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133 Cards in this Set
- Front
- Back
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Malignant Lymphomas vs. Leukemias
Lymphomas = Hodgkins or Non-hodgkins |
Malignant Lymphomas: SOLID MASSES
- frequently involves bone marrow - occ in peripheral blood *DIE from bleeding or infxn - replace marrow & compress organs Leukemias: NO solid masses - Hemopoietic cells (not just lymphocytes) - spreads throughout bone marrow & periph blood |
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Cells of lymphoid tissue
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1. LYMPHOCYTES (memory cells)
- B cells: CD19/20+ - T cells CD 3 & 7+ CD4 = Th, CD8 = Suppressor & cytotoxic 2. Macrophages or histiocytes - phagocytes & APC 3. Dendritic or langerhan's cells S100+ |
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Lymph Node regions
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Cortex: + follicle
- germinal centers = B cells - Mantle surrounds follicle = T & B cells - Interfollicular region = Marginal zone T & B cells Also: - Paracortex - Medullary cords - Subscapular sinus |
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Major Types of Lymphomas
- T vs B - Well vs Poorly differentiated |
80% B cell type
- 40% form neoplastic follicles --> become diffuse 20% T cell ALWAYS diffuse WELL DIFF: Small, mature lymphocytes; form follicles - SLOW proliferation (harder to tx) Poorly diff: big lymphocytes & diffuse - FAST prolif *very sensitive to tx |
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Precursor vs. Peripheral Lymphocytic Neoplasms
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PRECURSOR: TdT+
NO Ig or CD3 - no receptor gene arrangement yet PERIPHERAL: TdT- +sIg or CD3 (T cel receptor) TdT = terminal deoxynucleotidyl transferase |
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PERIPHERAL (MATURE) B-CELL NEOPLASMS
(8) |
1. Small Lymphocytic Lymphoma
2. Chronic Lymphocytic Leukemia 3. HCL (hairy cell leukemia) 4. Mantle Cell Lymphoma 5. Follicular Lymphoma 6. Marginal Zone Lymphoma 7. Diffuse Large B-Cell Lymphoma 8. Burkitt lymphoma (small non-cleaved) |
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PERIPHERAL (MATURE) T-CELL NEOPLASMS
(4) & 1 precursor t cell neoplasms |
1. Mycosis Fungoides
2. Sezary's Syndrome 3. Peripheral T cell Lymphoma (NOS) 4. Adult T-cell leukemia/lymphoma 1 Precursor = Lymphoblastic Lymphoma/Leukemia |
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Small lymphocytic lymphoma & Chronic lymphocytic leukemia
*hypogammaglobuilinemai = die from infxn* |
B-cell type with sIg (mature small lymphocytes)
- elderly - few symptoms, LONG survival (even w/o tx) - CD19/20/5/23+ --> CLL: mature small lymphocytes in peripheral blood #1 leukemia Develops into: - massive lymphadenopathy & organomegaly - smudge cells (crushed nuclei) --> Aggressive Lymphoma (rare) |
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CLL STAGING
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STAGE
0: Peripheral & marrow lymphocytosis 1. stage 0 + lymphadenopathy 2: stage 0 + splenomegaly 3: stage 1 & 2 4: Peripheral & marrow lymphocytosis + anemia + thrombocytopenia **pancytopenia & ^ tissue involvement = poorer prognosis |
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HAIRY CELL LEUKEMIA (HCL)
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NO LYMPHADENOPATHY
- splenomegaly - marrow infiltration = pancytopenia - B cells are TRAP+ & RAGGED EDGES **Worse prognosis than CLL, esp when treated as CLL* TX: Splenectomy, a-IFN, chemo |
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MANTLE CELL LYMPHOMA
=( |
CD19/20/5+
(CD23 NEGATIVE) t(11;14) bcl-1 or PRAD-1 = ^^ cyclin D1 *VERY AGGRESSIVE* - Widely disseminated at time of diagnosis - hard to tx with chemo |
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FOLLICULAR LYMPHOMAS
ALWAYS B CELL (forms follicles) #2 most common type of non-Hodgkins lymphoma (DLBCL is #1) |
CD19/20/10+
t(14;18) bcl-2 gene (anti-apoptosis) *Widely disseminated at time of diagnosis, but SLOW GROWTH = die in 7-9 years Usually --> higher grade lymphoma - larger cell type (cleaved or not; aka DLBCL) - diffuse pattern |
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FOLLICULAR VS FOLLICULAR CELL
*any lesion w/ follicles is a B CELL LYMPHOMA* |
Follicular: forms neoplastic germinal centers
F Cell: Malignant cell ORIGINATING from the germinal center - doesn't tell you if pattern is diffuse or nodular (follicular) |
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MARGINAL ZONE LYMPHOMA
(ESP EXTRA-NODAL) |
Marginal zone B cells just outside of mantle layer
Any disseminated lymphoid tissue: - Nodal - Splenic - EXTRA NODAL (MALT) EXTRA-NODAL: *DISSEMINATE LATE - poorer prognosis if lymph nodes are involved - glandular tissue = previous chronic inflamation - H. pylori --> Stomach MALToma is most common - can progress to higher grade |
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DIFFUSE LARGE B CELL LYMPHOMA
- poorer prognosis? |
DIFFUSE
BIG B-CELLS Aggressiveness is proportional to cell type: - B cell (CD19/20+): Ranges from follicular large cell lymphomas (no longer follicular) --> immunoblastic lymphoma Poorer Prognosis: ABC type & Bcl-2 expression |
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BURKITT LYMPHOMA
(small non-cleaved cell) |
AFRICAN KIDS
- HIGH GRADE B CELL LYMPHOMA (CD19/20/10+; Like follicular lymphoma) STARRY SKY: benign histiocytes in background of malignant blasts t(8;14) c-myc makes TONS of Ig (nuclear reg sequence) - can be leukemic - RAPIDLY fatal AFRICAN TYPES: - EBV (100%) - Jaw bone & abd viscera (ovaries) Sporadic cases in Europe & US = GI tumors |
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LYMPHOBLASTIC LYMPHOMA/LEUKEMIA
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PRECURSOR T CELL TYPE:
cd3+ & Tdt+ 40% of childhod lymphomas - used to be very aggressive (now good tx) - Mediastinal Involvement (thymic-like cells) & CNS/skin |
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T CELL MALIGNANCIES OF THE SKIN
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CD4+ Th Cells
1. MYCOSIS FUNGOIDES: =) - fungus-like plaques - clusters of lymphocytes in epidermis = Patrier abscesses - can progress --> 2. Sezary's Syndrome: =( - diffuse infiltration of skin = erythroderma - also in peripheral blood RED SKIN - Sezary cells in blood look like Adult T-cell leukemia (HTLV-1) |
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PERIPHERAL T CELL LYMPHOMA (NOS)
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NOS = not otherwise specified
Malignant cells are CD3+ &/OR CD7+ always TdT- the MORE cells there are or the BIGGER they are, the more AGGRESSIVE |
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ADULT T CELL LEUKEMIA/LYMPHOMA)
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HTLV-1 infxn
Caribbean & Japan - endemia CD4+ leukemia: large cells + skin lesions + hypercalcemia HIGH GRADE = POOR PROGNOSIS *CELLS LOOK LIKE SEZARY'S* |
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Non-Hodgkins Lymphoma & treatment effectiveness
t cell lymphomas are usually WORSE than its B cell counterparts |
FAST GROWING cells are MOST SENSITIVE to tx
- Low grade ML = LONG srvivals - cure rate approaching 50% with radiation/marrow transplant (stem cell rescue) Cures in pURE large cell lymphoma (50% cure in <55yo) |
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AIDS-ASSOCIATED LYMPHOMA
4 |
Usually a HIGH GRADE B-cell type
1. Burkitts 2. DLBCL *Either 1 or 2 originate in CNS usually 3. Primary effusion Lymphoma - HHV-8 & EBV+ - large cell malignancy in body cavities (no masses) |
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POST-TRANSPLANTATIONAL LYMPHOPROLIFERATIVE DZ
(PT-LPD) |
EBV causes lymphoid hyperplasia
- looks like lymphoma - usually b-cell type - REGRESS w/ decreased immunosuppression **if no regression, then it IS lymphoma |
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HODGKIN'S LYMPHOMA
dx? prognosis? |
REED-STERNBERG CELLS (RS)
- multinucleated or multilobed nuclei - owl eyed eosinophilic nucleoli TO DX: NEED RS cells = CD30/15+ - Negative for cd45/20 = LCA + eosinophils & plasma cells WORSE PROGNOSIS: - ^ RS cells - few lymphocytes - detectable symptoms (fever, wt loss, fatigue (b symptoms) |
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TYPES OF HODGKIN'S LYMPHOMA
- CLASSICAL (95%) - NONCLASSICAL (don't need to know) |
1. LYMPHOCYTE RICH - 5%
few RS cells - men with peripheral lymph nodes involved - early stage - BETTER prognosis (90% cure) 2. Lymphocyte Depletion (LD) <5% - Frequent RS cells - OLD men with retroperitoneal or visceral dz - Severe cellular immunity fail (AIDS) - Cure rate <40% 3. MIXED CELLULARITY: 20-25% - intermediate findings - middle aged pt with cervical & chest or abd dz - cure rate 75% 4. NODULAR SCLEROSIS:65% - Thick bands of collagen (sclerosis) - Lacunar cells (RS cells in clear spaces) - YOUNG tps w/ cervical & mediastinal dz - 85% cure =) |
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STAGING IN HODGKINS DZ
"a" - no symptoms "b" + symptoms (>10% wt loss, fever, night sweats) |
Staging by PE alone is crappy
I: single lymph node region or single extra-lymphatic site II: 2+ regions on SAME SIDE of diaphragm III. Involves regions on BOTH sides of diaphragm - spleen may be involved (3s) - local extralymphatic organ may be involved (3E) IV.Diffuse involvement of 1+ extra-lymphatic (non-local) organs or tissues - liver involved - nodes may or may not be involved |
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ASSOCATIONS of Hodgkin's dz with OTHER neoplasms
- treated vs untreated hodgkins - sarcomas |
UNTREATED HODGKIN'S:
- CLL - FOLLICULAR LYMPHOMA: esp lymhpocyte predominant Hodgkin's TREATED: - Immunoblastic lymphoma (AML - usually therapy related) SARCOMAS: - Kaposi's sarcoma (Immunosuppression) |
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PLASMA CELLS
DEFINITION |
Differentiated end-stage B lymphocytes
- secrete/produce 1 homogeneous Ig product = M component (monoclonal component = from single clone) |
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PLASMA CELL DISORDERS
(3) |
1. Multiple myeloma & variants
- non-secretory - smoldering/asymptomatic - plasma cell leukemia 2. Plasmacytoma - solitary: bone or extraosseous 3. Precursor lesion = MGUS |
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MULTIPLE MYELOMA
- Ig - virus - clinical & COD - marrow - incidence Bence Jones proteins = light chains |
OLD BLACK MEN
MONOCLONAL IgG or IgA HHV-8 found in dendritic cells & plasma Clinical: - OAF (TNF, IL-1, IL-6) --> lytic bone lesions & hypercalcemia - Bone marrow infiltration --> pancytopenia - Renal insufficiency: amyloidosis & BJ proteins (proteinuria) MAIN COD: Infxn & renal failure Marrow: >10% abnormal/clonal plasma cells - or symptomatic w/ 5-10% - plasmacytoma w/ weird morphology |
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MULTIPLE MYELOMA
- symptomatic vs smoldering - prognosis CRAB: - Calcium ^ - Renal Failure - Anemia - Bone lesions |
STAYS IN THE BONE MARROW!!!
>30% plasmacytosis symptomatic: - M-protein in serum or urine - Bone marrow clonal plasma cells or plasmacytoma ***CRAB: related organ/tissue impariment = end organ damage** most important ASYMPTOMATIC/SMOLDERS: - Mprotein in serum @ myeloma levels - >10% clonal plasma cells in marrow - NO related organ/tissues (nO crab) WORSE PROG: - ^ Serum IL-6, b2 microglobulin, hypodiploidy - survive 1 yr w/o tx - survive 2-3 yrs w/ only chemo (best with MARROW TRANSPLANT) |
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SOLITARY MYELOMA
(PLASMACYTOMA) |
Clonal proliferation of plasma cells
- idential to plasma cell myeloma, but LOCALIZED growth pattern 1. Bone: eventually become MM 2. Extramedullary: (outside bone) usually does NOT become MM |
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MGUS = MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE
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<10% Plasma cells in marrow (normal)
Electrophoresis shows monoclonal protein - no evidence of plasma cell disorder - remains stable for may years MOST DO NOT PROGRESS OT MM (more likely if BJ or M protein is HIGH) *NO lytic bone lesions or other symptoms/infxns* |
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LYMPHOPLASMACYTIC LYMPHOMA
(WALDENSTROM'S MACROGLOBULINEMIA OF HYPERVISCOSITY) *don't confuse w/ lymphoBLASTIC lymphoma = t cell* |
1. HIGH IgM (unlike MM)
2. spreads out into periph (UNLIKE MM) 3. Hepatosplenomegaly AND lymphadenopathy 4. older men 5. Hyperviscosity syndrome: Visual problems, neuro, bleeding, cryoglobulinemia **Hep C infxn may be involved (tx w/ IFN) |
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MYELOID VS LYMPHOID CELLS
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HEMATOPOIETIC -->
1. LYMPHOID - B/T/NK 2. MYELOID : - Granulocyte: baso/neutro/eosino - Monocyte - Megakaryocyte - Erythrocyte **myeloid neoplasms rarely make masses** - leukemias Lymphomas are ONLY lymphocytes |
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MORBIDITY AND MORTALITY IN LEUKEMIA/LYMPHOMA
*RELATED TO TOTAL TUMOR BURDEN** |
BONE MARROW FAILURE
- can be due to tx - pancytopenia = die from infection or bleeding *Pallor, dyspnea, lethargy, infxns, spontaneous bruises, bleeding gums* *Lymphomas also make solid masses that cause organ dysfxn (PRESSSSS) |
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CHRONIC VS ACUTE ANEMIA
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CHRONIC: excess neoplastic MATURE
- few divide; but still mature - SLOWLY prog - CLL vs CML ACUTE: neoplastic BLASTS (>20%) - most divid - RAPID prog - CAN'T mature - ALL vs AML |
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MAJOR CLASSES OF MYELOID NEOPLASMS (3)
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1. myeloPROLIFERATIVE diseases (MPD)
chronic leukemias: excess mature, normal myeloid cells - granulocytosis, polycythemia, thrombocythemia 2. myeloDYSPLASTIC syndrome (MDS) - Maturing abnormal or dysplastic (non-maturing) myeloid cells - short half life - PANCYTOPENIA: less mature cells in blood 3. ACUTE Myelogenous/granulocytic Leukemia (AML) - EXCESS myeloid BLASTS (>20% marrow) |
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CHRONIC LEUKEMIAS
- MYELOPROLIFERATIVE DISORDERS GENERAL |
mtt of PLURIPOTENT hematopoietic stem cells --> excess MATURE cells
can progress to acute leukemia or other MPD CML, ET, MMM, PV common findings: - hypercellular marrow (--> fibrosis in MF) ^ WBC with Left shift |
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CHRONIC MYELOGENOUS LEUKEMIA
CML / CGL - serum findings - tests - chromosomal abnormality - clinical |
Mature GRANULOCYTOSIS
- all granulocytic stages in peripheral blood - LOW LAP (high in other MPDs) - ^ serum B12 (carried in neutrophils by transcobalamine) - Thrombocytosis - Ph1 chromosome = reciprocal t(9;22) = BCR/ABL fusion gene --> TK for RAS, JAK/STAT, AKT is always ON - hypercellular marrow ^ WBC with left shift CLINICAL: - 50-60s - Splenomegaly: extra-med hematopoiesis - BONE PAIN: marrow expansion - Leukostasis: visual, neuro problems, priapism |
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CML
- TX - COURSE/PROG |
COURSE
- mild (chronic phase) = 4 years - ALL CASES END IN BLASTIC CRISIS ---> AML *hard to treat but super delayed now thanks to GLEEVEC TX: GLEEVEC (imatinib) - blocks BCR/ABL TK - former tx: a-IFN - CURE = Bone marrow transplant; esp if <50 yo |
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ESSENTIAL THROMBOCYTHEMIA
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Platelet count > 0.6-1 million/microL
Marrow: megakaryocytic hyperplasia without fibrosis (but actually looks the same as PV) clinical: Thrombosis --> hemoorhage - Splenomegaly - die in TEN years w/ tx MTT: (SAME AS MMM & PV) - JAK2: drives prolife - MPL: receptor for thrombopoietin is always ON |
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MYELOFIBROSIS WITH MYELOID METAPLASIA
MMM (aka agnogenic myeloid metaplasia) |
Neoplastic Megakaryocytes
--> release GF that causes fibroblastic proliferation = MYELOFIBROSIS - Extramedullar hematopoiesis = hepatosplenomeg (myeloid metaplasia) - hypersplenism - progressive refractory anemia (Myelophthisis) - dacryocytes & leukoerythroblastemia mtts: - jak2 & mpl |
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PRIMARY POLYCYTHEMIA
(RUBRA VERA) - classical proliferative phase - labs - |
Neoplastic clone of RBC precursors UNRESPONSIVE TO erythropoetin
CLASSICAL PROLIF PHASE: - late midlife - plethora & dyspean = circulatory stagnation - headaches & itching AFTER SHOWERS (histamine from basophils0 **only one with itching** - Splenomegaly late - Peptic ulcer --> Fe deficiency anemia - ^ Incidence of fatal thrombosis (abnormal platelet fxn& #) LABS: ^ Platelets Decreased EP ^ RBC mass >95% JAK2 mtt |
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PRIMARY POLYCYTHEMIA
- tx - prog |
TX:
- Die in MONTHS w/o tx (thrombosis/bleeding) - Regular phlebotomy - allows years - Myelosuppressive agents: not best PROGNOSIS: - live 13 years - die from other causes Proliferative phase can progress to: - Spent phase (slow erythropoiesis --> stable) - Myelofibrosis (AMM-MF) *** AML (after P-32 & chemo)**** |
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MYELODYSPLASTIC SYNDROMES
(REFRACTORY ANEMIAS) |
Ineffective & defective cell development
--> dysplastic & dysfunctional mature cells PANCYTOPENIA ***MOST COMMON HEMATOPOIETIC NEOPLASM*** Features: - Deformed, hunchback RBCs - Hypercellular marrow - pancytopenia (weird cells apoptose in marrow0 - 30-50% --> AML (preleukemia) - DIE from infxns & bleeding |
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ACUTE LEUKEMIAS
GENERAL - CLINICAL |
RAPIDLY PROGRESSIVE =(
- normal AND abnormal clones in marrow * Leukemia cells don't replicate faster --> they replace normal cells bc they proliferative w/o maturing to nonproliferative stage CLINICAL: 2' Bone marrow fail 2' disease or tx - Anemia <-- pallor, dyspnea, tired - Neutropenia --> ^ risk of infxn - Thrombocytopenia: spontaneous bruises, bleeding gums DEATH FROM INFXN OR BLEEDING |
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ACUTE LEUKEMIAS
- LABS (periph & bone marrow) |
1. Peripheral blood:
- BLASTS in blood (elevated in leukemic phase, but absent in aleukemic phase) - Anemia (normocytic, normochromic) - absolute neutropenia (<1000) - Thrombocytopenia 2. BONE MARROW: - Diagnosis: >20% blasts - Remission: <5 % blasts - Relapse: >10% blasts post-tx |
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ACUTE MYELOGENOUS LEUKEMIA
AML - TYPES - M types = not otherwise specified |
AML WITH..
- Genetic Aberrations - MDS (myelodysplastic features) - Therapy-related (P-32) - NOS (m types - FAB classifications) M TYPES: M0-M3: Myeloid (M3: promyelocyte) M4: Myeloid and monocyte (AMMoL) M5: Pure MONOBLASTIC leuk m6: Eyrthroleukemia (anemia, not polycythemia) M7: Megakaryoblastic leukemia (down's syndrome & old) |
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AML
- CLINICAL - POOR PROG - TX |
CLINICAL:
- iNFANTS & ELDERLY mainly - Myelodysplasia can be preleukemic phase - Often have Auer rods (esp M3): ABSENT in ALL - Hyperleukocytosis (>100 x 10^9) --> leukostasis M3: t(15;17) = damaged Vit A receptor M4 & M5: gum hypertrophy (monoblasts) POOR PROG: - >55 yo - Any chromsomal abnormality (esp Ph1) - Prior leuk, myelodysplasia, chemo - Hyperkeukocytosis > 100,000/microL (high tumor burden) TX: more difficult than ALL - less selectivity in myelotoxic drugs for leukemic cells vs. normal marrow cells - Many go into remission --> die in 1.5-3 years only 10-30% long term survivors =( |
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ACUTE LYMPHOCYTIC/BLASTIC LEUKEMIA
ALL - GENERAL - GOOD PROG v sPOOR *overall, good prognosis: 90+% achieve complete remission - KIDS ARE CURED MORE THAN ADULTS |
PEAK AGE 3-7 YO
Classify: Surface Ags - Common ALL: 80% (pre b-cell type) CD19/10/TdT+ *best* - Null-ALL: no T or B markers, TdT+ - T-ALL: T Ag/ TdT+ - B-ALL: sIg+, TdT neg *WORST; like burkitt's type* but it's the rarest GOOD PROGNOSIS - Common ALL (calla+, TdT+, neg for all T cell markers & sIg) - Hyperdiploidy (51-60 chrom) POOR PROG: - ^ wbc: high tumor burden - very young <1yo or >11 yr & adults - black males - meningeal involvement - t cell leukemia (mediastinal involvemet) - sIg+ - Ph1+ (CML) - Hypodiploidy |
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ANTECEDENT STEM CELL DISORDERS
(transform into AML) |
AML IS RESISTANT TO TX
1. Myelodysplastic syndromes (30-50%) 2. PNH (rare) 3. MPD: - CML: used to be all cases --> blastic crisis - Ess. Thrombo: lowest rate to AML - Myelofibrosis: 10% to AL - PV: 30% to myelofibrosis (not really AML) |
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toxic exposure and leukemias
**farmers are also at increased risk** |
1. Radiation: ^ risk of ALL, AML, CML
(not really CLL) - Atom bomb survivors 2. CHEMO: GET AML - alkylating agents: take longer (2-4 yr) *used to tx Hodgkin's & Breast CA - Topoisomerase Inhibitors: ACUTE leukemia FAST (~months) 3. BENZENE |
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Chromosomal inherited disorders & LEUKEMIAS
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DOWNS SYNDROME:
^ risk of ALL & AML(M7) Bloom's syn: ALL & AML Fanconi's syn: AML only Ataxia-Telangiectasia: ALL, lymphoma |
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GENERAL ANTIGENS
45 / 34 / 30 / 10 / TdT / Cyclin D1 / 25 / 103 |
CD45: Leukocyte common antigen / common leukocytic antigen (LCA/CLA)
*Plasma Cells & RS cells don't have this CD34: Hemopoietic precursor (blast cells) & endothelial cells CD30: Activated T&B cells; RS cells (also CD15+, CD45neg) CD10: CALLA - ALL, Burkitt, Follicular TdT: Nuclear Terminal deoxynucleotidyl transferase - B&T Lymphoblasts - only in precursor leukemias & lymphomas Cyclin D1: bcl-1 (mantle cell lymphoma) CD25 & CD103: hairy cell leukemia |
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T CELL ANTIGENS
43 / 3 / 4 / 8 / 5 |
IF NO CELL MARKERS EXCEPT CD43+ = T CELL
- CD 3: Pan-T cells - CD 4: T helper cells - CD 8: T suppressor/cytotoxic cells - CD 5: Pan-T cells except B-cell CLL is also positive |
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B CELL ANTIGENS
19/20 |
19: Pan-B cells (except plasma cells)
20: More mature pan-B cells |
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MYELOID/MONOCYTIC ANTIGENS
14 / 15 / 33 |
- CD 14: Monocytes, macrophages
- CD 15: Myeloid series; Reed-Sternberg cells - CD 33: Myeloid/monocytic series |
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STORAGE HISTIOCYTES
- GEN on boards; not exams |
NON-NEOPLASTIC dz
- genetic blocks of metabolism problems 1. Gaucher's Disease: lipid storage - kerasin or glucocerebroside - Adults (NO mental retard) - Crinkled tissue paper cytoplasm 2. Niemann-Pick Disease: Lipid storage - kids + mental retard - soap bubble cytoplasm 3. Hurler's disease: mucopolysacc & glycolipid - gargoylism: coarse face - coarse blue cytoplasm granules *carb storage diseases usually don't cause mental retard; DO cause problems in liver/heart/kidneys |
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LANGERHANS CELL HISTIOCYTOSIS
- Cell type - disease? compound stored? - types |
APC macro
- Proliferation of well differentiated, slight atypical histiocytes + multinuc giant cells & eosinophils aka histiocytosis X - Nuclear Grooving S100+ Birbeck/Langerhans granules 1. Eosinophile granuloma 2. HAND-SCHULER CHRISTIAN DZ 3. Letterer-Siwe disease 1-->3 INCREASINGLY MORE MALIGNANT/SEVERE (MORE DIFFUSE) |
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EOSINOPHILIC GRANULOMA
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HISTIOCYTOSIS:
- usually in adults - usually solitary lesion of bone (unifocal) - most are readily cured |
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Hand-Schuler-Christian disease (more malignant)
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Histiocytosis
- classically in children - multifocal lesions with skeleton primarily involved - classical: diabetes insipidus when (posterior) pituitary and calvarium involved (base of skull) - other viscera may be involved, depending on the criteria used - seldom fatal with treatment if limited to bones |
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Letterer-Siwe disease (most malignant)
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Histiocytosis
- classically infants and young children - multi-system involvement (disseminated – like leukemia), especially skin and lymphoid system - rapidly fatal without treatment |
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QUALITATIVE DISORDERS OF NEUTROPHILS & MONOCYTES
- NAME |
1. CHRONIC GRANULOMATOUS DISEASE
2. Chediak-Higashi Syn 3. Myeloperoxidase Deficiency 4. May-Hegglin Anomaly 5. Leukocyte adhesion molecule deficiency CGD, Myeloperox, LAM-D = look like normal cells (no granules etc) |
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CHRONIC GRANULOMATOUS DISEASE
*cells can show somewhat toxic granulation during an infxn* |
X-LINKED OR AUTO RECESSIVE
NEGATIVE NBT stain Recurrent infxns & abscesses - Staph, serratia, salmonella, candida Morphologically normal neutrophils -Deficient NADPH - low levels of H2O2 - can't kill cells with catalase (breaks down H2O2, which bacteria makes) *strep can't make catalase* |
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CHEDIAK-HIGASHI SYNDROME
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AUTO RECESSIVE
LOOKS LIKE SUPER TOXIC GRANULATION - abnormal, giant lysosomes - NEUTROPENIA: impaired fxn - DEFECTIVE PLATELETS: long bleeding time *can die from infxn or bleeding |
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MYELOPEROXIDASE DEFICIENCY
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AUTO RECESSIVE
- NO MPO-H2O2 system Makes h2o2 but NOT HALDIDE - no ^ bacterial infxns, only CANDIDA (in diabetics) NBT+ (makes h2o2 |
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MAY-HEGGLIN ANOMLY
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Defective Megakaryocytic maturation
- thrombocytopenia w/ giant, bizarre platelets (^ bleeding time) - Dohle bodies (light blue crystals) in neutrophils *NO ^ risk of infxn |
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LEUKOCYTE ADHESION MOLECULE DEFICIENCY
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CD11/CD18 Heterodimer deficiency
- Functional leukocyte abnormalities (adhesion, chemotaxis, oxidative burst, degranulation) = RECURRENT INFXNS (skin/ear/gums) Neutrophilia (can't marginate = ^ in WBC - no PMNs at site of infxn = less pus - DELAYED wound healing (delayed separation of umbilical cord. |
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SPLEEN PATHOLOGY
- inflamm - congestion - (neoplasia - other slide) |
WHITE PULP: lymphocytes sheating arterioles
RED PULP: vascular rich areas between white pulp - blood leaves arterioles, enters red pulp --> veins INFLAMM: - White pulp enlarges (spleen enlarges) CONGESTION: - back pressure from heart or cirrhotic liver fills up RED Pulp - hypersplenism can trap blood elements (NOT the same as splenomeg) |
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SPLEEN NEOPLASIAS
- LYMPHOMA - LEUKEMIA & rupture |
Carcinoma never involves the spleen
LYMPHOMA: expands white pulp - Slow growth: uniform growth (cobblestones = small crowded nodules) - Fast growth: nodules of unequal size *Hodgkin's dz can grow slow but make it look like fast growth (boulders) LEUKEMIA: RED PULP turns into white pulp - cute surface is UNIFORM; gray, smooth - BIGGEST SPLEENS = Chronic MPDs (CML) RUPTURE: - TRAUMA #1 CAUSE - Spontaneous rupture = infectous mono, MALARIA, typhoid fever & leukemia |
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LYMPHADENOPATHY
- BIOPSY |
ENLARGED, PAINFUL LYMPH NODS
AVOID nodes subject to frequent inflamm - inguinal & submandibular BEST NODES for gen. lymphadenopathy - Lower cervical - Axillary (farther away from dirty areas; unobscrued from previous dz) |
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GRANULOMAS
- suppurative vs epithelioid vs drug induced |
Demonstrations of organism is important
= Monocytes changed into epithelioid cells - French fry nuclei; elongated cells; layer together - also see multi-nuc giant cells & chronic inflamm ( Th cells) 1.Suppurative (drippy pus); Stellate granulomas - Cat scratch dz: arm/axilla - Lymphogranuloma venerum (groin) 2. Epithelioid: NO pus - Caseating (necrosis): TB, fungi - Non-caseating: Sarcoidosis, berylliosis *if on bowel wall of bowel dz pt = cROHN'S 3. DRUGS: Dilantin: can stimulate lymphoma or be associated w/ it |
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Categories of abnormal hemostasis
- results |
1. Bleeding / Hemorrhage problem
A. Platelet problem (production fail or dysfunction) - mainly skin/mucous membrane bleeding or worse - small vessels, minor injuries - can't form the initial unstable plug = Petechiae, Ecchymoses, Purpura, Epistaxis *esp in lower limbs / back if supine B. FIBRIN (coagulation) problem - Bleeding into large hematomas in soft tissues (mm) or body spaces (joints) - Can't form a STABLE plug - "late re-bleeding" --> hematoma = Hypovolemia, death, distorting mass, menorrhagia, GI bleeds (more serious) 3. Thrombosis / Embolism - DVT 4. BOTH hemorrhage & thrombosis (DIC) - long PT & PTT, low platelet |
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Types of Platelet Problems leading to Bleeding / Hemorrhage
(Thrombocytopenia) - failure of production - failure of survival |
PRODUCTION FAIL
1. Marrow Wipe out - aplastic anemia, myelophthisis, malignancy, drugs 2. B12 or folate def 3. Myelodysplasia - esp in elderly SURVIVAL FAIL 1. ITP: immune/idiopathic thrombocytopenic pupura 2. TTP vs HUS - Thrombotic thrombocytopenic pupura - Hemolytic Uremic Syndrome DISTRIBUTION FAIL - hypersplenism (splenic sequestration) *Spleen has 80% of platelets instead of normal 20% |
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Types of Platelet Problems leading to Bleeding / Hemorrhage
(Platelet Dysfunction) |
1. ASPIRIN: failure of aggregration
2. Uremia / Azotemia - toxins from renal failure- inhibits COX & increases prostacyclin secretion 3. Von Willebrand's Disease - vW factor def & factor 8 def - ristocetin aggreg test |
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COAGULATION DISORDERS
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1. Fibrin problem
2. Inherited, single factor defect - Hemophilias *Hemophilia A is most common - Factor 8 - x-linked recessive |
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IMMUNE THROMBOCYTOPENIC PUPURA
(TTP) |
platelet problem: survival fail
( IgG against the platelet. Type II HPY) AutoAb destorys platelets after 1. Viral Infxn 2. Drugs: Quinidine/quinine (bitters) or sulfa CLASSIC TRIAD: - Thrombocytopenia - Megakaryocytic hyperplasia in marrow - Normal size spleen - even tho macros are clearing this (in AIHA, there's hypersplenism) tx: steroids (inhibits macros), splenectomy, immunosuppression |
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TTP: THROMBOTIC THROMBOCYTOPENIC PURPURA
RENAL FAILURE: ADULTS = TTP; KIDS = HUS |
platelet problem: survival fail
- Infection or vWF abnormal = Platelet clumping & thrombocytopenia - platelet thrombi, fragmented RBCs, multi-organ ischemia DX: - Gingival or muscle biopsy = platelet thrombi - PT & PTT normal PENTAD OF CLASSIC TTP: 1. RBC frags 2. Thrombocytopenia 3. Fever 4. CNS deterioration w/ lethargy 5. Renal failure in ADUUULT!!! mechanism: - super BIG vWF multimers (def. of ADAMTS-13 = vWF-cleaving protease) - Neutralized by autoAbs (2' viral infxn) - Usu doesn't reoccur after tx - Usually dramatic remission w/ plasma xchange transfusions |
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HEMOLYTIC UREMIC SYNDROME
RENAL FAILURE: ADULTS = TTP; KIDS = HUS |
platelet problem: survival fail
E. coli 0157:H - Shiga-like toxin --> Hemorrhagic colitis = Endothelial dysfxn --> activates platelets - Most common cause of renal failure in KIDS - NONE/LITTLE CNS dz (vs TTP) - Spontaneously resolves; supportive care * NORMAL ADAMTS-13 * |
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IMMUNE THROMBOCYTOPENIC PUPURA
(TTP) |
platelet problem: survival fail
( IgG against the platelet. Type II HPY) AutoAb destorys platelets after 1. Viral Infxn 2. Drugs: Quinidine/quinine (bitters) or sulfa CLASSIC TRIAD: - Thrombocytopenia - Megakaryocytic hyperplasia in marrow - Normal size spleen - even tho macros are clearing this (in AIHA, there's hypersplenism) tx: steroids (inhibits macros), splenectomy, immunosuppression |
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TTP: THROMBOTIC THROMBOCYTOPENIC PURPURA
RENAL FAILURE: ADULTS = TTP; KIDS = HUS |
platelet problem: survival fail
- Infection or vWF abnormal = Platelet clumping & thrombocytopenia - platelet thrombi, fragmented RBCs, multi-organ ischemia DX: - Gingival or muscle biopsy = platelet thrombi - PT & PTT normal PENTAD OF CLASSIC TTP: 1. RBC frags 2. Thrombocytopenia 3. Fever 4. CNS deterioration w/ lethargy 5. Renal failure in ADUUULT!!! mechanism: - super BIG vWF multimers (def. of ADAMTS-13 = vWF-cleaving protease) - Neutralized by autoAbs (2' viral infxn) - Usu doesn't reoccur after tx - Usually dramatic remission w/ plasma xchange transfusions |
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HEMOLYTIC UREMIC SYNDROME
RENAL FAILURE: ADULTS = TTP; KIDS = HUS |
platelet problem: survival fail
E. coli 0157:H - Shiga-like toxin --> Hemorrhagic colitis = Endothelial dysfxn --> activates platelets - Most common cause of renal failure in KIDS - NONE/LITTLE CNS dz (vs TTP) - Spontaneously resolves; supportive care * NORMAL ADAMTS-13 * |
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ASPIRIN
- Effects on bleeding |
Failure of platelet aggregation
DESTROYS COX - irreversible damage - no production of PGI2 (--> TXA2, vasoconstrictor) - most common cause of platelet dysfxn *but MILD* - Endothelial cells also have COX Also occurs w/ NSAIDs (reversible) |
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body's natural anticoagulants
**Platelets = only cells to carry Thromboxane Synthase* |
1. Heparin (GAG)
2. PGI2 - vasodilator 3. t-PA: tissue plasminogen activator 4. Protein C & S - Vit K dependent - neutralize Factor 5 & 8 (NOT SER proteases) |
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UREMIA / AZOTEMIA
- Defect - Txs (not on exam) |
PLATELET DYSFXN
2' RENAL FAILURE (serum BUN > 60mb/dL - assc'd with toxins from renal failure DEFECTS: - COX inhbition - Endothelium: Increases Prostacyclin secretion (inhib TXA2) TX: - Dialysis - Platelet [ ] - DDAVP (like oxytocin): super-large multimers of vWF from endothelial cell Weibel-Palade bodies - Concentrates: vWF - Cryoprecipitate (vWf, 8 residue) |
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vWF disease
*vWF = adhesion factor & carrier protein for Factor 8C |
#1 Genetic bleeding dz
= Low vWF & Factor 8 1:1 levels of VWF: 8C - <60% vWF = disease *If this pt takes aspirin = HIGH risk of bleeding DX: Measure vWF in plasma 1. Ristocetin Aggreg - does not bind to platelets w/o vwF 2. Electrophoresis: dif types of vWF deficiencies 3. Ratio of vwf: 8C = 1 Always |
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COAG FACTORS INVOLVED IN WHICH PATHWAYS?
- what tests use which pathway? - INTRINSIC - EXTRINSIC - COMMON |
INTRINSIC: 12, 11, 9, 8
Extrinsic: 7 Common: 10, 5, 2, 1 Prothrombin Time (PT): 7, 10, 5, 2, and 1 - Extrinsic + common Partial thromboplastin Time (PTT) 12, 11, 9, 8, 10, 5, 2, and 1. - Intrinsice & common |
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TESTS FOR PLATELET ABNORMALITIES
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1. platelet count
- aspirin: normal platelet count 2. bleeding time - prolonged - coag disorders don't nec. have a prolonged bleeding time. 3. ristocedin cofactor assay (for vWB Dz) - most sens test for vWB dz |
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HEMOPHILIAS
(COAG disorders; failure of fibrin production) *more serious consequences* - TYPES (Hem A & B look identical) - DIFFERENTIATION - genetics |
X-linked rec: skips generations; males only
h. A: Factor 8 def (85%) x-linked rec. - PTT long, but pT normal, decreased plasma factor 8 h. B (Christmas dz): Factor 9 def x-linked rec. - Factor 9 = enzyme - long PTT, normal PT, decreased plasma factor 9 h. C: Factor 11 (rare) - Autosomal recessive - > 50% = Ashkenazi Jews - Not as severe bleeding as Hemophilias A or B |
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Non-hemophilia coagulation disorders
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1. Factor 12 Deficiency (Hageman factor)
- NO CLINICAL DZ 2. Factor 13 deficiency: autosomal recessive - tx like hemophilia - dx: Factor 13 assay (clot solubility test: dissolves in 5M urea) - PTT & PT are normal (tests end w/ clot formation; don't care about cross linking) |
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ANTIBODIES & BLEEDING
- COAGULATION PROBLEMS |
1. Alloantibodies
- result of tx (transfusions) - Anti-8 in 20% of hemophilia A pts 2. Autoantibodies: no inciting exposure - assc'd with pregnancy/postpartum, adults > 55yo - primary autoimmune disorders |
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THROMBOSIS
(DVT) - tx - process normally prevented by Antithrombin III (inactivates Ser proteases) & Protein C/S (inactivates cofactors 5 & 8) |
Due to:
1. Venous injury / stasis (bed rest) 2. Hereditary (Protein C / S or antithrombin III def) 3. Frequently multifactorial (multiple hit theory) NOT platelet-initiated - can break loose & embolize tx: 1. Heparin immediately (monitor w/ ptt) - inhibits all serine proteases (binds and increases antithrombin III axn - esp contra Factors 2 & 10) 2. Coumadin immediately (monitor w/ PT) - prolongs PT, but its anti-thrombotic effect is not evident til 48-72 hrs lager |
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Difference bw hemophilia A (factor 8 def) and vWB dz
*both have high PTT* |
EASY, MAIN DIFF:
- VWB DZ: Long bleeding time (platelet prob & coag prob) - Hem A: Normal bleeding time Hemophilia A only has one factor that is deficient: 8 anticoagulant; they have normal 8 Ag levels and normal vWF levels. vWDz has ALL 3 things decreased: 8 Ag, factor 8 anticoagulant (mildly decreased), and vWF. pts with hemophilia A it’s an X linked recessive dz, therefore males get the dz. Whereas vWDz is Autosomal dominant *ADH & estrogen increases synthesis of all 3 components of factor 8 |
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DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
- THROMBOSIS & bleeding - common causes? - what also looks like DIC? |
COMMON CAUSES:
1. Gram neg sepsis 2. Tumor 3. Injury MECH: - intravascular thrombi consume platelets & coag factors = Low Platelet & Long PT & PTT (loss of 1, 8, 5) Fibrin clot formation: - schistocytes (spherocytes) - organ failure form ischemia =( *HIT can look like this - but HIT will have normal PT / PTT) |
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HIT (WHITE CLOT SYNDROME)
aka Heparin-Induced Thrombocytopenia - what - clinical pres - management |
Heparin + Ab = thrombosis
(Type 2 HYP; thrombocytopenia) Ab combines w/ PF4-heparin combo - attaches to Fc receptors - activated platelets from thrombi --> ischemia - Platelets release stuff to make endothelial cells "stickY' clinical: - SUDDEN drop (>50%) in platelets (can be still normal) *corrects when heparin is dc'd* - Thrombosis despite heparin - Increasing heparin resistance TX: - DC HEPARIN - alts: LMW, heparinoids, coumadin |
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CAUSES OF HYPERCOAGULABILTY IN NORMAL-looking ADULTS
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1. Hereditary (60-70%)
- APCR 2. Anti-phospholipid syndromes *most common acquired cause* - 10-15% cases) 3. Occult malignancy 4. Nephrotic syndrome |
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APCR
(Factor V Leiden or Activated Protein C Resistance) - molecular defect - dx - incidence |
DEFECT:
- Point mtt in factor V gene ---> Normal clot, but resistant to cleavage by Activated Protein C DX: - APC-R: Fxnal test - PCR: definitive olecular test INCIDENCE: - VENOUS THROMBOSIS CASES: 20-60% - asymptomatic Caucasians 3-10% RISK LEVEL: - HOMO: 80X ^ risk of thrombosis - Hetero: 5-10x ^ risk of thrombosis |
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ANTI-PHOSPHOLIPID SYNDROME
- assc'd with ? - presentations - lab dx - tx Lupus anticoagulant (not an anticoagulant, but the opposite: thrombogenic) and anti-cardiolipin antibodies. Both of these antibodies cause vessel thrombosis. *false positive VDRL - cardiolipin* - NEG FT-ABS |
Anti-Phospholipid Abs
(Lupus anticoagulants (LA)) - assc'd with THROMBOPHILIA (NOT hemophilia) Presentations - Venous: DVT, PE - Arterial: Migraine, TIA, memory loss, strokes, MI - Spontaneous Abortion: 15% abortions; mainly 2nd semester LAB DX: - Abnormal PTT (phospholipid-dep); corrected by platelet phospholipid - Normal PT TX: - COUMADIN (monitored by PT) |
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MALIGNANCY & HYPERCOAGULABILITY
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10% Incidence of thromboembolic dz in CA populations
- Higher rate of Post-op venous thrombosis (40%) Pancreatic CA >50% Trousseau's Syndrome - multiple sites of superficial phlebitis on ext. assc'd with occult CA DIC - extensive carcinomatosis - M3 (promyelocytic) type of AML *probably release of tumor products, vascular stasis, etc. = hypercoag |
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NEPHROTIC SYNDROME & HYPERCOAGULABILITY
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1. Proteinuria from massive loss of plasma proteins in renal dz
2. Assc'd with Thrombosis - 35% get renal vein thrombosis - 20% get DVT elsewhere 3. Mainly loss of Antithrombin III |
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MECHANISMS OF REJECTION
- GENERAL |
*Classically hLA, but blood type even more important*
- involves T cell & B cell/Ab immunity 1 Direct Pathway: ACUTE rxns - Host CD8+ & CD4+ vs. Donor APCs - cytotoxic & delayed hypersens rxn 2. INDIRECT: CHRONIC rxns - Host T cell vs. Host APC + Donor Ag - cd8+ CTL can't seem to recognize / kill graft 3. Ab-Mediated rxns = Humoral rejection - pre-formed anti-donor Abs or - Abs made post-transfusion to donor HLA = rejection vasculitis |
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T-cell mediated REJECTION
DIRECT PATHWAY (ACUTE RXNS) - cells involved - results |
Donor Dendritic Cells Express
- HLA class I & II - Co-stim B7-1 & B7-2 Host CD8+ T cells --> MHC I - Perforin-granzyme-dep killing - Fas-fas ligand-dep killing (CTL expresses Fas ligand) Host CD4+ T cells (Th1) = MHC II - Delayed hypersensitivity rxn (cytokines: IFN-y) - Increased vasc perm - accum of lymphocytes/monocytes - activate macros --> graft injury |
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T-cell mediated REJECTION
INDIRECT PATHWAY (CHRONIC RXNS) - CELLS INV |
Host T cells vs. host dendritic cells & donor Ags
- Th1 also activate B cells --> plasma cells (but they suck) = delayed hypersensitivity rxns - CD8+ CTLs can't seem to recognize / kill graft tissue in indirect pathway *not a big player in indirect pathway* |
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AB-MEDIATED REACTIONS
HUMORAL REJECTION pre formed abs vs post-transplant abs - mechanism |
PRE-formed anti-donor Abs (from previous rejection/sensitization)
= HYPER-ACUTE rxn Post-Transplant - host makes anti-MHC Abs MECHANISM: - C' Dep Cytotoxicity - Induced inflamm from cytokines - ADCC (MAC attack) (ab-dep cell-mediated cytoxicity = macros & NKs) |
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MORPHOLOGY OF RXN TYPES OF REJECTION OF RENAL TRANSPLANTS
- stages/changes of arteritis |
Lesions occur sequentially as rejection worsen
(Gets worse as you go down) 1. Earliest, Mildest change = interstitial lymphocytosis & monocytosis (NOT neutrophils) 2. Mild tubulitis (lymphocytes & monocytes) 3. Intimal arteritis *Severity of arteritis determines severity of rejection* STAGES OF ARTERITIS 1-3: Nonspecific; indirect damage to smooth mm from outside inflamm 4-5: Nonspecific; direct activation of endothelium & WBC attch 6-11: Specific; WBCs under endothelium & into arterial media w/ smooth mm necrosis, Thrombus! |
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HYPERACUTE REJECTION
- TIME FRAME - CELLS INVOLVED - RESULT - TX? |
Minutes-Hours post-transplant
Pre-formed Abs & C' deposited on Endothelium - Rapid accum of neutrohpils in aa - Endothelial damage & thrombosis --> Fibrinoid necrosis of vascular wall & renal infarcts *MUST REMOVE rejected organ* Clinical: often recognized during SX of transplantation = renal cyanosis, mottling, flaccidity, minor hematuria |
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ACUTE (sudden) CELLULAR REJECTION
- TIME FRAME - RESULTS - CELLS INVOLVED - TX |
MOST COMMON; BEST PROG
Days post-tranpslant if not immunosuppressed - if immunosuppressed = months/years later suddenly T cells which express activation Ag (alpha chain of IL-2 receptor) - Many lymphocytes & monocytes in capillaries / tubules; - BUT ARTERIOLES ARE SPARED - may have focal acute tubular necrosis or atn CLINICAL: Increasing creatinine levels & progressive renal failure tx: Immunosuppression - responds quickly; reverses rejection DON'T CONFUSE THIS W/ CYCLOSPORIN NEPHROTOXICITY - biopsy: if no interstitial damage but arterioles involved, it's cyclosporin's fault |
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ACUTE HUMORAL REJECTION
- CELlS - RESULTS - TX *Necrotizing vasculitis & fibrinoid necrosis* |
Same as cellular rejection (days if not immunosuppressed)
Anti-Donor Abs formed POST-transplantation DEPOSIT w/ COMPLEMENT: - oN ENDOTHELIUM: Necrosis, neutrophilic infiltration of arterioles (necrotizing vasculitis) and/or - Progressive intimal thickening w luminal narrowing (fibrinoid necrosis) = glomerular/tubular atrophy w/ necrosis *Deposition of C4 in vessels = Ab-dep classical C' pathway TX: B-cell depleting agents (mycophenolate mofetil) |
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CHRONIC REJECTION
- TIME FRAME - CELLS - RESULTS |
4-6 mo Progressive rise of serum creatinine
Usu T cell mediated; slow, delayed hypersensitivity rxn (indirect pathway of cellular rejection: CD4 Th1) - Interstitial fibrosis w/ lymphocytes, plasma cells, eosinophils - Dense, obliterative intimal fibrosis of renal cortical arteries >>> chronic renal ischemia w/ glomerular loss & tubular atrophy |
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INCREASING GRAFT SURVIVAL
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1. Match HLA Ags
- Related donor matching of Class 1 HLA has good effect (not that big a dif on non-related donor) - Unrelated match for MHC 1 & 2 = Best *Even HLA-matched unrelataed donors likely to have rxns 2. Immunosuppressive therapies - Cyclosporine: inhibit IL-2 exp - Azathioprine: inhibit WBC - Steroids: inhib inflamm - Anti-CD3: kills T cells - Anti-IL2: blocks T cell act - Mycophenolate mofetil: inhib plasma cells - Retuximate: anti-cd20 (B CELL) |
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RISKS OF IMMUNOSUPPRESSION
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1. Opportunistic fungal & viral infxn
2. PT-LPD (EBV - Post-transplantational lymphoproliferative dz ---> B cell lymphoma 3. HPV-induced squamous cell carcinomas 4. Kaposi Sarcoma HHV-8 |
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ORGAN TRANSPLANTS WHERE HLA MATCHING DOESN'T MATTER
WHY? |
1. LIVER
2. HEART 3. PANCREAS 4. LUNG *Availability & size of organ takes precedence over HLA match* - HLA match might not even be done |
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LIVER TRANSPLANT UNIQUE PROBLEMS
"STILL EASIEST TO TRANSPLANT" - acute vs chronic *seems like most complications result after BMT* |
REJECTION PROBLEMS:
- Mild; fairly good prognosis NON-REJECTION PROBLEMS: - Damage from cytotoxic drugs - Graft vs Host dz post-BMT A. Acute: damaged hepatocytes & bile duct cells - don't biopsy; can bleed - Clinical dx: tender hepatomeg, ascites, wt gain, jaundice B. Chronic: SOS (veno-occlusive dz) - 25% pts w/ allogeneic BMT - Obliteration of sinusoids by cellular debris & then fibrosis --> Portal HTN |
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HEART TRANSPLANT PROBLEMS
SHORT TERM VS LONG TERM |
Transplantation mostly for Dilated CM & Ischemic Heart dz
- 60% survival after 5 yrs SHORT TERM: Denervated heart - Need regularly scheduled endomycoardial biopsy - catch early, reversible rejection (Only interstitial lymphocytosis = very reversible) - > myocardiocyte damage/fibrosis, more likely irreversible rejection LONG TERM: - Diffuse stenosing intimal proliferation of INTRAMURAL coronary arterioles " Graft Arteriopathy " = Silent MI, CHF, sudden death (arrhythmia) *Chronic damage from cytokines suspected |
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HEMATOPOIETIC CELLS PROBLEMS
- uses - types of transplants |
USES:
- Hematologic malignancies - aplastic anemias - inherited immunodeficiency Myeloablative bmt: pt receives chemo or radiation to kill off diseased cells (wipe out marrow) Non-myeloablative: chemo used to suppress marrow - transplantation is for graft vs. DISEASE effect against tumor cells 4 major problems of BMT 1. GVHD 2. ABO mismatched tranpslant 3. Transplant rejection 4. Immunodeficiency |
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GVHD
GRAFT VS HOST DISEASE - usual contexts - results - chronic GVHD *so severe that BMT only done on hLA-match donor & host* - matched siblings = least GVHD |
GRAFT ATTACKING HOST
- transplant immunocompetent cells to immunologically crippled host Usual Context: - Allogenic BMT - Transplant organ rich in lymphocytes (liver) - Transfuse un-irradiated blood (donor is homozygous for HLA allele) Days-Weeks: any organ, but esp 1. Skin: gen. rash --> desquamation (can denude) 2. Liver: jaundice (destroy small bile ducts) 3. Intestines: bloody diarrhea - CD8+ cells attacking epithelial cells of SI crypts 4. Immune System: donor cells WIPE OUT host's immune cells = classic CHRONIC GVHD ~ SCLERODERMA - can be insidious onset 1. Extensive cutaneous injury; dermal fibrosis 2. destroy appendages 3. Cholestatic jaundice 4. Esophageal strictures 5. Devastated immunity (bad infxns) *Redcued by depletion of donor T cells --> Decreased BMT success --> Decreased rate of cures of leukemia (no graft vs leukemia effect) |
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Immunodeficiency in BMT
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LEAVES HOST OPEN TO INFXNS
CAUSE: 1. Prior tx or radiation 2. Myeloablative preparation for a graft 3. Delay in repopulation of hosts immune system 4. Attack of host's immune system by donor lymphocytes **CMV = MOST IMPORTANT INFXN (ESP PNEUMONIA) |
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types of grafts
- autograft - isograft/syngraft -allograft -xenograft |
HISTOCOMPATIBLE
1. AUTOgraft 2. ISO/SYN-graft: same genetic composition - identical twins - practically an auto-graft HISTO-IN-COMPATIBLE 1. Allograft: w/in same species 2. Xenograft: different species |
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FETAL MECHANISMS OF PROTECTION AGAINST REJECTION
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1. Placenta makes mucoprotein to coat fetal cells/Ags
2. Production of immunosuppressive hormones - High hCG & Progesterone 3. Production of maternal Abs that block immune recognition - IgG4: does not activate C' or mediate ADCC |
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HLA
(human leukocyte Ag) |
MHC provokes STRONGEST graft rejection
- Polymorphic - co-dominant expression *also minor histocompatibility loci |
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Tests for histocompatibitliy Ags
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1. ABO testing
- ABO Ags are NOT just on RBCs = immediate, hyperactue rejection (anti-Ab is IgM) 2. Serological Detection of Preformed Abs - Donor lymphocytes + Recipient serum + C' (less surviving cells = more preformed Abs) 3. Chromium release Assay (NK cells) - Donor Lymphocytes (labeled w/ Cr-51) + Recipient Lymphocytes (incubate 4 hr) - coUNT AMT. OF RELEASED 51Cr (More radioactvitiy released = more donor cells killed) 4. One-Way Mixed Lymphocyte Reaction (CTL) - takes FOUR days - Donor (irradiated) lymphocytes + Recipient lymphocytes (incubate 4 days) - 3H-Thymidine pulse (incubate 4 hr) - Count amt of 3H-Thymidine uptake *More uptake = More INcompatibility |
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TRANSFUSION EFFECT
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Blood transfusions prior to transplantation = better prognosis
- greatest benefit when hLAs don't match 100% - Increased benefit w/ multiple transfusion (as long as Abs did not develop against donor's cell) *Generalized immunosuppression observed after blood transfusion* |
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IMMUNOSUPPRESSIVE AGENTS
- Mechanisms of Cyclosporine & antilymphocytic globulin |
1. Anti-Inflamm
- Prednisone (adrenocorticosteroid) 2. Anti-Metabolites: - azathioprine 3. Cytotoxic - X-irradiation - Antilymphocyte Globulin: Anti-T cell Abs & Anti-thymocytes - Cyclosporine: Inhibits Th cells 4. Tacrolimus (FK506) - similar axn to cyclosporine (2nd line drug) |
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CYCLOSPORINE
- AXN - SEs |
Fungal byproduct
- cyclic peptide Inhibits synthesis & secretion of IL-2 by activated Th cells - INdirectly inhibits clonal expansion of graft-specific T cytotoxic cells *NOT toxic to bone marrow - less incidence of infxn *KIDNEY & LIVER DAMAGE = main complications - usually reversible (watch out for toxicity - mm. biopsy) |
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CONSEQUENCES OF IMMUNOSUPPRESSION
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1. INFXN:
- Pneumococcus - CMV - E. coli - PCarinii - Candida albicans 2. NEOPLASMS - skin - anogenital - non-hodgkins - Kaposi's sarcoma GVHD - dermatitis - diarrhea - fever, FTT - death (sever) |
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"GOOD" ORGANS TO TRANSPLANT
(GOOD SURVIVAL) |
#1. CORNEA
- relatively priveileged site - sequestered from blood & lymphatic circulation - don't need immunosuppression really >90% success BONE: 90% Long term survival "self" bone regenerates - very common |
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Anti-ABO Abs vs. Anti-Rh-D Abs
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Anti-ABO
- Naturally occuring (bacteria in gut express them) - Fix C' --> Intravascular hemolysis (fatal) Anti-Rh-D: -NOT naturally occurring - VERY antigenic (crosses placenta as IgG) - do NOT fix C' --> destroyed by monocytes & macros in SPLEEN & LIVER --> Hepatosplenomegaly |
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"Strength" of an Ab & high frequency alleles
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strength of dilution at which the Ab still causes agglutination
- low titers less likely to cause sig hemolysis - INCREASE in Ab titer = additional exposure (ex// from fetus) High freq alleles: high presence in a population. |
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Abs to PLATELETS
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MC: Anti-HLA
- follow exposure (NOT naturally occuring) Rarely: refractoriness/rejection can be due to anti-HPA-1a - >98% of pts are positive for HPA-1a --> NO anti-HPA-1A **it's the 2% of pts homozygous for HPA-1b that are at risk --> anti-HPA-1a can even go on to destroy OWN platelets --> Thrombocytopenia & post-transfuion pupura *Platelets express a small amt of A & B Ags - not as big a factor as HLA & HPA though |
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NEONATAL ALLOIMMUNE THROMBOCYTOPENIA
(NAIT) |
Mom has Abs to Ags on baby's platelets
- degree of thrombocytopenia depends on strength of Ab MC: Anti-HPA-1a - transfuse w/ Ag-negative platelets (usually from mom) |
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Transfusion Associated GVHD
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Living lymphocytes transfused into recipient
" transplanted immune system " MC: Donor is a close HLA match (family; japan) - Homozygous donor, heterozygous recipient - Recipient doesn't recognize as foreign - DONOR attacks HOST **Fatal in 90% cases** tx: irradiate blood w/ 2500 cGRAY - precludes lymphocyte proliferation & prevents GVHD |
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TRALI
(transfusion related acute lung injury) *UK excludes plasma collected from women (women tend to have more abs than men) |
ARDS-like capillary leak syndrome
- NON-cardiogenic pulmonary edema within 6 hrs of transfusion = Resp distress + pulmonary edema w/o penumonia, volume overload, or Heart failure REQUIRE INTUBATION - freq resolves spont. (5-10% fatal) - #2 MC COD post-transfusion |
