Midterm Flashcards
1
Q
Where do blood cell progenitors derive from embryologically
A
Yolk sac
2
Q
Where do definitive hematopoietic stem cells arise from
A
Mesoderm of the intraembryonic aorta/gonad/mesonephros region; they then migrate to liver which becomes the chief site of blood cell formation until shortly before birth
3
Q
What are the formed elements of the blood
A
Red cells, granulocytes, monocytes, platelets, lymphocytes
4
Q
What are the progenitors of neutrophils,eosinophils basophils, platelet, and erythrocytes
A
- neutrophils: myeloblasts
- Monocytes: monoblast
- eosinophil: eosinophiloblast
- basophils: basophiloblast
- platelets: megakaryoblast
- erythrocytes: erythroblast
5
Q
What are the characteristis of HSCs
A
Pluripotent and self renewal capability
6
Q
What factors are expressed on every early committed progenitor
A
Receptors for KIT ligand, FLT3 Ligand; EPO, CS and thrombopoietin act on committed progenitor cells with more restricted differentiation potentials
7
Q
What is the morphology of bone marrow
A
Megakaryocytes lie next to sinusoids and extend cytoplasmic processes that busy off into bloodstream to produce platelets; red cell precursors surround macrophages (nurse cells) that provide iron for hemoglobin; if marrow architecture distorted can lead to leukoerythroblastosis (release of immature precursors into peripheral blood); in normal adults, fat:hematopoietic elements is 1:1; in plastic anemia, fat cells increase; in hemolytic anemia’s, fat is lost
8
Q
What is the most common cause of lymphopenia
A
HIV, after therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition, acute viral infections (lymphocyte redistribution in last case)
9
Q
What can cause neutropenia
A
- Inadequate or ineffective granulopoiesis: suppression o HSC (aplastic anemia, tumors, granulomatous dz - accompanied by anemia and thrombocytopenia), suppression of committed granulocytic precursors via drugs, megaloblastic anemia and myelodysplastic syndromes, congenital syndromes (kostmann)
- increased destruction or sequestration of neutrophils in periphery: immune mediated injury (SLE), splenomegaly, increased peripheral utilization (overwhelming bacterial, fungal, or rickettsial infections)
10
Q
What is the most common cause of agranulocytosis
A
Drug toxicity: alkylating agents and antimetabolites in cancer treatment, aminopyrine, chloramphenicol, sulfonamides (ab mediated destruction of mature neutrophils), chlorpromazine (toxic to precursors), thiouracil, phenylbuazone
11
Q
What is LGL leukemia
A
Can cause severe neutropenia; monoclonal proliferation’s of large granular lymphocytes
12
Q
What is the morphology of the bone marrow in neutropenia
A
Vary with cause; with destruction of neutrophils in periphery, marrow is hypercellular (also with ineffective granlopoiesis - megaloblastic anemia’s and myelodysplasic syndromes); if destroy precursors - marrow hypocellularity
13
Q
What infections are a result of agranulocytosis
A
Ulceration necrotizing lesions of gingiva, floor of mouth, Bucal mucosa, pharynx (agranulocytosis angina); covered by gray to green-black necrotic membranes; *high is for Candida and aspergillus; bacteria grow in colonies (botryomycosis)
14
Q
What is the peripheral blood leukocyte count influenced by
A
- size of myeloid and lymphoid precursor and storage cell poools in BM, thymus, circulation, and periphery
- rate of release of cells from storage pools into circulation
- proportion of cells that are adherent to bv walls (marginal pool)
- rate of extravasation of cells from blood into tissue
15
Q
What are the mechanisms and causes of leukocytosis
A
- increased production in marrow: chronic infection or inflammation (GF dependent), paraneoplastic (Hodgkin, GF dependent), myeloproliferative disorders(chronic myeloid leukemia, GF independent)
- increased release from marrow stores: endotoxemia, infection, hypoxia
- decreased margination: exercise, catecholamines
- decreased extravasation into tissues: glucocorticoids
16
Q
What mediates the release of mature granulocytoes from BM during infection
A
TNF and IL-1; if prolonged, will stimulate macrophages, BM stromal cells, and T cells tp prude increased mounts of hematopoietic growth factors
17
Q
What happens in sepsis or severe inflammatory disorders (Kawasaki)
A
Leukocytosis is accompanied by morphological changes in neutrophils ie: toxic granulation (axurophilic granules), Dohle bodies (patches of dilated ER that appear as sky-blue cytoplasmic puddles), cytoplasmic vacuoles
18
Q
What are the causes of leukocytosis
A
- neutrophilic leukocytosis: acute bacterial infections (pyogenic), sterile inflammation caused by tissue necrosis (burns, MI)
- eosinophilic: allergic disorders, asthma, hay fever, parasite infections, drug reactions, malignancies (Hodgkin), AI (pemphigus, dermatitis herpetiformis), Vasculitis, atheroembolic dz
- basophils: rare indicative of myeloproliferative dz (CML)
- monocytosis: chronic infections (TB), bacterial endocarditis, rickettsiosis, malaria, AI (SLE), IBD
- lymphocytosis: chronic immune stimulation (TB, brucellosis), viral infections (Hep A, CMV, EPV), bordatella pertussis
19
Q
What does acute nonspecific lymphadentitis of specific sites indicate
A
- cervical: teeth or tonsils
- axillary or inguinal: extremities
- mesenteric: appendicitis
20
Q
What is follicular hyperplasia
A
Caused by stimuli that activate humoral immune responses; large ablong germinal centers surrounded by naive B cells (mantle zone); tingible-body macrophages ; causes: rheumatoid arthritis, toxoplasmosis, early stages of infection with HIV *features favoring reactive vs neoplastic hyperplasia: preservation of LN architecture (interfolliciular T cell zone and sinusoids), marked variation in shape and size of follicles, presence of frequent mitotic figures, phagocytic macrophages and recognizable light and dark zones
21
Q
What is paracortical hyperplasia
A
Caused by a stimuli that triggers T cell mediated immune responses (acute viral infection) hypertrophy of sinusoidal and vascular endothelial cells
22
Q
What are sinus histiocytosis
A
Aka reticular hyperplasia; increase in number and size of cells that line lymphatic sinusoids; prominent in LN draining cancers such as carcinoma of breast; but nonspecific
23
Q
Are LN in chronic reactions tender
A
No; only acute; common in inguinal an axillary nodes
24
Q
What is hemophagocytic lymphohistiocytosis
A
Reactive condition marked by cytopenias and signs and sx of systemic inflammation related to macrophage activation; referred to as macrophage activation syndrome; some forms are familial
25
What is the pathogensis of hemophagoytic lymphohistiocytosis
*systemic activation of macrophages and CD8 cytotoxic T cells; phagocytosis blood cell progenitors and formed elements in peripheral tissues; sx of systemic inflammation; shock-like picture and cytopenia
26
What are familial forms of HLH associated with
Several mutations; all impact ability of cytotoxic T cells and NK cells to properly form or deploy cytotoxic granules; high levels of IFN-gamma, TNFalpha, IL-6, IL-12, IL-2R
27
What is the most common trigger for HLH
Infection, most EBV
28
What are the clincial features of HLH
ACute febrile illness assoc with HSM; hemophagocytosis seen on BM exam but not required to make diagnosis nor is it sufficient; anemia, thrombocytopenia, very high levels of plasma ferritin and soluble IL-2R; elevated liver function test and triglyceride levels; can progress to death if untreated; treat its immunosuppressive drugs and mild chemo; even with treatment, those who survive have significant sequelae such as renal damage and growth aNd mental retardation in children
29
What are the types of malignancies of white cells
- lymphoid neoplasms: B cell, Tcell, NK cell origin
- myeloid neoplasms: arise from early HSC progenitors; acute myeloid leukemia (accumulate in BM), myelodysplastic syndromes (ineffective hematopoietic aNd peripheral blood cytopenia), chronic myeloproliferative disorders (increased production of terminally diff myeloid elements)
- histiocytoses: uncommon; proliferative lesions of macrophages and dendritic cells; langerhans cell histiocytosis
30
Where are dominant negative mutations often seen
Acute Leukemias; causes arrest in differentiation
31
What is the function of AID (activation induced cytosine delaminase)
Causes class switching and somatic hypermutation (increases ab affinity for antigen); sufficient to induce MYC/Ig translocations in Normal germinal center B cells
32
What individuals are at increased risk for acute leukemia
Bloom syndrome, fanconi anemia, ataxia telangiectasia, Down syndrome, type I NF
33
What are the lymphotrophic viruses
HTLV-1: adult T cell leukemia/lymphoma
EBV: Burkett, Hodgkin lymphoma, B cell lymphomas arising insetting of T cell immunodeficiency and NK cell lymphomas
HHV-8: B cell lymphoma that presents as malignant effusion, often in pleural cavity
34
What are examples of chronic inflammation that have risk of lymphoid neoplasia
H pylori (B cell lymphoma), gluten sensitive enteropathy (T cell lymphoma), breast implants (T cell lymphoma), HIV (B cell)
35
What iatrogenic factors put people at risk or lymphoid neoplasia
Radiation and certain forms of chemo
36
What is the effect of smoking on risk of lymphoid neoplasia
Increased risk of acute myeloid leukemia
37
What are features of plasma cell neoplasms
Most often arise in BM and only infrequently involve LN or peripheral blood
38
How do Hodgkin and NH lymphomas present
Nontener LN; some NHL present its sx related to involvement of exranodal sites
39
How do lymphocytic Leukemias often present
Signs and sx of suppression of normal hematopoiesis
40
How does multiple myeloma (plasma cell neoplasm) present
Bony destruction of skeleton; presents with pain
41
What are the categories of lymphoid neoplasms
- precursor B cell: neoplasmas of immature B cells
- peripheral B cell: neoplasms of mature B cells
- precursor T cell
- peripheral T cell and NK cell
- Hodgkin lymphoma: neoplasms of reed-stern berg cells
42
What are the precursor B cell neoplasms
B cell acute lymphoblastic leukemia/lymphoma
43
What are the peripheral B cell neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic and nodal marginal zone lymphomas, extranodal marginal zone lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, plasacytoma/plasma cell myeloma, diffuse large B cell lymphoma, Burkitt lymphoma
44
What are the precursor T cell neoplasms
T cell acute lymphoblastic leukemia/lymphoma
45
What are the peripheral T cell and NK cell neoplasms
T cell prolymphocytic leukemia, large granular lymphocytic leukemia, MYC os is fungoides/sezary syndrome, peripheral T cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, enteropathy associated T cell lymphoma, paniculitis-like T cell lymphoma, hepatosplenic T cell lymphoma, adult T cell leukemia/lymphoma, extranodal NK/T cel lymphoma, NK cell leukemia
46
What are the Hodgkin lymphoma subtypes
Nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depletion
47
What is significant about the antigen receptor of neoplasms
They will all be the same
48
Which lymphoid neoplasias are not always disseminated at time of diagnosis
Hodgkin and marginal zone B cell lymphomas
49
What are the the CD markers associated with primarily T cell associated lymphoid neoplasia
- CD1: thymocytes and langherans
- CD3: thymoytes and mature T cells
- CD4: helper T cells, subset of thymocytes
- CD5: T cells and small subset of B cells
- CD8: cytotoxic T cells, subset of thymocytes nad some NK cells
50
What are the CD markers that re primarily B cell associated
- CD10: pre-Bcells and germinal center B cells
- CD19: pre-B cells and mature B cells but not plasma cells
- CD20: pre B cells after CD19 and mature B cells but not plasma cells
- CD21: EBV receptor; mature B cells and follicular dendritic cells
- CD23: activated mature B cells
- CD79a: marrow pre-Bcells and mature bcells
51
What are the primarily monocyte or macrophage associated CD markers
- CD11c: granulocytes, monocytes, macrophages; hairy cell Leukemias
- CD13: immature and mature monocytes and granulocytes
- CD14: monocytes
- CD15: granulocytes, reed-sternberg cells
- CD33: myeloid progenitors and monocytes
- CD64: mature myeloid cells
52
What are the primarily NK cell associated CD markers
- CD16: NK cells and granulocytes
| - CD56: NK cells and subset of T cells
53
What are the primarily stem cell and progenitor cell associated CD markers
CD34: pluripotent HSC and progenitor cells of many lineages
54
What re the activation CD markers
CD30: activated B, T cells and monocytes; Reed-Sternberg cells
55
What is the CD present on all leukocytes
CD45
56
What is the diff in Hodgkin and NHL in terms of spread
Hodgkin spread in orderly fashion; NHL spreads widely early in course and less predictable
57
What is acute lymphoblastic leukemia/lymphoma
Neoplasms composed of immature B or T cells (lymphoblasts); B-ALLs manifest in childhood as leukemia; T-ALLs manifest in adolescent males as thymic lymphomas; Hispanics have highest incidence; peaks in incidence at 3 for B-ALL; T-ALL peaks in adolescence
58
What is the pathogensis of ALL
Chrom ab that dysregulate the expression and function of TF required for normal B and T cell development; T-ALLs have GOF in NOTCH1; B-ALLs have LOF in PAX5, E2A, EBF or balanced 12;21 translocation involving ETV6-RUNX1; promote arrest and increased self renewal; hyperdiploidy and hypo diploids only seen in B-ALL
59
What is the cell of origin for burkitt lymphoma
Germinal center B cell; translocations involving MYC-Ig 8;14 - subset is EBV related; clin presentation: adolescents or young adults with extranodal masses; aggressive
60
What is the cell of origin of diffuse large B cell lymphoma
Germinal center or postgerminal center B cell; rearragnemts o BCL6, BCL or MYC; presents at all ages but more common in adults; appears as rapidly growing mass; aggressive
61
What is the cell of origin of extranodal marginal zone lymphoma
Memory B cell; translocations: 11;18, 1;14, 14;18 - MALT1-IAP2, BCL10-IgH, MALT-IgH union genes; arises at extranodal sites in adults with chronic inflammatory dz; indolent
62
What is the cell of origin for follicular lymphoma
Germinal center B cell; translocation: 14;18 - BCL2-IgH; presents in older adults with generalized LAD and marrow involvement; indolent
63
What is the cell of origin of hairy cell leukemia
Memory B cell; activating BRAF mutation; seen in older males with pancytopenia and splenomegaly; indolent
64
What is the cell of origin of mantle cell lymphoma
Naive B cell; 11;14 translocation - cylinD-IgH fusion; older males with disseminated dz; moderately aggressive
65
What is the cell of origin of multiple myeloma/solitary plasmacytoma
Post germinal colter bone marrow homing plasma cell; diverse rearragnemtns involving IgH; 13q deletions; myeloma seen in older adults with lytic bone lesions, hypercalcemia, and renal failure; moderately aggresive; plasmacytoma - see isolated plasma cell masses in bone or soft tissue; indolent
66
What is the cell of origin for small lymphocytic lymphoma/ chronic lymphocytic leukemia
Naive B cell or memory B cell; trisomy 21, deletions of 11q, 13 and 17p; seen in older adults with BM, LN, spleen and liver dz; AI hemolysis and thrombocytopenia; indolent
67
What is the cell of origin of adult T cell leukemia/lyphoma
Helper T cell; HTLV-1 povirus present in tumor cells; presents in adults with cutaneous lesions, marrow involvement and hypercalcmia; mainly in Japan, west Africa and Caribbean; aggressive
68
What is the cell of origin of peripheral T cell lymphoma
Helper or cytotoxic T cell; no specific chrom ab; seen in older adults with LAD; aggresive
69
What is the cell of origin of anaplastic large cell lymphoma
Cytotoxic T cell; rearrangements o ALK (anaplastic large cell lymphoma kinase); seen in children and young adults with LN and soft tissue dz; aggresive
70
What is the cell of origin of extranodal NK/Tcell lymphoma
NK cell (common) or cytotoxic T cell (rare); EBV associated; seen in adults with destructive extranodal masses; most commonly sinonasal; aggressive
71
What is the cell of origin of mycosis fungoides/sezary syndrome
Helper Tcell; no chrom ab; seen in adult patients with cutaneous patches, plaques, nodules or generalized erythema; indolent
72
What is the cell of origin of large granular lymphocytic leukemia
2 types: cytotoxic T cell and NK cell; point mutations in STAT3; seen in adult patients with splenomegaly, neutropenia and anemia;
73
What is the morphology of ALL
In leukemia presentation: marrow is hypercellular and packed with lymphoblasts; mediastinal thymic masses occur in most T-ALLs and more likely to be assoc with LAD and splenomegaly; scant basophils cytoplasm; starry sky appearance; compared to myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli and smaller amounts of cytoplasm that usually lacks granules *also lymphoblasts are myeloperoxisdase neagtive
74
What staining is positive in ALL
Immunostaining for terminal deoxynucleotidyl transferase (TdT)
B-ALL: CD19 and PAX5; CD10; in very mature B-ALL, CD10 is negative; IgM in late pre-B ALLs
T-ALL: CD1, CD2, CD5, CD7; more mature CD3, CD4, CD8
75
What are the clinical features of ALL
- abrupt stormy onset within days to weeks of first sx
- sx related to depression of BM function; fatigue due to anemia ,fever (neutropenia), bleeding (thrombocytopenia)
- mass effects: bone pain resulting from marrow expansion and infiltration of subostium, generalized LAD, HSM, testicular enlargement, in T-ALL - compression of vessels and airways in mediastinum
- CNS manifestations such as HA, vomiting and nerve palsies resulting from meningeal spread (more common in ALL than AML)
76
What factors are assoc with a worse prognosis in ALL
Age <2 yrs (b/c involve translocations involving MLL gene), presentation in adolescence or adulthood, peripheral blood blast counts >100,000 (high tumor burden)
77
What are good prognostic factors in ALL
Age btw 2-10, low white cell count, hyperdiploidy, trisomy of chromosomes 4,7,10, presents of 12;21
78
What dos the 9;22 translocation form of ALL do
Creates fusion gene that encodes an active BCR-ABL tyrosine kinase; treatment with BCR-ABL kinase inhibitors in combo with chemo is effective
79
What is the most common leukemia in adults in the western world
chronic lymphocytic leukemia; median age: 60; more common in males
80
What is the pathogensis of CLL/SLL
Most common anomaly is deletion of 13q14.3, 11q, 17p, and trisomy 12q; tumors with unmutated Ig segments (naive B cell origin) have a more aggresive course;GOF in notch1 receptor; tour cells rely on signals enervated b B ell receptor transducer by BTK (defective in x linked BTK)
81
What is the morphology of CLL/SLL
LN diffusely effaced by infiltrated of small lymphocytes; proliferation centers - *pathognomonic for CLL/SLL; blood contains large numbers of small round lymphocytes with scant cytoplasm; smudge cells*; BM almost always involved by interstitial infiltrates or aggregates of tumor; also seen in splenic white and red plump and hepatic portal tracts
82
What is the immunophenotype of SLL/CLL
Pan Bcell markers; CD19 and CD20; CD23, CD5
83
What is the clinical presentation of CLL/SLL
Asymptomatic at diagnosis; when sx, nonspecific - fatiguability, weight loss, anorexia; generalized LAD, HSM; leukopenia or Leukocytosis; disrupts normal immune function hypogammaglobulinemia hemolytic anemia or thrombocytopenia due to abs produced by NON-neoplastic B cells
84
What correlates with a worse outcome of CLL/SLL
Presence of deletions of 11q and 17p; lack of somatic hypermutation, expression of ZAP-70, presence of NOTCH1 mutation
85
How is CLL/SLL treated
Gentle chemo and immunotherapy with abs against CD20
86
What factors impacts patient survival in CLL/SLL
It can transform to more aggresive tumor; most commonly in form of diffuse large B cell lymphoma (richter syndrome) - rapidly enlarging mass in LN or spleen; not good survival
87
What is the most common form of indolent NHL in the US
Follicular lymphoma; presents in middle age and affects both genders equally; strongly assoc with chrom translocations involving BCL2 14;18; devoid of apoptosis cells; mutations in MLL2 (encodes histone methyltranserase that regulations gene expression - epigenetics impt) response to therapy influenced by surrounding microenvironment
88
What is the morphology of follicular lymphoma
Predominantly nodular or diffuse pattern in involved LN; 2 cell types present: small cells with irregular or cleaved nuclear contours (centroytes) and larger cells with open nuclear chromatin, several nucleoli (centroblasts); BM involved in most cases - paratrabecular lymphoid aggregates* splenic white pulp and hepatic portal triads frequently involved
89
What is the immunophenotype of follicular lymphoma
CD19, CD20, CD10, surface Ig, BCl6; CD5 NOT expressed; BCL2 in most cases
90
What are the clinical features of follicular lymphoma
Painless generalized LAD; involvement of extranodal sites is uncommon; incurable, but follows indolent waxing and waning course; survival not improved by aggressive therapy; palliative care with low dose chemo or immunotherapy when become sx; histo transformation occurs in half of cases most commonly to diffuse B cell lymphoma; can also transform to burkitt lymphoma; not long survival after transformation
91
What is the most common form of NHL
Diffuse large B cell lyphoma; slight male predominance; median age 60 but can occur in young adults and kids
92
What is the pathogenesis of DLBCL
Dysregulation of BCL6 (required for formation of normal germinal centers) - product of somatic hypermutation that results in overexpression of BCL6; BCL6 normally represses expression of factors t hat promote germinal center B cell diff, growth arrest, and apoptosis; some assoc with 14;18 translocation; mutations in p300 (histone acetylase) and CREBP
93
What is the immunophenotype of DLBCL
CD19 CD20; variable expression of CD10 and BCL6
94
What are the subtypes of DLBCL
- immunodeficiency associated: occurs in setting of severe T cell immunodeficiency (HIV and allogeneic BM transplant); usually infected with EBV restoration of T cell immunity may lead to regression
- primary effusion lymphoma: malignant pleural or ascitic effusion mostly in patients with advanced HIV or older adults; tumor cells are anaplastic and fail to express surface B or T cell markers but have long as IgH gene arrangements; in all cases* tumor cells are infected with HHV-8
95
What are the clinical features of DLBCL
Presents as rapidly enlarging mass at nodal or extranodal site; can arise anywhere; waldeyer ring (oropharyngeal lymphoid tissue) commonly involved; extranodal sites include GI, skin, bone, brain; BM involvement uncommon; aggressive and rapidly fatal without treatment; with chemo good prognosis; anti-CD20 improves outcome; if have a MYC translocation, worse prognosis
96
What are the categories of burkitt lymphoma
African (endemic) burkitt lymphoma; sporadic (nonendemic) burkitt lymphoma, and subset of aggresive lymphomas occuring in individuals with HIV; histologically identical but differ in clinical, genotype, and virologic characteristics
97
What is the pathogenesis of burkitt lymphoma
All forms assoc with translocations of MYC on chrom 8 that leads to increased MYC protein levels; Warburg effect - increases genes that are required for aerobic glycolysis *fastest growing human tumor; 8;14 translocation (IgH locus) or 2;8 (Igk) or 8;22 (gamma light chain); breakpoint in sporadic in class switch regions; in endemic in VDJ sequences
98
What are all endemic burkitt lymphomas infected with
latent EBV; also present in 1/4 of HIV assoc tumors and some sporadic cases
99
what is the morphology of burkitt lymphoma
Diffuse infiltrate of intermediate size lymphoid cells; coarse chromatin, several nucleoli; high mitotic index and numerous apoptotic cells - phagocytosed by macrophages which creates starry sky appearance; in BM, royal blue cytoplasm containing clear cytoplasmic vacuoles
100
What is the immunophenotype of burkitt
IgM, CD19, CD20, CD10, BCL6; does not express BCL2 (unlike other tumors of germinal center origin)
101
What are the clinical features of burkitt lymphoma
Both endemic and sporadic found mainly in children; most manifest as tumors in extranodal sites; endemic usually presents as a mass involving mandible and abdominal viscera (kidneys, ovaries, and adrenal glands); sporadic appears as mass involving ileocecum and peritoneum; involvement of BM and peripheral blood uncommon; very aggressive but responds well to intense chemo
102
What are the plasma cell neoplasms referred to as
Dyscrasias; most common and deadly is multiple myeloma; identified by monoclonal Ig in blood (M component); neoplastic plasma cells can synthesize excess light chains and complete Igs; light chains can be excreted in urine (bence-jones protein)
103
what are the terms used to describe abnormal Igs in plasma cell neoplasms
Monoclonal gammapathy, dysproteinemia, paraproteinemia
104
What pathologies are associated with abnormal igs
- multiple myeloma (plasma cell myeloma): presents as tumorous masses scattered throughout skeletal system; solitary myeloma (plasmacytoma) is variant that presents as single mass in bone or soft tissue; smoldering myeloma is variant with lack of sx and a high plasma M component
- waldenstrom macroglobulinemia: high levels of IgM lead tot sx related to hyperviscosity of blood; older adults in association with lymphoplasmacytic lymphoma
- heavy chain dz: monoclonal gammopaty seen in assoc with lymphoplasmacytic lymphoma and small bowel marginal zone lymphoma (malnourished - Mediterranean lyymphoma); synthesis of free heavy chain
- primary or immunocyte assoc amyloidosis: monoclonal proliferation of plasma cells secreting light chains (usually gamma) that are deposited as amyloid
- monoclonal gammopathy of undetermined significance: patients w/o sx who have small to moderately large M components in blood; common in older adults and low, but constant rate of transformation to sx monoclonal gammopathies, mostly multiple myeloma
105
What is multiple myeloma
Plasma cell neoplasm assoc with lytic bone lesions, hypercalcemia, renal failure, and acquired immune abnormalities; can spread in late course to LN and extranodal sites; higher in men and Africans; peak incidence age 65
106
What is the pathogenesis of multiple myeloma
Assoc with frequent rearrangements involving IgH locus with cyclinD1 and D3; deletions on chrom 17p that involves TP53 indicate poor outcome; frequent mutationis of NFkB; survival of tumor dependent on IL-6* - high levels seen in active dz and assoc with poor prognosis; MIP1alpha up regulates express ion of receptor activator of NFkB (RANKL) which activates osteoclasts (increased bone resorption) - hypercalcemia and breakdown of bone
107
what is the morphology of multiple myeloma
Destructive plasma cell tumors involving axial skeleton; most effected: vertebral column, ribs, skull, pelvis, femur, clavicle, scapula; lesions begin in medullary cavity and erode callous bone, destroy the bony cortex; bone lesions appear as punched out defects on radiograph and consist of soft gelatinous red tumor masses; some variants can have flame cells with fiery red cytoplasm, Mott cells with multiple grasp like cytoplasmic droplets; globular inclusions (Russell bodies - if cytoplasmic) (duthcer bodies if nuclear) *M protein causes rouleaux formation
108
what is the immunophenotype of multiple myeloma
CD138 (adhesion molecule aka syndecan-1), often express CD56
109
what are the clinical features of multiple myeloma
Pathologic fractures and chronic pain; hypercalcemia - neuro sx, weakness, lethargy, constipation, polyuria; recurrent bacterial infxn; renal insufficiency - trails infections as COD; can cause amyloidosis if AL type; most common monoclonal lgis IgG
110
What does definitive diagnosis of multiple myeloma rely on
Bone marrow exam; often gives rise to normochomic anemia
111
What is assoc with a good outcome of multiple myeloma
Translocations involving cyclin D1; deletions of 13q, 17p, ad 4;14 translocation have more aggressive course
112
What is being explored s a treatment for multiple myeloma
Proteasome inhibitors; thalidomide also has activity against myeloma
113
What is solitary myeloma (plasmacytoma)
Solitary lesion of bone o soft tissue; extraosseous lesions found in lungs, oronasopharynx or nasal sinuses; progresses to multiple myeloma but can take 10 years; extraosseus can be cured by local resection
114
What is smoldering myeloma
Middle ground btw multiple myeloma and monoclonal gammopathy; asymptomatic; about 75% progress to multiple myeloma in 15 years
115
What is monoclonal gammopathy of uncertain significance
Most common plasma cell dyscrasia; asymptomatic Nd serum M protein <3gm/dL; 1% envelop symptomatic plasma cell neoplasm (multiple myeloma)
116
What is lymphoplasmacytic lymphoma
B cell neoplasm of older adults that usually presents in 6th or 7th decade; substantial reaction of tumor cells undergo. Terminal differentiation to plasma cells; secretes IgM -> hyperviscosity syndrome known as waldenstrom macroglobulinemia; does not have complications of renal and amyloidosis like multiple myeloma
117
What is the pathogensis of lymphoplasmacytic lymphoma
All have mutations in MYD88 (encodes adaptor protein for signaling evens that activate NFkB and augment signals downstream of Bcell receptor
118
What is the morphology of lymphoplasmacytic lymphoma
Marrow contains infiltrate of lymphocytes, plasma cells, and plasmacytoma lymphomcytes accompanied by mast cell hyperplasia; Russell bodies or dutcher bodies; at diagnosis usually disseminated to LN, spleen, and liver; infiltration of n roots, meninges and brain can also occur
119
What is the immuophenotype of lymphoplasmacytic lymphoma
CD20 and surface Ig; secrets IgM or IgG or IgA
120
What are the clinical features of lymphoplasmacytic lymphoma
Nonspecific complaints; half have LAD, HSM; anemia is common; autoimmune hemolysis caused by gold glutinous (IgM binds to red cells at temp <37 degrees)
121
What symptoms do patients with IgM secreting tumors
Hyperviscosity syndrome: visual impairment (venous congestion, totuosity and distention of retinal veins, retinal hemorrhages and exudates), neuro problems (HA, dizziness, deafness, stupor from sluggish blood flow), bleeding (formation of complexes btw macroglobulinemia and clotting factors), cryoglobulinemia (precipitation of macroglobulinemia at low temps - raynauds and cold urticaria)
122
Is lymphoplasmacytic lymphoma curable
No; symptoms alleviated by plasmapharesis; median survival is 4 years
123
What is extramedullary plasmacytoma
Solitary mass usually in aero digestive tract; rarely progresses to systemic dz
124
What is mantle cell lymphoma
Uncommon; presents in 5ht-6th decade and shows male predominance
125
What is the pathogenesis of mantle cell lymphoma
11;14 translocation involving IgH locus and cylin D1
126
What is the morphology of mantle cell lymphoma
Generalized LAD; 40% have peripheral blood involvement; extranodal involvement: bon marrow, spleen liver and gut; can produce polyp like lesions - most likely to spread in this fashion of all NHL; nodular appearance; proflieration of small lymphocytes with irregular to deeply clefted nuclear contours
127
What is the immunophenotype of mantle cell lymphoma
cyclin D1; CD19, CD20 and high levels of IgM and D; usually CD5+ and CD23 - (distinguishes it from CLL/SLL); lacks somatic hypermutation
128
What are the clinical features of mantle cell lymphoma
Painless LAD; sx related to gut and spleen common; prognosis is poor* blastoid variant and proliferative expression assoc with even shorter survival
129
What are marginal zone lymphomas
Arise within LN, spleen or extranodal tissues; often referred to as MALTomas; somatic hypermutation - memory B cell origin
130
What are the 3 exceptional characteristics of marginal zone lymphomas
- often arise within tissue involved by chronic inflammatory disorders; ie: sjogren, hashimotos, h pylori
- remain localized for prolonged periods spreading only late in course
- may regress if inciting agent is eradicated
131
What translocations are specific for mantle zone lymphomas
11;18 14;18 1;14 - all unregulated function of BCL10 or MALT1 which activate NFkB; with further Clonal evolution, spread to distant sites and transformation to DLBCL can occur
132
What is hairy cell leukemia
Disease of middle aged white males; median age of 55
133
What is the pathogensis of hairy cell leukemia
Assoc with activating point mutations in BRAF (serine/threonine kinase) - downstream of RAS in MAPK cascade; mutation is valine to glutamate substitution (also sen in melanoma and langerhans cell histiocytosis)
134
What is the morphology of hairy cell leukemia
Fine hairlike projections; on blood smear has round, oblong nuclei and pale blue cytoplasm with bleblike projection; cannot be aspirated - “dry tap” and are only seen in marrow biopsies; splenic red pulp usually heavily infiltrated leading to obliteration of white pulp and beefy red. Gross appearance; hepatic portal triad involved frequently
135
What is the immunonphenotype of hair cell leukemia
CD19 CD20, surface Ig (IgG), CD11c, CD25, CD103, annexin A1
136
What are the clinical features of hairy cell leukemia
Result from infiltration of BM, liver, spleen; massive splenomegly*, hepatomegaly not as common; LAD is rare; pancytopenia, infections - risk of atypical mycobacterial infections; indolent course; sensitive to gentle chemo; relapse in 5 or more years; BRAF inhibitors produce excellent response; excellent prognosis
137
What is peripheral T cell lymphoma unspecified
Face LN diffusely and are typically composed of pleomorphic mixture of malignant T cells; prominent infiltrate of reactive cells; express CD2, CD3, CD5, and either alphabeta or deltagamma T cell receptor; most present with LAD, eosinophilia, pruritis ever and wight loss; worse prognosis than mature B cell neoplasms
138
What is anaplastic large cell lymphoma (ALK positive)
Uncommon; presence of rearrangements of ALK gene on chrom 2p23; break ALK locus and lead to ALK fusion proteins - trigger JAK/STAT signaling; horseshoe shaped nuclei and voluminous cytoplasm (hallmark cells) clusters around venules and infiltrates lymphoid sinuses mimicking met carcinoma *ALK is not present in normal lymphocytes; occurs in children or young cults and involves soft tissue and have good prognosis; if no ALK rearrangement (adults) poor prognosis; both express CD30
139
What is adult T cell leukemia/lymphoma
Neoplasm of CD4 cells only observed in adults infected with HTLV-1; skin lesions, generalized LAD, HSM, peripheral blood lymphocytosis and hypercalcemia; cloverleaf or flower cells; HTLV-1 encodes Tax that is an activator of NFkB; most p resent with rapidly progressive dz that is fatal within months to 1 year
140
What else can HTLV-1 infection lead to
Progressive Demyelinating dz of CNS and SC
141
What is mycosis fungoides
Different manifestation of a tumor of CD4 helper T cells that home to the skin; progresses through premycotic phase, plaque phase and tumor phase; epidermis and dermis infiltrated by neoplastic T cells which have cerebriform appearance
142
what is sezary syndrome
Variant in which skin involvement is manifested as generalized exfoliative erythroderma; in contrast to mycosis fungoides, skin lesions rarely proceed to tumefaction; associated leukemia of sezary cells with charactestic cerebriform nuclei
143
What is the immunophenotype of s early syndrome and mycosis fungoides
adhesion molecule cutaneous leukocyte antigen (CLA) and chemokine receptors CCR4 and CCR10; indolent tumors
144
What is large granular lymphocytic leukemia
T and NK cel variants; adults; in T cell dz (CD3 positive) -> lymphocytosis and splenomegaly; NK dz (CD3 negative, CD56) more subtle; mutations in STAT3; neutropenia and anemia ; T cell indolent; NK more aggressive
145
What is felty syndrome
Complication of large granular lymphocytic leukemia; triad of RA, splenomegaly, and neutropenia
146
What is extranodal NK/T cell lymphoma
Rare in US; Asia; presents as destructive nasopharyngeal mass; surrounds and invades small vessels leading to extensive ischemic necrosis; large azurophilic granules seen in cytoplasm; assoc with EBV but tumor cells do not express CD21; CD3 -; highly aggresive but respond well to radiation, not hemo; prognosis is poor
147
What is the presentation of Hodgkin lymphoma
Arises in single node or chain of nodes and spreads first to anatomically continuous lymphoid tissues; reed stern berg cells (neoplastic giant cells) derived from germ center or post germ center B cells
148
What are the subtypes of Hodgkin lyphoma
Nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depletion, lymphocyte predominance
149
What are the classical forms of Hodgkin
Nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depletion; have similar immunophenyote.
150
What is the pathogenesis of Hodgkin
Ig genes of reed sternberg cells have undergone VDJ recombination and somatic hypermutation; don’t express B cell specific genes; activation of NFkB
151
How can NFkB b activated in Hodgkin
- EBV infection
- EBV +tumor cells express latent membrane proline 1 (LMP-1) encoded by EBV genome that upregulates NFkB
- result of acquired LOF in IkB or A20 (TNF alpha induced protein 3 or TNFAIP3)
- rescues crippled germ center B cells that cannot express Igs from apoptosis
- gains in REL Proto-oncogene
152
What is the morphology of Hodgkin
Reed-Sternberg cells are large with multiple nuclei or single nucleus with multiple lobes; mononuclear variants; lacunae cells seen in nodular sclerosis type have folded or multilobate nuclei
153
What conditions can cells that resemble reed sternberg cells be seen
Mono, solid tissue cancers, and large cell NHL
154
What does the diagnosis of Hodgkin lymphoma depend on
Reed sternberg cells in background of non-neoplastic inflammatory cells
155
What is the morphology of the nodular sclerosis type of Hodgkin
Most common* lacunae variant Reed-Sternberg cells; deposition of collagen in bands that divide involved LN into circumscribed nodules *PAX5, CD15 and CD30 positive, negative for other B cell markers, T cell markers, and CD45; not assoc with EBV; equal in males and females; *involves lower cervical, supraclavicular and mediastinal LN; excellent prognosis
156
What is the morphology of mixed cellularity type Hodgkin
LN usually diffusely effaced by infiltrate; *diagnostic reed sternberg cells usually plentiful - most are infected with EBV; immunophenotype same as nodular sclerosis; more common in males, older age, and systemic sx; very good prognosis
157
What is the morphology lymphocyte-rich type Hodgkin
Uncommon; reactive lymphocytes make up majority of infiltrate; LN diffusely effaced; *presence of mononuclear variants and diagnostic Reed-Sternberg cells; excellent prognosis
158
What is the morphology of the lymphocyte depletion type of Hodgkin
Least common form*; abundance of reed sternberg cells; *most infected with EBV; occurs in old adults, in HIV+ ppl of any age and in non industrialized countries; less favorable outcome
159
What is the morphology of the lymphocyte predominance type of Hodgkin
Uncommon; effaced by nodular infilatred of small lymphocytes with variable number of macrophages; reed-sternberg hard to find contains lymphocytic and histioctic variants which have multilobed nucleus resembling popcorn kernel* - express B cell markers typical of germinal center B cells (CD20, BCL6, neg for CD15 and CD30); can transform to DLBCL; not assoc with EBV; males <35, cervical or axillary LAD; excellent prognosisi
160
What are the clinical features of Hodgkin
Presents as painless LAD; patients with nodular sclerosis or lymphocyte predominance tend to have stage I-II dz and free of systemic sx; cutaneous immune unresponsiveness (anergy) also seen; factors released from Reed-Sternberg cells suppress Th1 immune responses
161
How does Hodgkin spread
Nodal dz first -> splenic dz, hepatic dz and then marrow and other tissues; staging involves PE, radiologic imaging of ab, pelvis, chest and bx of BM; tumor stage rather than histo subtype is most impt for prognosis
162
How can you cure low stage localized Hodgkin
Field radiotherapy; but risks lung cancer, melanoma, an breast cancer; patients treated with early chemo regimens containing alkylating agents had high incidence of secondary tumors (AML)
163
What factors do Reed-Sternberg cells release
TNF, bFGF (leads to fibrosis); IL-5, galectin-1 (enhances Treg response), inhibits Th1 and CTL with IL-10; M-CSF, IL-13 which binds to a receptor on its membrane
164
What is the common feature among myeloid neoplasms
Origin from hemtopoietic progenitor cells; present with sx related to altered hematopoiesis
165
What are the categories of myeloid neoplasia
- acute myeloid Leukemias: accumulation of immature myeloid forms (blasts) in BM and suppresses normal hematopoiesis
- myelodysplastic syndromes: defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis leading to cytopenias
- myeloproliferative disorders: increased production of. One or more types of blood cells
166
What are the manifestations of myeloid neoplasms influenced by
- position of transformed cell within the hierarchy of progenitors
- effect of transforming events on differentiation
167
What is acute myeloid leukemia
Tumor of hematopoietic progenitors caused by acquired oncogene culture mutations that impede differentiation leading to accumulation of immature myeloid blasts in marrow; leads to marrow failure and anemia, thrombocytopenia and neutropenia; occurs at all ages but rises throughout life (peak in 60s)
168
What is the classification of AML
Heterogenous; 4 categories: AML with genetic aberrations, AML with MDS-like features, AML therapy related and AML NOS
169
What are the AML with genetic aberrations
- AML w/ (8;21)(q22;q22) RUNX1/ETO fusion: favorable prognosis; full range of myelocytic maturation; auger rods easily found; abnormal cytoplasmic granules
- AML w/ inv(16)(p13;q22); CBFB/MYH1 fusion: favorable prognosis; myelocytic and monocytes diff; abnormal eosinophilic precursors with ab basophilic granules
- AML w/ t(15;17)(q22;11-12); RARA/PML fusion: favorable; numerous Auer rods in bundles primary granules prominent; high incidence of DIC*
- AML w/ t(11q23;v) diverse MLL fusion: poor, monocyte diff
- AML w normal cytogenetic and mutated NPM: favorable; detected by immuno histo staining for NPM
170
What are the AML with MDS like features
- with prior MDS: poor prognosis; diagnosis based on clin history
- AML with multilineage dysplasia: poor; maturing cells with dysplastic features typical of MDS
- AML with MDS-like cytogenetic aberrations: poor assoc with 5q, 7q, 20q aberrations
171
What is AML therapy related
Very poor prognosis; if following alkylation or radiation therapy, 2-8 year latency period; MDS like cytogenic aberrations; if following topoisomerase II inhibitor (etoposide) 1-3 year latency, translocations involving MLL
172
What is AML NOS
- AML, min diff: intermediated prognosis; neg for myeloperoxidase, myeloid antigens detected on blasts by flow cytomegalovirus
- AML without maturation: intermediate; >3% of blasts pos for myeloperoxidase
- AML with myelocytic maturation: intermediate; full range of myelocytic maturation
- AML with myelomonocytic maturation: intermediate; myelocytic and monocyte diff
- AML with monocytes maturation: intermediate; nonspecific esterase positive monoblasts and pro monocytes predominate in marrow
- AML with erythroid maturation:: intermediate; erythroid/myeloid subtype >50% dysplastic maturing erythroid precursors and >20% myeloblasts; pure erythroid subtype defined by >80% erythroid precursors without myeloblasts
- AML with megakarytocyte maturation: intermediate; blasts of megakaryocytic lineage; detected with abs against megakaryocyte markers (GPIIb/IIIa or vWF); assoc with marrow fibrosis; *most common AML in Down syndrome
173
What are the most common rearrangements seen in AML
Genetic aberrations disrupt genes encoding TF required for normal myeloid diff; *2 most common are t(8;21) and inv(16) - disrupte RUNX and CBFB genes respectively which encode polypeptide that bind each other to form RUNX1-CBF1beta required for normal hematopoiesis
174
What growth factor signaling pathways are mutated in AML
Ex: AML with t(15;17) - acute promyelocytic leukemia; creates retinoids acid receptor fusion with PML which interferes with terminal diff of granulocytes - can be overcome with all-trans retinoids acid or arsenic trioxide; but this is not enough to cause dz; also have mutations in FLT3 (RTK)
175
What epigenomic mutations have been seen in AML
Genes that influence DNA methylation or histone modifications; mutations of cohesion complex (proteins that regulate 3D structure of chromatin)
176
What is the diagnosis of AML based on
Presence of at least 20% myeloid blasts in the BM; myeloblasts have delicate nuclear chromatin, 2-4 nucleoli and lots of cytoplasm containing peroxidase pos granules; auer rods - distinct needle like azurophilic granules (acute promyelocytic leukemia is most prominent), monoblast: folded or lobulated nuclei, lack serum rods
177
What is aleukemic leukemia
When blasts are entirely absent from blood in AML
178
What marker do myeloid blasts express
CD34 (marker of pluripotency) and CD33 (marker of immature cells) but not CD64
179
What are AMLs arising de novo in younger adults assoc with
Balanced chromosomal translocations particularly t(8;21), inv(16) and t(15;17)
180
What are AMLs following myelodysplastic syndromes or exposure to DNA damaging agents assoc with
Deletions or monosomies invovling chrom 5 and 7; lack translocations *exception is those that arise after treatment with topoisomerase II inhibitors - assoc with translocations involving MLL gene on chrom 11q23
181
What are the clinical features of AML
Present within weeks or months of onset of sx with complaints related to anemia, neutropenia and thrombocytopenia (fatigue, fear and spontaneous mucosal and cutaneous bleeding); infections in oral cavity, skin, bladder, kidneys, colon usually caused by fungi, pseudomonas and commensals; tumors with monocytes diff infiltrate skin(leukemia cutis) and gingiva; CNS spread less common than ALL; can present as localized soft tissue mass known as myeloblastoma, granuloccytic sarcoma or chloroma
182
What is the prognosis of AML
Difficult to treat; *AML with 15;17 treated with all-trans retinoids acid and arsenic salts has best prognosis; AMLs with 8;21 or inv(16) have good prognosis with chemo especially in absence of KIT mutations; prognosis is dismal for AMLs that follow MDS or genotoxic therapy to that occur in older adults (treat with hematopoietic stem cell transplant)
183
What are myelodysplastic syndromes
Group of Clonal stem cell disorders characterized by maturation defects assoc with ineffective hematopoiesis and high risk of transformation to AML; BM is replaced by Clonal progeny of neoplastic multipotent stem cell that can differentiate but does so in an ineffective and disordered fashion; all forms can transform to AML, but the ones after therapy (t-MDS) occur more frequently and rapidly
184
What is the pathogenesis of MDS
- epigenetics: mutations in DNA methylation and histone modifications
- RNA splicing factors: mutations involving 3’ end of RNA splicing machinery
- TF
- 10% have LOF in TP53 high correlates with complex karyotype and poor clinical outcom
- assoc with chrom ab including monosomies 5 and 7 deletions of 5q (RPS14) 7q 20q Nd trisomy 8 (MYC located here)
185
What is the morphology of MDS
Hypercellular at diagnosis; most characteristic finding is disordered diff affecting erythroid, granulocytic, monocytes and megakaryocytic lineages; *ring siderobblasts, erythroblast with iron-laden macrophages, megaloblastoid maturation (as seen in B12 and folate def) and nuclear budding abnormalities (misshapen nuclei); pseudo-pelger-Huet cells (neutrophils with only 2 nuclear lobes); pawn ball megakaryocytes (single nuclear lobes or multiple separate nuclei); myeloid blasts increased but make up less than 20% of marrow; blood contains pelger-huet, giant platelets, macrocytes and poikilocytes
186
What are the clinical features of primary MDS
Older adults (mean age 70); half discovered incidentally on blood testing; when sx present with weakness, infections and hemorrhages; worse outcomes predicted by higher blast counts and more severe cytopenias as wel las presence of multiple Clonal chrom ab
187
What are the tyrosine kinase mutations in myeloproliferative disorders
- chronic myelogenous leukemia: BCR-ABL fusion
- polycythemia Vera: JAK2 point mut
- essential thrombocythemia: JAK2 point mut; MPL point mut
- primary myelofibrosis: JAK2 and MPL point mut
- systemic mastocytosis: KIT point mut
- chronic eosinophilic leukemia: FIP1L1-PDGFRA fusion (common)and PDE4DIP-PDGFRB fusion (rare - responds to imatinib therapy) assoc with Loeffler endocarditis
- stem cell leukemia:: FGFR1 fusion genes
188
What is the median survival in primary MDS
9 - 24 month; in tMDS only 4-8 months
189
What are the treatment options for MDS
Allogeneic hematopoietic stem cell transplant in younger patients; older patients treated with supportive abx Nd transfusions
190
What is the common pathogenic features of myeloproliferative disorders
Mutated constitutively active tyrosine kinase or other abberations in pathways that lead to growth factor independence
191
What are the common clinical features of myeloproliferative disorders
- increased proliferative drive in BM
- Homing of neoplastic stem cells to secondary hematopoietic organs producing extramedullary hematopoiesis
- variable transformation to spent phase characterized by marrow fibrosis and peripheral blood cytopenias
- variable transformation to acute leukemia
192
What is CML
BCR-ABL fusion - created by a reciprocal (9;22)(q34;q11) translocation (philly chrom); cell of o robin is pluripotent hematopoietic stem cell
193
What is the pathogenesis of CML
Activation of RAS and JAK/STAT; preferentially drive proliferation of granulocytic and megakaryocytic progenitors and causes ab release of immature granulocytic forms from marrow into blood *does not effect diff so will have mature elements in peripheral blood
194
What is the morphology of CML
Hypercellular marrow *scattered macrophages with abundant wrinkled green-blue cytoplasm called sea-blue histiocytes ; increased deposition of reticulum is typical; blood reveals leukocytosis (often >100,000); platelets increased; spleen is enlarged (increased red pulp) and contains infarcts of varying age
195
What are the clinical features of CML
Adults primarily but can occur in children; peak indigene 5th-6th decade; mild anemia and hyper metabolism bc increased cell turnover leading to fatigue, weakness, weight loss, anorexia; dragging sensation in ab (splenomegaly) or LUQ pain due to splenic infarct; slow progression even without treatment - median survival 3 years
196
What is the accelerated phase of CML
Half of patients experience it; increasing anemia and thrombocytopenia; additional ab (trisomy 8, isochromosome 17q or duplication of Ph chrom seen); within 6-12 months terminates in a picture resembling acute leukemia (blast crisis)
197
What mutation has been linked to lymphoid blast crisis in CML
Mutations that interfere with activity of Ikaros (transcription factor that regulates diff of hematopoietic progenitors) - also seen in BCR-ABL positive B-ALL
198
How is CML treated
BCR-ABL inhibitors
199
What is polycythemia Vera
Characterized by increased marrow production of red cells, granulocytes, and platelets (panmyelosis)
200
What are the serum erythropoietin levels in polycythemia Vera
Low; (secondary forms have high); increased hematocrit leads to increased viscosity and sliding; thrombocytopenia and ab platelet function (prone to thrombosis and bleeding)
201
What is the pathogenesis of polycythemia Vera
Valine to phenylalanine sub at 617; mutation in JAK2; if 2 mutated copies, higher white cell count, more sig splenomegaly, sx prutrits and greater rate of progression to spent phase
202
What is the morphology of polycythemia Vera
Marrow is hypercellular; increase in red cell progenitors is subtle and accompanied by increase in granulocytic precursors and megakaryocytes; blood contains increased number of basophils and abnormally large platelets; late in course, PCV progresses to spent phase characterized by extensive marrow fibrosis accompanied by increased extramedullary hematopoiesis in splen and liver
203
What are the clinical features of polycythemia Vera
Uncommon; adults; abnormal blood flow particularly on low-pressure venous side; patients are plethora can and cyanotic due to stagnation and deoxygenation of blood; HA, dizziness, HTN, and GI sx common; intense pruritis and peptic ulcer can occur (release of histamine from basophils); high cell turnover gives rise to hyperuricemia sx gout seen sometimes; DVT, MI, stroke; can cause budd chiari if thrombosis in hepatic vein or bowel infarction; minor hemorrhages common
204
What is the prognosis for PCV without treatment
Die in months of diagnosis; treatment is maintaining red cell mass levels by phlebotomy - median survival is 10 years
205
What is a spent phase of PCV
Clinical and anatomic features of primary myelofibrosis develop; undergoes this transition in 15-20% of patients after an average period of 10 years; marked by appearance of obliterative fibrosis in BM and extensive extramedullary hematopoiesis (spleen)
206
What can PCV transform to
AML; but often lacks JAK2 mutations; transformation to ALL is rarely seen
207
What is essential thrombocytosis
Assoc with point mut in JAK2 (more common) or MPL - RTKs normally activated by thrombopoietin; remaining cases have mut in calreticulin
208
What are the clinical manifestations of essential thrombocytosis
Elevated platelet counts; separated from PCV and primary myelofibrosis based on absence of polycythemia and marrow fibrosis; iron deficiency is common; megakaryocytes markedly increased
209
What is a characteristic symptom of essential thrombocytosis
Erythromelalgia - throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates
210
What is the median survival for essential thrombocytosis
Indolent; 12-15 years; thrombotic complications most likely in patients with very high platelet counts and homozygous JAK2 mutations; therapy is gentle chemo to suppress thrombopoiesis
211
What is the hallmark of primary myelofibrosis
Development of obliterative marrow fibrosis; leads to cytopenias and extramedullary hematopoiesis; histo is identical to spent phase of myeloproliferative disorders
212
What is the chief pathologic features of primary myelofibrosis
Extensive deposition of collagen in marrow by non-neoplastic fibroblasts; caused by 2 factors released by megakaryocytes: platelet derived growth factor and TGFbeta
213
What is the morphology of primary myelofibrosis
Early marrow is hypercellular; megakaryocytes are large, dysplastic and abnormally clustered - have unusual nuclear shapes (cloud like); with progression marrow becomes hypocellular and fibrotic; veery late, marrow can turn to bone (osteosclerosis)
214
What are the blood findings of primary myelofibrosis
Premature release of uncleared erythroid and early granulocytes progenitors (leukoerythroblastosis); tear-drop shaped red cells (dacryocytes) seen
215
What are the clinical features of primary myelofibrosis
Less common than PCV and ET; >60 yo; comes to attention bc of normochromic normocytic anemia and splenomegaly; can by complicated by hyperuricemia and secondary gout; white count normal or mildly reduced usually but can be elevated early on; more difficult to treat than PCV and ET; median survival is 3-5 years; use JAK2 inhibitors
216
What is histiocytosis
Proliferative disorders of dendritic cells or macrophages
217
What are the langerhans cell histiocytoses
Spectrum of proliferation’s of special type of immature dendritic cell (langerhan cell)
218
What is the most common mutation in langerhans cell histiocytosis
Valine to glutamate substitution at residue 600 in BRAF (seen in hairy cell leukemia also)
219
What do langerhans cells look like
Abundant vacuolated cytoplasm and vesicular nuclei containing linear grooves or. Folds; presence of birbeck granules in cytoplasm is characteristic* - pentalaminar tubules with dilated terminal end producing tennis racket like appearance which contain langerin; express HLA-DR S-100 and CD1a
220
What is multifocal multisystem langerhans cell histiocytosis (letterer-siwe dz)
Occurs before 2 years of age; development of cutaneous lesions resembling seborrheic eruption caused by infiltrates of langerhans cells ver font and back of trunk and scalp; most have HSM, LAD, pulm lesions and destructive osteolytic bone lesions; anemia, thrombocytopenia and predisposition to recurrent infections (otitis media and mastoiditis); in some instances can be anaplastic and referred to as langerhans cell sarcoma; *if untreated rapidly fatal; with chemo, 5 year survival
221
What is unifocal and multifocal unisystem langerhans cell histiocytosis (eosinophilic granuloma)
Proliferation of langerhans admixed with eosinophils, lymphocytes, plasma cells and neutrophils; arises within medullary cavities of bones (most commonly calvarium, rib and femur); less commonly, unisystem lesions of identical histo arise in skin, lungs or stomach; unifocal lesions most commonly affect skeletal system in older children or adults and is indolent (spontaneous healing to local excision); multifocal unisystem dz usually affects young kids - present with mult erosive bony masses, involvement of post pit stalk leads to DI *Hand-Schiller-Christian triad (DI, calvarial bone defects and exopthalamos); treated successfully with chemo or spontaneous recovery
222
What is pulmonary langerhans cell histiocytosis
Adult smokers; regress spontaneously when quit smoking; reactive proliferation’s of langerhans cells; some associated with BRAF mutations
223
What do langerhan’s cells express
Normal epidermal: CCR6;; their neoplastic counterparts express CCR6 and CCR7 which allows them to migrate into tissues that express CCL20 (ligand for CCR6 in skin and bone) and CCL19 and 21 (ligands for CCR7 in lymphoid organs)
224
What are the 4 functions of the spleen
- phagocytosis of blood cells and particulate matter: RBCs undergo deformation during passage from cords into sinusoids; if deformability is decreased, become trapped in cords and phagocytosed by macrophages; also responsible for pitting of RBCs (inclusions - Heinz bodies and Howell-jolly bodies are excised)
- ab production: dendritic cells present to T cells; T and B cell interaction at edges of white pulp lead to gen of ab secreting plasma cells found in red pulp
- hematopoiesis: compensatory
- sequestration of formed blood elements: platelets sequestered in red pulp producing thrombocytopenia
225
What are asplenic patient susceptible do
Pneumococci, meningococcal, haemophilus influenzae
226
What sx does splenomegaly cause
Dragging sensation; discomfort after eating; hypersplenism - anemia, leukopenia, thrombocytopenia via sequestration of elements
227
What is nonspecific acute splenitis
Enlargement of spleen as a result of blood-borne infections; caused by microbiologic agents themselves and cytokines released; spleen enlarged and soft; major feature is acute congestion of red pulp which can face lymphoid follicles; white pulp can undergo necrosis *especially when causative agent is hemolytic strep
228
What are the disorders assoc with splenomegaly
- infections: mono, TB, typhoid, brucellosis, CMV, syphilis, malaria, histoplasmosis, toxoplasmosis, kala-azar, trypanosomiasis, schisto, leishmaniasis, echinococcosis
- congestive states related to portal HTN: cirrhosis, portal or splenic v thrombosis, cardiac failure
- lyphohematogenous disorders: Hodgkin, NHL, lymphocytic leukemia, multiple myeloma, myeloproliferative disorders, hemolytic anemia’s
- immune inflamm conditions: RA, SLE
- storage dz: gaucher, Niemann-pick dz, mucopolysaccharidoses
- amyloidosis, primary neoplasms and cysts, secondary neoplasms
229
What causes congestive splenomegaly
Chronic venous outflow obstruction may be caused by intrahepatic disorder or extrahepatic that directly impinge upon portal or splenic veins; lead to splenic or portal v HTN; right heart failure
230
What is the morphology of congestive splenomegaly
Marked enlargement; organ is firm; capsule is thickened and fibrous; red pulp is congested early but becomes fibrotic with time; deposits of collagen in BM of sinusoids; results in excessive destruction of blood cells because slow blood flow so longer exposure
231
What are the most common neoplasms of the spleen
Lymphangiomas and hemangiomas
232
What does complete absence of the spleen usually occur with
Other congenital abnormalities such as situs inversus and cardiac malformations; hypoplasia is more common
233
What is an accessory spleen (spleniculi)
Common; small spherical structures; can ve found anywhere in ab cavity; impt in hereditary sphere Tyson’s and immune thrombocytopenia purpura where splenectomy is used as treatment
234
What are the most common predisposing conditions to splenic rupture
Mono, malaria, typhoid, lymphoid neoplasms; chronically enlarged spleens unlikely to rupture because toughening of extensive reactive fibrosis
235
What can cause the thymus to involute
Exposure to severe illness and HIV
236
What is thymic hyperplasia
Appearance of B ell germinal centers within the thymus which is referred to as thymic follicular hyperplasia; *most frequently encountered in myasthenia graves; sometimes seen in graves, SLE, scleroderma, RA, and other AI dz
237
What is a thymoma
Tumors of thymic epithelial cells; also contain benign immature T cells (thymocytes); 3 subtypes: tumors that are cytologically benign and noninvasive, tumors that are cytologically benign but invasive or metastatic, tumors that are cytologically malignant (thymic carcinoma); in all c ategories occur in adults >40 yo males and females equally; most in anterior superior mediastinum
238
What is the morphology of noninvasive thymoma
Composed of medullary-type epithelial cells or mix of medullary and cortical; elongated or spindle shaped
239
What is the morph of invasive thymoma
Cytologically benign but locally invasive; more likely to met; cortical cells; *penetrate through capsule into surrounding structures; extensive invasion poor outcome
240
What is the morph of thymic carcinoma
Fleshy invaisve masses; can met to lungs; micro: squamous cell carcinomas; next most common is lymphoepithelioma like carcinoma (sheets of cells with indistinct borders that looks like nasopharyngeal carcinoma; EBV related)
241
What are the clinical features of thymomas
Impingement of mediastinal structures; myasthenia gravis; also assoc with hypogammaglobulinemia, pure red cell aplasia, graves, pernicious anemia, dermatomysotis-polymyositis and cushing; cortical thymoma rich in thymocytes more likely to be assoc with AI dz
242
How is anemia usually diagnosed
Reduction in hematocrit (ratio of packed red cells to total blood volume) and hemoglobin concentration of the blood
243
What are microcytic hypochromic anemia’s caused by
Disorders of hemoglobin synthesis (mostly iron deficiency)
244
What are macrocytic anemia’s caused by
Abnormalities that impair maturation of erythroid precursors in bone marrow
245
What are the most useful red cell indices
Mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, red cell distribution width
246
What can anemia cause
Dyspnea on mild exertion, hypoxia can cause fatty change in the liver, myocardium and kidney
247
What are the classifications of anemia according to underlying mechanisms
Blood loss
Increased red cell destruction
Decreased red cell production
248
What are the inherited genetic defects that can lead to hemolysis
- red cell membrane disorders: hereditary spherocytosis; hereditary elliptocytosis
- hexose monophosophate shunt enzyme def (G6PD def and glutathione synthetase def)
- glycolytic enzymes def (Pyruvate kinase and hexokinase def)
249
What acquired genetic defects can cause increased hemolysis
Def of phosphatidylinositol-liked glycoproteins (paroxysmal nocturnal hemoglobulinuria)
250
What inherited genetic defects an lead to decreased red cell production
- stem cell depletion: fanconi anemia; telomerase defects
| - defects affecting erythroblast maturation: thalassemia syndromes
251
What infection can cause decreased red cell production
Parvovirus B19
252
What happens to white cells during significant bleeding
The decrease in BP stimulates adrenergic hormone which mobilizes granulocytes and results in leukocytosis; initially red cells are normochromic and normocytic but as marrow production increases there is an increase in reticulocyte count (reticulocytosis - macrocytes)
253
What features do all hemolytic anemia’s share
Short life of RBC, elevated EPO, accumulation of hemoglobin degredation products
254
What causes extravascular hemolysis
Alterations that make the red cell less deformable; some hemolobin will escape phagocytes which leads to decreases in plasma haptoglobin (alpha globulin that binds free hemoglobin); Benefit from splenectomy
255
What can cause intravascular hemolysis
Trauma (cardiac valves , thrombotic narrowing, repetitive physical trauma), complement, parasites; toxic injury via clostridial sepsis (digest red cell membrane)
256
What is the manifestation of intravascular hemolysis
Anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, aNd jaundice; as serum haptoglobin is depleted, free hemoglobin oxidizes to methemoglobin which is brown; renal prox tubules reabsorb most of fisted hemoglobin and methemoglobin but some passes into urine (red-brown color); iron can accumulate in tubule cells (renal hemosiderosis)*NO splenomegaly
257
What is the serum bilirubin in all hemolytic anemia’s
Unconjugated
258
What is the morphology of hemolytic anemia
Increased number of erythroid precursors (normoblasts) in marrow; prominent retioculocytosis; accumulation of hemosiderin in spleen, liver and BM; elevated biliary excretion of bilirubin promotes formation of pigment gallstones (cholelithiasis)
259
What is hereditary spherocytosis
Inherited disorder caused by intrinsic defects in red cell membrane skeleton that renders them spheroid, less deformable and vulnerable to splenic sequestration and destruction; AD
260
What is the pathogenesis of hereditary spherocytosis
Insufficiency of membrane skeletal components; usually ankyrin and band 4.2 binds section to ion transporter (band 3); mutations most commonly affect ankyrin, band 3, spectrin, or band 4.2 (most are frameshift or nonsense); *splenectomy - stay in spleen and eaten by macrophages; also depletes them of lactose, decreased pH
261
What is the morphology of hereditary spherocytosis
Small dark staining red cells on smear that lack central zone of pallor; not pathognomonic; reticulocytosis, marrow erythroid hyperplasia, hemosiderosis and mild jaundice; cholethiasis; moderate splenomegly
262
What is the diagnosis of hereditary spherocytosis based on
Family hx, hematologic findings and laboratory evidence; in 2/3 of patients red cells are abnormally sensitive to osmotic lysis when incubated in hypotonic salt solutions; also have increased mean cell hemoglobin concentration (due to dehydration by loss of K and water)
263
What are the clinical features of hereditary spherocytosis
Anemia, splenomegaly(only hemolytic anemia with splenomegaly) and jaundice; in compound heterozygotes can present as jaundice at birth and requires transfusion; chronic hemolytic anemia; can have aplastic crises usually triggered by parvovirus infection(kills red cell progenitors so cant compensate); hemolytic crises cause by mono (less sig than aplastic crises); splenectomy decreases sx but risk of sepsis
264
What is glucose 6 phosphate dehydrogenase deficiency
G6PD reduces NADP to NADPH which then provides reducing equivalents needed for glutathione to reduced glutathione; X linked recessive; G6PD- (black) and Mediterranean cause most severe dz;
265
What kind of hemolysis is characteristic of G6PD def
Episodic; cause by exposures that generate oxidant stress (most commonly infections - viral hep, pneumonia and typhoid most common); drugs (antimalarials, sulfonamindes, nitrofurantoin)and food(fava bean); extra and intravascular hemolysis
266
How do oxidants cause hemolysis in G6PD def
Exposure causes cross linking of reactive sulfhyryl groups on globin chains which become denatured and form membrane bound precipitates known as Heinz bodies (seen as dark inclusions within red cells stained with crystal violent); Heinz bodies can damage membrane to cause intravascular hemolysis; as they pass through spleen, Heinz bodies plucked out (bite cells and spherocytosis)
267
Which cells are at risk for hemolysis in G6PD def
Only older red cells; hence self limited; because only limited, no splenomegaly or gallstones
268
What is sickle cell
Point mutation in beta globin that promotes polymeriztion of deoxygenated hemoglobin leading to red cell distortion, hemolytic anemia, microvascular obstruction and ischemic tissue damage
269
What is the normal hemoglobin in adults
HbA (alpha2beta2) and small amounts of HbA2 (alpha2delta2) and fetal HbF (alpha2gamma2)
270
What hemoglobin is seen in sickle cell
HbS
271
Why does sickle cell provide protection against malaria
- parasites consumes O2 and decrease intracellular pH which promote sickling; cleared more rapidly by phagocytes in spleen and liver
- sickling impairs formation of membrane knobs containing a protein made by parasite called PfEMP-1 (implicated in adhesion of infected cells to endothelium - causes cerebral malaria)
272
What is the pathogenesis of sickle CLL
HbS polymers stack into polymers when deoxygenated which converts red cell cytosol into viscous gel; with continued deoxygenation, HbS assemble into long needle-like. Fibers within red cells producing distorted sickle or holly leaf shape
273
How does interaction of Hb change the rate of sickling
interaction of HbS with other types of hemoglobin: in heterozygotes HbA prevents HbS polymerization; HbF does so even more (reason infants aren’t sx till 5 months); HbC - HbSC (HbS HbC heterozygotes) lose solute and water and become dehydrated which increases intracellular concentration of HbS - sx sickling disorder but milder than sickle cel
274
How does the mean cell hemoglobin concentration affect the rate of sickling
Higher HbS concentrations increase the probability that aggregation and polymerization will occur; intracellular dehydration which increases mean cell hemoglobin concentration facilitates sickling; conditions that decrease MCHC will reduce dz severity (ex: homozygous for HbS but also have alpha-thalassemia which reduces Hb synthesis)
275
How does intracellular pH affect sickle cell disease severity
Decrease in pH reduces oxygen affinity of hemoglobin which increase the fraction of deoxygenated HbS and will increase sickling
276
How does the transit time of red cells through microvascular beds affect sickle cell
Slow transit times increases aggregation (ie: spleen and BM and vascular beds that are inflamed)
277
How does sickling cause damage to red cells
HbS polymers herniate through membrane and project from the cell ensheathed by lipid bilayer -> influx of Ca2+ which induces cross linking of membrane proteins and activates efflux of K+ and H2O - become dehydrated and rigid and become irreversibly sickled
278
Are microvascular conclusions related to the number of irreversibly sickled cells
No; more dependent on inflammation; reduction in NO plays a part
279
What is the morphology of sickle cell
In blood, variable numbers of irreversibly sickled cells; Howell-jolly bodies (nuclear remnants) present in some red cells due to asplenia; BM is hyperplastic; bone resorption results in prominent cheekbones an change in the skull that resembles a crew cut on X-ray; pigment gallstones and hyperbilirubinemia; first have splenomegaly then have splenic infarction (autosplenectomy); vascular occlusions anywhere (if pulm a can cause cor pulmonale); in adults, leg ulcers
280
What are the clinical features of sickle cell
Moderately severe hemolytic anemia assoc with reticulocytosis, hyperbilirubinemia; vaso-occlusive crises (pain crises): episodes of hypoxia injury and infarction that cause severe pain most commonly bone, lungs, liver, brain, spleen, and penis; in kids: hand-foot syndrome or dactylitis of bones; acute chest syndrome: vaso-occlusive crisis involving lung - presents with fever, cough, chest pain, pulm infiltrates
281
What affect can sickle cell have specific to males
Priapism; hypoxia damage and ED
282
What is the most common cause of mortality in sickle cell
Vaso-occlusive crises
283
What is a sequestration crisis
Occur in children with intact spleens; rapid splenic enlargement, hypovolemia and sometimes shock; can be fatal; needs exchange transfusion
284
What is aplastic crises
Infection of red cell progenitors by parvovirus B19 which causes transient cessation of erythropoietin and sudden worsening of anemia
285
What can chronic hypoxia cause in sickle cell
Impaired growth; organ damage; sickling in renal medulla causes hyposhenuria (inability to concentrate urine)
286
What are common infections in ppl with sickle cell.
Pneumococcus pneumoniae aNd haemophilus infelunzae septicemia and meningitis
287
What is a treatment for sickle cell
Hydroxyurea: increases red cell HbF, has antiinflammatory effect
288
What are the thalassemia syndromes
Inherited mutations that decrease the synthesis of either alpha or beta globin gains of hemoglobin A leading to anemia, tissue hypoxia and red cell hemolysis; alpha encoded on chrom 16 and beta encoded on chrom 11; endemic in Mediterranean; decrease red cell production and lifespan
289
What mutations caus beta thalassemia
- beta0 mutations: assoc with absent beta globin synthesis; chain terminator mutations most common - mostly caused. By new stop codon within an exon
- beta+ mutations: reduced beta globin synthesis; splicing mutations most common cause and most lie within introns; promoter region mutations also assoc with this kind
290
How does impaired beta globin synthesis result in anemia
- deficit in HbA synthesis produces underhemoglobinized hypochromic microcytic red cells with subnormal oxygen transport capacity
- diminishes survival of red cells resulting from imbalance in alpha and beta globin; red cell precursors form insoluble unpaired alpha chains which damages the membrane and undergo apoptosis - thus have impaired erythropoiesis - those that do leave the marrow undergo extravascular hemolysis
291
What effects does severe beta thalassemia have on the marrow
Erythroid hyperplasia and extramedullary hematopoeisis; expanding mass of red cell precursors erodes bony cortex, impairs bone growth and produces skeletal abnormalities; can cause cachexia in severe cases
292
What complication does ineffective erythropoeisis in beta thalassemia cause
Excessive absorption of dietary iron; ineffective erythropoeisis suppresses hepcidin - secondary hemochromatosis
293
What are the clinical symptoms of beta thalassemia
Anemia; those with 2 beta thalassemia alleles (B+/B+, B0B0 or B+B0) have transfusion dependent anemia called Beta thalassemia major; those with one allele have microcytic anemia referred to as minor or trait
294
What is beta thalassemia intermedia
2 defective beta globin genes and an alpha thalassemia defect which improves effectiveness of erythropoiesis and red cell survival
295
What are the features of beta thalassemia major
Most common in Mediterranean and parts of Africa; anemia manifests 6-9 on this after birth; major re cell hemoglobin is HbF which is elevated
296
What is the morphology of beta thalassemia major
Blood smear shows severe red cell ab: variation in size (anisocytosis), shape (poikilocytosis), microcytosis, and hypochromia; target cells (hemoglobin collects in center); reticulocyte elevated but not to level you would think; in bones of fate and skull marrow erodes existing cortical bone and induces new bone formation “crewcut appearance” on XR; iron overload damages heart, liver and pancreas
297
Are the unpaired alpha chains in beta thalassemia visible on blood smear
No
298
What is the outcome of beta thalassemia
Need transfusions or die at early age; in those who survive, impt cause of death is cardiac dz - treat with iron chelators to prevent; can survive till 3rd decade but overall grim
299
What are the features of beta thalassemia minor
Asymptomatic; hypochromic, microcytosis, basophilic stippling; increase in HbA2 (diagnostic); HbF normal or slightly increased
300
What happens to newborns with alpha thalassemia
Excess unpaired gamma globin chains form gamma tetramers known as hemoglobin Barts; in older children and adults, excess beta chains form beta4 tetramers known as HbH; both of these are more soluble than the alpha tetramers so hemolysis and infective erythropoeisis isn’t as severe as beta thalassemia
301
What is the most common cause of alpha thalassemia
Deletion
302
What is the silent carrier state of alpha thalassemia
Deletion o single alpha globin gene; asymptomatic and have slight microcytosis
303
What is alpha thalassemia trait
Deletion of 2 alpha genes from single chrom (more common in Asians) or deletion of one alpha gene from 2 chrom (Africans); people with the former have kids with a risk of HbH or hydrops fetalis; microcytic minimal anemia; HbA2 normal or low
304
What is hemoglobin H dz (HbH)
Caused by a deletion of 3 alpha globin genes; most common in Asians; tetramers of HbH form - extremely high affinity for oxygen and therefore not useful for oxygen delivery leading to tissue hypoxia disproportionate to level of hemoglobin; HbH also prone to oxidation which causes it to precipitate and form intracellular inclusions that promote red cell sequestration; result is moderate anemia resembling beta thalassemia intermedia
305
What is the most severe form of alpha thalassemia
Hydrops fetalis; deletion of all 4 alpha globin; gamma tetramers have high affinity for oxygen and little delivered to tissues; survival in early development due to expression of zeta chains which binds to gamma chains; fetal distress becomes apparent in 3rd trimester; infants can be saved with intrauterine transfusion; fetus shows pallor, edema, and massive HSM; lifelong dependence on blood transfusions for survival with assoc risk of iro overload
306
What is paroxysmal nocturnal hemoglobinuria
Results from acquired mutations in phosphatidlinositol glucan complementation Group A gene (PIGA) which is essential for synthesis of membrane assoc complement regulatory proteins *only hemolytic anemia caused by acquired genetic defect; X linked - single acquired mutation needed
307
What proteins are PNH blood cells deficient in
Decay-accelerating factor or CD55, membrane inhibitors of reactive lysis or CD59 (most important bc inhibitor of C3 convertase which prevents spontaneous activation of alternative complement pathway), and C8 binding protein
308
What kind of hemolysis is seen with PNH
Intravascular (caused by MAC); damage by complement or lysis; chronic hemolysis without dramatic hemoglobinuria is most common; tendency for them to lyse at night is bc decreased blood pH at night which increases activity of complement; loss of heme iron in urine (hemosiderinuria) leads to iron deficiency
309
What is the leading cause of disease-related death in people with PNH
Thrombosis; venous involving hepatic, portal or cerebral veins; some can develop AML or myelodysplastic syndrome
310
How is PNH diagnosed
Flow cytometry; treated with eculizumab (inhibits conversion of C5 to C5a) - lowers need for transfusions and risk of thrombosis but increased risk of serious or fatal meningococcal infections; only cure is HSC transplant
311
How do you test for immuonhemolytic anemia’s
Direct Coombs antiglobulin test; tests for abs or complement on red cells - patients red cells are mixed with abs to immunoglobulin or complement
Indirect Coombs: patients serum tested for its ability to agglutinate red cells bearing antigens
312
What are the warm ab type (IgG abs active at 37 degrees C) immunohemolytic anemia
Primary (idiopathic)
| Secondary: autoimmune disorders (SLE), drugs, lymphoid neoplasms
313
What are the cold agglutinin type (IgM abs below 37 degrees C) immunohemolytic anemia’s
Acute (mycoplasma infection, mono)
| Chronic: idiopathic, lymphoid neoplasms
314
What are the cold hemolysis type (IgG abs below 37 degrees C) immunohemolytic anemia’s
Rare; occurs mainly in children following viral infections
315
What is the most common type of immunohemolytic anemia
Warm ab type; mostly extravascular hemolysis; IgG coated red cells bind to Fc receptors on phagocytes which remove membrane d urging partial phagocytosis -> converts them to spherocytes which are sequestered
316
What causes drug induced immunohemolytic anemia
- antigenic drugs: usually follows large IV doses of drug 1-2 weeks after; ie penicillin and cephalosporins bind to red cell membrane and recognized by anti drug abs (in penicillin induced bs only bind to drug) in quinidine induced abs recognize complex of drug and membrane protein; act as opsonin
- tolerance breaking drugs: alpha methyldopa; induces production of abs against red cell antigens (usually Rh)
317
What causes cold agglutinin type immunohemolytic anemia
Mycoplasma, EBV, CMV, influenza and HIV - self limited in these circumstances
Chronic cold agglutinin occurs in assoc its B cell neoplasms; clinical sx result from binding of IgM to red cells in areas where temp is lower )(fingers, toes, ears); vascular obstruction caused by agglutinate red cells results in pallor, cyanosis, and raynaud
318
What is the cold hemolysin type of immunohemolytic anemia
Responsible for paroxysmal cold hemoglobinuria; rare; causes substantial and sometimes fatal intravascular hemolysis and hemoglobinuria; abs are IgGs that bind to P blood group antigen on red cell surface in peripheral regions; complement mediated lysis occurs when cells recirculate to warm areas; most seen in kids following viral infections (in this setting, transient and most recover); treatment with removing offending agent - if doesn’t work immunosuppressive drugs and splenectomy
319
What is the most significant cause of hemolysis related to trauma of RBCs
Cardiac valve prosthesis and microangiopathic disorders (seen with DIC but also occurs with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant HTN, SLE and disseminated cancer)- mostly mechanical valves; * results in red cell fragments (schistocytes) burr cells, helmet cells, and triangle cells in blood smear
320
What is the common feature of megaloblastic anemia
Impairment of DNA synthesis that leads to ineffective hematopoiesis and abnormally large erythroid precursors and red cells; 2 forms: pernicious (B12) and folate deficiency anemia
321
What are the causes of megaloblastic anemia
- decreased intake of B12 (vegetarian)
- impaired absorption of B12: intrinsic factor deficiency (pernicious anemia, gastrectomy), malabsorption states, diffuse intestinal dz (lymphoma, systemic sclerosis), ileal resection - fish tapeworm infestation
- folic acid deficiency (alcoholism, anticonvulsants, oral contraceptives, hemodialysis)
- increased requirement of folic acid: pregnancy, disseminated cancer
- methotrexate
322
Why does b12 and folate def cause anemia
Both are cofactors for formation of thymidine
323
What is the morphology of megaloblastic anemia
Macro-ovalocytes; lack central pallor - appear hyperchromic but MCHC is not elevated; variation in size (anisocytosis) and shape; reticulocyte count low; neutrophils are larger and show nuclear hypersegmentation; marrow is hypercellular; giant metamyelocytes and band forms
324
What is pernicious anemia
Caused by autoimmune gastritis that impairs production of intrinsic factor
325
Describe the absorption of B12
Freed from food via pepsin and binds haptocorrin -> in duodenum released from haptocorrin by pancreatic proteases and associates with intrinsic factor -> goes to ileum where it is endocytosed by ileal enterocytes that express cubilin (receptor for IF) -> B12 assoc with transcobalamin II and is secreted into plasma -> liver; also goes through a B12 independent pathway which is why you can treat with high doses of B12
326
What is B12 required for
- conversion of homocysteine to methionine; in same reaction N5methyl FH4 is converted to FH4 which is needed for conversion of dUMP to dTMP (building block of DNA); anemia improves if give folic acid
- isomerization of methylmalonyl coA to succinylcholine coA-> def lead sto increased plasma and urine methylmalonic acid; leads to buildup of methylmalonate and propionate and formation of FA into neuronal lipids - > neuro complications of B12 def
327
Are the neuro sx caused by B12 def cured with folate
No; may actually worsen
328
What population does pernicious anemia occur in
All races; older adults; rare younger than 30; have tendency to form abs against multiple self antigens
329
What is the pathogenesis of pernicious anemia
Autoimmune attack on gastric mucosa; chronic atrophic gastritis; type I ab that blocks binding of B12 to IF - found in plasma and gastric juice; type II abs ovens binding of IF-B12 to ileal receptor; type III present in most cases - recognize alpha and beta subunits of gastric proton pump but not specific for pernicious anemia; abs are used for diagnosis but not pathology; autoreactive T cells initiates injury and triggers formation of autoabs; assoc with AI adrenalitis and thyroiditis
330
What can cause vit B12 def other than pernicious anemia
Achlorhydria; gastrectomy; loss of exocrine pancreases function
331
What is the morphology of pernicious anemia
Fundic gland atrophy; replace by mucus secreting goblet cells (intestinalization); tongue becomes beefy, shiny, glazed (atrophic glossitis); Demyelination of dorsal and lateral spinal tracts -> spastic paresis, sensory ataxia and paresthesias in lower limbs
332
What is the diagnosis of pernicious anemia based on
Megaloblastic anemia, leukopenia with hypersegmented granulocytes, low serum B12, and elevated serum levels of homocysteine and methylmaloic acid; confirmed with increase in hct after parenteral administration of B12
333
What are elevated homocysteine levels a risk for
Atherosclerosis and thrombosis; B12 can cure everything except risk of gastric carcinoma
334
What is the proper name for folic acid deficiency
Deficiency of pteroylmonoglutamic acid
335
What is FH4 involved in
Purine synthesis, conversion of homocysteine to methionine, deoxythymidylate monophosphate (dTMP) synthesis
336
What are the richest sources of folic acid
Green vegetables
337
What is unique about folate deficiency in alcoholics with cirrhosis
Caused by trapping in liver, excessive urinary loss and disordered folate metabolism under these circumstances, accompanied by general malnutrition and cheilosis, glossitis and dermatitis
338
What does methotrexate inhibit
Dihydrofolate reductase
339
What are the lab values of folate def
Megaloblastic anemia; high homocysteine but low methylmalonate; no neuro changes
340
What is important to do before beginning folate therapy for folate deficiency
Make sure it is not B12 deficiency (bc can worsen neuro sx)
341
Who is iron deficiency anemia common in
Toddlers, adolescent girls and women of child bearing age
342
What are the major sites of iron storage
Liver and mononuclear phagocytes
343
Where is iron absorbed
Proximal duodenum
344
How is iron absorbed
Nonheme iron converted to Fe2+ (ferrous) by b cytochromosomes and STEAP3; then transported by divalent metal transporter DMT1; transported into blood via ferry port in coupled to oxidation to Fe3+ by Hephaestin and ceruloplasmin; Fe3+ binds to transferrin and delivers it to marrow
345
What does hepcidin do
Binds to ferroportin and inhibits iron absorption (causes it to be endocytosed)
346
What are mutations that disable TMPRSS6 related to
Microcytic anemia; it is an hepatic transmembran serine protease that normally suppresses hepcidin production when iron stores are low; affected patients have high hepcidin resulting in reduced iron absorption and failure to respond to iron therapy
347
How does secondary hemochromatosis occur in diseases assoc with ineffective erythropoiesis
Ineffective erythropoiesis suppresses hepcidin production even when iron stores are high
348
What is the absorption of inorganic iron enhanced by
Ascorbic acid, citric acid, amino acids and sugars; inhibited by tannates (tea), carbonates, oxalates, and phosphates
349
Where does dietary iron inadequacy occur
- infants: small amounts of iron in milk - cow’s milk contains more but bioavailability is poor
- impoverished
- older adults: poor dentition
- teenagers because eat junk
350
What malabsorption syndromes can cause iron deficiency
Sprue, fat malabsorption, and chronic diarrhea; gastrectomy (decreases acidity of prox duodenum and increases speed of gut contents passing through)
351
What is the most common cause of iron deficiency
Chronic blood loss
352
What kind of anemia does iron deficiency produce
Hypochromic microcytic anemia
353
What is the morphology of iron deficiency
BM shows increase in erythroid progenitors; disappearance of stainable iron from macrophages in BM (Prussian blue); “pencil cells”
354
What are the clinical features of iron deficiency anemia
Koilonychia, alopecia, atrophic changes in tongue and gastric mucosa and intestinal malabsorption; pica - eat clay and flour and move their limbs during sleep; *esophageal webs with microcytic hypochromic anemia and atrophic glossitis - Plummer Vinson syndrome
355
What does the diagnosis of iron deficiency anemia depend on
Lab; Hb and Hct low; iron and ferritin low and total plasma iron binding capacity is high; elevated transferrin levels but low saturation; low hepcidin
356
What is the most common cause of anemia in hospitalized patients
Anemia of chronic disease; reduction in proliferation of erythroid progenitors and impaired iron utilization
357
What chronic illnesses are associated with anemia of chronic disease
- chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abscess)
- chronic immune disorders (RA, regional enteritis)
- neoplasms (carcinomas of lung and breast and Hodgkin)
358
What are the features of anemia of chronic disease
Low serum iron, reduced total iron binding capacity, abundant stored iron in tissue macrophages; *IL-6 stimulate increase in hepcidin production - results in progenitors starved for iron; EPO low; mild; can be normocytic and normochromic or hypochromic and microcytic; high ferritin level
359
What is aplastic anemia
Syndrome of chronic primary hematopoietic failure and pancytopenia; mostly autoimmune
360
What viral infections can cause aplastic anemia
Viral hepatitis of non-A non-B non-C non-G type
361
What is Fanconi anemia
AR; defects in multiprotein complex required for DNA repair; marrow hypofunction -> aplastic anemia; accompanied by hypoplasia of kidney and spleen and bone anomalies (mostly thumbs or radii)
362
What defects are seen in some cases of adult-onset aplastic anemia
Inherited telomerase defects; premature stem cell exhaustion and marrow aplasia
363
What are most cases of aplastic anemia caused by
Idiopathic
364
What chemical agents can cause aplastic anemia
Alkylating agents, antimetabolites, benzene, chloramphenicol, inorganic arsenicals; phenylbutazone, methyhlphenylethylhydantoin, carbamazepine, penicillamine, gold salts
365
What physical agents can cause aplastic anemia
Whole body irradiation, viral infections, CMV, EBV, herpes zoster
366
What is the pathogensis of aplastic anemia
Autoreactive T cell clones; think GPI-linked proteins may be targets and explains why aplastic anemia is assoc with PNH
367
What is the morphology of aplastic anemia
Hypocellular BM; fat cells, fibrous stroma and scattered lymphocytes and plasma cells remain; dry tap aspiration so need BM biopsy; granulocytopenia and thrombocytopenia
368
What are the clinical features of aplastic anemia
Any age in either sex; pancytopenia; NO splenomegaly; macrocytic and normochromic anemia; reticulocytopenia is the rule; need BM biopsy to rule out myelodysplastic syndromes (hypocellular vs hypercellular BM); bone marrow transplant is treatment of choice
369
What is pure red cell aplasia
Primary marrow disorder in which only erythroid progenitors are suppressed; can occur in assoc with thymoma or large granular lymphocytic leukemia, drugs, AI, or parvovirus infection; resection of thymoma leads to improvement; otherwise immunosuppressive therapy; in parvovirus B19, transient and unimportant - only if immunosuppressed or already have severe hemolytic anemia
370
What is myelophthisic anemia
Marrow failure in which space-occupying lesions replace normal marrow; *most common cause is met cancer - breast, lung and prostate; can occur with granulomatous dz; also a feature of spent phase of myeloproliferative disorders; abnormal release of nucleated erythroid precursors and immature granulocytic forms from marrow (leukoerythroblastosis) and tear drop shaped red cells
371
What are the features of anemia due to chronic renal failure
Proportional to the severity of uremia; caused by diminished synthesis of EPO; also see platelet dysfunction due to uremia
372
What is the anemia associated with liver failure
Macrocytic due to lipid abnormalities which cause RBCs to acquire phospholipid and cholesterol as they circulate
373
What endocrine disorder is associated with anemia
Hypothyroidism - normochromic normocytic anemia
374
What is polycythemia
High red cell count with increase in hemoglobin; can be relative when there is hemoconcentration due to decreased plasma volume or increase in total red cell mass
375
What can cause relative polycythemia
Dehydration; stress polycythemia (gaisbock syndrome); usually hypertensive, obese, and anxious
376
What is absolute polycythemia
- primary: results from intrinsic abnormality of hematopoietic precursors
- secondary: when red cell progenitors are responding to increased levels of EPO
377
What is the most common cause of primary polycythemia
Polycythemia Vera
378
What familial mutations can cause primary polycythemia
Mutations in EPO receptor that induce EPO-independent receptor activation
379
What are causes of secondary polycythemia
EPO secreting tumors; inherited defects that lead to stabilization of HIF-1alpha
380
What is prothrombin time
PT; assesses extrinsic and common coagulation pathways clotting of plasma after addition of exogenous source of tissue thrombophlebitis and Ca2+ ions is measured; prolonged PT can result from def of factor V, VII, X, prothrombin or fibrinogen
381
What is partial thromboplastin time
PTT; assesses intrinsic and common clotting pathways; clotting of plasma after addition of kaolin, cephalon and Ca2+ ions measured; kaolin activates factor XII and cephalon substitutes for platelet phospholipids; prolongation of PTT results from dysfunction of factors V, VIII, IX, X, XI, XII, prothrombin or fibrinogen
382
What are the absolute secondary cause of polycythemia
*high EPO (primary has low EPO); lung dz, high altitude living, cyanotic heart dz, paraneoplastic (RCC, HCC, cerebellar hemangioblastoma), hemoglobin mutants with high O2 affinity, chuvash polycythemia (VHL mutations), prolyl hydroxylase mutations
383
What do bleeding disorders caused by vessel wall abnormalities usually present as
Small hemorrhages (petechiae and purpura) in skin or mucus membranes (gingiva) - usually; but can present with bleeding into joints, mm, subperiosteal locations or menorrhagia, nosebleeds GI bleeds or hematuria; platelet counts and PT PTT are normal
384
What are the conditions in which abnormalities in the vessel wall cause bleeding
- infections: petchial and purpura hemorrhages; *meningoccocemia, infective endocarditis and rickettsioses
- drug reactions drug induced immune complexes deposit in vessel walls which leads to hypersensitivity (leukocytoclastic) Vasculitis
- Scurvy and ehlers Danlos: microvascular bleeding bc weak vessel walls; cushing syndrome (protein wasting effects of corticosteroids production causes loss of perivascular supporting tissue)
- henoch-schonlein purpura: systemic immun disorder; colicky ab pain, polyarthralgia and acute glomerulonephritis; immune comple deposition in vessels and mesangial regions
- hereditary hemorrhagic telangiectasia (weber-Osler-rendu): AD; mutations that modulate TGFbeta signaling; dilated, tortuous blood vessels with thin walls; most common bleeding under mucous membranes of nose, tongue, mouth, and eyes and GI tract
- perivascular amyloidosis: weaken vessel walls and cause bleeding; mostly with AL amyloidosis - mucocutaneous petechiae
385
What vessel wall abnormalities is most associated with serious bleeding
Hereditary hemorrhagic telangiectasia
386
What is the PT and PTT in thrombocytopenia
Normal
387
Where are hemorrhages most likely as a result of thrombocytopenia
Small vessels; skin and mucous membranes of GI and GU tracts; intracranial bleeding*
388
What are the categories of causes of thrombocytopenia
- decreased platelet production: depress marrow (aplastic anemia and leukemia) drugs and alcohol;; HIV myelodysplastic syndrome
- decreased platelet survival: immune thrombocytopenia (destruction caused by deposition of abs on platelets - alloabs an arise when platelets are transfused or cross placenta) non immune (DIC and thrombotic microangiopathies; also mechanical heart valves)
- sequestration
- dilution: massive transfusions can produce dilutional thrombocytopenia
389
What is chronic immune thrombocytopenia purpura
Caused by auto ab mediated destruction of platelets; secondary forms occur in SLE, HIV, B cell neoplasms (CLL)
390
What is the pathogensis of chronic immune throbocytopenic purpura
Auto abs against platelet membrane glycoproteins (IIb-IIIa or Ib-IX); most are IgG - act as opsonins and are phagocytosed; improved by splenectomy
391
What is the morphology of chronic ITP
Spleen is normal size; marrow reveals modestly increased number of megakaryocytes; peripheral blood reveals abnormally large platelets
392
What are the clinical features of chronic ITP
Adults women <40; bleeding into skin and mucosa; pinpoint hemorrhages (petechiae) ecchymoses; easy bruising, nosebleeds, bleeding into gums; may manifest as melena, hematuria or excessive menstrual low; *subarachnoid and intracerebral hemorrhage fatal complications but are rare; no splenomegaly or LAD; low platelets increased megakaryocytes; PT and PTT normal; respond to glucocorticoids; also can give anti-CD20 (rituximab); TPO mimetic can increase platelet production
393
What is acute immune thrombocytopenic purpura
Autoabs to platelets *disease of childhood occurring equally in both sees; sx appear after viral illness; self limited resolves in 6 months
394
What drugs are most commonly implicated in drug-induced thrombocytopenia
Quinine, quinidine, vancomycin - bind platelet glycoproteins to create antigenic determinants that are recognized by abs; also platelet inhibitory drugs that bind glycoproteins IIb-IIIa
395
What is heparin induced thrombocytopenia
- type I: rapidly after onset of therapy; little clinical important most likel a result of direct platelet aggregating effect of heparin
- type II: less common but more severe; 5-14 days after therapy leads to life threatening venous and arterial thrombosis; caused by abs that recognize complexes of heparin and platelet factor 4-> activates platelets and promotes thrombosis; risk is lowered with use of low molecular weight heparin
396
What is HIV associated thrombocytopenia
Impaired platelet production and increased destruction; CD4 and CXCR4 (receptor and coreceptor for HIV) are found on megakaryocytes which allows HIV to infect them - prone to apoptosis; also causes B cell hyperplasia which predisposes to production of autoabs
397
What is thrombotic microangiopathy
Includes TTP and HUS; caused by insults that lead to excessive activation of platelets which deposit as thrombi in small bv
398
What is TTP
Fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro deficits and renal failure
399
What is HUS
Microangiopathic hemolytic anemia and thrombocytopenia but NO neuro defects, prominent acute renal failure, occurs frequently in children
400
What makes TTP and HUS different from DIC
Activation of coagulation cascade is not of primary importance *PTT and PT are normal
401
What are the causes of TTP
Deficiency of ADAMTS13 - inherited or acquired
402
What are the causes of HUS
- typical: E. coli O157:H7 (endothelial damage by shiga like toxin)
- atypical: alternative complement pathway inhibitor deficiency (complement factor H, membrane cofactor protein CD46 or factor I - inherited) (autoabs - acquired)
- other assoc: drugs (cyclosporine, chemo) radiation, BM transplant, HIV, pneumococcal sepsis, SLE, lymphoid neoplasms
403
What is another name for ADAMTS13
VWF metalloprotease - normally degrades very high molecular weight multiverses of vWF; in its absence these multiverses accumulate in plasma and promote platelet activation and aggreagation
404
When does inherited TTP present
Adolescence; symptoms are episodic; other factors (superimposed vascular injury or prothrombotic state) must be present to trigger full blown TTP
405
How is TTP treated
Plasma exchange (removes autoabs and provides functional ADAMTS13)
406
What is the atypical HUS associated with
Relapsing and remitting course
407
How is HUS treated
Typical is treated supportively
408
What are the classifications of inherited disorders of platelet function
Defects in adhesion, defects of aggregation and disorders of platelet secretion
409
What is Bernard shoulder syndrome
Defective adhesion of platelets to subendothelial matrix; AR caused by deficiency of platelet membrane glycoproteins complex Ib-IX (receptor for vWF); affected patients have severe bleeding tendency
410
What is glanzmann thrombocytopenia
Defective platelet aggregation; AR; fail to aggregate in response to ADP, collagen, epi or thrombin bc of deficiency of glycoproteins IIb-IIIa (integrin that participates in bridge formation btw platelets by binding fibrinogen); severe bleeding tendency
411
What are the disorders of platelet secretion
Characterized by defective release of mediators of platelet activation such as thromboxanes and granule bound ADP; called storage pool disorders
412
What are the acquired defects in platelet function
Aspirin and uremia
413
How does bleeding due to isolated coagulation factor deficiencies manifest
Large posttraumatic eccymoses or hematomas OR prolonged bleeding after a laceration; often occurs into GI and GU t facts Nd into weight bearing joints (hemarthrosis)
414
What factor is deficiency in hemophilia A
VIII
415
What factor is deficient in hemophilia B
IX
416
What does vitamin K deficiency result in impaired synthesis of
Factors II, VII, IX, X and protein C; will also be deficient in these factors with severe liver dz
417
What are the 2 most common inherited disorders of bleeding
Hemophilia A and von willebrand dz
418
What is factor VIII a cofactor for
factor IX (which converts X to Xa)
419
What is the relationship btw factor VIII and vWF
Factor VIII binds vWF which stabilizes factor VIII
420
How is vWF measured
Ristocetin agglutination test - mix patients plasma with formalin-fixed platelets and ristocetin (activates vWF and induces it to bind glycoproteins Ib-IX and form bridges)
421
What is the most common inherited bleeding disorder
Von willebrand; mild bleeding t end envy; unnoticed until Hemostasis stress (surgery or dental procedure); most common sx - spontaneous bleeding from mucous membranes, excessive bleeding from wounds, menorrhagia; AD but some AR exist
422
What are the categories of Von willebrand dz
- type I and III: assoc with quantitative defects in vWF; type I is AD: mild to moderate deficiency *most common type 3 is AR associated with very low levels of vWF and has severe manifestations (deletion or framshift in both alleles)
- type 2: qualitative defects in vWF; 2A is most common of these; AD; vWF in normal amounts but missense mutations present that lead to defective mutlimer assembly - mild to moderate bleeding
423
What happens to platelets in vWF
Normal count by have defects in platelet function; will have secondary decrease in factor VIII bc cannot be stabilized by vWF(prolongation of PTT in type 1 and 3) but bleeding into joints not seen
424
How can you treat von willebrand dz
Desmopressin (stimulates vWF release) before surgery; or infusions of plasma concentrations containing factor VIII and vWF
425
What is the most coon hereditary dz assoc with life threatening bleeding
Hemophilia A (Factor VIII def); some can have no family hx; most severe deficiencies result from inversion involving the X chrom that completely abolishes synthesis o factor VIII
426
Are petechiae seen in hemophilia A
No
427
What are the lab values for hemophilia A
Prolonged PTT but normal PT (abnormality in intrinsic pathway)
428
How is hemophilia A treated
Infusions of recombinant factor VIII; some with severe dz develop abs that bind and inhibit factor VIII bc perceived as foreign
429
What are the lab values or hemophilia B
Prolonged PTT;; Normal PT
430
How is clotting initiated
Exposure of tissue factor which combines factor VII to activate factor X and IX; activation of factor X leads to generation of thrombin; thrombin converts fibrinogen to fibrin and feedsback to activate factors IX, VIII, and V, and stimulates fibrin crosslinking
431
How is clotting stopped in areas that dont need it
As thrombin encounters uninsured vessels it is converted to anticoagulant through bindin to thrombomodulin -> activates protein C which inhibits factor V and VIII
432
What 2 major mechanisms trigger DIC
- Release of tissue actor or other poorly characterized procoagulants into circulation
- widespread injury to endothelial cells
433
What can the procoagulants that cause DIC be derived from
Placenta in obstetric complications or tissues injured by burns or trauma; mucus released by adenocarcinoma can act as procoagulants by directly activated factor X
434
What is implicated in DIC of sepsis
TNF; induces endothelial cells to express tissue factor and to decrease expression of thrombomodulin; also upregulates adhesion molecules which can damage endothelial cells by ROS
435
What cancers are most commonly associated with DIC
APL and adenocarcinoma of lung, pancreas, colon and stomach
436
What are the consequences of DIC
- widespread deposition of fibrin within microcirculation l eating to ischemia and microangiopathic hemolytic anemia
- consumption of platelets and clotting factors and activations of plasminogen leading to hemorrhagic diathesis; plasmin cleaves fibrin and digests factors V and VIII
437
What is the morphology of DIC
Thrombi found in brain, heart, lungs, kidneys, adrenals spleen and liver; can have bl renal cortical necrosis; PE and fibrin exudation crating hyaline membranes; can cause Waterhouse friderichsen syndrome; unusual form of DIC occurs in assoc with giant hemangiomas (kasabach-Merritt syndrome) in which thrombi form within the neoplasm
438
What are the clinical features of DIC
Can be fulminant (endotoxic shock or amniotic fluid embolism) or insidious ad chronic (carcinomatosis or retention of dead fetus); most are obstetric patients and tends to be reversible with delivery of fetus; *microangiopathic hemolytic anemia, dyspnea, cyanosis, resp failure, convulsions, coma, oliguria, renal failure, sudden or progressive circulatory shock; acute - tends to be bleeding; chronic tends to be thrombotic
439
What is the most common complication of blood transfusion
Febrile nonhemolytic reaction: fever and chills within 6 hours of a transfusion of red cells or platelets; caused by inflammatory mediators derived from donor leukocytes; respond to antipyretics
440
What allergic reactions can occur as a result of blood transfusions
Occurs when blood products containing certain antigens are give to previously sensitized recipients; most likely occur in patients with IgA def* - triggered by IgG abs that recognize IgA in infused blood product
-urticarial allergic reactions may be triggered by presence of allergen in donated blood that is recognized by IgE abs in recipient; most common but generally mild; respond to antihistamines
441
What causes acute hemolytic reaction to blood transfusions
IgM abs against donor red cells that fix complement; lead to hemoglobinuria; fever shaking and chills and flank pain appear rapidly; direct Coombs is positive unless all donor cells Lysenko; can progress to DIC, shock, acute renal failure or death
442
What causes delayed hemolytic reactions of blood transfusions
Abs that recognize red cell antigens that the recipient was sensitized to previously; caused by IgG abs to foreign protein antigens and are assoc with positive direct Coombs test, low haptoglobin and elevated LDH; abs to Rh, Kell, and Kidd induce sufficient complement activation to cause severe and fatal reactions identical to those resulting from ABO mismatches; other abs that do not fix complement result in red cell opsonization, extravascular hemolysis and spherocytosis - minor
443
What is transfusion related lung injury
Severe and frequently fatal complication; factors in transfused blood product trigger the activation o neutrophils in lung microvasculature; occurs more frequently in people with preexisting lung dz; *most common abs are those that bind MHC antigens (usually class I); often found in multiparous women; more likely in transfusions that contain fresh frozen plasma and platelets presentation: sudden onset resp failure during or soon after transfusion; diffuse bl pulm infiltrates that do not respond to diuretics; fever, hypotension and hypoxemia; treatment is supportive
444
What are infectious complications of transfusions
Bacterial and viral
| Bacterial more common from skin - more common in platelet preparations bc must be stored at room temp
445
What are the treatments for anemia of chronic renal disease
Epoetin Alfa, hydryoxyurea, eculizumab
446
What are the drugs for neutropenia
Filgrastim, pegfilgrastim, sargramostim, plerixafor
447
What are the drugs for thrombocytopenia
Oprelvekin, Romiplastin, eltrombopag
448
What are the causes of microcytic anemia (Wolff question)
Iron deficiency, anemia of inflammation, copper deficiency, lead poisoning, congenital sideroblastic anemia’s
449
What is iron therapy
- oral: 200-400 mg ferrous per day in 2-3 divided doses with only water/juice (food inhibits absorption); not enteric coated and not sustained release; causes N, constipation, anorexia, heartburn, vomiting, and diarrhea and dark stools
- parenteral (colloid) iron: required if iron malabsorption, intolerance of oral therapy, noncompliance; iron dextran, sodium ferric gluconate and iron-sucrose and ferumoxytol; Side effects same as oral
450
What is acute iron toxicity
Seen in young children who accidentally ingest iron tablets; sx -> necrotizing gastroenteritis with vomiting, ab pain, bloody diarrhea leading to shock lethargy and dyspnea; severe Met acidosis, coma and death; *treat its bowel irrigation and parenteral deferoxamine (chelating) DONT use charcoal
451
What is a source of B12 for vegetarians
Fortified breakfast cereals
452
How much B12 do you need per day
2 micrograms
453
What is the effect of nitrous oxide on B12
Inhaled for analgesia; inactivates cyanocobalamin
454
What is the treatment of B12 def
- oral B12 even if pernicious anemia
| - parenteral therapy used if neuro sx are present
455
What can high doses of folate therapy cause
Hypotension and hypoglycemia
456
What does epoetin alpha do
Stimulates erythropoiesis; increases reticulocyte count and RBC count, Hb, and Hct; used for anemia due to chronic kidney dz, cancer chemo, zidovudine treatment for HIV; administered IV or SQ; incrased risk of thrombosis, pain
457
What does hydroxyurea do
Targets ribonucleotide reductase - S cycle arrest; boosts level of HbF; lowers concentration of HbS; administered orally; toxicities - cough or hoarseness, fever, lower back or side pain, painful or difficult urination
458
What is eculizumab
Monoclonal ab that binds to C5 and inhibits cleavage to C5a and C5b inhibits complement mediated intravascular hemolysis in PNH and atypical HUS; given IV for 4 weeks; toxicities: infections (must give meningococcal vaccine before use), URI, MSK pain, anemia, leukopenia, HTN, HA, insomnia, UTI
459
What are the presenting sx of neutropenia
Low grade fever, sore mouth, odynophagia, gingival pain and swelling, skin abscesses, recurrent sinusitis and otitis, sx of pneumonia, perirectal pain
460
What is Neutropenic fever
Life threatening complication of chemo; >101; <21 points is high risk for febrile neutropenia
461
What is filgrastim
G-CSF; regulates production of neutrophils; used to decrease incidence of infection in patients with nonmyeloid malignancies receiving myelosuppressive chemo or BM transplant; used to mobilize cells into periphery for collection; administer IV or SQ 24 hrs after chemo; can cause bone pain, splenic rupture and ARDS; pegfilgrstim is longer lasting
462
What is sargamostim
GM-CSF; increases production of neutrophils, eosinophils Nd monocytes; used to accelerate recovery of myeloid cells after autologous BM transplant; used following chemo in patients >55 with AML to decrease incidence of infections; given IV or SQ; can cause gasping syndrome in premature infants; fluid retention, sequestration of granulocytes, SVT
463
Is filgrastim or sargramostim more likely usd
Filgrastim has fewer effects so usually wins; use only if incidence of febrile neutropenia is estimated at > 20% (primary prophylaxis) only use i delay or reduction of chemo would prevent full doses of potentially curative chemo (secondary prophylaxis)
464
What is plerixafor
Partial agonist of CXCR4 receptor (homing of HSC to BM); mobilizes HSC from BM to plasma; used in patients who dont mobilize SC for transplant with G-CSF; used in patients with lymphoma and multiple myeloma; SQ; hypersensitivity reaction; has potential to mobilize leukemia cells
465
What drugs cannot be used for thrombocytopenia
Thrombopoietin (autoabs that caused severe thrombocytopenia); stem cell factor (found on mast cells and causes severe allergic reactions)
466
What are the megakarytocyte growth factors used for thrombocytopenia
- IL-11: oprelvekin: activates cell surface cytokine receptors to stimulate growth of multiple lymphoid and myeloid cells; used for prevention of thrombocytopenia in patients receiving chemo; can cause hypokalemia and bloodshot eyes
- romiplostim: recombinant thrombopoietin - peptides that link to ab fragments; activates MPL thrombopoietin receptor to increase platelet count; used for patients with chronic immune thrombocytopenia purpura (ITP) who have insufficiency response to corticosteroids or splenectomy
467
What is eltrombopag
Oral non-peptide TPO receptor agonist; increases platelet count in health individuals, ITP and hep C; used for ITP and hep C; side effects: hepatotoxicity when in combo with IFN and ribavirin
468
What drugs cause hemolytic anemia
Cephalosporins most common (ceftriaxone and cefotetan); penicillin (esp piperacillin); Dapson, levodopa, levofloxacin, methyldopa, nitrofurantoin, NSAIDs, phenazypyridine, quinidine
469
What causes drug induced thrombocytopenia
Immune: heparin
| Non immune: quinidine, furosemide, NSAIDs, penicillin, sulfonamides, ranitidine, gold
470
What are the alkylating agents
- bisamines: cyclophosphamide, mechlorethamine, melphalan chlorambucil
- nitrosoureas: carmustine, streptozocin
- aziridines: thiotepa
- alkylsulfonate: busulfan
- non-classic: procarbazine, dacarbazin, bendmustine
- platinum analogs: cisplatin, carboplatin, oxaliplatin
471
What are the antimetabolites
- antifolates: methotrexate, pemetrexed, pralatrexate
- fluoropyrimidines: 5FU, capecitbine, TAS-102
- deoxycytidine analogs: cytarabine and gemcitabine
- purine antagonists: 6 thiopurines, fludarabine and cladribine
472
What natural products are used for cancer
- vinca alkaloids: vinblastine, vincristine, vinorelbine
- taxanes and other anti-microtubule: paciltaxel, docetaxel, carbazitaxel, ixabepilone, eribulin
- epipodophyllotoxins: etoposide
- camptothecins: topotcan, irinotecan
473
What are the anti-tumor abx
- anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, deraxane
- mitomycin
- bleomycin
474
What are the tyrosine kinase inhibitors
Imatinib, dasatinib, nilotinib, bosutinib, ponatinib
475
What are the growth factor receptor inhibitors
-mab, erlotinib, afatininb, zip-afliberceept sorafenib, sunitinib, pazopanib
476
When is primary chemo used
If no surgical option; Hopkins and NHL, choriocarcinoma, germ cell cancer, AML, burkitt’s wilms tumor, embryonal rhabdo, ALL
477
What are the mechanisms of resistance for alkylating agents
- increase in DNA repair enzymes (MGMT)
- decreased transport of drug
- increased expression of glutathione
478
What are the mechanisms of resistance of antimetabolites
- inhibition of metabolism into active metabolites (cytarabine)
- decreased drug transport
- decreased formation of polyglutamate metabolites by folyl polyglutamate synthase (needed for methotrexate, pemetrexed and pralatrexate)
479
What are the drugs with a MOA disruption of tubulin polymerization
Vinblastine, vincristine, vinorelbine
480
Which drugs enhance tubulin polymerization
Paclitaxel, docetaxel, cabazitaxel
481
What are the topoisomerase inhibitors
I: topetecan and irinotecan
II: etoposide
482
Which natural product has neurotoxicity as a side effect
Vincristine
483
Which natural products have hypersensitivity as a side effect
Paclitaxel and docetaxel
484
Which natural product has diarrhea as a side effect
Topotecan and irinotecan
485
What is the MOA of antitumor abx
- inhibition of topoisomerase 2, generation of free radicals - doxorubicin
- induce DNA cross links: mitomycin
- DNA fragmentation and strand breaks due to free radical formation: bleomycin
486
What are the mechanisms of resistance of antitumor abx
Point mutations in topoisomerase II (doxo), increased expression of MDRP (doxo and mitomycin), upregulation of bleomycin hydrolase (inhibits bleomycin iron binding)
487
What antitumor abx has an adverse effect of blue discoloration of nails, sclera and urine
Mitoxantrone
488
What are the immune checkpoint inhibitors
- PD-1 inhibitors: Nivolumab and pembrolizumab - used for melanoma, NSCLC, Hodgkin
- PD-L1 inhibitors: atezolizumab, avelumab, durvalumab: used for bladder cancer, NSCLC, Merle cell skin cancer
489
What is the treatment for ALL
one of: 6 mercaptopurine, cyclophosphamide, vincristine, daunorubicin
Combo of vincristine and prednisone with one above agent used to induce remission
490
What is used to prevent CNS leukemia (ALL)
Intrathecal Methotrexate
491
What is the treatment for AML
Cytarabine in combo with anthracycline - most active
-idarubicin is preferred
During period of induction do platelet transfusion to prevent bleeding, GSF,, abx
492
What do you do after remission is achieved in AML
High dose cytarabine or HSC transplant
493
What is the first line therapy for CML
Imatinib
Dasatinib and nilotinib
Busulfan also effective
494
What is the treatment for CLL
Chlorambucil (with prednisone), cyclophosphamide
COP: cyclophosphamide, vincristine, prednisone
CHOP: cyclophosphamide, vincristine, prednisone, doxorubicin
Bendamustine also approved
Fludarabine also effective alone or in combo with cyclyophosphamide or mitoxantrone or rituximab
495
What are the treatments for stage I and IIa Hodgkin
ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine
496
What are the treatments for stage III and IV Hodgkin
MOPP: mechlorethamine, vincristine, procarbazine and prednisone
ABVD: doxorubicin, bleomycin, vinblastine, decarbazine
Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone
497
What is the treatment for NHL (Diffuse)
CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone
Or R CHOP
498
What is the treatment for nodular (follicular) NHL
Bedamustine and rituximab
499
What is the treatment for multiple myeloma
Melphalan and prednisone
500
What is the treatment for breast cancer
Stage I: surgery
| stage II: CMF - cyclophosphamide, methotrexate, 5FU; FAC: 5FU, doxorubicin, cyclophosphamide
501
What is the treatment for prostate cancer
Mitoxantrone and prednisone
*docetaxel and prednisone is standard of care
502
What is the treatment for colorectal cancer
- FOLFOX: leucovorin, 5FU and oxaliplatin
| - XELOX: capecitabine and oxaliplatin
503
What is the treatment for metastatic colorectal cancer
- FOLFIRI: leucovorin, 5FU, irinotecan; ziv-aflibercept added if progression observed with oxaplatin based chemo
- FOLFOX or FOLFIRI with bevacizumab or cetuximab/panitumumab
- TAS-102
504
What is the treatment for NSCLC
Bevacizumab in combo with carboplatin and paclitaxel with non-squamous histo
- if squamous - cisplatin or carboplatin with cetuximab
- maintenance chemo: pemetrexed after stabilized with 4 cycles of platinum based chemo
505
What is the treatment of NSLCL with molecular testing available
- erlotinib: first line with EGFR mutations
- afatinib: metastatic NSCLC with EGFR deletions
- osimertinib: met EGFR
506
What is the treatment for SCC of the lung
Cisplatin and gemcitabine with necitumumab
| -nivolumab used for cancers that have progressed after standard treatment
507
What is the treatment for small cell lung cancer
- cisplatin + etoposide or cisplatin + irinotecan
| - topotecan is second line if failed
508
What is the treatment for ovarian cancer
- stage I: radiotherapy; cisplatin and cyclophosphamide
- stage III and IV: carboplatin and paclitaxel
- recurrent: topotecan or doxorubicin
509
What is the treatment for testicular cancer
PEB: cisplatin, etoposide, bleomycin
510
What is the treatment for malignant melanoma
Dacarbazine, temozolomide, cisplatin, IFN alpha, IL-2
| -nivolumab, pembrolizumab for unresectable or met
511
What is the treatment for brain cancer
Carmustine
PCV: procarbazine, lomustine, vincristine
-temozolomide for glioblastoma
-bevacizumab alone or in combo with chemo
