ACUTE LEUKEMIAS

Risk Factors: Inheritance/Genetic (defects in DNA repair Bloom Syndrome, Fanconi Anemia, ataxia telageiectasia), certain viruses, Chemotherapy (esp. Topoisomerase Inhibitors), Radiation/Chemicals/Smoking (Benzene is possibly linked to Myeloid leukemia) Symptoms: Fatigue due to anemia / often febrile (Neutropenia) / Petechiae (bleeds due to Thrombocytopenia) / Bone pain w/ pressure / HYPERcellular bone marrow / Can see CNS sx: meningeal involvement and bleeding - - - -NOTE: AML and ALL will look VERY similar in presentation CBC: DONT use WBCs as a predictor - -WBCs can be , , or not change ; Anemia, neutropenia, Thrombocytopenia are all often seen Bone Marrow: Hypercellular > 20% blasts (primitive cells w/ lg nuclei, N/C ratio, nucleoli) Name ALL: Lymphoctytic / Lymphoblastic Age Kids<15 (4yr peak) Blood Micro. 80% pre-B (CDs 10, 19) Pre-T (7,2,3) Specific Labs TdT Postive PAS Positive Prognostic Labs Good Young age HYPERploidy PreB Poor T9:22 transloc. Pre-T Blasts>100k AML: 60 or Myelocytic/Myelogenous/Myeloblastic over Blasts with AUER rods and cytoplasmic granules Myeloperoxidase Poor Positive -5q;7q deletions: M1-M3 dev. From MDS -AML caused by CD34, CD33 therapy - - -tends to be 5,7 types -11q deletions Chloroma: a granulocytic sarcoma green in color (progresses to AML in wks to yrs) Leukemia Cutis: skin involvement: gingival monoblastic infiltrate Other Pre-T assoc. Mediastinal masses cause resp. issues due to compression Therapy and Prognosis Combo Chemotherapy 95% remission 2/3 Cure rate - -but there are tx sequelae Bone marrow transplant in adults is curative Combo Chemotherapy 60% remission; 15-30% cure rate (Chemo) Bone marrow transplant is curative PML initial tx is Retinoic acid

Chronic Leukemias
CLL: If there are enlarged lymph nodes consider Small Lymph Lymphoma (SLL) SLL: Enlarged lymph nodes predominate clinical picture / diffuse round cells replace LN, infiltrate liver, bone marrow Both are often asymptomatic at onset / cause of death is normally an infection or secondary process die with, not of, the chronic leukemia CML: BCR-Abl Translocation within stem cell in 100% / t(9:22) / Granulocytosis with notable left shift / RAS, JAK/STAT, and AKT pathways unregulated CBC: Leukocytes are ALWAYS increased; Anemia, neutropenia, Thrombocytopenia are all often seen Bone Marrow: Hypercellular with < 20% - - - - -(recall that acute cases are over 20% often times) Name CLL and SLL: Chronic Lymphocytic Leukemia Small Lymphocytic Leukemia Age >50 (60) M>F Most common western leukemia Blood Micro Smudge Cells Lymphocytosis >4000/ul up to 200k Small cells that appear mature and maybe nucleated RBCs -Anemia in 10%, thrombocytopenia in <10% (Antiimmune med.) LEFT shift granulocytosis (Bands, metas, myelos, pros, Eosinophils, basophils Specific Labs CD 19, 20, 23 and CD5 (an early marker) HypoGammaglobulinemia in many Positive: Direct antihuman globulin test (Coombs Test) Prognostic Labs Good -Slow, insidious -SLL is initial presentation Other Therapy and Prognosis Good prognosis if Zap 70 NEGTIVE and WBC count is on lower side - -live for 10+ years Palliative Therapy - Anti CD20 Poor -Rap. progressive -Zap 70 positive -Trisomy 12 -11q, 17q deletions Bone marrow transplant in younger patients

CML: Chronic Myelogenous Leukemia

Any age 20-60

BCR-Abl translocation (t(9:22))

Neutrophils are ALWAYS increased Sx of Splenomegaly present: Early satiety, LUQ pain, fever and night sweats due to metabolism Uric Acid

-3yr survival w/o Tx Can shift into an ACCELLERATED Phase (BLAST crisis): you enter acute lymphoid (70%) or myeloid status Long remission if using IMATINIB (A tyrosine kinase inhibitor) Bone marrow trans.

Most common Chronic myeloPlatelets are proliferative INCREASED dramatically or Anemia

Leukocyte Alkaline Phosphatase

Leukemias Acute Promyelocytic Leukemia: t(15;17) - -blocks maturation past pro-myelocyte phase/ Cytoplasmic granules and Auer rods / Release of granules causes DIC / Tx is RA (to allow maturation and halt DIC) followed by combination chemo / M3 classification Sx: Evidence of bleeds (hematochezia, hemorrhages in eye, Petichiae (reported as a rash), severe thrombocytopenia, Prolonged PT and PTT, elevated DDimer, decr. Fibrinogen) Hairy Cell Leukemia: Prone to infection w/ atypical mycobacteria (MAC) as a consequence of monocytopenia / RARE disease / Splenomegaly / NO LYMPH node involvement / cells look to have hair-like extension coming off of them / may present as febrile due to atypical infection

Name Acute Promyelocytic Leukemia (M3)

Age Any (2060)

Blood Micro Azurophilic (blue/prurple) granulocytes Thrombocytopenia Peripheral Smear: Cytoplasmic granulocytes and Auer Rods

Specific Labs MPO positive t(9;22)

Prognostic Labs

Other PT and PTT D-Dimer Fibrinogen

Therapy and Prognosis Retinoic Acid followed by Chemo

Hairy Cell Leukemia Middle age (4050) M>F; 4:1 Mono Markers: CD11, CD22 HAIRY cells B cell Markers: CD19 and CD20 Wright Stain TRAP stain (tartaric acid resistant phosphatase) Massive Splenomegaly is COMMON Pancytopenia from splenic sequestration and BM issues Tx: -Interferon and Nucleoside analogues (95% to 5yrs, 80% past 10) Under 5 w/o tx

Myelo-dysplastic Syndromes (MDS)

-Clonal Stem Cell Disorders Characterized by: Ineffective Hematopoiesis CYTOPENIAS and an risk for progression to AML (pre-leukemia) / DYPLASTIC maturation resulting in Dysfunctional progeny cells Incidence: Age >50 w increased risk as you age / 2x as common as leukemia in those over 50 / Males > F / insidious onset Etiology: Most commonly idiopathic / Therapy induced (Myelosuppressive chemotherapy drugs (TOPOISOMERASE inhibitors), Radiation) / Onset 2-8 yrs after tx Prognostic Indicators: BAD: 7q, Therapy induced MDS is bad, Blast counts Good: 5q, 20q, -y / Peripheral blood Morphology: Pancytopenia / MCV / Poikilocytosis / Pseudo-Pelger-Huet Cells (bi-nucleated granulocytes) Bone Marrow Morphology: HYPERcellular / Megaloblastoid maturation of RBCs (can look like B12/folate deficiency) / RINGED sideroblasts (not specific for myelodysplasias!!!) Clinical Features: REFRACTORY anemia or pancytopenia / 5q Syndrome (women, ringed siderblast anemia w/ normal platelet count, good prognosis Prognosis and Treatment: 9-29 months IN ALL types!!! / supportive tx can include FREQUENT transfusions and in some cases a bone marrow treansplant

Myelo-Proliferative Diseases (MPDs)

Definition: Clonal TRANSFORMATION of a Multipotent myeloid progenitor cell (except in the case of CML as the stem cell is Pleuripotent) Features common to all MPDs: HYPER-cellular BM / Splenomegaly (extramedullary hematopoiesis) / May terminate in pt w/ bone marrow FIBROSIS / may transform to AML 5 Primary Examples : CML, Polycythemia Vera, Essential Thrombocytosis/thrombocythemia, Primary myelofibrosis, Systemic mastocytosis Polycythemia Vera: Etiology: Point mutation in JAK2 / ERYTHROCYTOSIS (primary characteristic) and polycythemia / Granulocytosis and Thrombocytosis IN ALL patients / Pathophysiology: Erythropoietin INDEPENDENT (cytokine independent) erythroid proliferation Clinical Features: Splenomegaly (clogged at first then used for erythropoiesis) / Plethoric (excess body fluid) and Cyanotic complexion (stagnation/deoxygenation of blood) / Excessive histamine release from basophils (resulting in Peptic ulceration and intense pruritis) / hyperuricemia/thrombosis in 25% (DVTs, MI, Stroke, Budd-Chiari Syndrome if in hepatic vein) Essential Thrombocytosis/ Thrombocythemia: Uncommon / Thrombocytosis >600k!! / Essential and reactive forms / Thrombosis and Hemorhage are likely / EPISODIC in nature!! Reactive Thrombocytosis: COMMON!!! / Causes: an acute phase reaction (acute, chronic) / ASPLENISM / Fe+ Deficiency Anemia / rebound after myeloid suppression tx / Acute Blood Loss Primary Myelofibrosis: Granulopoiesis and Megakaryo-poiesis / FIBROSIS in BM / Erythropoiesis shifts to Spleen Enlarged spleen / Myeloid Metaplasia in full disease / Pathogenesis: Neoplastic megakaryocytes release fibrogenic growth factors (PDGF and TGF-B) Fibrosis suppresses normal hematopoiesis / Clinical features: Massive splenomegaly (>3000) / Hyperuricemia / thrombosis or hemorrhage (causes of death usually) / Transform into AML / Lab Findings: TEAR DROP erythrocytes (not diagnostic but a clue that RBCs are being made in the spleen) / left shifted WBCs and nucleated RBCs / Basophillic stippling of erythrocytes (they are immature) Mastocytosis: Abnormal accumulation of mast cells in tissue (GI, skin, BM, Spleen) / c-Kit mutation / Cutaneous form is most frequent - - -RASH / Mast cells in nodes, skin, spleen, BM, GI tract / elevated serum Tryptase / recurrent anaphylactic episodes (w/ pruritus, flushing, asthma, rashes) Name Polycythemia Vera Age Blood micro -Erythrocytosis (primary feature) -Thrombocytosis -Granulocytosis Erythropoietin GIANT platelets!! Specific Labs Histamine levels may be high Hgb may be normal to extremely HIGH - -like around 28 Prognostic Labs JAK2 Mutation Other -Splenomegaly -Plethoric w/ Cyanotic compl. -HTN & HA -Peptic Ulc. and Pruritis -Thrombosis Therapy and Prognosis JAK2 inhibitors Phlebotomy to maintain normal RBC mass -13yrs -risk of conversion to AML to 15% from 2% w chemo or radiation

Essential Thrombocytosis / Thrombocythemia

Thrombocytosis > 600k!!

Giant Platelets in periph.

Megakaryocytes in BM (mega. Hyperplasia)

JAK2 Mutation

Other MPD features not present

Reactive Thrombocytosis Primary Myelo-Fibrosis >60

COMMON Leukoerythroblastosis: -Left shift WBCs -Nucleated RBCs -TEAR DROP erythrocytes Look for excess inflammatory mediators: Histamine, prostaglandin D2, thromboxane, etc. JAK2 mutations in 50% Variable prognosis of 1-5yrs

Systemic Masto-Cytosis

50-70

Elevated serum Tryptase

c-Kit Mutation

Anaphylactic episodes (pruritis, flushing, asthma) Rash

Indolent form is good Tx: H1 and H2 Receptor Antagonists

Langerhans Cell Histiocytosis (LCH)

General info: Proliferative disorders of Immature Dendritic (Langerhans) cells / Mostly Neoplastic (MONOclonal) / Cell Morphology: vesicular nuclei w/ linear grooves / BIRBECK granules seen under EM / Eosinophils are abundant (Eosinophillic infiltrates are common) / When testing we look for CD1a Acute Disseminated Langerhans Cell Histiocytosis (LCH): Also called Letter-Siwe Disease / Multi-system Langerhans infiltrates / Under age of 2 / Clinical signs: Seborrhic eruption (skin rash), Lymphadenopathy, hepatosplenomegaly (causing abdominal distension), Pulmonary lesions / Signs of Bone marrow involvement: Anemia, thrombocytopenia, predisposition for infection - - - may progress to Osteolytic Bone Lesions / Eosinophillic Granuloma: a Unifocal or Mutlifocal UNI-system disease / Less aggressive than disseminated form / Langerhans cells mixed with Lymphs, eosinophils, plasma cells, and PMNs / Common Locations: Bone, medullary cavity (calvarium, ribs, femur), skin, stomach, lungs of SMOKERS (regresses w/ cessation of smoking!!) / May regress spontaneously!! Hand-Schuller-Christian Triad: A form of eosinophilic granuloma / CALVARIAL bone involvement / Diabetes Insipidus (Pituitary stalk involvement) / Exophthalmos - - - - -Piss a lot and their eyes are bulging out Name Age Blood Micro Specific Labs Prognostic Labs Other Seborrhic eruption - -(a persistent rash) -Abd. Distension / lymphadenopathy Prognosis and Therapy Rapidly fatal w/o tx Responds well to chemo - -may relapse Less aggressive/ Good prognosis (may even regress spontaneously) Tx may include local excision Calvarial bone involvement CD1a Diabetes Insipidus Exophthalmos

Acute Disseminated LCH

<2

BIRBECK granules seen under EM / Eosinophils are abundant Langerhans cells mixed w/ Eosinophils, lymphs, plasma, and PMNs BIRBECK granules seen under EM Langerhans cells mixed w/ Eosinophils, lymphs, plasma, and PMNs BIRBECK granules seen under EM

CD1a

Eosinophilic Granuloma

Kids > 5 Up to 30

CD1a

Hand-Schuller-Christian Triad

Children

Plasma Cell Neoplasms (dyscrasias)

Dyscrasia: refers to abnormal material in the blood----and related disorders

General Info: Neoplasms of terminally differentiated B Cells / secretion of A SINGLE homogenous (monoclonal) immunoglobulin or a fragment of it - - Monoclonal Gammapathy / Might See: M Protein or Component (from Myeloma), Uncoupled Light chain (L), Uncoupled Heavy Chain (H) - - -uncoupled L and H production can occur in isolation or together / Types: Multiple Myeloma, Lymphoblastic lymphoma (Waldenstroms Macroglobulinemia), H chain Disease, Prim. Immunocyte-associated amyloidosis, Monoclonal gammopathy of undetermined significance (MGUS)

Multiple Myeloma: Plasma cell neoplasms at multiple sites w/I bone marrow / Etiology: Genetic, blacks, radiation, chronic antigenic stimulation (so more
common in chronic inflammation pts - - HIV;RA;osteomyelitis), MGUS may progress into a multiple myeloma / aberrant IL-6 signaling from infiltrate plasma cells Osteoclast activation and Lytic Bone destruction / Excess immunoglobulin effects: Serum hyperviscosity, Proteinurea, suppression of normal immunity risk of infection!!! / Morphology: Punched out bone lesions (overactive osteoclasts weaken bone and release Ca2+) / Bence-jones protein precipitate in urine renal tubules (toxic immunoglobulin precipitate blocks tubules) / Bone marrow Plasmacytosis (abnormal cells with Russell bodies (Ig cytoplasmic inclusions)), can have systemic amyloidosis , plasma cell leukemia if late/ Requirements for Dx: Damage in organs and 1 or more of following (CRAB): Hypercalcemia, Renal insufficiency, Anemia, Bone Lesions

Solitary Plasmacytoma: Precedes Multiple Myeloma by 10-20 yrs / Localized tumor of Plasma cells / M-protein component is minimal or absent / can be
removed with surgery / can occur outside of bone and be removed

MGUS: Monoclonal Gammopathy (most common one) / M-protein is high but patient is ASYMPTOMATIC (Incidental discovery during routine chemistry ) /
considered a precancer (same genetics as multiple myeloma) / Amount of Ig a predictor of later conversion to multiple myeloma

Lymphoplasmacytic Lymphoma: Indolent B-cell lymphoma of older adults / Lymph node involvement (liver and spleen too) / Portion of neoplastic cells
develop into plasma cells / Monoclonal IgM secretion Hyperviscosity syndrome (Waldenstroms Macroglobulinemia) / dDx: Lacks free light chains, no amyloidosis, no renal failure, no punched out bone lesions / Clinical Features: Lymphadenopathy, Hepatosplenomegaly, Anemia (bone marrow replacement, autoimmune hemolytic anemia due to cold), Reynauds syndrome (solar induced rash, blue-red fingertips), no hx of malar rash (feature of SLE), may be jaundiced, Cold Agglutinin Disease (cold causes IgM to agglutinate), Livedo Reticularis (mediated by IgM in patients with cryoglobulinemia)

Heavy Chain Diseases: Excess Ig Heavy chain is produced / Associated with lymphocytic leukemia and lymphomas / Mediterranean Lymphoma is an example
of a heavy Chain disease - - - - -Lymphomas of the SMALL INTESTINES, Alpha Chain excess Name Age Blood / BM Micro Specific Labs Plasmacytosis Plasma cells w/ one or more Russell bodies Mono Gammopathy (IgG usually) -IL-6 -M-Protein -IgG (most );IgA, IgD, Light chain, IgM -Bence-Jones protein in Urine Clincial Features -Bone Pain -Recurrant bacterial infections -Hypercalcemia -Sx of amyloidosis -Renal insufficiency Other Prognosis and Therapy Incurable disease so do Palliative care -Punched out bone -Rouleux (coin stack RBCs) For some chemo and transplant (w/o tx = 6-12mo) (w tx = 3 yrs +)

Multiple Myeloma

50-60

Solitary Plasmacytoma

40-50 Monoclonal Gammopathy

M-protein is minimal or absent M-Protein (but no symptoms of disease)

Localized Tumor of plasma cells Incidental Finding during routine chemistry Lymphadenopathy Hepatosplenomegaly Anemia Neurologic and Visual impariments Reynauds Phenomenon Cold-Agglutinin Disease Livedo Reticularis Lymphoma of the Small Intestine

Predates multiple myeloma by 10-20 yrs

Curable by surgery [IgG] predicts conversion to multiple myeloma

MGUS

5-10yr survival Lymph node involvement (liver and spleen too) Waldenstroms Macroglobulinemia Indolent: Progressive Tx: Plasmapheresis to control blood viscosity May transform into a B-Cell lymphoma

IgM (monoclonal) Lymphoplasmacytic Lymphoma >50 Cd19, CD20 positive Plasma Cells

Mediterranean Lymphoma

Alpha-Chain

A type of Heavy Chain Disease

Spleen
General info: White Pulp: T-lymphocytes (sheets), Malpighian Corpuscles with B cell follicles / Red Pulp: Functions as filter (Cords of Bilroth, Sinusoids,
Phagocytic Macrophages) / Marginal Zone: /

Functions of the Spleen: Filter unwanted elements from blood (RBCs: Kills senescent, kills those w/ attached antibodies, Cleans inclusions away (Howell Jolly,
Heinz bodies), removes bacteria, macromolecules, debris) / Major secondary organ of immune system: Source of Lymphoreticular cells / Extrameduallry hematopoiesis in some circumstances / Reserve pool and storage for RBCs and Platelets (Splenectomy will platelet count) /

Causes of Splenomegaly: Infections (mild; soft pulp; CMV and EBV; Perisplenitis: (fibrinous coating over spleen)) / Immunologic-inflammatory diseases: Felty
Syndrome (RA), SLE, amyloidosis, sarcoidosis, any non-specific infection / Congestive Splenomegaly: Due to HTN in Splenic Vein (RHF, cirrhosis, Portal vein thrombosis) / Storage Disease: Niemann Pick and Gauchers disease / Lympho-hematogenous Disorders: all Chronic Myelogenous diseases cause splenomegaly (CML, PV, and especially Primary Myelofibrosis (most massive)) , Chronic hemolytic anemias (Sickle cell anemia - -hypoxic infarction leads to auto-splenectomy with age)

Neoplasms of the Spleen: Metastasis are uncommon (lung, malignant melanomas, NEVER from colon cancers!!!) / Primary Malignancies of the Spleen:
Hemangiosarcoma (occurs in Spleen, liver, heart, rarely in other locals), Lympho-hematopoietic Malignancy (occurs as part of systemic involvement), Follicular Lymphoma, Large B Cell Lymphoma

Splenic Sequestration / Hypersplenism: Hypersplenism is a consequence of Splenomegaly / Hypersplenism Triad: Splenomegaly, Decrease in one or more
blood elements (anemia, thrombocytopenia, leukopenia), compensatory hyperplasia in bone

Splenic Infarcts: Occlusion of splenic vein leads to WHITE infarct / Could be due to: DIC, splenomegaly, emboli from heart, sickle cell anemia Splenic Rupture: ALWAYS Secondary to trauma or some other process / Causes: Blunt trauma, Surgical Trauma, Spontaneous Ruptures: Infectious
mononucleosis, malaria, acute splenitis, leukemia Name Blood / Bone Micro Hypersplenism Triad -Splenomegaly Hypersplenism - in 1 or more blood elements -Compensatory bone marrow hyperplasia Splenic infarcts Occlusion of splenic artery Acute Splenic Rupture Nucleated RBCs Howell-Jolly bodies Target Cells Clinical Feature Other A consequence of splenomegaly White Infarct in wedge shape

Will present differently based on what is deficient

Post-Splenectomy

Sharp LUQ pain LUQ pain Massive intra-abdominal hemorrhage Hypo-volemic Shock Vulnerability to some bacterial infections - - -especially encapsulated bacteria (S. Pneumoniae, Pneumococcus, meningiococcus)

Reactive Lymphadenitis: Acute and Chronic Reactive Hyperplasias

Causes of Lymphadenopathy: Lymphadenitis a.k.a. Reactive proliferations (Normal: Granulomatous / Acute / Chronic Non-specofic)), Metastatic malignancy,
Lymphoma

Acute Lymphadenitis: Presentations can give you a hint at what is causing infection / Follicular hyperplasia c necrosis: Pyogenic Infection

/ Folicular Hyperplasia and Suppurative Granuloma (Neutrophils and monocytes involved): Cat-Scratch Fever (bartanella) - -enlargement often in Axilla / Tularemia / Yersinia (Lymphogranuloma venereum

Chronic Non-Specific Lymphadenitis: Nodes are enlarged and non-tender / 3 Morphologic Patterns: Follicular Hyperplasia, Paracortical Hyperplasia,
Sinus Histiocytosis

Name Granulomatous Lymphadenitis

Lymph Nodes

Clinical Caseating: TB, Fungi (cocci) Non-Caseating: Sarcoidosis, and Early TB LOCALIZED (esp. in adults) Enlarged, tender lymph nodes Multiple intra-abdominal nodes of intestine Sx mimic acute appendicitis Can occur in any location - including the thymus

Other Can be necrotizing in nature as well

Prognosis and Therapy Acute Reactive Benign

Acute Nonspecific Lymphadenitis

Local enlargement (in adults) Generalized lymphadenitis occurs mostly in kids (sys. Viral or bacterial) Acute lymphadenitis

Generalized lymphadenitis in adults is likely lymphoma

Acute Reactive Benign

Mesenteric Lymphadenitis

Assoc. w/ entericolitis (Yersinia enterolytica) May see granules form Associated with: -Early HIV -RA -Drug Reactions / some viruses Other viral infections: CMV / varicella-zoster SLE (associated with necrosis) Likely due to drainage of inflammatory foci

Acute Reactive Self-limiting Benign

Follicular Hyperplasia (Chronic NS)

B cell Proliferation in Germinal Centers Apoptotic Bodies T-Cell Hyperplasia of immunoblasts Macrophage and Eosinophil infiltrate Increases Macrophages in sinuses of nodes (Subcapsular and Trabecular) Follicular hyperplasia w/ INTERfollicular macrophage collections

ParacorticalInterfollicular Hyperplasia (Chronic NS) Sinus Histiocytosis (Chronic NS) Mixed Patterns of Reactive hyperplasia

Infectious Mono-nucleosis (cervical nodes) Vaccinations (axillary nodes Common in nodes draining CANCER regions Toxoplasmosis associated

B-Cell Lymphoid Neoplasms

Lymphomas in General: 2/3 present as tissue masses which may be nodal or extra-nodal (skin, brain, intestines, etc..) in nature / All are considered malignant Neoplastic Monoclonal proliferations / wide variation in behavior / MOST are B-CELL in origin / T-Cell origins make up the rest ; NK and histiocytic / Biopsy with histologic examination is REQUIRED for dx / Hodgkins Lymphomas (4types) / Non-Hodgkins (all others) are in the majority: Precursor B, Peripheral B (many subtypes), Precursor T, Peripheral T / In general the post-germinal center (peripheral) cases do better

Diffuse Large B Cell Lymphoma: Aggressive (most common aggressive lymphoma of adults) / Occurs in all ages / Bcl-6 / Multiple forms / Can evolve from CLL
or other B cell cell lymphomas or be result if immunodeficiency / Immunodeficiency Associated Lymphoma: (Occurs when people are severely deficient in Tcells - -HIV, immunosuppression for transplants, congenital), when neoplastic cells are infected with EBV / initial tx is to try and restore immune function - -often does not work

Burkitt Lymphoma: 3 Types are known: African (endemic), Sporadic (non-endemic), HIV associated / STARRY SKY (pattern of larger apoptotic bodies against
backdrop of benign macrophages ) tingible body/ High mitotic index (rapid growth) / MYC oncogene always activated

MALToma / Marginal Zone Lymphoma: 2 Forms: Nodal and Extranodal / Extranodal: Autoimmune associated (Sjorgens (salivary glands -Xerostoma) ;
Thyroid-Hashimotos Thyroiditis) / Chronic infection (H. Pylori a common agent Giant rugai) / will see B-cells with various differentiation, including plasma / Pathogenesis: Reactive clonal proliferation over a long period Monoclonal transformation when a translocation occurs / May progress into Large B Cell Name Location Clinical Features Histology Morphology Immuno-phenotype and Genetics Therapy and Prognosis -Indolent(painless) -middle aged -Resistant to chemo. -Retuximab to control -50% transform into aggressive B-Cell -Survival < 1yr -Aggressive / Fast - EBV induced in HIV patients -Intensive Chemo -80% R ; 50% cured -Rapidly fatal w/o tx

Nodal Follicular Lymphoma

-general distribution of small nodular -no Hx of illness

B-Cell: 19,20,10

-Round to oval follicles composed of neoplastic cells -If in Spleen each corpuscle will be enlarged (patchy look)

t(14;18) overexpression of Bcl-2 blocks apoptosis -Bcl-2 immunostain (center of follicle)

Large B-Cell lymphoma (Immunodeficiency Associated)

Extra-nodal (often) Nodal

Extranodal Sites: GI, skin, bone (but NOT in the marrow) Waldeyers Ring (tonsils and adenoids)pharyngeal mass

B-Cell: 19,20,10

Can be destructive masses if in the liver or spleen

Bcl-6

African Burkitt Lymphoma (Endemic) Burkitt Lymphoma (HIV) (non-endemic) Sporadic Burkitt Lymphoma (US) Mantle Cell Lymphoma

Extranodal Extranodal Extranodal

Facial (often mandible) 100% assoc. w/ EBV!! 25% assoc w/ EBV Ileocecal masses (often) NO assoc. w/EBV (usually) -Spleen and BM involved -May resemble Follicular lymphoma Extranodal; (arise in chronic inflammation/infection sites) Sjorgen (enlarged parotid)(Xerostoma)MALTo ma / Stomach (giant rugai) MALToma

B-Cell: 19,20,10 19,20,10

Starry Night

MYC on chromosome 8 t(8;14) ; most common MYC / t(8;14) MYC / t(8;14)

-Responds well to chemo / cures in children and young adults / guarded prognosis in adults -f in youth -May cause ALL -Middle age (M>F) -3-4 yrs survival -Adults (middle age) -Slow growing -Remains localized for long period -Extranodal may regress entirely if agent removed

Nodal

B Cell: 5, 19,20 CD23Postgerminal memory B-Cells 19,20

Nave B Lymphocytes occupy much of germinal center Marginal zone of nodes in MALT B-cells w/various stages of differentiation (including plasma cells)

t(11;14) Bcl-1 (overexpression of Cyclin D1 gene)

MALToma / Marginal Cell Lymphoma

Nodal (M. zone lymphoma) Extranodal

may progress to Large B-Cell (systemic)

T-Cell Lymphomas
Peripheral T-Cell Lymphomas in General: More aggressive and less curable than B-cell lymphomas / Morphology: ALWAYS diffuse; infiltrates of ATYPICAL nodes ; Reactive Eosinophils, Macrophages (macrophages attracted by signals and can cause granulomas) / Immuno-histotyping: CD2, CD3, CD5 ; Positive for either CD4 or CD8 ; NEGATIVE for TdT / Common Clinical Features: Generalized lymphadenopathy ; Weight loss ; eosinophilia and pruritis in some Name Anaplastic Large Cell Lymphoma Location Clinical Features Soft tissue involvement and generalized lymphadenopathy Anemia and Neutropenia worse than expected by BM biopsy and splenomegaly May cause Felty Syndrome (R.Arthritis) - -may be initial complaint Splenomegaly with Neutropenia Neoplastic lymphocytes in: skin (skin pulled tight) / nodes / liver/spleen/BM CD4+ Peripheral Lymphocytosis Hypercalcemia and demyelination Chronic, Red, Exfoliative rash (exfoliative erythroderma) on skin (Premycotic phase) Plaques Tumor phases (spreads to involve nodes; BM (causes leukemia in some) Hx of unsuccessful tx for fungal infection (due to misdiagnosis) Histology CD 8+ CD 2;3 Morphology Lg cells w/ HORSESHOE shaped nuclei (cyto ) (resembles metastatic carcinoma) Immuno / Genetic Prognosis and Therapy ALK gene rearrangement Kids / young adults (TKs of JAK/STAT Good Prognosis and other pathways)

CD 8+ (or NK cells)

Large Granular Lymphocytic Leukemia

Lymphocytosis of cells with Abundant Blue cytoplasm (w a lot of granules)

Indolent (very uncommon) Tx: Low dose steroids

Nodal Adult T-Cell Leukemia/Lymphoma Extranodal

NO therapy HTLV-1 associated (japan;Caribbean) Fatal in months to a year

Mycosis Fungoides / Sezary Syndrome Skin (Both manifestations of Helper T Neoplasias)

Micro: Pautrier microabscess (infiltration to epidermis and upper dermis by Sezary Cells) CD4+ Sezary Cells: Neoplastic CD4+ cells / lg, immature lymphoid cells with CEREBRIFORM nucleus (seen in smears)

Indolent (often misdiagnosed as fungal infection) Slowly progressive

Nasopharynx at midline ; nose ; testes Extranodal NK/T Cell Lymphoma Extranodal Ischemic necrosis may be first sign (tumors surround vessels Ischemia

Aggressive Poorly responsive to therapy

Hodgkins Lymphoma
General Info: Arises from single node (or chain) / predictable progression from start point / REED-STERNBERG CELLS (defining feature of HL cross-eyed owl) /
Ages affected: Teens to 32yrs and the elderly / Malignant transformation of germinal or post-germinal B-Cell (EBV implicated in some cases) / Reed-Sternberg Cells: Binucleated/bilobed giant cells w/ mirror image nuclei / Produce and release a tone of cytokines to attract other cell types Infiltrates: Eosinophils and Macrophages Fibrosis ; Basophils ; Th2 cells, etc Clinical Findings: Nodal Involvement: Cervical Node enlargement Horse Collar ; Mediastinal node Enlargement Resp. Compression cough and dyspnea ; Occasionally Axillary (20%)and inguinal / Splenomegaly / Fevers (pel-epstein pattern) / wt. loss / generalized nodal enlargement (most likely in cervical, axillary, mediastinal) / Generalized Pruritis / Cutaneous Anergy Staging of Hodgkins Lymphoma: Even highstages have GOOD prognosis Systemic Systems: A (Symptoms are absent) ; B (Fever (Pel-epstein pattern ---cyclic fevers w 1-2 wk intervals), Night sweats, loss of body weight over 10% in 6 months before Dx) Ann Arbor Staging: Stage 1: single node or region ; Stage 2: 2 or more nodes on SAME side of diaphragm (vertically) ; Stage 3: Nodes on both sides of diaphragm to include spleen or a localized extranodal location ; Stage 4: Diffuse extra lymphatic disease (liver, BM, Lung, etc) Classical Forms of Hodgkins Lymphoma: Nodular Sclerosis / Mixed Cellularity / Lymphocyte Rich / Lymphocyte Depleted Name Location Clinical Features Histology Morphology Genetics / immuno Prognosis and Therapy Good Prognosis: Always Cervical Node enlargement Lymphocyte rich form starts in Horse Collar Unknown No symptoms at dx nodes Mediastinal node Enlargement malignant Poor prognosis: Hodgkin Lymphoma (resp. issues possible) Reed-Sternberg RS cells have the transformation of bone pain is present / (general) (localized Generalized Prutritis Cells cross-eyed owl germinal or post Sx are present (B) to single (due to eosinophils) germinal B-Cell axial Cutaneous Anergy Combination Chemo group) (Will not react to a skin test!!) for tx Lacunar RS variant Can arise Young M or F Nodes: Mediastinum / cervical Collagen bands Nodular Sclerosis in Background of: CD15 and CD30 Most common / supraclavicular (form nodules Thymus benign lymphs, eos, Good prognosis macro. Abundant RS cells, Young and old / M>F Mixed Cellularity Fever and Night Sweats (B-sx) histiocytes, eos, Px:Poorer but still lymphs good Can arise CD 20+ Lymphocyte Cervical and Axillary ; L and H (popcorn) Young males in Predominant Mediastinal mass variant of RS cell EXCELLENT prognosis Thymus CD15,30 negative Lymphocyte Elderly / HIV / NonPOOREST prognosis Depleted industrialized / EBV assoc.

Thymus
Development: 2nd Pharyngeal pouch is primary origin / 4th pouch contributes 2 parathyroids / Grows until puberty then involutes to small size / 2 Fused lobes
composed of individual lobules / Ectopic Locations: Neck and Pleura / Developmental Disorders: DiGeorge (aplasia, hypoplasia) ; Thymic Cysts (usually smaller than 4cm and discovered during surgery)

Normal Microscopic Features: Hassall Corpuscles (Spindled Thymic epithelial cells around a keratinized center) / T-Lymphocytes (CD 1,2,3,4,8 markers) /
Myoid cells (Muscle like)

Autoimmune Diseases that cause Thymic Hyperplasia: Myasthenia Gravis (75% of cases) ; Graves Disease ; Collagen Vascular Disease (scleroderma, SLE,
RA, etc..)

Tumors Arising from Thymus: T-lymphoblastic / 2 Types of Hodgkins Lymphoma: (Nodular Sclerosis and Lymphocyte Predominant) / Germ Cell Tumors
(Teratomas, etc..) / Thymoma: Thymic epithelial cell tumors (age > 40 ; Anterior, Superior mediasinum) and Paraneoplastic

Thymomas: Adults > 40yrs / Composed of spindle shaped thymic / Benign or Malignant (Local invasion diagnostic)(Thymic Carcinomas have Squamous cell
histology) / Clinical Course: may be asymptomatic at first but seen on imaging, pressure sx may be present. Name Auto-Immune Hyperplasias Thymoma Effect on Thymus Hyperplasia Composed of Spindle shaped thymic Anterio-Superior Mediastinum Clinical Features 1st seen on imaging in asymptomatic pt. May produce pressure sx 50% assoc. w/ Myasthenia gravis Could be associated w/ Pure Red Cell hyperplasia Histology Morphology Lymph Follicles (B Cells) Spindle shaped thymic

Adult > 40

Polycythemia Polycythemia= erythrocytosis risk of thrombosis Types of Polycythemia: Relative / Absolute (Primary: erythropoietin low - - Polycythemia Vera) and (Secondary: Erythropoietin High) Relative Polycythemia: Due to dehydration / Possible Causes: Hantavirus Infection (causes capillary leak but RBCs stay in circulation) ; Stress polycythemia (Gaisbocks Syndrome)( stress and anxiety assoc. w/ obesity and HTN) Name Polycythemia Vera Type 1 Absolute CBC RBC mass RBC volume PMNs & Platelets RBC RBC Chemistry Erythropoietin Pathology Clonal proliferation of myeloid stem cells Normal Reaction Hormone releasing neoplasm Renal Cell Carcinoma and others that release erythropoietin Cause JAK2 Mutation

Absolute Polycythemia (due to normal causes) Absolute Polcythemia (Paraneoplastic)

2 Absolute 2 Absolute

Erythropoietin Erythropoietin (inappropriately)

Bleeding / Hemorrhagic Diathesis: Increased Fragility of Blood Vessels

Diathesis: Condition that makes a person more prone to a certain disease - -in this case bleeding diseases / Categories: Fragility of blood vessels / Platelet deficiency or dysfunction / Derangement of coagulation / Combination Tests to do ON ALL bleeders: PT, PTT, Platelet Count (150k-350k is norm) / Specific Tests when Indicated: vWF assay, Platelet function test Intrinsic Pathway: aPTT (activated partial thromboplastin time) XII, XI, IX, VIII, X / Extrinsic Pathway: PT (Prothrombin time) / Common Pathway: X,V,II Vessel Wall Abnormalities: General: Non-thrombocytopenic purpora ; Normal PT, PTT, and platelets / 4 types: Vasculitis ; Impaired Collagen Support ; Hereditary and Acquired ; Amyloid / Vasculitis can also be associated with: collagen vascular diseases like RA and SLE / Drug reactions: Hypersensitivity reactions and lymphoclastic reactions / Due to unknown Antigen - - - Henoch-Schonlein Purpora Name Category Causes / Morphology Labs Clinical findings Other Endothelium is infected and Normal : rash - -crops of petechiae V. W. Infective Vasculitis hemorrhage is the result (PT, PTT, Subungual hemorrhages (secondary Active infection Abnormal (Meningococcemia, Rickettsia) Platelet) to infective emboli) -Collagen vascular diseases: RA ; SLE Normal : Deposition of immune Immune/Inflamamtory -Drug reactions: hypersensitivity (PT, PTT, complexes into vessel Vasculitis and lymphoclastic Platelet) walls causes inflammation -Unknown antigen: H-S Purpora Palpable Purporic rash / Colicky abd. Bleed Polyarthralgia Acute glomerulonephritis (severe cases) Swollen gums w/ hemorrhage Purpora assoc. w/ hair follicles

Henoch-Schonlein Purpora (Vasculitis) Scurvy Impaired Collagen

Unknown Antigen Look for prior Resp. infection Deficient vitamin C

Normal : (PT, PTT, Platelet) Normal : (PT, PTT, Platelet) Normal : (PT, PTT, Platelet) Normal : (PT, PTT, Platelet) Normal : (PT, PTT, Platelet)

IgA immune complex deposition Defective synthesis

Ehlers-Danlos

Inherited Impaired Collagen Impaired Collagen Impaired Collagen

Poor vascular support leads to easy bleeding

HYPER-mobility Bleeds

Inherited defect in synthesis

Cushings-Syndrome

Loss of vascular support

Will see redistribution of fat (moon facies and buffalo hump) Bateman or Actinic Purpora Bruise very easily

Corticosteroid use causes protein wasting Thin collagen due to aging

Elderly Collagenous Atrophy

As we age the collagen is wore thin

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu)

Tortuous, thin walled vessels Inherited (AD) Vessels are very superficial and are easily borken

Fe+ due to bleeds (may cause anemia)

-Young age of onset -Mucosal Bleeds : (Mouth, tongue, lips, nasal mucosa) -Thin walled vessels visible in mouth and under nails -May see AVMs in brain , lung, liver -May 1st see due to anemia complaints (Anemia secondary to Fe loss which are secondary to bleeds) Racoon Eyes

Autosomal dominant Vessels are thin walled and prone to break - hemorrhage can be life threatening Defective protein accumulation -monoclonal plasma cells and multiple myeloma may cause as well -Alzheimers amyloid w/o the alzheimers -2nd most common cause of non-traumatic cerebral hemorrhage

Systemic Amyloidosis

AL Amyloid

Often as a result of chronic infection / inflammation Cerebral meningeal and cortical vessels are affected Familial tendency

AL Amyloid most times

Cerebral Amyloid Angiopathy (CAA)

A Amyloid Accumulation

A amyloid in biospy

Non-traumatic cerebral hemorrhage

Bleeding / Hemorrhagic Diathesis: Platelet Deficiency or Dysfunction

Normal Platelet Function: Primary hemostasis-platelet plug / Phospholipid platform for coagulation (<30k spontaneous / 30k-50k post-traumatic bleeder) Manifestations of Thrombocytopenia: <30k spontaneous / 30k-50k post-traumatic bleeder / NORMAL: PT and PTT!!! / Petechiae (associated these with platelet issues) / Ecchymoses / Purpora / Mucosal Small Vessel bleeds: oral, nose, GU Possible Causes of thrombocytopenia in general: production ; platelet survival ; Splenic Sequestration ; Dilutional (i.e. massive transfusion) Platelet Production: Drugs (etOH, Thiazides, Cancer therapy) ; Viral Infection of megakaryocytes (HIV) ; part of pancytopenia Causes of Pancytopenia: Aplastic Anemia ; Myelophthisic Disorders (metastatic cancer, leukemia-lymphoma, myeloproliferative diseases, granulomas) ; Ineffective Megakaryopoiesis (B12 and Folate, Myelodysplasia) Decreased Platelet Survival: Microangiopathic Hemolytic Anemia (DIC; Hemolytic Uremic Syndrome (HUS); Thrombotic Thrombocytopenic Purpora (TTP)) ; Malignant HTN ; Heparin Induced thrombocytopenia / Giant hemangiomas (entire extremity involved) / Prosthetic Heart Valves / Sepsis (generalized endothelial activation takes them out) / Immune Mediated : (Circulating Immune complexes: (SLE vasculitis complexesthrombosis) Anti-platelet Antibodies: anti-HPA (membrane glycolipids) as w/ neonatal thrombocytopenia/Anti-HLA) / may cause platelets to aggregate causing thrombi / Antibody may activate platelets causing aggregation and clumping in vessels / Secondary Causes of Auto-Antibodies: Drug Associated (Heparin (Type 1 and Type 2), sulfonamides) ; Infections: (HIV, CMV, Infectious Mononucleosis) / SLE / CLL Microangiopathic Hemolytic Anemias caused by Thrombotic Microangiopathies: Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpora (TTP) Common Features of TTP and HUS: Thrombocytopenia (Platelets) / Intravascular thrombi / Microangiopathic hemolysis / Large von Willebrand Factor complexes (due to endothelial injury) / Platelet aggregation Hyaline thrombi (in microvascular) Mechanical lysis of RBCs (Anemia) Schisocytes in peripheral smears and likely Spherocytes and Bilirubin (unconjugated) / Name Splenic Sequestration Pathology sequestration of platelets in the spleen -Maternal antibodies against fetal HPA cross placenta -Immune mediated platelet destruction -Unknown cause -IgG autoantibodies target common GP epitopes -Destroyed in Spleen -Megakaryocytes in BM can be damaged Clinical Splenomegaly present in 90% Extensive petechiae and scattered purpora at birth Abrupt onset: Petechiae rash, Purpora, ecchymosis Normal sized Spleen Hx of VIRAL illness Lab / Morphology Thrombocytopenia Thrombocytopenia Rest of CBC: NORMAL Normal PT and PTT IgG auto-antibodies BM: Megakaryocytes, Thrombocytopenia w/ lg platelets (megathrombocytes) IV immunoglobulin ; steroids for severe thrombocytopenia If sx persist over 6mo switch to chronic tx method Any age following recent viral infection tx Splenectomy Notes Normal sequestration is 30*35% (same for RBCs) Fetal HPA is inherited from the father Immune mediated destruction

Neonatal Thrombocytopenia

Acute Idiopathic/Primary Immune Thrombocytopenia

Chronic Idiopathic/Primary Immune Thrombocytopenia Heparin Induced Thrombocytopenia (Type 1) Heparin Induced Thrombocytopenia (Type 2)

Insidious onset Have to exclude secondary causes before you suspect Unfractionated Heparin causes aggregation but NO CLOTTING Unfractionated Heparin Anti-body to HeparinPlatelet Factor 4 complex HIV infection of Megakaryocytes in BM Molecular mimicry: HIV gp120 resembles gpIIb and gpIIIa (crossreaction) Deficiency in ADAMTS vWF protease Ultra-large monomers of vWF (another micro-angiohemolysis - - -like HUS) Ingestion of : E Coli / Shiga Toxin

Insidious onset of mucosal bleeds (in dependent areas??) Hx of easy bruising, epistaxis and bleeding gums IMMEDIATE Sx of Thrombocytopenia but no clotting 5-14 Days After initial tx 50% in platelets Intravascular thrombi

Immunosuppression/modulation -Anti-CD20 (Rutuximab) -Iv Immunoglobulins Splenectomy as last resort Thrombocytopenia Discontinue use Discontinue Use and NEVER use again (Flag chart as Allergic to Heparin!!!) Treat the HIV / AIDs

F > M ; Adults<40 Risk for intra-cranial Hemorrhage Splenectomy removes site of breakdown and antibody production Most common Anti-body complex (ABPF4) activates platelets cousing intravascular thrombi

HIV associated Thrombocytopenia

Sx of thrombocytopenia and possibly HIV infection

Thrombocytopenia

Give something to boost platelet production (or give platelets)

(Insert Omar joke here)

Thrombotic Thrombocytopenic Purpora (TTP)

Classic PENTAD of Sx: -Fever (prodrome) -Micro-Angio Anemia -Thrombocytopenia -Renal failure -Transient neurological defects

ADAMTS Thrombocytopenia Anemia (RBCs) Schisocytes and spherocytes in smear Uncon. bilirub.

Fatal w/o tx Plasmaphoresis with PLASMA exchange

Hemolytic Uremic Syndrome (HUS) (Epidemic Type)

Shiga toxin upregulates vWF creating a clump of pro-aggregation signaling

Sx of TTP except for the neurological -BLOODY Diarrhea followed days later w/ Renal Failure

Thrombocytopenia Anemia Schisocytes and spherocytes in smear Uncon. bilirubin

freq in adult FEMALES Causes of Deficiency: -hereditary -Auto-antibody -2 to infection/drugs/gynecologic disease Children and Elderly Genetic predisposition (another micro-angiohemolysis - - -like TTP but w/ different clinical pres. items) Non-epidemic HUS: other defects HUS sequalae

Supportive Care only DO NOT give antibiotics: May result in further toxin release!!!

Bleeding / Hemorrhagic Diathesis: Clotting Factor Deficiencies

Factor XIII and vWF deficiencies most common Factor VIII, Factor IX : X-Linked / vWF Deficiency: Types 1 and 2 are AD ; Type 3 is AR / All others are Autosomal Recessive Factors behind deficiency if not genetic: Liver Disease / Vitamin K deficiency: 7,9,10,2, and Proteins C and S / DIC: Uses up factors, fibrin, platelets vWF extends t1/2 of Factor VIII- -so when vWF is deficient it may present like factor VIII deficiency (Hemophlia A) von Willebrand Disease: General clinical presentation: Menorrhagia, Excessive bleeding, Bleeding Time / Type2 vW Disease: A qualitative deficiency in 25% of vW Disease patients (Multiple subtypes: A,B,M,N) / Lab Tests to Perform for these Patients: Ristocetin Test and vWF immuno-assay if you suspect deficiency, PT, PTT, Platelets normal except in type 3 / A primary hemostasis disease General Features of Clotting Factor Deficiencies: Large ecchymosis and Hematomas / Hemarthrosis (weight bearing joints especially) / Prolonged bleeds (days) / GI and GU bleeds Disseminated Intravascular Cagulation (DIC): Two Primary Mechanisms: 1) TF or Thromboplastin Release (Placental release, cancer products (mucin, enzymesPML)) 2) Widespread Endothelial damage (sepsis (toxins, LPS), IL-1 and TNF from monocytes) / Possible Causes: Septic Shock (menningiococcemia) / Obstetric Accidents (abruption, amniotic fluid embolism, retained dead fetus) / Cancer / Major trauma to brain / Snake Bite / Hemolytic Transfusion Reaction Name Inheritance Clinical Labs tx Notes vW Disease Type 1 AD Menorrhagia, mucosal bleeds Normal Platelet count DDAVP (desmopressin) DDAVP causes vWF release Mild Bleeding bleeding vWF (Avoid Aspirin) Ristocetin Test or Bleeding Time Normal PTT immunoassay to dx vWF Disease Type 3 AR Excessive bleeding Normal Platelet count Humate (FVIII-vWF Acts like Hemophilia A Hemarthrosis vWF (severe def) complex) Ristocetin Test or Bleeding time PTT Cryoprecipitate immunoassay to dx Factor VIII Deficiency X-linked Hemorrhage post-trauma (days) PTT and normal PT Factor VIII infusions (may Most common (X and New) (Hemophilia A) Hemarthrosis develop resistance) Failure of Synthesis () Spontaneous bleeds Abnormal factor VIII -FEIBA to fix this Hemosideridin in CT NO petechiae assay (20-30 per yr w/o tx) Factor VIII Assay Factor IX Deficiency X-linked Hx of reccurent GI bleeds PTT Factor IX activity/antigen (Hemophilia B) (recessive) Severe bleeds lasting days Abnormal factor IX Clinically indistinguishable assay from Hemophilia B Factor XI Deficiency AD More common in women?? PTT Ashkenazi Jews FamHx of severe bleeds Normal bleed time Common AD (2nd to vWF) Disseminated Purpura Fulminans (Infarcted Platelets Remove underlying Thrombo-hemorrhagic Intravascular Bleed patches of skin) Fibrin Cause Consumptive coagulopathy (DIC) Acute DIC: Shock, acute renal Clotting Factors Micro-angiopathic anemia failure, ARDS (SOB ad Cyanosis), D-dimer Simultaneous anti- and Renal Issues: Circulatory failure pro-coagulant -isolated infarcts or comaDeath replacement -Diffuse Cortical Necrosis Chronic DIC: (Cancer most times) Adrenal Gland Issues: Trossueu Syndrome: Recurrant Treat sequalae -b/l hem. and necrosis DVTs w/o bleeding diathesis Waterhouse-Friderichsen Non-bacterial endocarditis Syn.

Transfusions and Blood Bank Information: Immuno-hematology

General Information: Restrict number of transfusions it is a risk Blood Group Antigens Information: Autosomal Bi-allelic inheritance / Type O and Rh- negative are Recessive / ABO group is the most important for selection and transfusion of blood / Match blood antigens to prevent formation of Alloantibodies or specific T cell receptors / IgM forms to CHO based Antigens / Protein antigens stimulate T cells class switch in B cells IgG / AB group antigens are determined by DIRECT hemagglutination (mix patient RBCs w/ specific antiserums) ABO Blood Group System: Antigens exist on GLYCOLIPID H present on virtually all cells of body / locus codes for sugar transferase that attaches a sugar to H Antigen (Point mutation here gives you the O blood type (inactive enzyme (O) can be inherited) / with no mutation A or B antigens occur / Blood groups and associated serum Allo-antibodies: Type O (NO ANTIGENS = Universal donor - - does have A and B antibodies though so reacts severely to transfusions); Type A (reacts to type B) ; Type B (reacts to type A) ; Type AB has NO ANTIBODIES (universal recipient) / Hemolytic transfusion reaction if blood not matched / Genotypes: Type A: AA, or AO (similar for type B) ; Type O: OO ; Type AB: AB Forwards and Backwards blood typing: Forward Type determines type: Blood exposed to A and B antigens in separate tubes / Back Type confirms the forward results: Patients serum added to manufactured RBCs with known antigen (like indirect Coombs) Antibody Characteristics (Thermal Amplitude): Cold Acting at 4: IgM RBC agglutination (direct) and Fix complement (cold Hemolysins) / Warm Acting at 37: Complement C1423 (spleen) and C56789 (MAC) / WAIHA constitutes the vast majority Direct Antihuman Globulin Tests: (DAT, Coombs): Patients RBCs (sensitized in vivo) exposed to Coombs reagent (anti-human IgG) Coombs serum will react with bound antigens and cause agglutination / Positive test implies antibody is present against some component of RBCs and there is a risk of the following / Risk of Autoimmune hemolytic anemia (cold), Hemolytic transfusion rxn, Hemolytic disease of newborn Indirect Antihuman Globulin Test: Checks patient Serum for circulating ATYPICAL antibodies - (Antibody SCREEN)- -RBCs (w/ antigen) from a manufacturer exposed to patients serum which may or may not contain antibodies (In VITRO sensitization) Cells washed to remove unbound antibodies Cells exposed to Anti-human globulins that will bind to any bound anti-bodies observed for agglutination Atypical Antibodies: antibodies to anything except A and B are atypical / Prior transfusions and Pregnancy can lead to acquisition / Only screening for D (D=Rho=Rh+) is done on regular basis as it is VERY immunogenic / if is has any letter AFTER K the antibody is less clinically significant / D is dead, Kid and Kell Kill, Duffy dies but Lewis lives / Duffy: RBCs and in CNS ; often ABSENT in some AFRICANS (malaria receptor) - -so dont give them Duffy blood / ABO Incompatibility Issues: Auto-Hemolytic Anemia / Hemolytic Disease of the Newborn (mother has antibodies against fetus blood type) / Hyper-Acute Solid organ transplant rejection / Immune Hemolysis: Reactions to RBCs: Immune Hemolysis (Type II hyper) 2 Pathways (1) complement 5-9 MACIntravascular Lysis) (2) C1423 Extravascular Lysis in Spleen) / Alloimmune (lysis of transfused RBCs) / Autoimmune (Lysis of SELF-RBCs)

Implications of Auto-Antibodies: Incompatible with ALL DONORS / Positive Direct Antihuman globulin (DAT, Coombs) test / Storage Lesions: 2,3BPG , O2 starvation, ATP, RBC survival, RBC Lysis frees Hb, K+, Fe, cell wall rigidity interrupts flow Type of Transfusion Indications Contraindications Notes Atypical antigens to common Antigen negative blood is RARE antigen Frozen Rare Units NO universal donor for those with high risk atypical antigens -Rare blood type Preserved in Glycerol for up to 10Years -Autologous units Acute blood loss Packed RBC Transfusion Chronic anemia (Hb7) NOT effective in auto-immune hemolysis tx C. Anemia (Hb>7w/doc.) Platelet Count <50k w/ bleed Thrombotic Platelet Transfusion Platelet count<30k Thrombocytopenic Not effective in Auto-Immune Thrombocytopenia Documented dys. in bleeder Puropora (TTP) PT, PTT, AND: Fresh Frozen Plasma -pt is bleeding For those with Coagulation factor(s) -Anticipated surgery Tx of bleeding due to: VII, Contains: Factor VIII, Fibrinogen, vWF Cryoprecipitate fibrinogen, or vWF Severe neutropenia in an WBC Transfusion Apheresis (taken from) is from a SINGLE DONOR immunosuppressed pt. When plasma proteins must be removed: Washed RBCs -IgA deficiency -Hx of allergic transfusion rxns Immuno-nave or immunoCMV Negative -Neonates, diseased, organ recipients compromised individuals Deficiency is known factor(s): Factor Concentrates vWF and VIII (Humate) Humate is an example IX, Some auto-immune Diseases: -Treatment of ITP Gamma globulin of a sort is given Immune Serum Globulin -kawasaki Tx of Immunodeficiencies Tx of Immunodeficiencies (Brutons and Common Variable) Exposure to infectious disease

Immune Mediated Transfusion Reactions

Types of Immune Transfusion Reactions: Febrile Non-hemolytic / Allergic: (hives are common); anaphylaxis can be fatal if it occurs / Acute Hemolytic / Delayed Hemolytic / Transfusion Related Acute Lung Disease (TRALI) / Transfusion Related Immunomodulation (TRIM) Apheresis: Removal of whole blood from a pt. that is then centrifuge separated into components which can be re-transfused into donor or a recipient / Types of Apheresis: Platelets, WBCs (Leukapheresis for leukemia), Plasma clotting factors and globulins, RBCs Plasmapheresis Implicated in: Goodpastures disease, Thrombocytopenic Purpora (TTP), Myasthenia Gravis, Guillain-Barre Name Clinical Predisposing Factors Pathology Graft vs. Host Transfusion Rxn Skin Rash Compromised Cell mediated T-lymphocytes from DONOR Diarrhea immunity blood attack recipient tissues Jaundice Transfusion Related Acute Sudden Pulmonary edema Most associated with the HLA or Granulocyte specific Lung Disease (TRALI) that progresses to ARDS transfusion of Fresh Frozen antibodies Free Radical Plasma damage to pulmonary vasculature Acute Hemolytic Transfusion Reaction w/I 1st 15 cc (so really fast!!!) Burning at injection site Hemoglobinurea (pink to red) Acute renal failure (oliguria) May progress to DIC 3-10 days post transfusion Signs due to Hemolysis: Indirect Bili Jaundice Anemia Positive DAT!!! (+ Coombs) Possible multiple organ failure Risk of cancer reoccurance Misidentification of Patient Unidentified Atypical Abs

Notes Immunodeficient ; Lymphoma

Delayed Hemolytic Transfusion Reaction

Unidentified Antibody is reactivated (takes time to ramp up)

Prevent by matching HLA type -MOST COMMON fatal rxn -Immediate and life threatening rxn -Lysed donor WBCs release toxic contents (ex. ROSs) ABO Incompatibility results in Can be Fatal immune rxn Compliment Activation Immediate Tx: Stop transfusion hemolysis of transfused RBCs immediately and start IV (extra- and intra-) fluids, diuretics, and mannitol to spare kidneys!! Immune reaction due to some latent antibody that went unoticed

Transfusion Related Immunomodulation (TRIM)

May be related to: -Inflammatory cytokine rel. -Neutrophil activation

Fetal Hydrops
Definition: Accumulation of fluid during INTRAUTERINE GROWTH leading to generalized edema w/ asites (massively enlarged Liver and Spleen a part of it) in a fetus or neonate Possible Causes not blood related: Cardiovascular issues, Chromosomal abnormalities, Thoracic issues (herniation), Twin to twin transfusion, Infection other than parvovirus, misc. malformations Non-Immune Hydrops: 1)Homozygous -Thalassemia 2)Aplastic Anemia due to Parvovirus B19 Immune Hydrops: Hemolytic disease in fetus or newborn / Maternal immune system is reacting to Fetal blood group antigen (inherited from the father) / Assumes prior pregnancy that has sensitized the maternal immune system incompatible with pregnancy / Most commonly to ABO but these are rarely serious - - -more severe is to D antigen (Rh- mother to Rh+ baby); also bad if mom has atypical antibodies Pathogenicity of Rh Hemolytic Disease of Newborn: First pregnancy rarely affected (Mom is immunized and generates IgM antibodies that are too large to cross placenta) Second pregnancy with reactive fetal blood type generates a class switch in mother to IgG (which CAN cross the placenta) Fetal RBCs are attacked and hemolyzed Anemia / Jaundice / Kernicterus / Massive Spleen and liver enlargement (trying to deal with those broken down as well as replace those lost) Cardiac decompensation Fetal Hydrops Prevention of Rh Hemolytic Disease of Newborns: 1)Rh- mothers are given RHOGAM at: 28wks gestation / 72 hrs before estimated birth / During any amniocentesis procedure or abortion (Rhogam binds to anti-Rh antibodies until baby is born) 2)Pregnant women are screened for atypical antibodies (if screen is positive titers are monitored throughout pregnancy) ; If titers rise fetal hemoglobin levels are monitored ; If bilirubin levels rise we do intrauterine transfusions as well as a transfusion shortly after birth ABO incompatibility : -occurs about 25% or the time and is rarely serious / -IgM so cant cross placenta / -A and B antigens poorly expressed in newborns -Tx: UV light exposure to break up unconjugated bilirubin - - - -transfusion of O cells in AB plasma if severe Consequences of Hemolytic Disease of Newborn: Erythroid Hyperplasia / Extrameduallry hematopoiesis (blueberry muffin skin manifestation) (liver and spleen) / Erythroblastosis Fetalis (extrameduallry hematopoiesis / nucleated RBCs in circulation destroyed by spleen / Large Pale Placenta / fetal hydrops) / Hydrops Fetalis (failure of fetal heart due to Albumin synthesis) Consequences of Jaundice and Bilirubin: Kernicteris: Unconjugated bilirubin builds up in the brain (Permanent brain damage, retardation, deafness) / Brain and CNS will be edematous and have a yellow pigment (even gray matter of spinal cord) Lab Testing for Hemolytic Disease in Newborns: Anemia, Unconjugated bilirubin, Infant has +DAT, Mother has +Indirect, (If it is an ABO incompatability there will be NO FINDINGS in the mother)

Lead Poisoning Common Presentation of Occupational Lead Exposure: Clinical: HA/Fatigue/Abd pain q gray discoloration of gingival margin Labs: Hgb low / Serum Cr (renal failure) / Microcytic Anemia / Basophillic Stippling in normoblasts Acquisition of Lead: Inhaled common occupational route (gun powder, fine paint, fumes) / Ingested in contaminated foods (lead plates, lead lined cans, toys, etc) / Children absorb more lead than adults Storage: Uptake and storage in BONE and TEETH - - - - -t1/2 of 30 yrs Pathogenesis: Inhibits incorporation of heme iron into Heme Siderblastic Anemia (Ringed Siderblasts in peripheral smears) Enzymes inhibited: -aminovulinic Acid Dehydratase / Ferrochetalase Exposed children heal more slowly Competes for Ca2+ for uptake (bone, nerve, brain development issues) Inhibits membrane associated enzymes (Hemolysis of RBCs and renal damage) - - -- - -impairs Vitamin D uptake Non-Hematologic Sx of Lead Poisoning: Lead line on gums / Adults: HA/memory loss/demyelination (FOOT DROP) /Renal disease / Cognitive impairment at low doses Hematologic Consequences of Lead Exposure: Microcytic Anemia w/ COURSE Basophilic stippling - - - - -(Fine basophilic stippling is not associated with lead) / Central pallor of more than 1/3

Anemia Iron Deficiency Chronic Disease Thalassemia Beta

Serum Iron

TIBC Transferrin Normal

Transferrin % Saturation Normal to increased

Ferritin Level Normal to increased

Other Findings Fe in BM BM Iron Abnormal Hgb electro. (dont make enough) Normal Hgb electro. (Fe not incorporated) Ringed Sideroblasts Basophilic Stippling

Normal

Thalassemia Alpha Sideroblastic Anemias (Lead)

Normal

Normal

Normal to increased

Normal to increased

Normal to decreased

Increased

Increased

Red Blood Cells: Objective Review

3 Major Common Features of Hemolytic Anemia: RBC life span / Accumulation of Hgb catabolism products / erythropoiesis in BM Where Hemolytic Anemia Occurs: Premature destruction generally takes place in spleen within mononuclear phagocyte system (extravascular) / Rarely takes place within the vascular compartment (intravascular) Intravascular Hemolysis Features: Anemia / Hgb in urine and blood / Jaundice / Hemosiderinurea / Serum Haptoglobin (binds Hgb loose in plasma) Extravascular Hemolysis Features: RBCs are either injured, flagged as foreign by immune system (C3/C4), or are deformed in some nature which does not allow them to travers sinusoids of spleen (get trapped in splenic cords) / Anemia and Jaundice / Splenomegaly / Morphology of Hemolytic Anemias: Erythropoietin leads to Normoblasts in BM / Reticulocytosis in peripheral blood / Bilirubin promotes the formation of gallstones / Hemosiderosis in chronic cases Normal Hemoglobin: Tetramer of 4 Globin chains (Adult: HbA = 22 commonly or HbA2: 22 (3%) ; Fetal: 22) / Most serious hemoglobinopathies are B globin mutations Sickle Cell Disease: Hereditary / Abnormal Hgb B-globulin (Point mutation: switch of Valine for Glutamine) referred to as HbS / Cells sickle when oxygen gets low ( adhesion, slow RBC transport, can block microvasculature) / Higher incidence in blacks of malaria regions / 2 Major Consequences: Chronic hemolytic Anemia ; Occlusion of small blood vessels (Infarcted tissues and Ulceration in stagnant areas/ Extravascular and Intravascular destruction Name Clinical Labs Pathogenesis tx Other -Splenomegaly Intrinsic Defect in Spheroidal cells 75% AD (European) -Jaundice membrane skeleton Reticulocytosis AR more severe Hereditary -Parvovirus may cause aplastic (ankyrin) Splenectomy Cells destroyed in cords of Spherocytosis crisis Do osmotic fragility tests Bilroth of spleen -Other sx of H.An. (Extravascular (Extravascular) -Look at FHx destruction) Infarction of bones, brain, kidney, eyes, etc Bad B-Globin creates HbS Give O2 -Leg Ulcers Pigmented gallstones phenotype Give fluids Extravascular and Sickle Cell Disease -Spleen is enlarged in Hyperbilirubinemia Treat Pain intravascular destruction CHILDREN Point mutation: switch of -Auto-splenectomy by Valine for Glutamine adolescents or adults Abnormal erythroblasts that are beta globin Severe (need transfusions) deficient: ineffective Named for what is deficient -Thal Major May see iron overload -globulin inclusions transfuse production (die in BM) HbA type Hemoglobin (Secondary hemochromatosis) and extravascular destruction Point Mutations leading to various defects -Thal Intermedia Less Severe -Thal Major Minor Asymptomatic w/ mild or absent anemia (RBC abnormalities still seen) Gene Deletions

Silent Carrier: -Thalassemia

Asymptomatic Carrier of gene deletion

-a/aa --/-a

Children may have excessive -globin (4= Barts Hemoglobin) HbB hemoglobin in adults (-globin inclusions) Less severe hemolytic anemia and ineffective erythropoiesis

HbH Disease: -Thalassemia

Severe; looks like -Thal Intermedia

HbB hemoglobin in adults (4) (-globin inclusions)

Switch to

Hydrops Fetalis -Thalassemia

Lethal in utero without transfusion --/-Has Barts Hemoglobin (until 9 months) Primary Idiopathic w/ potential Secondary Leukemias and lymphomas Associated w/ Mycoplasma and Infectious Mono

Can see Barts up until 9 months when switch to adult Hgb occurs!!

Warm Immunohemolytic Anemia Cold-Agglutinin

IgG Active at 37 degrees IgM Below 37 (4 degrees C) Marked Anicytosis (oval macrocytes w/ lack of central pallor) Reticulocytes iron Nucleated RBCs Hypersegmented, lg Neutrophils Spinal Cord demyelination Dorsal horn degen. Lateral tract degen.

Megaloblastic Anemia

May have iron overload for years

Blasts accumulate in BM Ineffective erythropoiesis and early megablast death Hemolysis

Pernicious AnemiaCNS

Spastic Paraparesis Sensory Ataxia Severe Parasthesias in Lower Limbs

Sensory and motor pathways affected by the B12 Deficiency Give B12 w/ Folate - - prompt reticulocytosis response

Folate Deficient Anemia

Can present much like Pernicious Anemia but w/ different neural sx

Easy to treat w/ folate and miss B12 deficiency

Tx w/ folate alone will cause reticulocytosis but will not halt neurologic changes!!

Normoblasts in BM Disappearance of stainable Fe from MP cells in Marrow Dx Criteria: Hgb and Hct Serum Fe Ferritin Total Binding capacity Transferrin Saturation RBCs Peripheral Smear: Microcytic, Hypochromic, lg central pallor Progressive depletion of reserves with no anemia Fe stores diminished Anemia

Iron Deficient Anemia

If in western adults its a GI bleed until proven otherwise (Look for cancer or bleeding lesions) Anemia will not be present for as long as Iron reserves in BM last- - - --appears at depletion

Serum Iron Total Binding Capacity Anemia of Chronic Disease Erythroid production and Impaired Iron Utiliization Abundant stored iron in MP cells Serum Ferritin

Erythroid production and Impaired Iron Utiliization Anemia due to Bone Marrow Hypoproliferation ( Erythropoietin response to anemia)

Suggests a defect in REUSE of iron as there seems to be an issue in getting Fe out of storage Erythropoietin due to: IL-1, TNF, IF- - -and others factors triggered by chronic disease High serum ferritin, reduced total binding capacity, and increased storage RULE OUT iron deficiency anemia though cells in smear may look alike

Erythropoietin