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: DON’T 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 Age Blood Micro. Specific Labs Prognostic Labs Other Therapy and Prognosis

ALL: Lymphoctytic / Lymphoblastic

Kids<15 (4yr peak)

80% pre-B (CDs 10, 19) Pre-T (7,2,3)

TdT Postive PAS Positive

Good Young age HYPERploidy PreB Poor T9:22 transloc. Pre-T Blasts>100k

Pre-T assoc. Mediastinal masses cause resp. issues due to compression

Combo Chemotherapy 95% remission 2/3 Cure rate - -but there are tx sequelae Bone marrow transplant in adults is curative

AML: Myelocytic/Myelogenous/Myeloblastic

60 or over

Blasts with AUER rods and cytoplasmic granules

Myeloperoxidase Positive M1-M3 CD34, CD33

Poor -5q;7q deletions: dev. From MDS -AML caused by 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

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 Age Blood Micro Specific Labs Prognostic Labs Other Therapy and Prognosis

CLL and SLL: Chronic Lymphocytic Leukemia Small Lymphocytic Leukemia

>50 (60) M>F Most common western leukemia

Smudge Cells Lymphocytosis >4000/ul up to 200k Small cells that appear mature and maybe nucleated RBCs -Anemia in 10%, thrombocytopenia in <10% (Anti-immune med.)

CD 19, 20, 23 and CD5 (an early marker) Hypo-Gammaglobulinemia in many Positive: Direct anti-human globulin test (Coomb’s Test)

Good -Slow, insidious -SLL is initial presentation Poor -Rap. progressive -Zap 70 positive -Trisomy 12 -11q, 17q deletions

Good prognosis if Zap 70 NEGTIVE and WBC count is on lower side - - -live for 10+ years Palliative Therapy - - Anti CD20 Bone marrow transplant in younger patients

CML: Chronic Myelogenous Leukemia

Any age 20-60 Most common Chronic myelo-proliferative

LEFT shift granulocytosis (↑Bands, metas, myelos, pros, Eosinophils, basophils Platelets are INCREASED dramatically or ↓ Anemia

BCR-Abl translocation (t(9:22)) ↓Leukocyte Alkaline Phosphatase

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.

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 D-Dimer, 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 Age Blood Micro Specific Labs Prognostic Labs Other Therapy and Prognosis

Acute Promyelocytic Leukemia (M3) Any (20-60)

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

MPO positive t(9;22)

↑PT and PTT ↑ D-Dimer ↓Fibrinogen

Retinoic Acid followed by Chemo

Hairy Cell Leukemia Middle age (40-50) M>F; 4:1

HAIRY cells B cell Markers: CD19 and CD20 Mono Markers: CD11, CD22

Wright Stain TRAP stain (tartaric acid resistant phosphatase)

Massive Splenomegaly is COMMON Pancytopenia from splenic sequestration and BM issues

Tx: α-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 Age Blood micro Specific Labs Prognostic Labs Other Therapy and Prognosis

Polycythemia Vera -Erythrocytosis (primary feature) -Thrombocytosis -Granulocytosis ↓↓Erythropoietin GIANT platelets!!

Histamine levels may be high Hgb may be normal

to extremely HIGH - -like around 28

JAK2 Mutation -Splenomegaly -Plethoric w/ Cyanotic compl. -HTN & HA -Peptic Ulc. and Pruritis -Thrombosis

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 COMMON

Primary Myelo-Fibrosis >60 Leukoerythroblastosis: -Left shift WBCs -Nucleated RBCs -TEAR DROP erythrocytes

JAK2 mutations in 50%

Variable prognosis of 1-5yrs

Systemic Masto-Cytosis 50-70 Look for excess inflammatory mediators: Histamine, prostaglandin D2, thromboxane, etc.

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 Prognosis and Therapy

Acute Disseminated LCH <2

BIRBECK granules seen under EM / Eosinophils are

abundant

CD1a

Seborrhic eruption - -(a persistent

rash)

-Abd. Distension / lymphadenopathy

Rapidly fatal w/o tx

Responds well to chemo - -may relapse

Eosinophilic Granuloma Kids > 5 Up to 30

Langerhans cells mixed w/ Eosinophils, lymphs, plasma, and

PMNs

BIRBECK granules seen under EM

CD1a

Less aggressive/ Good prognosis

(may even regress spontaneously)

Tx may include local

excision

Hand-Schuller-Christian Triad Children

Langerhans cells mixed w/ Eosinophils, lymphs, plasma, and

PMNs BIRBECK granules

seen under EM

CD1a

Calvarial bone involvement

Diabetes Insipidus

Exophthalmos

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 (Waldenstrom’s 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 (Waldenstrom’s 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 Clincial Features Other Prognosis and Therapy

Multiple Myeloma 50-60

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

-Bone Pain -Recurrant bacterial

infections -Hypercalcemia

-Sx of amyloidosis -Renal insufficiency

-Punched out bone -Rouleux (“coin

stack” RBCs)

Incurable disease so do Palliative care

For some chemo and

transplant (w/o tx = 6-12mo)

(w tx = 3 yrs +)

Solitary Plasmacytoma 40-50 M-protein is

minimal or absent

Localized Tumor of plasma cells

Predates multiple myeloma by 10-20

yrs Curable by surgery

MGUS Monoclonal

Gammopathy

M-Protein (but no symptoms

of disease)

Incidental Finding during routine

chemistry

[IgG] predicts conversion to multiple

myeloma

Lymphoplasmacytic Lymphoma

>50

IgM (monoclonal)

Cd19, CD20 positive

Plasma Cells

Lymphadenopathy Hepatosplenomegaly

Anemia Neurologic and

Visual impariments

Reynauds Phenomenon

Cold-Agglutinin

Disease

Livedo Reticularis

Lymph node involvement (liver

and spleen too)

Waldenstrom’s Macroglobulinemia

5-10yr survival

Indolent: Progressive

Tx: Plasmapheresis to control blood viscosity

May transform into a

B-Cell lymphoma

Mediterranean Lymphoma ↑↑↑Alpha-Chain Lymphoma of the

Small Intestine 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 Gaucher’s 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 Clinical Feature Other

Hypersplenism

Hypersplenism Triad -Splenomegaly

-↓ in 1 or more blood elements -Compensatory bone marrow

hyperplasia

Will present differently based on what is deficient A consequence of

splenomegaly

Splenic infarcts Occlusion of splenic artery Sharp LUQ pain White Infarct in wedge shape

Acute Splenic Rupture LUQ pain

Massive intra-abdominal hemorrhage Hypo-volemic Shock

Post-Splenectomy Nucleated RBCs

Howell-Jolly bodies Target Cells

↑ 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 Lymph Nodes Clinical Other Prognosis and Therapy

Granulomatous Lymphadenitis

Caseating: TB, Fungi (cocci) Non-Caseating: Sarcoidosis, and Early TB

Can be necrotizing in nature as well

Acute Reactive Benign

Acute Nonspecific Lymphadenitis

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

LOCALIZED (esp. in adults) Enlarged, tender lymph nodes

Generalized lymphadenitis in adults is likely lymphoma

Acute Reactive Benign

Mesenteric Lymphadenitis

Acute lymphadenitis Multiple intra-abdominal nodes of intestine Sx mimic acute appendicitis

Assoc. w/ entericolitis (Yersinia enterolytica) May see granules form

Acute Reactive Self-limiting Benign

Follicular Hyperplasia (Chronic NS)

B cell Proliferation in Germinal Centers Apoptotic Bodies

Can occur in any location - -including the thymus

Associated with: -Early HIV -RA -Drug Reactions / some viruses

Paracortical-Interfollicular Hyperplasia (Chronic NS)

T-Cell Hyperplasia of immunoblasts Macrophage and Eosinophil infiltrate

Infectious Mono-nucleosis (cervical nodes) Vaccinations (axillary nodes

Other viral infections: CMV / varicella-zoster SLE (associated with necrosis)

Sinus Histiocytosis (Chronic NS)

Increases Macrophages in sinuses of nodes (Subcapsular and Trabecular)

Common in nodes draining CANCER regions

Likely due to drainage of inflammatory foci

Mixed Patterns of Reactive hyperplasia

Follicular hyperplasia w/ INTER-follicular macrophage collections

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 T-cells - -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 (Sjorgen’s (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

Follicular Lymphoma Nodal

-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)

-Indolent(painless) -middle aged

-Resistant to chemo.

-Retuximab to control

-50% transform into

aggressive B-Cell -Survival < 1yr

Large B-Cell lymphoma (Immunodeficiency

Associated)

Extra-nodal (often)

Nodal

Extranodal Sites: GI, skin, bone (but NOT in the

marrow)

Waldeyer’s Ring (tonsils and adenoids)”pharyngeal mass”

B-Cell: 19,20,10

Can be destructive masses if in the liver or

spleen

Bcl-6

-Aggressive / Fast - EBV induced in HIV

patients -Intensive Chemo

-80% →R ; 50% cured -Rapidly fatal w/o tx

African Burkitt Lymphoma (Endemic)

Extranodal Facial

(often mandible) 100% assoc. w/ EBV!!

B-Cell: 19,20,10

Starry Night

MYC on chromosome 8

t(8;14) ; most common

-Responds well to chemo / cures in

children and young adults / guarded

prognosis in adults Burkitt Lymphoma (HIV)

(non-endemic) Extranodal 25% assoc w/ EBV 19,20,10 MYC / t(8;14)

Sporadic Burkitt Lymphoma (US)

Extranodal Ileocecal masses (often)

NO assoc. w/EBV (usually) MYC / t(8;14)

-↑f in youth -May cause ALL

Mantle Cell Lymphoma Nodal

-Spleen and BM involved

-May resemble Follicular lymphoma

B Cell: 5, 19,20

CD23-

Naïve B Lymphocytes occupy much of germinal center

t(11;14) → Bcl-1 (overexpression of

Cyclin D1 gene)

-Middle age (M>F) -3-4 yrs survival

MALToma / Marginal Cell Lymphoma

Nodal (M. zone

lymphoma)

Extranodal

Extranodal; (arise in chronic inflammation/infection sites)

Sjorgen (enlarged

parotid)(Xerostoma)→MALToma / Stomach (giant rugai)→

MALToma

Post-germinal memory B-Cells

19,20

Marginal zone of nodes in MALT

B-cells w/various

stages of differentiation

(including plasma cells)

may progress to Large B-Cell (systemic)

-Adults (middle age) -Slow growing

-Remains localized for long period

-Extranodal may regress entirely if agent removed

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 Location Clinical Features Histology Morphology Immuno / Genetic Prognosis and Therapy

Anaplastic Large Cell Lymphoma

Soft tissue involvement and

generalized lymphadenopathy

CD 8+

CD 2;3

Lg cells w/ HORSESHOE shaped nuclei (↑cyto ) (resembles metastatic

carcinoma)

ALK gene rearrangement

(TKs of JAK/STAT and other pathways)

Kids / young adults Good Prognosis

Large Granular Lymphocytic Leukemia

Anemia and Neutropenia worse than expected by BM

biopsy and splenomegaly May cause Felty Syndrome (R.Arthritis) - -may be initial

complaint

Splenomegaly with Neutropenia

CD 8+

(or NK cells)

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

granules)

Indolent (very uncommon)

Tx: Low dose steroids

Adult T-Cell Leukemia/Lymphoma

Nodal

Extra-nodal

Neoplastic lymphocytes in: skin (skin pulled tight) / nodes / liver/spleen/BM

Peripheral Lymphocytosis

Hypercalcemia and demyelination

CD4+ HTLV-1 associated (japan;Caribbean)

NO therapy

Fatal in months to a year

Mycosis Fungoides / Sezary Syndrome

(Both manifestations of

Helper T Neoplasias)

Skin

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)

CD4+

Micro: Pautrier microabscess

(infiltration to epidermis and upper dermis by

Sezary Cells)

Sezary Cells: Neoplastic CD4+ cells / lg,

immature lymphoid cells with CEREBRIFORM

nucleus (seen in smears)

Indolent

(often misdiagnosed as fungal infection)

Slowly progressive

Extranodal NK/T Cell Lymphoma

Extra-nodal

Nasopharynx at midline ; nose ; testes

Ischemic necrosis may be first sign (tumors surround

vessels → Ischemia

Aggressive

Poorly responsive to therapy

Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s Lymphoma: Nodular Sclerosis / Mixed Cellularity / Lymphocyte Rich / Lymphocyte Depleted

Name Location Clinical Features Histology Morphology Genetics / immuno Prognosis and Therapy

Hodgkin Lymphoma (general)

Always starts in nodes

(localized to single

axial group)

Cervical Node enlargement “Horse Collar”

Mediastinal node Enlargement (resp. issues possible) Generalized Prutritis (due to eosinophils) Cutaneous Anergy

(Will not react to a skin test!!)

Reed-Sternberg Cells

RS cells have the “cross-eyed owl”

Unknown malignant

transformation of germinal or post germinal B-Cell

Good Prognosis: Lymphocyte rich form

No symptoms at dx Poor prognosis: bone pain is present /

Sx are present (B)

Combination Chemo for tx

Nodular Sclerosis Can arise

in Thymus

Nodes: Mediastinum / cervical / supraclavicular

Lacunar RS variant

Background of: benign lymphs, eos,

macro.

Collagen bands (form nodules

CD15 and CD30 Young M or F

Most common Good prognosis

Mixed Cellularity Fever and Night Sweats (B-sx) Abundant RS cells,

histiocytes, eos, lymphs

Young and old / M>F

Px:Poorer but still good

Lymphocyte Predominant

Can arise in

Thymus

Cervical and Axillary ; Mediastinal mass

L and H (popcorn) variant of RS cell

CD 20+

CD15,30 negative

Young males EXCELLENT prognosis

Lymphocyte Depleted

Elderly / HIV / Non-

industrialized / EBV assoc. POOREST prognosis

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 Hodgkin’s 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 Effect on Thymus Clinical Features Histology Morphology

Auto-Immune Hyperplasias Hyperplasia Lymph Follicles (B Cells)

Thymoma Composed of Spindle shaped thymic Anterio-Superior Mediastinum

1st seen on imaging in asymptomatic pt. May produce pressure sx 50% assoc. w/ Myasthenia gravis Could be associated w/ Pure Red Cell hyperplasia

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 (Gaisbock’s Syndrome)( stress and anxiety assoc. w/ obesity and HTN)

Name Type CBC Chemistry Pathology Cause

Polycythemia Vera 1° Absolute ↑RBC mass ↑RBC volume ↑PMNs & Platelets

↓ Erythropoietin Clonal proliferation of myeloid stem cells

JAK2 Mutation

Absolute Polycythemia (due to normal causes)

2° Absolute ↑RBC ↑Erythropoietin Normal Reaction

Absolute Polcythemia (Paraneoplastic)

2° Absolute ↑RBC ↑Erythropoietin (inappropriately)

Hormone releasing neoplasm

Renal Cell Carcinoma and others that release erythropoietin

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

Infective Vasculitis V. W.

Abnormal

Endothelium is infected and hemorrhage is the result

(Meningococcemia, Rickettsia)

Normal : (PT, PTT, Platelet)

“rash” - -crops of petechiae Subungual hemorrhages (secondary

to infective emboli) Active infection

Immune/Inflamamtory Vasculitis

-Collagen vascular diseases: RA ; SLE

-Drug reactions: hypersensitivity and lymphoclastic

-Unknown antigen: H-S Purpora

Normal : (PT, PTT, Platelet)

Deposition of immune complexes into vessel

walls causes inflammation

Henoch-Schonlein Purpora (Vasculitis)

Unknown Antigen

Look for prior Resp. infection

Normal : (PT, PTT, Platelet)

Palpable Purporic rash / Colicky abd. Bleed

Polyarthralgia Acute glomerulonephritis (severe

cases)

IgA immune complex deposition

Scurvy Impaired Collagen

Deficient vitamin C Normal : (PT, PTT, Platelet)

Swollen gums w/ hemorrhage Purpora assoc. w/ hair follicles

Defective synthesis

Ehlers-Danlos Inherited Impaired Collagen

Poor vascular support leads to easy bleeding

Normal : (PT, PTT, Platelet)

HYPER-mobility Bleeds

Inherited defect in synthesis

Cushings-Syndrome Impaired Collagen

Loss of vascular support Normal : (PT, PTT, Platelet)

Will see redistribution of fat (moon facies and buffalo hump)

Corticosteroid use causes protein wasting

Elderly Collagenous Atrophy

Impaired Collagen

As we age the collagen is wore thin

Normal : (PT, PTT, Platelet)

“Bateman” or Actinic Purpora Bruise very easily

Thin collagen due to aging

Hereditary Hemorrhagic Telangiectasia

(Osler-Weber-Rendu)

Inherited (AD)

Tortuous, thin walled vessels

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)

Autosomal dominant

Vessels are thin walled and prone to break - -

hemorrhage can be life threatening

Systemic Amyloidosis AL Amyloid Often as a result of chronic

infection / inflammation AL Amyloid most times

“Racoon Eyes”

Defective protein accumulation

-monoclonal plasma cells and multiple myeloma

may cause as well

Cerebral Amyloid Angiopathy (CAA)

Aβ Amyloid Accumulation

Cerebral meningeal and cortical vessels are affected

Familial tendency

Aβ amyloid in biospy

Non-traumatic cerebral hemorrhage

-Alzheimer’s amyloid w/o the alzheimers

-2nd most common cause of 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 →complexes→thrombosis) 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 Pathology Clinical Lab / Morphology tx Notes

Splenic Sequestration ↑ sequestration of

platelets in the spleen Splenomegaly present in

90% Thrombocytopenia Splenectomy

Normal sequestration is 30*35% (same for RBCs)

Neonatal Thrombocytopenia

-Maternal antibodies against fetal HPA cross

placenta -Immune mediated platelet destruction

Extensive petechiae and scattered purpora at

birth

Thrombocytopenia Rest of CBC: NORMAL

Normal PT and PTT

Fetal HPA is inherited from the father

Immune mediated

destruction

Acute Idiopathic/Primary

Immune Thrombocytopenia

-Unknown cause -IgG autoantibodies target common GP

epitopes -Destroyed in Spleen

-Megakaryocytes in BM can be damaged

Abrupt onset: Petechiae “rash”, Purpora,

ecchymosis

Normal sized Spleen

Hx of VIRAL illness

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

Chronic Idiopathic/Primary

Immune Thrombocytopenia

Insidious onset

Have to exclude secondary causes before

you suspect

Insidious onset of mucosal bleeds (“in

dependent areas”??)

Hx of easy bruising, epistaxis and bleeding

gums

Immuno-suppression/modulation -Anti-CD20 (Rutuximab)

-Iv Immunoglobulins

Splenectomy as last resort

F > M ; Adults<40

↑Risk for intra-cranial Hemorrhage

Splenectomy removes site of breakdown and ↓ antibody production

Heparin Induced Thrombocytopenia

(Type 1)

Unfractionated Heparin causes aggregation but

NO CLOTTING

IMMEDIATE Sx of Thrombocytopenia

but no clotting Thrombocytopenia Discontinue use Most common

Heparin Induced Thrombocytopenia

(Type 2)

Unfractionated Heparin

Anti-body to Heparin-Platelet Factor 4

complex

5-14 Days After initial tx

Intravascular thrombi 50%↓ in platelets

Discontinue Use and NEVER use again

(Flag chart as Allergic to Heparin!!!)

Anti-body complex (AB-PF4) activates platelets cousing intravascular

thrombi

HIV associated Thrombocytopenia

HIV infection of Megakaryocytes in BM

Molecular mimicry: HIV gp120 resembles gpIIb

and gpIIIa (cross-reaction)

Sx of thrombocytopenia and possibly HIV

infection Thrombocytopenia

Treat the HIV / AIDs

Give something to boost platelet production (or

give platelets)

(Insert Omar joke here)

Thrombotic Thrombocytopenic

Purpora (TTP)

Deficiency in ADAMTS vWF protease →

Ultra-large monomers of vWF

(another micro-angio-hemolysis - - -like HUS)

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

↑ freq in adult FEMALES Causes of Deficiency:

-hereditary -Auto-antibody

-2° to infection/drugs/gynecologic

disease

Hemolytic Uremic Syndrome (HUS) (Epidemic Type)

Ingestion of : E Coli / Shiga Toxin

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

Supportive Care only

DO NOT give antibiotics: May result in further

toxin release!!!

Children and Elderly Genetic predisposition

(another micro-angio-

hemolysis - - -like TTP but w/ different clinical pres.

items)

Non-epidemic HUS: other defects →HUS sequalae

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, enzymes-PML)) 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 Mild Bleeding bleeding ↑ Bleeding Time

Normal Platelet count ↓vWF Normal PTT

DDAVP (desmopressin) (Avoid Aspirin)

DDAVP causes vWF release Ristocetin Test or immunoassay to dx

vWF Disease Type 3 AR Excessive bleeding Hemarthrosis ↑Bleeding time

Normal Platelet count ↓↓↓vWF (severe def) ↑ PTT

Humate (FVIII-vWF complex) Cryoprecipitate

Acts like Hemophilia A Ristocetin Test or immunoassay to dx

Factor VIII Deficiency (Hemophilia A)

X-linked Hemorrhage post-trauma (days) Hemarthrosis Spontaneous bleeds NO petechiae

↑PTT and normal PT Abnormal factor VIII assay

Factor VIII infusions (may develop resistance) -FEIBA to fix this (20-30 per yr w/o tx)

Most common (X and New) Failure of Synthesis (↑) Hemosideridin in CT Factor VIII Assay

Factor IX Deficiency (Hemophilia B)

X-linked (recessive)

Hx of reccurent GI bleeds Severe bleeds lasting days

↑PTT Abnormal factor IX assay

Factor IX activity/antigen Clinically indistinguishable from Hemophilia B

Factor XI Deficiency AD More common in women?? FamHx of severe bleeds

↑↑PTT Normal bleed time

Ashkenazi Jews Common AD (2nd to vWF)

Disseminated Intravascular Bleed (DIC)

Purpura Fulminans (Infarcted patches of skin) Acute DIC: Shock, acute renal failure, ARDS (SOB ad Cyanosis), Circulatory failure →coma→Death Chronic DIC: (Cancer most times) Trossueu Syndrome: Recurrant DVTs w/o bleeding diathesis Non-bacterial endocarditis

↓Platelets ↓Fibrin ↓Clotting Factors ↑ D-dimer

Remove underlying Cause Simultaneous anti- and pro-coagulant replacement Treat sequalae

Thrombo-hemorrhagic Consumptive coagulopathy Micro-angiopathic anemia Renal Issues: -isolated infarcts or -Diffuse Cortical Necrosis Adrenal Gland Issues: -b/l hem. and necrosis Waterhouse-Friderichsen 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 anti-serums) 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 Coomb’s) 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, Coomb’s): Patients RBCs (sensitized in vivo) exposed to Coomb’s reagent (anti-human IgG) → Coomb’s 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 don’t 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 →MAC→Intravascular 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, Coomb’s) 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

Frozen Rare Units

Atypical antigens to common antigen

-Rare blood type -Autologous units

Antigen negative blood is RARE

NO universal donor for those with high risk atypical antigens Preserved in Glycerol for up to 10Years

Packed RBC Transfusion Acute blood loss

Chronic anemia (Hb≤7) C. Anemia (Hb>7w/doc.)

NOT effective in auto-immune hemolysis tx

Platelet Transfusion Platelet Count <50k w/ bleed

Platelet count<30k Documented dys. in bleeder

Thrombotic Thrombocytopenic

Puropora (TTP) Not effective in Auto-Immune Thrombocytopenia

Fresh Frozen Plasma ↑ PT, PTT, AND:

-pt is bleeding -Anticipated surgery

For those with ↓ Coagulation factor(s)

Cryoprecipitate Tx of bleeding due to: ↓ VII,

↓fibrinogen, or ↓vWF

Contains: Factor VIII, Fibrinogen, vWF

WBC Transfusion Severe neutropenia in an immunosuppressed pt.

Apheresis (“taken from”) is from a SINGLE DONOR

Washed RBCs

When plasma proteins must be removed:

-IgA deficiency -Hx of allergic transfusion rxns

CMV Negative Immuno-naïve or immuno-compromised individuals

-Neonates, diseased, organ recipients

Factor Concentrates Deficiency is known factor(s):

vWF and VIII (Humate) IX,

Humate is an example

Immune Serum Globulin

Some auto-immune Diseases: -Treatment of ITP

-kawasaki Tx of Immunodeficiencies

Exposure to infectious disease

Gamma globulin of a sort is given

Tx of Immunodeficiencies (Bruton’s and Common Variable)

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: Goodpasture’s disease, Thrombocytopenic Purpora (TTP), Myasthenia Gravis, Guillain-Barre

Name Clinical Predisposing Factors Pathology Notes

Graft vs. Host Transfusion Rxn Skin Rash Diarrhea Jaundice

Compromised Cell mediated immunity

T-lymphocytes from DONOR blood attack recipient tissues

Immunodeficient ; Lymphoma Prevent by matching HLA type

Transfusion Related Acute Lung Disease (TRALI)

Sudden Pulmonary edema that progresses to ARDS

Most associated with the transfusion of Fresh Frozen Plasma

HLA or Granulocyte specific antibodies → Free Radical damage to pulmonary vasculature

-MOST COMMON fatal rxn -Immediate and life threatening rxn -Lysed donor WBCs release toxic contents (ex. ROSs)

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

Misidentification of Patient Unidentified Atypical Abs

ABO Incompatibility results in immune rxn → Compliment Activation →Immediate hemolysis of transfused RBCs (extra- and intra-)

Can be Fatal Tx: Stop transfusion immediately and start IV fluids, diuretics, and mannitol to spare kidneys!!

Delayed Hemolytic Transfusion Reaction

3-10 days post transfusion Signs due to Hemolysis: ↑Indirect Bili →Jaundice Anemia Positive DAT!!! (+ Coomb’s)

Unidentified Antibody is reactivated (takes time to ramp up)

Immune reaction due to some latent antibody that went unoticed

Transfusion Related Immunomodulation (TRIM)

Possible multiple organ failure ↑ Risk of cancer reoccurance

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 α-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: δ-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 Serum Iron TIBC Transferrin Transferrin % Saturation Ferritin Level Other Findings

Iron Deficiency ↓

↑ ↓ ↓ ↓Fe in BM

Chronic Disease ↓

↓ ↓ ↑ ↑ BM Iron

Thalassemia Beta Normal Normal Normal to increased Normal to increased Abnormal Hgb electro. (don’t make enough)

Thalassemia Alpha Normal Normal Normal to increased Normal to increased Normal Hgb electro.

(Fe not incorporated)

Sideroblastic Anemias (Lead)

↑ Normal to decreased Increased Increased Ringed Sideroblasts Basophilic Stippling

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 = α2β2 commonly or HbA2: α2δ2 (3%) ; Fetal: α2γ2) / 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

Hereditary Spherocytosis

-Splenomegaly -Jaundice

-Parvovirus may cause aplastic crisis

-Other sx of H.An. -Look at FHx

Spheroidal cells Reticulocytosis

Do osmotic fragility tests

Intrinsic Defect in membrane skeleton

(ankyrin)

(Extravascular destruction)

Splenectomy

75% AD (European) AR more severe

Cells destroyed in cords of Bilroth of spleen (Extravascular)

Sickle Cell Disease

Infarction of bones, brain, kidney, eyes, etc…

-Leg Ulcers -Spleen is enlarged in

CHILDREN -Auto-splenectomy by adolescents or adults

Pigmented gallstones Hyperbilirubinemia

Bad B-Globin creates HbS phenotype

Point mutation: switch of

Valine for Glutamine

Give O2 Give fluids Treat Pain

Extravascular and intravascular destruction

β-Thal Major Severe (need transfusions)

May see iron overload (Secondary hemochromatosis)

α-globulin inclusions

Abnormal erythroblasts that are beta globin deficient: ineffective

production (die in BM) and extravascular

destruction

transfuse Named for what is deficient

HbA type Hemoglobin

Point Mutations leading to various defects

Gene Deletions

β-Thal Intermedia Less Severe

β-Thal Major Minor Asymptomatic w/ mild or

absent anemia (RBC abnormalities still seen)

Silent Carrier: α-Thalassemia

Asymptomatic Carrier of gene deletion

-a/aa Children may have excessive γ-globin

(γ4= Bart’s Hemoglobin)

HbB hemoglobin in adults (β-globin inclusions)

Less severe hemolytic anemia and ineffective

erythropoiesis

HbH Disease: α-Thalassemia

Severe; looks like β-Thal Intermedia

--/-a

HbB hemoglobin in adults (β4)

(β-globin inclusions)

Switch to

Hydrops Fetalis α-Thalassemia

Lethal in utero without transfusion

Has Bart’s Hemoglobin

(until 9 months)

--/-- Can see Bart’s up until 9 months when switch to

adult Hgb occurs!!

Warm Immuno-hemolytic Anemia

Primary Idiopathic w/ potential Secondary Leukemias and lymphomas

IgG

Active at 37 degrees

Cold-Agglutinin Associated w/ Mycoplasma

and Infectious Mono

IgM

Below 37 (4 degrees C)

Megaloblastic Anemia

May have iron overload for years

Marked Anicytosis (oval macrocytes w/ lack of

central pallor) ↓ Reticulocytes

↑ iron Nucleated RBCs

Hypersegmented, lg Neutrophils

Blasts accumulate in BM Ineffective erythropoiesis and early megablast death

↑Hemolysis

Pernicious Anemia-CNS

Spastic Paraparesis Sensory Ataxia

Severe Parasthesias in Lower Limbs

Spinal Cord demyelination

Dorsal horn degen. Lateral tract degen.

Sensory and motor pathways affected by the

B12 Deficiency

Folate Deficient Anemia

Can present much like Pernicious Anemia but w/

different neural sx

Easy to treat w/ folate and miss B12 deficiency

Give B12 w/ Folate - - -

prompt reticulocytosis

response

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

changes!!

Iron Deficient Anemia

↑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

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

Anemia of Chronic Disease

↓Erythroid production and Impaired Iron Utiliization

↓ Serum Iron

↓ Total Binding Capacity

Abundant stored iron in MP cells

↑Serum Ferritin

↓Erythroid production and Impaired Iron

Utiliization

Anemia due to Bone Marrow Hypo-proliferation

(↓ Erythropoietin response to anemia)

Erythropoietin

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-γ - -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