin rash and cystic skeletal defects
- Multiple organ involvement possible
- Infants

EOSINOPHILIC GRANULOMA
- Benign
- No skin involvement
- Pathologic fracture
- Adolescent

HAND-SCHULLER-CHRISTIAN DISEASE
- Malignant
- Scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child

89

Pathology of temporal (giant cell) arteritis

- Granulomatous vasculitis that involves branches of the carotid artery
- Biopsy reveals inflamed vessel wall with giant cells and intimal fibrosis
- Lesions are segmental

90

Pathology of Takayasu arteritis

Granulomatous vasculitis that classically involves the aortic arch at branch points

91

Pathology of polyarteritis nodosa

- Early lesion consists of transmural inflammation with fibrinoid necrosis that eventually heals with fibrosis, creating a "string of pearls" appearance on imaging
- Usually involves renal artery (hypertension), mesenteric artery (abdominal pain with melena) as well as other arteries to cause skin lesions and neurologic disturbances
- Lungs are spared

92

Pathology of Buerger disease

Necrotizing vasculitis involving the digits

93

Pathology of Wegener granulomatosis

Necrotizing granulomatous vasculitis involving nasopharynx, lungs and kidneys

94

Pathology of microscopic polyangiitis

- Necrotizing vasculitis involving multiple organs, especially lung and kidney
- Abssent nasopharyngeal involvement
- No granulomas

95

Pathology of Churg-Strauss syndrome

- Necrotizing granulomatous inflammation with eosinophils involving multiple organs, especially lungs and heart
- Asthma and peripheral eosinophils are often present

96

Pathology of Henoch-Schonlein purpura

Vasculitis due to IgA immune complex deposition

97

Fibromuscular dysplasia

- Developmental defect of the blood vessel wall
- Results in irregular thickening of large and medium sied arteries, especially the renal artery
- Important cause of secondary hypertension in young females

98

Pathogenesis oft atherosclerosis

1. Damage to endothelium allows lipids to leak into the intima
2. Lipids are oxidized and then consumed by macrophages via scavenger receptors resulting in foam cells
3. Inflammation and healing leads to deposition of extracellular matrix and proliferation of smooth muscle

99

Angiosarcoma

- Malignant proliferation of endothelial cells
- Highly aggressive
- Common sites include skin, breast, and liver
- Liver angiosarcoma is associated with exposure to PVC, arsenic, and thorotrast