Exam 1

Reactive Neutrophilia

Circulating Immature Neutrophils

Left shift/bandemia: ↑ bands, metamyelocytes → bacterial infection

Leukemoid reaction: Left shift and high neutrophil count secondary to inflammation due to infection/sepsis, sterile inflammation, or paraneoplastic G-CSF or cytokine production

Leukoerythroblastic reaction: Left shift plus presence of nucleated RBCs and tear drop RBCs (dacrocytes) → bone marrow–occupying (myelophthisic) lesion with extramedullary hematopoiesis

Agranulocytic Angina

Ulcerative, necrotizing lesions of the gingiva, mouth, pharynx

Ulcers of Skin, Vagina, Anus or GI tract (Cecum)

Risk of severe, life-threatening bacterial (Lungs, Urinary tract) or deep fungal infections caused by Aspergillus or Candida

Skin/mucosal Bacterial colonies may grow with little inflammatory response (Botryomycosis/Bacterial Pseudomycosis)

Neutropenic Fever

Empiric antibiotic therapy should be instituted immediately in all febrile neutropenic patients

Empiric antifungal therapy in patient who do not respond to empiric antibacterial therapy

Chronic myeloid leukemia

BCR-ABL fusion gene due to t(9;22) (Philadelphia chromosome)

Fusion protein has constitutive non-receptor tyrosine kinase activity → uncontrolled myeloid proliferation

Leukocytosis

Granulocytosis with full spectrum of maturation

“Left shift” with ↑ eosinophils and ↑ basophils

Blasts may be present in peripheral blood but <10%

Platelets increased

Leukocyte alkaline phosphatase (LAP) score decreased

Bone marrow hypercellular with increased myeloid-to-erythroid (M:E) ratio

Anemia → fatigue, weakness

Weight loss, anorexia

Splenomegaly due to neoplastic extramedullary hematopoiesis

Causes dragging sensation or fullness in the left upper quadrant

Early satiety

Left upper quadrant abdominal pain due to splenic infarction

Hypermetabolic state from increased cell turnover

Fever and night sweats

Hyperuricemia due to DNA purine catabolism → gout, nephrolithiasis, or uric acid nephropathy

Can progress to acute leukemia

Chronic Lymphocytic Leukemia

Small, mature-appearing lymphocytes on blood smear

“Smudge cells” often present due to fragile lymphocytes

Neoplastic cells are B-cells expressing CD19+, CD20+, and CD23+

Co-express aberrant T-cell marker CD5+

Hypogammaglobulinemia common

Autoimmune hemolytic anemia (AIHA)

Immune thrombocytopenic purpura (ITP)

Transformation to more aggressive malignancy: Prolymphocytic leukemia or Large B-cell lymphoma (Richter transformation)

Acute Lymphoblastic Leukemia

Pre-B:

Leukemic (marrow and blood involvement)

Preschool children (peak age ≈3 years)

Pre-T:

Mass (lymphoma) in the mediastinum (thymus) or lymph nodes

May rapidly progress to a leukemic phase

Adolescent and young adult males

Prognosis worse than pre-B type

Anemia

Thrombocytopenia

Bone marrow is hypercellular and packed with lymphoblasts

>20% of marrow cells to be blasts

Acute Myeloid Leukemia

Mutations in transcription factors for differentiation

Blasts replace normal bone marrow

Anemia, neutropenia, and thrombocytopenia (pancytopenia)

Activating mutations in genes controlling the epigenome (methylation, acetylation)

Disabling mutations affecting TP53

Activation of pro-growth receptor or signaling pathways

Diagnosis requires >20% myeloid blasts in the bone marrow

Auer rods form by abnormal fusion of azurophilic granules

Blasts with azurophilic (Primary) granules (lysosomes containing Myeloperoxidase)

Poor Prognostic Factors:

>50 years

AML arising from prior myelodysplasia or following chemotherapy/radiation (therapy-related AML)

Cytogenetic abnormalities: deletions of chromosomes 5 or 7

TP53 mutations or translocations involving chromosome 11 (KMT2A/MLL)

Therapy-related AML

Very poor prognosis

Following alkylating agent therapy or radiation:

Latency 2–8 years

Associated with deletions of 5q-, 7q-, or 20q-

Following topoisomerase II inhibitor therapy:

Latency 1–3 years

Hallmark abnormality: MLL gene rearrangements

Acute promyelocytic leukemia

t(15;17) → PML-RARα fusion protein

Excellent prognosis if treated promptly before development of DIC

Promyelocytes contain abundant cytoplasmic granules and Auer rods

Release of granules can trigger disseminated intravascular coagulation (DIC) → medical emergency

Normal retinoic acid receptor α (RARA) binds retinoids (vitamin A) to induce maturation of promyelocytes into neutrophils

Translocation t(15;17) creates a PML::RARA fusion receptor that fails to respond to physiologic vitamin A levels

Resulting receptor dysfunction blocks differentiation at the promyelocyte stage

Polycythemia vera

Clonal proliferation of myeloid stem cells with predominant increase in red cell mass

Activating JAK2 V617F mutation

Increased RBC production independent of erythropoietin

EPO low

Leukocytosis and thrombocytosis

Hyperviscosity due to increased hematocrit

Plethoric (ruddy) complexion, headache, dizziness, pruritus (especially after hot shower), hypertension, and thrombosis or bleeding

Splenomegaly due to extramedullary hematopoiesis

Bone Marrow: Erythroid hyperplasia

Clotting\thrombosis lead to Stroke and MI

Spent phase: progressive marrow fibrosis with cytopenias

May transform into acute myeloid leukemia (AML)

Treatment:

Phlebotomy to maintain normal hematocrit

JAK2 inhibitors

Essential thrombocythemia

Chronic myeloproliferative disorder with sustained thrombocytosis

Clonal proliferation of megakaryocytes; often with JAK2, CALR, or MPL mutation

Platelet production increased independent of thrombopoietin regulation

Persistent elevated platelet count

Episodes of thrombosis and bleeding due to dysfunctional platelets

Microvascular occlusion may cause erythromelalgia (burning pain in hands/feet)

May transform into myelofibrosis or AML

Giant platelets on peripheral smear

Dysplastic Megakaryocytes in bone marrow

Primary myelofibrosis

Clonal myeloproliferative neoplasm with marrow fibrosis and extramedullary hematopoiesis

JAK2, CALR, or MPL mutations

Neoplastic megakaryocytes release PDGF and TGF-β → fibroblast activation → progressive marrow fibrosis

Hematopoiesis shifts to spleen and liver

Anemia and fatigue

Massive splenomegaly with early satiety and abdominal discomfort

Leukoerythroblastic blood picture with teardrop RBCs and nucleated precursors

Infection, hemorrhage, and cachexia in advanced disease

May evolve into acute myeloid leukemia (AML)

Bone marrow hypocellular, diffusely fibrotic marrow with numerous dysmorphic Megakaryocytes (some clustered) & enlarged trabecula (osteosclerosis)

Multiple myeloma

Plasma cell proliferation and survival—MYC, cyclin D, or IL-6

Clonal malignant proliferation of plasma cells in bone marrow producing a monoclonal immunoglobulin

Major translocations involve IgH locus

High IL-6 levels promote plasma cell growth and survival

Bone marrow features:

Sheets of plasma cells with eccentric nuclei, clock-face chromatin, and perinuclear hof

Increased osteoclast activation via RANKL and reduced osteoblast activity → lytic bone lesions

Diagnostic criteria (CRAB): Hypercalcemia, Renal failure, Anemia, Bone lesions

Lab findings: M-spike on SPEP, monoclonal light chains in urine (Bence Jones protein), and >10% clonal plasma cells in marrow

Rouleaux on blood smear (stack of coins)

↑ Beta 2 microglobulin

Imaging: multiple “punched-out” lytic bone lesions on skull or spine

Bone pain

Anemia and fatigue (marrow replacement)

Infections (norm Ig not produced)

Renal failure (light chain cast nephropathy, hypercalcemia, or amyloidosis)

Neurologic symptoms (Hyperviscosity from M protein)

Anisocytosis

Variation in RBC size (↑ RDW)

Microcytosis

Decreased MCV (small cells)

Macrocytosis

↑ MCV (large cells)

Hypochromia

Decreased MCH, ↑ area of central pallor

Polychromatophilia

Bluish tint, young RBCs (Reticulocytes)

Poikilocytosis

Abnormally shaped RBCs

Spherocyte

Spherical, without area of central pallor

Schistocyte

Fragmented; irregularly shaped

Intravascular mechanical destruction of RBCs (fragmentation hemolysis)

Sickle cell

Curved, banana shaped

Target cell

Mexican hat

Spleenectomy

Dacrocyte

Tear drop shape

Extravascular hematopoiesis

Howell-Jolly Body

Remnants of RBC nuclei that are normally removed by the spleen

Basophilic Stippling

Remnants Ribosomal RNA in RBC

Coarse: lead and heavy metal poisoning

Spherocytes

Sign of Extravascular Hemolysis

Schistocytes

Sign of Intravascular Hemolysis

Extravascular Hemolysis

Immune: due to antibodies bound to RBCs

Macrophages bind Fc tails & Complement of opsonized RBCs -> Phagocytosis (partial phagocytosis of bits of membrane -> Spherocytes)

Non-immune: Intrinsic RBC membrane abnormalities (Hereditary or Acquired)

Macrophage recycling of heme groups

Protein Globin chains recycled; Fe saved & stored as Ferritin or Hemosiderin

Heme group -> Bilirubin (unconjugated)

Anemia, splenomegaly & jaundice

↑ Bilirubin (unconjugated/indirect)

Blood smear: Spherocytes

Intravascular Hemolysis

RBCs lyse inside vessels -> free Hb into plasma -> binds to Haptoglobin -> Hapto/Hgb cleared by Macrophages; excess free Hgb filtered by kidneys -> Hemoglobinuria

Fe saved as Ferritin or Hemosiderin

Anemia, Hemoglobinemia, Hemoglobinuria (brown urine from oxidized Hb/methemoglobin), Hemosiderinuria & Jaundice (↑ unconjugated bilirubin)

Massive hemolysis chills, fever, hypotension, hemoglobinuria, renal failure, back pain, or DIC

↓ Haptoglobin

↑ Bilirubin (unconjugated/indirect)

↑ LDH

Schistocytes if due to trauma (micro/macro angiopathic)

Hemoglobinuria (may result in Acute Renal failure)

Warm Autoantibody Autoimmune hemolytic anemia

IgG against RBC protein Ag

Half are idiopathic (primary); others are secondary to autoimmune disease (SLE), drugs or lymphoid neoplasms (CLL or Lymphoma)

Auto-Ab acts as opsonin → Hemolysis mostly EXTRAVASCULAR by Macrophages → Spherocytes

+DAT

Drugs may bind to RBC surface & act as Antigens (penicillin, cephalosporins), Haptens (Quinidine) or break self-tolerance (α-methyldopa)

No blood is compatible for transfusion

Cold Autoantibody Autoimmune hemolytic anemia

IgM binds to individual RBC polysaccharide Ag I/i in cold areas (fingers, toes, ears) & deposits opsonizing C3b → rewarming at core organs disassociates IgM but leaves behind C3b → extravascular hemolysis (DAT + for Complement only)

May appear transiently after infections (Mycoplasma pneumonia, IM or other viruses) or persist as chronic hemolysis from B-cell neoplasms (Waldenstrom) or idiopathic

IgM also Agglutinates RBCs in cold, exposed, parts of body (Cold Agglutinin Disease) inducing Acrocyanosis (necrosis if severe), Raynaud phenomenon, or Livedo Reticularis

Paroxysmal Nocturnal Hemoglobinuria

Common Myeloid Progenitor stem cell

Acquired LOF mutation in PIGA on X chromosome which makes a phospholipid that protects myeloid cell membranes (RBC, Platelets & Neutrophils) from lysis by Complement

Loss of CD55 & CD59

RBC: Hemolytic Anemia w/ episodes of intravascular hemolysis

Complement activation of platelets: thrombosis leading cause of death

Thrombi in large veins and Thrombocytopenic

Neutrophils: lysed; neutropenia (infections)

From pre-existing Aplastic Anemia and can progress to Myelodysplasia or AML

DAT (-)

Normocytic or macrocytic anemia with normal or ↑ Retic count

Over time may become Fe deficient due to Hemosiderinuria

G6PD Deficiency 

Heinz bodies

Bite cells

Spherocytes

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)

↓ NADPH → ↓ Glutathione peroxidase

Oxidative damage

Most are asymptomatic

Inherited as X-linked recessive

Triggers: Infections (pneumonia, viral hepatitis, etc.), drugs (anti-malarials, sulfonamides, others) & foods (Fava beans)

Presents as Hemoglobinuria (dark urine)

Self-limited

Blood smear: Denatured Globin chains precipitate (Heinz bodies) & damage membrane

Severe damage -> intravascular hemolysis

Less severe damage -> extravascular hemolysis

"Bite cells": removal of Heinz bodies by Spleen

Spherocytes

Jaundice, fatigue, back pain, tachypnea, tachycardia & dark urine

↓ hemoglobin, ↑ reticulocytes, ↑ LDH, ↑ unconjugated bilirubin, ↓ Haptoglobin, Hemoglobinuria

PYRUVATE KINASE DEFICIENCY HEMOLYTIC ANEMIA

Autosomal recessive

Mutations in RBC enzyme in glycolytic pathway producing ATP

Chronic extravascular hemolysis

RBC maturation also affected (ineffective erythropoiesis) -> results in Fe overload

+/- Anemia

↑ Retic count

Negative DAT

Hyperbilirubinemia, gallstones, Fe overload

Hx of transfusions

Hereditary spherocytosis

Spherocytes

Hereditary spherocytosis

Autosomal dominant

Intrinsic Defect in RBC Membrane cytoskeletal tethering proteins → make RBCs spheroid ↓ lifespan to 10-20 days due to sequestration & destruction in spleen (Extravascular hemolysis)

Anemia, Splenomegaly & Jaundice

Osmotic fragility test (RBCs rupture more easily in a hypotonic solution)

Aplastic Crisis due to Parvovirus B19 infection which destroys RBC progenitors

Artefactual Pseudohyperkalemia (K+ leaks out of cells with cooling after draw)

Bilirubin gallstones

Splenectomy is definitive Rx

↑ MCHC (because of shape)

MCV low or normal (mix of small spherocytes + large Retics)

Sickle Cell Disease

Sickle Cell Disease

Autosomal recessive point mutation in β-globin gene -> HbS = both β-globins mutated

HbS prone to polymerization into needle-like crystals when deoxygenated

Distorted RBCs become “sticky” & adhere to endothelium -> results in episodes of microvascular obstruction & tissue ischemia (Vaso-Occlusive Crisis)

Inflammation

Extravascular hemolysis

Normocytic Anemia, ↑ Bilirubin (unconjugated/indirect), ↑ Retics

Smear: irreversibly sickled cells

Pre & Post-capillary microvascular occlusions cause the hallmark of the disease: Recurrent, unpredictable episodes of Microvascular occlusion: Vaso-occlusive (“Pain”) Crises

Bones: painful bone crises common, particularly in children

Bone pain is due to bone marrow infarction in bones with the most bone marrow activity

X-ray appearance: frontal & parietal bossing & prominent maxilla due to marrow hyperplasia expanding the bone

X-ray of skull -> “Hair-on-end” pattern

BM biopsy: Erythroid hyperplasia; foci of infarction (necrosis) during crises

Lungs: Acute Chest Syndrome

Sickle Cell Disease

Fever, cough, chest pain

Ischemia due to pneumonia -> Sickling -> more ischemia-> more sickling

Most common cause of death

Sickle Cell Complications

Priapism

Liver: multiple infarcts → failure

Kidney: Papillary Necrosis is a common renal manifestation of vaso-occlusion → isosthenuria (inability to concentrate urine) → prone to dehydration → kidney failure

Brain: Stroke (common in children), retinopathy (loss of visual acuity/blindness); loss of cognitive function over time

Salmon-patch hemorrhage in retina

Gallbladder: Cholelithiasis (bilirubin stones) common in children

Avascular necrosis of Femoral or Humeral heads 

Leg Ulcers: impaired healing of minor trauma

Growth delay: Children small & thin; delayed sexual development

Aplastic Crisis with Parvovirus B19

Autosplenectomy due to infarcts

Sequestration Crisis: In younger children (usually < 5) with still intact spleens, massive entrapment of sickled cells by the spleen → rapid splenic enlargement, hypovolemia & even fatal shock

Β-THALASSEMIA

No Beta production

β-Thalassemia Minor:

Mild microcytic hypochromic anemia with Target cells; ↑ RBC count

β-Thalassemia Intermedia: Intermediate

β-Thalassemia Major:

6-9 months of age

↓ RBC production

Unpaired α chains precipitate in RBC precursors & damage membrane → apoptosis (ineffective erythropoiesis)

↑ Splenic hemolysis.

Severe anemia

Smear: Microcytic, hypochromic with Anisocytosis, Poikilocytosis (Targets, fragmented RBCs, basophilic stippling), variable Retics, NRBCs

BM: Erythroid hyperplasia

Hair on end pattern on skull X-ray caused by longstanding hyperplasia of the bone marrow

Extramedullary Hematopoiesis (skeletal abnormalities/Hepatosplenomegaly)

Facial bone hyperplasia

Iron Overload (↑ Ferritin): ineffective erythropoiesis suppresses Hepcidin (↑ Fe absorption from gut) + multiple transfusions → severe Fe overload which damages liver, heart & pancreas

Α-THALASSEMIA

Decrease production of α-chains due to deletion of 1, 2, 3 or all 4 alleles

1 Silent Carrier

2: Microcytosis with mild or no anemia

3: Hemoglobin H Disease- Moderate or Severe microcytic anemia; may be iron overloaded

4:  Hydrops Fetalis (Nonimmune Hydrops)- Lethal in utero or shortly after birth

Corrected Reticulocyte Count

Reticulocyte % adjusted for patient’s degree of anemia

< 2% → Inadequate marrow response (hypoproliferative anemia)

• 2% → Appropriate marrow response (blood loss or hemolysis)

Aplastic anemia

Chronic failure/injury of Common Myeloid Progenitor Stem Cell

Pancytopenia

Most commonly Autoimmune, but deficiency of stem cell Telomerase

1/3 have associated expanded PNH clones

Markedly Hypocellular or Acellular bone marrow

↓ Reticulocytes

Pancytopenia; mild macrocytosis

↑ Erythropoietin level (EPO)

Parvovirus intranuclear inclusions

Parvovirus intranuclear inclusions

Pure red cell aplasia

Selective suppression of committed marrow erythroid precursors

Parvovirus B19

Diamond-Blackfan Anemia:

1st year

Mutations in ribosomal protein genes; associated with numerous/characteristic physical abnormalities (thumbs); ↑ risk MDS, AML, other tumors

↑ Erythrocyte Adenosine Deaminase, Macrocytic anemia

Autosomal Dominant

Normocytic/Macrocytic anemia; Low retic count; high EPO

BM: normocellular with absent/arrested erythroid precursors

In Parvovirus infection, intranuclear inclusions

Megaloblastic Anemia showing megaloblastic erythroid precursors

Megaloblastic anemias

Vit B12 (Cobalamin) or Folic Acid deficiency

Both are coenzymes required for synthesis of Thymidine in DNA

Abnormally large erythroid precursors (Megaloblasts) & macrocytic RBCs (Macrocytes)

Hypersegmented neutrophils

Macro-ovalocytes

Thrombocytopenia; Pancytopenia

↓ Reticulocyte count

Bone Marrow: Hypercellular marrow with hyperplasia of erythroid series; ↓ M:E ratio

Megaloblastic erythroid, myeloid & megakaryocytic series

↑ EPO

For B12: ↑ Methylmalonic acid (MMA) best for early deficiency

For folate: Increased Homocysteine

Pernicious Anemia

Megaloblastic Anemia caused by Vit B12 deficiency due to Autoimmune atrophic gastritis

Autoimmune atrophic gastritis destroys parietal cells which produce Intrinsic Factor (IF) required for Vit B12 absorption from the gut

Antibodies to Intrinsic Factor, Parietal Cells

Gastric Bx: fundic gland atrophy; intestinal metaplasia (↑ risk of gastric cancer)

Atrophic glossitis

Subacute Combined Degeneration of spinal cord: demyelination of the Dorsal + Lateral spinal tracts with loss of voluntary movement, stiffness, sensory ataxia, severe paresthesia in lower limbs

Tingling, "pins and needles" sensation in the hands or feet

Lost sense of touch

Wobbly gait and difficulty walking

Clumsiness & stiffness of the arms & legs

Dementia

Iron deficiency anemia

Microcytic, Hypochromic cells

Iron deficiency anemia

Functional Fe is carried in the blood by TRANSFERRIN

TIBC (Total Iron Binding Capacity) is an indirect measurement of Transferrin

Iron stored intracellularly as protein-iron complexes FERRITIN & HEMOSIDERIN (which is aggregated Ferritin)

Ferritin levels in blood correlate well with total body iron store

Iron balance is regulated by ABSORPTION in the duodenum

Hepcidin ↓ Duodenal Fe absorption

MICROCYTIC HYPOCHROMIC ANEMIA

Low serum Iron + Ferritin

High TIBC (Total Iron Binding Capacity), ↑ Transferrin

Low per cent saturation of serum Transferrin

↑ RBC distribution width (RDW) → variation in RBC size (anisocytosis)

↓ Reticulocyte count

↑ EPO

Thrombocytosis

BM: erythroid normoblastic hyperplasia with ↓ or absent stainable Fe

Koilonychia: Spoon nails

Angular cheilitis

PLUMMER-VINSON SYNDROME

Severe Fe deficiency anemia + esophageal webs + atrophic glossitis

↑ risk of Esophageal Squamous Carcinoma

Anemia of chronic disease

Decreased RBC production seen with chronic inflammatory conditions (infections/autoimmune) or malignancy due to ineffective use of iron stores

IL-6 -> ↑ liver production of Hepcidin → ↓ Fe absorption from the gut, & ↓ Fe transport from

Macrophage stores to erythroid precursors (deprive bacteria of iron)

EPO response muted

Normocytic or mildly Microcytic anemia

↓ serum iron, ↓ Saturation, but ↓TIBC + Ferritin

Mildly ↓ Retic count

PAPPENHEIMER BODIES IN RBCS

Abnormal granules of iron found inside red blood cells on routine blood stain

Sideroblastic anemia, sickle cell disease, post-splenectomy, & some

hemolytic anemias

Immune thrombocytopenia purpura

Destruction of platelets by Anti-platelet IgG autoantibody

Chronic ITP (> 12-month duration):

SLE, CLL (secondary) or primary (Idiopathic)

Autoantibodies opsonize platelets → Destroyed in the Spleen

Spleen normal size; BM mildly ↑ Megakaryocytes, some immature (single, non-lobulated nuclei), large platelets

Adult women (3:1 F:M)

Petechial bleeding (Skin & mucosa); ecchymoses (usually in dependent areas), epistaxis, gingival bleeding, easy bruising & bleeding with minor trauma, melena, hematuria, heavy periods

Acute ITP (< 12-month duration):

Mainly in childhood 1-2 weeks usually after a self-limited viral illness

Self-limited

Treatment:

Steroids

Intravenous Immunoglobulin

Splenectomy

Heparin-induced thrombocytopenia

Type I HIT: Thrombocytopenia immediately after start of Heparin Rx

Direct platelet-aggregating effect of Heparin

Not clinically significant

Type II HIT:

Onset typically between 5-10 days after the start of Heparin therapy

Defined as a decreased platelet count of >50% from baseline.

Development of Ab against the Heparin-Platelet Factor 4 complex

Binding of Ab to this complex ACTIVATES the platelets → Thrombosis & develop a consumptive thrombocytopenia

Venous & arterial thrombosis dominant effect despite the thrombocytopenia

Thrombotic microangiopathies

Fibrin strand- “Piano wire”

Schistocytes

Thrombotic microangiopathies

Thrombotic Thrombocytopenic Purpura (TTP) & Hemolytic Uremic Syndrome (HUS)

Excessive activation of platelets forming small vessel platelet rich thrombi (microthrombi composed primarily of platelets & Von Willebrand Factor) → Microangiopathic

Hemolytic Anemia causing widespread organ dysfunction & a consumptive Thrombocytopenia

Thrombotic Thrombocytopenic Purpura

ADAMTS13 deficiency- vWF not cleaved

Thrombocytopenia + Microangiopathic Hemolytic Anemia

Renal failure, fever & CNS involvement

Young adult; F>M; ↑ incidence in HIV

Fatigue, dyspnea, petechiae, or other bleeding

Weakness, dizziness, abdominal pain, easy bruising, or nausea & vomiting

Thrombocytopenia

Anemia due to mechanical hemolysis with Schistocytes (MAHA)

Gastrointestinal

Bleeding or purpura due to the consumptive thrombocytopenia

Neurologic: Coma, stroke, seizure, transient focal abnormalities, headache, confusion)

Hemolytic Uremic Syndrome

Microangiopathic Hemolytic Anemia + Thrombocytopenia + Renal impairment

Shiga-like Ecoli

Bloody diarrhea → sudden onset of bleeding manifestations

Atypical: Excessive Complement deposition & activation

Bernard-Soulier Syndrome

GpIb deficiency → defective adhesion

Giant platelets, thrombocytopenia

Glanzmann Thrombasthenia

GpIIb/IIIa deficiency → defective aggregation

Normal platelet count, absent aggregation

Hemophilia A

Factor VIII deficiency

X-linked recessive

Spontaneous hemarthroses, muscle hematomas

Hemophilia B

Factor IX deficiency

X-linked recessive

Clinically indistinguishable from Hemophilia A

Disseminated Intravascular Coagulation (DIC)

Systemic activation of coagulation

Widespread microthrombi + consumption of clotting factors & platelets

Thrombosis and bleeding

Causes:

Sepsis (endotoxin, cytokine storm)

Trauma

Obstetric complications (amniotic fluid embolism, placental abruption)

Malignancy (acute promyelocytic leukemia, adenocarcinoma)

Nephrotic syndrome

Transfusion reactions

Prolonged PT and aPTT

Thrombocytopenia

Low fibrinogen

High D-dimer

Schistocytes on peripheral smear

Bleeding: petechiae, ecchymoses, oozing from IV sites/surgical wounds

Microthrombi: organ dysfunction (renal failure, respiratory distress, CNS changes)

Acute hemolytic reactions

Within minutes to hours of transfusion

Preformed recipient antibodies (usually anti-A or anti-B) bind donor RBCs → complement-mediated intravascular hemolysis

Fever, chills, flank pain, hypotension, hemoglobinuria

May progress to DIC, shock, acute renal failure

Positive direct antiglobulin (Coombs) test

Hemoglobinemia, low haptoglobin, elevated LDH and bilirubin

Delayed hemolytic reactions

Days to weeks after transfusion

Anamnestic IgG response to minor RBC antigens → extravascular hemolysis

Mild jaundice, low-grade fever, unexpected drop in hemoglobin

Usually less severe than acute reaction

Positive direct antiglobulin (Coombs) test

Elevated bilirubin and LDH, no hemoglobinemia or hemoglobinuria

Transfusion-Related Acute Lung Injury (TRALI)

Immune-mediated reaction from donor anti-HLA or anti-neutrophil antibodies

Acute non-cardiogenic pulmonary edema within 6 hrs of transfusion

Hypoxemia, dyspnea, bilateral infiltrates, normal BNP

Stop transfusion, supportive O₂, avoid diuretics

Prognosis: Usually recovers in 48–96 hrs

Transfusion-Associated Circulatory Overload (TACO)

Volume overload or rapid transfusion exceeding cardiac capacity

Dyspnea, hypertension, JVD, pulmonary edema, elevated BNP

Worsens with fluids; improves with diuretics

Give diuretics, O₂, slow future transfusions

Infectious mononucleosis

EBV in saliva

Infects oropharyngeal and nasopharyngeal epithelial cells and mature B cells (via CD21)

Reactivation may occur via EBV Latent Membrane Protein (LMP-1), which mimics co-stimulatory CD40 B-cell receptor

Induces division and production of numerous polyclonal antibodies (Monospot test)

Specific antibodies against EBV are also produced

CD8+ T lymphocytes, NK cells, and specific antibodies control disease; usually self-limited

The lymphocytosis and “atypical lymphocytes” in peripheral blood are mostly CD8+ (cytotoxic) lymphocytes, with some NK cells

Residual small number of latently infected B cells persist for life

Atypical lymphocytes: increased cell size, abundant cytoplasm, indented or folded nucleus

Lymph nodes: paracortical expansion by atypical lymphocytes

Spleen: enlarged due to infiltrates of atypical lymphocytes

Liver: hepatitis with atypical lymphocytes infiltrating portal and sinusoidal areas, with foci of apoptosis or parenchymal necrosis

EBV-associated malignancies include Burkitt lymphoma, some large B-cell lymphomas, some Hodgkin lymphomas, nasopharyngeal carcinoma, extranodal NK/T-cell lymphoma, and gastric carcinomas

Infectious mononucleosis Diagnosis

Acute infection: positive VCA IgM ± VCA IgG; negative anti-EBNA

Past infection: positive VCA IgG and anti-EBNA

Infectious mononucleosis Clinical Presentation

Young adults: fatigue, ± fever, sore throat

Enlarged tonsils; generalized lymphadenopathy (neck, axilla, groin)

Enlarged spleen: rapid enlargement with capsular stretching increases risk of rupture with minor trauma

Complications: autoimmune hemolytic anemia, thrombocytopenia, hepatitis. involve nervous system, eyes, kidneys, lungs, or heart

Infection more serious in T-cell immunodeficiencies

Follicular Lymphoma

Painless generalized lymphadenopathy

From Germinal center B-cell (Centrocyte)

CD10, 19, 20, BCL-6 & CD5

t(14;18) juxtaposing Ig Heavy chain genes (14) to BCL-2 -> ↑ BCL-2 expression -> ↓ Apoptosis

Transformation to aggressive B-cell lymphoma (DLBCL or sometimes Burkitt)

Nodes enlarged, often form matted masses

Small lymphocytes with cleaved nuclei

Follicle-like nodules of neoplastic cells without true germinal centers

Starry Sky

Burkitt lymphoma

Starry Sky

Burkitt lymphoma

Burkitt lymphoma

Highly aggressive B-cell neoplasm characterized by the overexpression of the Myc gene on Chromosome 8

Translocation is the IgH heavy chain locus t(8;14)

Starry Sky appearance due to evenly interspersed macrophages with apoptotic debris in cytoplasm

Intermediate to small cells with noncleaved nuclei, coarse chromatin, small multiple nucleoli & very high mitotic index

African (endemic) Burkitt:

Very strong association with EBV

Extranodal, facial; tends to involve mandible & abdominal visceral organs

Burkitt lymphoma in HIV:

Intermediate association with EBV

Extranodal sites (GI, Bone marrow)

Sporadic Burkitt lymphoma in the US:

Weak association with EBV

Usually presents as mass of ileocecum/peritoneum

Both endemic & sporadic tends to occur in children or young adults

Mantle cell lymphoma

Have t(11;14) -> Cyclin D1 gene overexpression promotes cell cycle progression

B-cell markers & CD5

Intermediate grade

Painless generalized lymphadenopathy

Blood involvement

Spleen, liver & gut

Extranodal marginal zone lymphoma

GI mucosa → Mucosal-Associated Lymphoid Tissue Lymphoma (MALT Lymphoma)

Memory B-cell origin

Extra-nodal tumors often arise in the context of chronic inflammation (autoimmune or infectious) such as Sjogren syndrome (salivary glands), Hashimoto Thyroiditis, H. pylori gastritis

Polyclonal inflammatory proliferation

B-cell clone emerges that still depends on Ag stimulated T-cell signaling

Over time, additional mutations acquired that render neoplastic cell growth Ag independent (usually translocations which ↑ MALT-1, BCL-10, NFκB)

Usually remains localized for long periods, but with further clonal evolution may transform to DLBCL

Mature (Peripheral) T-cell lymphoma

Post-thymic T cells (outside of the Thymus) in lymph nodes, gut, spleen or skin

TdT negative

NK Cell tumors due to HTLV-1

Diffuse effacement of nodes with infiltrates of variably sized T-cells admixed with eosinophils & macrophages

Loss of CD45, CD2,3,5,7, CD4/CD8

Monoclonal T-cell Receptor gene rearrangements by PCR

Generalized lymphadenopathy, fever, weight loss +/- eosinophilia & pruritus

Worse Px than B-cell lymphomas

ANAPLASTIC LARGE CELL LYMPHOMA

Mature T-cell tumor that involves nodal & extranodal sites, often skin

CD30 (Ki-1)

ALK (Anaplastic Lymphoma Kinase) translocation

ALK-negative tends to occur in older adults & has a worse Px

Large cells with horseshoe or “embryoid” nuclei & abundant cytoplasm

Sézary cells

Sézary syndrome

Typically present with a generalized pruritic exfoliative Erythroderma + circulating malignant T-cells (Leukemia of “Sézary” cells)

Sézary cell leukemia: absolute Sézary cell count of > 1000 with a clonal T-cell Receptor rearrangement with characteristic hyperconvoluted, “cerebriform” nucleus

Classic R-S Cell

Hodgkin Lymphoma

Classic R-S Cell

Hodgkin Lymphoma

Lacunar R-S cell in Nodular Sclerosis Hodgkin Lymphoma

Mononuclear R-S cell in Mixed Cellularity Hodgkin Lymphoma

Hodgkin Lymphoma

B-cell germinal/post-germinal center cell derived tumors

Vast bulk of the tumor is made up of inflammatory & reactive cells (small lymphocytes, plasma cells, histiocytes, eosinophils & variable fibrosis) which harbor the sparsely scattered, malignant giant cells (Reed-Sternberg cells)

R-S cells are the malignant cells in HL

Large Binucleated/bilobed nucleus with prominent eosinophilic nucleoli

Show activation of NF-kB by EBV proteins

Cytokines produced by the R-S cells attract the background infiltrate

CD15 + CD30

Arises in a single node or group of nodes

Classical subtypes:

Nodular Sclerosis (NS)- Lacunar R-S variants

Mixed Cellularity (MC)- Mononuclear variants

Lymphocyte rich 

Lymphocyte Depletion

Hodgkin Lymphoma Clinical Presentation

Non-tender adenopathy in a single or group of axial nodes

Cervical neck nodes → Horse collar- symmetric, bilateral node enlargement

Mediastinal nodes- common in NS type → cough, dyspnea

Less commonly, non-axial nodes: Axillary nodes, inguinal nodes, retroperitoneal

Initially spreads predictably to contiguous node groups

Late: spread to Liver, Spleen, & finally to BM & other tissues

“B” symptoms:

Fevers

Night sweats

Weight loss

Worse prognosis

Nodular Sclerosis Hodgkin Lymphoma

Prognosis excellent

Young adults or adolescents

Frequently involves mediastinum, lower cervical & supraclavicular nodes

Usually EBV negative

Histology: Collagen bands form nodules; Classic R-S cells rare, Lacunar RS cells

CD15 + CD30

Background benign lymphs, plasma cells, eosinophils, macrophages

Mediastinal nodes → cough, dyspnea

Mixed Cellularity Hodgkin Lymphoma

Biphasic age incidence (peaks in young & older adults)

M > F

Likely older age, B symptoms & advanced stage at Dx

Diagnostic RS cells + Mononuclear variants plentiful in background of benign lymphs, plasma cells, eosinophils, & macrophages

Usually EBV related

Abundant classic RS cells + mononuclear variants (CD15+, CD30+)

Lymphocyte rich Hodgkin Lymphoma

Predominantly small lymphocytes, but diagnostic R-S cells & Mononuclear variants present

EBV + sometimes

CD15+, CD30+

Very good to excellent Px

Lymphocyte Depletion Hodgkin Lymphoma

Paucity of lymphocytes with numerous atypical R-S cells

Older adults, HIV infected, or in third world; almost all EBV+

CD15+, CD30+

Px: least favorable

Popcorn cells

Nodular lymphocyte-predominant Hodgkin Lymphoma

Lymphocyte-predominant Hodgkin Lymphoma

D20+

NOT associated with EBV

Cervical, axillary, or inguinal lymphadenopathy

Tends to skip anatomic node regions (non-contiguous spread)

B-symptoms less common

More likely to recur

Indolent with Excellent prognosis

Can progress to Diffuse Large B-cell Lymphoma

Most common in men 30-50 y/o