CVH Block 3

Pediatric Hematology, Anemias, White Blood Cell Disorders, Antiplatelets and Anticoagulants, Pediatric Cardiology Murmurs

Iron Deficiency Anemia

• Etiology/Mechanism: Inadequate iron intake, excessive cow’s milk, rapid growth, prematurity, chronic blood loss, malabsorption

• Typical clinical presentation: often asymptomatic; pallor, fatigue, irritability, PICA, developmental concerns, spoon-shaped nails in severe disease

• Key Clues: Toddler with excessive milk intake and poor iron intake

Thalassemia Trait

• Etiology/Mechanism: Inherited reduction in alpha or beta - globin synthesis

• Typical clinical presentation: mild hypochromic, microcytic anemia; usually few symptoms

• Key Clues: Severe microcytosis with relatively mild anemia

Thalassemia Major

• Etiology/Mechanism: Severe globin-chain synthesis defect causing ineffective erythropoiesis and hemolysis

• Typical clinical presentation: severe anemia, jaundice,e hepatosplenomegaly, growth failure, bone and focal abnormalities, marrow expansion

• Key Clues: Maxillary hyperplasia and chronic transfusion needs

Lead Poisoning

• Etiology/Mechanism: Environmental lead exposure, often associated with PICA or lead-based paint

• Typical clinical presentation: Microcytic anemia, abdominal pain, constipation, vomiting, psychomotor slowing, seizures, encephalopathy

• Key Clues: PICA + basophillic stippling

Anemias of inflammation

• Etiology/Mechanism: increase hepcidin traps iron intake macrophages and decreases intestinal iron absorption

• Typical clinical presentation: chronic, usually mild anemia; may be microcytic or normocytic

• Key Clues: underlying chronic infection or inflammatory disease

Megaloblastic Anemia

• Etiology/Mechanism: Vitamin B12 or Folate deficiency; medications seems a phenytoin

• Typical clinical presentation: Macrocytosis, pallor, fatigue, glossitis, hypersegmented neutrophils, neurological symptoms suggest B12 deficiency

• Key Clues: Macrocytes + hypersegmented neutrophils

Hemolytic Anemia

• Etiology/Mechanism: Premature RBC destruction due to hemoglobin, membrane, enzyme, immune, or microanglopathic disorders

• Typical clinical presentation: pallor, jaundice, dark urine, fatigue, splenomegaly, reticulcytosis, pigment gallstones

• Key Clues: Anemia + evidence of RBC destruction

Sickle Cell Disease

• Etiology/Mechanism: HbS polymerization causes RBC suckling, hemolysis, vasooclussion, and functional asplenia

• Typical clinical presentation: Dactylitis, painful crises, acute chest syndrome, aplastic crisis, splenic sequestration, stroke, priapism, severe infection

• Key Clues: Symptoms begin after HbF declines, usually at 3-6 months

Hereditary Spherocytosis

• Etiology/Mechanism: RBC membrane defect causing spherical RBCs and splenic destruction

• Typical clinical presentation: chronic hemolytic anemia, jaundice, splenomegaly, pigment gallstones, hemolytic or aplastic crises

• Key Clues: Spherocytes w/o central pallor

G6PD deficiency

• Etiology/Mechanism: X-lined enzyme deficiency causing susceptibility to oxidative stress

• Typical clinical presentation: Episodic hemolysis after infection, fava beans, or oxidant medications; jaundice and dark urine

• Key Clues: Bite or blister cells after an oxidative trigger

Autoimmune hemolytic anemia

• Etiology/Mechanism: Antibodies bind RBCs and promote immune destruction

• Typical clinical presentation: Acute anemia, jaundice, fatigue, and sometimes splenomegaly

• Key Clues: often follows infection or autoimmune disease; direct Coombs positive

ITP

• Etiology/Mechanism: Antibody-medicated platelet destruction, commonly after viral infection

• Typical clinical presentation: petechaie, purpura, bruising, epistaxis or mucosal bleeding’ usually isolated-thrombocytopenia

• Key Clues: child with sudden petechiae after viral illness and no splenomegaly

TAR syndrome

• Etiology/Mechanism: congenital thrombocytopenia with absent radii

• Typical clinical presentation: Bleeding tendency and bilateral absent radii; thumbs are usually preserved

• Key Clues: thrombocytopenia + absent radii

Wiskott-Aldrich syndrome

• Etiology/Mechanism: X-linked cytoskeletal disorder affecting platelets and lymphocytes

• Typical clinical presentation: eczema, recurrent infections, immunodeficiency, and thrombocytopenia

• Key Clues: small platelets, unlike ITP

Iron deficiency

• Mechanism: chronic blood loss in US (cancer, PUD, menses), malabsorption, poor diet

• Labs: decrease iron, decrease ferritin, increase TIBC, decrease %sat, increase RDW

• Epidemiology: US adult men and post-meno women: cancer, PUD. Pre-meno women: menses, pregnancy

• Unique features: Remember, not dietary in US…looks for occult loss/malabsorption (duodenum), koilonychia (uncommon)

Anemia of chronic disease

• Mechanism: liver makes hepcidin as acute phase reactant —> blocks iron release from stores; suppresses erythropoietin

• Labs: decrease iron, increase ferritin, decrease TIBC, decrease %sat

• Epidemiology: hospitalized patients, autoimmune conditions, cancer, chronic infections

• Unique features: low serum iron despite high ferritin

Lead Poisoning

• Mechanism: Pb inhibits ferrocheletase, blocking heme synthesis disturbs pumps —> hemolysis

• Labs: increase iron, increase ferritin, decrease TIBC, increase %sat

• Epidemiology: miners, industrial workers, children (ingest lead paint/dust or toys)

• Unique features: ringed sideroblasts (trapped iron in mitochondria); Prussian blue stain, basophilic stippling

Sideroblastic anemia

• Mechanism: blocks in mitochondrial heme pathway participant —> iron trapped in mitochondria

• Labs: increase iron, increase ferritin, decrease TIBC, increase %sat

• Epidemiology: rare (<1 per 100k), congenital mutation of ALAS, thiamine deficiency (cofactor for ALAS); alcoholics

• Unique features: ringed sideroblasts (trapped iron in mitochondria); Prussian blue stain, basophillic staining

Alpha Thalassemia, Hydrops details with Hb Barts

• Mechanism: Deletion of all four alpha-globin alleles —> fetus accumulates gamma-tetramers that won’t release oxygen —> anoxia

• Labs: Hb Barts (gamma-tetramers), uncleared RBCs, target cells

• Epidemiology: Southeast Asian (cis del) and Africans (trans del) pop., fetal and neonatal

• Unique features: edema, hepatosplenomegaly, death in utero, death without in utero transfusion

Alpha Thalassemia, HbH disease

• Mechanism: ¾ alpha globin alleles deleted or mutated —> excess beta forms HbH —> poor O2 exchange; spleen removes

• Labs: HbH (beta tetramers) on electrophoresis, target cells

• Epidemiology: southeast Asian and African populations, HbCS in Mediterranean, iron overload by adulthood

• Unique features: Hepatosplenomegaly, extramedullary hematopoiesis, symptoms related to chronic hemolysis (gallstones)

Alpha-Thalassemia Minor (trait)

• Mechanism: 2/4 alpha-globin alleles deleted —> milks anemia that is usually asymptomatic

• Labs: small amt of HbH on electrophoresis, microcytic, hypochromic

• Epidemiology: southeast Asian (- - / alpha alpha) and African (- alpha/- alpha) populations

• Unique features: carriers are classically asymptomatic (minimal anemia)

Alpha-Thalassemia minima (silent carrier)

• Mechanism: ¼ alpha-glob in alleles deleted —> no anemia; asymptomatic

• Labs: normal electrophoresis, may produce mild hypochromia

• Epidemiology: southeast Asian and African populations (alpha alpha/-alpha), est. 5% of world population carries an alpha-Thal variant

• Unique features: goes undiagnosed, or shows up during reproductive counseling

Transfusion - dependent Thalassemia (Beta-Thal major)

• Mechanism: severe point mutation in both beta-globin alleles - alpha inclusions —> cells die in marrow, or spleen removes

• Labs: Absent HbA, increase HbA2, increase HbF

• Epidemiology: Mediterranean, South Pacific, India, Africa, Asia. Jaundice, dark urine, hepatosplenomegaly at 6 months

• Unique features: target cells, basophilic stippling, fragmented RBCs, splenomegaly, iron overload

Non-transfusion - dependent Beta-Thalassemia (that. Intermediate)

• Mechanism: Milder point mutation in both Beta globin alleles —> alpha inclusions —> cells die in marrow, or spleen removes

• Labs: absent or decrease HbA (not as severe as major), increase HbA2, increase HbF

• Epidemiology: Mediterranean, South Pacific, India, Africa, Asia, usually develops later in life that Beta-thaw major

• Unique features: same as for Beta-that major, but not as severe, no transfusion necessary unless physiological stress

Beta-Thalassemia minor

• Mechanism: Point mutation in one beta globin allele —> some alpha accumulation —> target cells

• Labs: mildly decreased HbA, increase HbA2, increase HbF

• Epidemiology: Mediterranean, South Pacific, India, Africa, Asia. Asymptomatic or with mild anemia

• Unique features: mild symptoms of anemia or asymptomatic, target cells, basophilic stippling

Aplastic Anemia

• Mechanism: genetic/chemical/viral or autoimmune marrow suppression —> pancytopenia

• Labs: pancytopenia, low retic count, empty, fatty marrow biopsy

• Epidemiology: immune-mediated associated with drugs and viral infection, fanconi = genetic

• Unique features: “dry tap” on marrow biopsy, pancytopenia with cardio, facial and skeletal defects = Fanconi anemia

Anemia of chronic renal failure

• Mechanism: Reduced erythropoietin —> less production; uremia —> destruction

• Labs: low retic count, signs consistent with hemolysis, uremia

• Epidemiology: patient with renal failure; dialysis

• Unique features: echinocytes (burr cells) due to toxic effects of uremia

Myelophthisic anemia

• Mechanism: pathologic process replaces marrow (eg osteosclerosis, cancer)

• Labs: teardrop cells (dacrocytes), low retic count

• Epidemiology: older adults 9bc more likely to get cancer), pts with diseases with impact marrow

• Unique features: teardrop cells, symptoms related to disease that is causing marrow replacement (eg Gaucher’s)

Pure Red Cell Aplasia (PRCA)

• Mechanism: IgG antibodies target erythroblasts or erythropoietin; sometimes drug

• Labs: anemia with zero reticulocyte response, no other marrow elements impacted

• Epidemiology: association with thymoma and large-cell granular lymphocyte leukemia

• Unique features: anemia is only manifestation; absent reticulocytes

Sickle Cell Anemia

• Mechanism: Autosomal recessive mutation in beta-globin —> polymerization of HbS with low O2, low H2O

• Labs: disease = no HbA, but HbS on electrophoresis, trait = half HbA, half HbS; sickle cells

• Epidemiology: populations from geographic areas with endemic malaria

• Unique features: dactylitis (infants); pain crises, autosplenctomy; infections (childhood deaths); priapism *acute chest (adult deaths)

Hereditary spherocytosis

• Mechanism: genetic mutation in RBC cytoskeleton - membrane anchor —> membrane belles —> spheroctyes (spleen traps)

• Labs: spherocytes, increase MCHC and RDW, osmotic fragility test, increase bilirubin

• Epidemiology: Northern European descent

• Unique features: splenomegaly!!, jaundice, gallstone, risk of aplastic crisis or hemolytic crisis

G6PD deficiency

• Mechanism: X-linked recessive mutation causing G6PD misfolding —> shorter half-life esp. with oxidant stress

• Labs: Heinz bodies on supravital stain, hemoglobinuria, degamacytes

• Epidemiology: symptoms coincide with oxidant stress (anti-malarial), African and Mediterranean descent

• Unique features: acute hemoglobinuria and back pain associated with consuming oxidants (ex: sulfa drugs or fava beans)

Pyruvate kinase deficiency

• Mechanism: no conversion of phosphoenolpyruvate to pyruvate —> decrease ATP pumps —> RBC destruction

• Labs: hemoglobinuria, increase iron stores, echinocytes due to increased intracellular Sodium

• Epidemiology: Pennsylvania Amish communities

• Unique features: echinocytes (burr cells) due to intracellular increase Na+, splenomegaly; jaundice, extra medullary hematopoiesis

Paroxysmal nocturnal hemoglobinuria

• Mechanism: Acquired stem cell mutation in PIGA —> no GPI —> cells cannot inactivate complement

• Labs: Hemoglobinuria, sucrose screening test

• Epidemiology: lower RR during sleep —> respiratory acidosis —> complement damage

• Unique features: thrombosis! (Hepatic and portal veins) bc platelets also lysed, AML develops in 10%

Warn Antibody Immunohemolytic Anemia

• Mechanism: produce antibodies against common RBC antigens like Rh Factor —> splenic destruction

• Labs: Coombs (DAT) positive for both IgG and C3, spherocytes

• Epidemiology: associated with SLE, CLL, viral infections, associated with drugs

• Unique features: splenectomy may be necessary, chronic

Cold Agglutinin Immunohemolytic Anemia

• Mechanism: IgM binds RBCs at cold temperatures —> fixes complement —> hemolysis, IgM pentamer —> RBC cluster

• Labs: Coombs (DAT) positive for C3 but not IgG (except at low temp), hemoglobinuria

• Epidemiology: children after viral illness or immunization, adults with syphillis, lymphoma, CLL

• Unique features: NO acrocyanosis, severe hemoglobinuria; systemic pain

Microangiopathic Hemolytic Anemia

• Mechanism: vascular obstruction causes shearing of RBCs as they pass through circulation

• Labs: schistocytes, signs of intravascular hemolysis

• Epidemiology: DIC, TTP, HUS, HELLP, prosthetic heart valves, aortic stenosis

• Unique features: schistocytes, fibrin split products (D-dimers) when thrombotic, leads to Fe-deficiency anemia

Folate Deficiency Anemia

• Mechanism: Folate needed for DNA synthesis —> diminished erythropoiesis

• Labs: megaloblasts in peripheral smear, increased homocysteine

• Epidemiology: associated with decreased absorption (jejunum) and increased demand (pregnancy, cancer)

• Unique features: sore tongue, cheilosis

Vitamin B12 deficiency anemia

• Mechanism: B12 needed for DNA synthesis —> diminished erythropoiesis

• Labs: megaloblasts in peripheral smear, increased homocysteine, increased MMA

• Epidemiology: associated with decreased absorption (ileum), stomach pathology (reduced IF), and autoimmune (IF antibodies)

• Unique features: similar to folate, but with neurological symptoms (parasthesias)

Orotic Aciduria

• Mechanism: uridine 5’ monophosphate (UMP) synthase defect —> increase orotic acid —> decrease pyrimidine synthesis

• Labs: megaloblasts in peripheral smear, increase orotic acid in serum and urine

• Epidemiology: AR inheritance, incredibly rare (but not rare on boards)

• Unique features: failure to thrive, developmental delays, cloudy urine from orotic acid crystals

Congential Hypoplastic (Diamond - Blackfan) Anemia

• Mechanism: AD inheritance of ribosomal protein mutation —> decrease ribosome synthesis, increase p53 activation

• Labs: Congential form of PRCA; see above

• Epidemiology: increased risk of myelodysplastic syndrome and AML, apparent in first year of life

• Unique features: craniofacial defects; thumb/upper extremity malformations (absent of triphalangeal thumbs)

Porphyrias (Porphyria Cutanea Tara as example)

• Mechanism: mutation in cytoplasmic heme pathway participant —> block in heme synthesis —> porphyrins increase

• Labs: increase in total porphyrin, dark urine, but tests negative for blood/heme

• Epidemiology: associated with sun or chemical exposure, exacerbated by alcohol, hepatitis C

• Unique features: skin blisters after UV exposure, dark urine, *only erythropoietic prophyrias cause anemia, not PCT

Infectious Mononucleosis

• Morphology: atypical lymphocytes (reactive CD8+ T cells)

• Labs: may have signs of liver dysfunction, heterophile or EBV-specific antibodies

• Epidemiology: adolescents, young adults, latent EBV infections puts at risk for B-cell lymphoma

• Unique features: fever, sore throat, lymphadenopathy, splenomegaly (proliferation of B- cells)

Cat SCratch disease (Bartonella henselae)

• Morphology: sarcoidosis-like granulomas with central necrosis

• Labs: may develop thrombocytopenia

• Epidemiology: 90% <18 y/o, coincident with cat scratch about 2 weeks prior

• Unique features: lymphadenopathy in neck, axilla

Classical Hodgkin lymphoma

• Morphology: Reed-Sternberg cella’s (giant cells with bled nuclei and large nucleoli)

• Labs: CD15+, CD30+, CD20-, lack translocations

• Epidemiology: modular sclerosis = adolescents, young adults; mixed cellular ire => 50 y/o males; immunodef; EBV

• Unique features: NS = RS cells in lacuna, fibrous bands; MC = benign inflammatory cells (eos, etc), classic night sweats, fever

Nodular Lymphocyte Predominant Hodgkin Lymphoma (Non-Classical)

• Morphology: lobulated nucleus (“popcorn cells”), lymphocytes cluster and form nodules

• Labs: CD15-, CD30-, CD20+, CD45+

• Epidemiology: rare, 30-50 y/o males

• Unique features: painless cervical or axillary lymphadenopathy, highly curable

Follicular Lymphoma

• Morphology: resembles follicular hyperplasia with follicular center B cells, but lymph nodes effaced

• Labs: t(14;18), BCL2+, CD19+, CD20+, CD10+, surface Ig+

• Epidemiology: most common indolent; older adults, 40% progress to large B cells lymphoma

• Unique features: indolent; lymphadenopathy, visceral site involvement uncommon (spleen most common); marrow

Mantle Cell Lymphoma

• Morphology: B cells resemble mantle zone of lymphoid follicles, buttock cells

• Labs: t(11;14), BCL1+ —> CyclinD1+, CD19+, CD20+, CD5+, surface Ig+ (IgM, IgD)

• Epidemiology: older males

• Unique features: aggressive, lymphadenopathy; marrow, more visceral involvement (GI common, spleen, liver)

Diffuse Large B Cell Lymphoma

• Morphology: B cells in diffuse growth pattern with large clear (open chromatin) nuclei and prominent nucleoli

• Labs: BCL6 rearrangements, CD19+, CD20+, surface Ig+ (IgM, IgD)

• Epidemiology: 60 y/o, most common aggressive, associated with immunosuppressed

• Unique features: extranodal common (brain, GI), rapidly enlarging mass, uncommon for bone marrow, spleen, or liver involvement

Burkitt Lymphoma

• Morphology: B cells with basophilic cytoplasm and tangible bodies (macrophages) —> starry-sky

• Labs: t(8;14); MYC+, CD19+, CD20+, CD10+, surface IgM+, kappa or lambda light chains

• Epidemiology: children, young adults, Africa = EBV infections puts

• Unique features: aggressive; usually extranodal: U.S = abdominal tumors (ileocecal), Africa = maxilla, mandible

Extranodal Marginal Zone Lymphoma (MALToma)

• Morphology: low grade mature B cell tumor arising in MALT (mucosa-associated lymphoid tissue)

• Labs: CD19+. CD20+, not high yield but: t(1;14), t(11;18)

• Epidemiology: infection with H.pylori (regresses with antibiotic therapy)

• Unique features: indolent; develops in setting of autoimmune disorders or chronic infection

Multiple Myeloma

• Morphology: clone of B cells differentiated into plasma cells, “fried egg” myeloma cells

• Labs: M component; increase Ca2+, Bence Jones proteins (free light chains), rouleaux formations

• Epidemiology: rare<65 y/o, preceding MGUS or other plasma cell dyscrasias

• Unique features: punched out bone lesions (axial skeleton); hypercalcemia, renal insufficiency; urolithiasis, recurrent infections, anemia

Lymphoplasmacytic Lymphoma

• Morphology: B cells resemble mantle with substantial # differ to plasma cells, Ig inclusions as Russell bodies and Dutcher bodies

• Labs: large mounts of IgM in serum electrophoresis (M spike)

• Epidemiology: 50-60 years old, 10% with cold agglutinin autoimmune hemolysis

• Unique features: hyperviscosity (Waldenstrom macroglobulinemia); visual impairment, neurologic problems, cryoglobulinemia

Primary amyloidosis

• Morphology: clonal proliferation of plasma cells that synthesize abnormal Ig

• Labs: Congo Red staining (apple - green birefringence), increase marrow plasma cells

• Epidemiology: 5-15% of multiple myeloma

• Unique features: no necessarily a neoplasm (most don’t have one), but can be caused by multiple myeloma

Monoclonal Gammopathy of Undetermined Significance

• Morphology: precursor plasma cell proliferation

• Labs: M component in serum, but not symptoms or neoplasm

• Epidemiology: 50 years old with monoclonal gammopathy, 1%/year evolve to plasma cells dyscrasia

• Unique features: no symptoms

Hairy Cell Leukemia

• Morphology: B cell tumor with fine, hairlike cytoplasmic extensions

• Labs: TRAP+, CD20+, surface Ig+

• Epidemiology: males >50 years old

• Unique features: marrow involvement —> pancytopenia, splenomegaly, no lymphadenopathy

Precursor B-Cell Acute Lymphoblastic Leukemia/Lymphoma

• Morphology: >20% B lymphoblasts in bone marrow (appear in marrow and spill into blood as leukemia)

• Labs: TdT+, CD10+, CD20+

• Epidemiology: peak incidence age 4, Down syndrome over 5 y/o

• Unique features: good prognosis = hyperdiploidy and t(12;21), bad prognosis = Ph ch and MLL translocation on ch 11

Precursor T-cell Acute Lymphoblastic Leukemia/Lymphoma

• Morphology: >20% T lymphoblasts (appear as thymic mass that progresses quickly to leukemic phase)

• Labs: TdT+, CD2+ to CD8+, Notch1 mutations

• Epidemiology: teenage males

• Unique features: thymic (mediastinal) mass, prognosis good if 2-10 years old, female, and low leukocyte count at diagnosis

Mycosis fungoides/Sezary syndrome

• Morphology: neoplasticism CD4+ T cells that home to skin (Pautrier microabscesses), cerebriform nuclei

• Labs: CD4+

• Epidemiology: older black males

• Unique features: erythrodermic skin rash; plaques and nodules, becomes exfoliating and in blood = Sezary (poor prognosis)

Adult T-cell leukemia/lymphoma

• Morphology: neoplasticism proliferation of mature CD4+ T cells

• Labs: CD4+, HTLV-1 infection, lymphocytosis

• Epidemiology: HTLV-1 endemic areas; Japan, Caribbean, Middle East, tropical Africa, males > 55 years old

• Unique features: rash, lymphadenopathy, hepatosplenomegaly, lytic bone lesions

Peripheral T-cell lymphoma

• Morphology: mature neoplastic T cells and NK cell proliferations; too heterogeneous to summarize

• Labs: mature T cell (CD3+), but too diverse to characterize here

• Epidemiology: too diverse to summarize

• Unique features: very aggressive tumors with disseminated disease, poor prognosis

Acute Myelogenous Leukemia

• Morphology: >20% myeloblasts in bone marrow (leads to decreased function of RBCs, granulocytes, platelets)

• Labs: MPO+ (can see as Auer rods), or MPO-APL, t(15;17)

• Epidemiology: adults; APL assoc. with DIC; retinoic acid receptor, can arise from myelodysplastic syndrome

• Unique features: Acute monocytic = lysosomal esterale +; gingival infiltrates, Acute megakaryoblastic = Down syndrome <5 y/o

Myelodysplastic syndrome

• Morphology: marrow replaced with transformed multipotent stem cell that can differentiate (abnormally)

• Labs: loss of ch 5 or 7, megaloblasts or ringed sideroblasts

• Epidemiology: 50-70 years old, may progress to AML

• Unique features: infections, anemia, and/or bleeding (one or all), may response to immunosuppressants

Chronic Myelogenous Leukemia

• Morphology: >100k elevation of neutrophils, basophils, metamyelocytes, myelocytes in blood

• Labs: t(;22) Ph ch, LAP-, hyper cellular marrow

• Epidemiology: adults 25-60 years old

• Unique features: blast crisis: transforms to AML or ALL (Trisomary 8; 2x Ph ch) —> hepatosplenomegaly (extramedullar hematopoiesis)

Polycythemia vera

• Morphology: neoplastic proliferation of erythroid, granulocytic, and megakaryocytic

• Labs: low EPO despite increase RBC ct, basophila, hypercellular marrow

• Epidemiology: late middle age, JAK2 mutations, 2-15% transform to AML, associated with gout

• Unique features: liver spleen, heart enlargement, spent phage = marrow fibrosis, itching/peptic ulcers associated with basophil histamine release

Essential thrombocytopenia

• Morphology: neoplastic proliferation of platelets and other mature myeloid cells

• Labs: elevated platelet count

• Epidemiology: increased risk of thrombosis or bleeding, rarely transform to AML or have marrow fibrosis

• Unique features: headache or visual changes, no gout

Primary Myelofibrosis

• Morphology: marrow fibrosis develops early (due to release of PDGF and TGF-beta from neoplastic megakaryocytes)

• Labs: teardrop-shaped RBCs, leukoerythroblastosis, marrow fibrosis

• Epidemiology: >50 years of age (peak 65), 5-15% transform to AML, associated with gout

• Unique features: extreme hepatosplenomegaly (extra medullary hematopoiesis)

Mastocytosis

• Morphology: mast cells accumulate in skin (cutaneous form) or in bone marrow, liver, spleen, GI tract (systemic form)

• Labs: D816V mutations in KIT gene

• Epidemiology: cutaneous, children and resolves by puberty, systemic, adults and persists

• Unique features: symptoms similar to allergic rxn, cutaneous —> Darier’s sign, systemic —> bone involvement, liver, spleen, GI, lymph nodes

Langerhans Cells Histiocytosis

• Morphology: neoplastic Langerhands cells that lead to skeletal lesions, skin eruptions, and predispose to infection

• Labs: CD1a+, S-100+, langerin+, HLA-DR+, Birbeck granules

• Epidemiology: usually children

• Unique features: Letterer-Siwe = skin eruptions, otitis media, osteolytic lesions, Hand-Schuller-Christian = diabetes insipidus, exophthalmos, and calvarial def.

Aspirin

MOA: Irreversible COX-1 inhibition —> decrease TXA2 —> decrease platelet aggregation

Key Adverse effects: GI irritation/ulcer, bleeding, tinnitus, salicylate toxicity, bronchospasm in aspirin- exacerbated respiratory disease

When to give: Acute coronary syndrome; secondary prevention on non-cardioembolic ischemic stroke/TIA; with a P2Y12 inhibitor for DAPT; NOT FOR DVT/PE

Clopidogrel

MOA: Irreversible P2Y12 blockade —> decrease Gp 2b/3a activation

Key Adverse effects: bleeding; reduced effect in CYP2C19 poor metabolizers; rare TTP

When to give: alternative to aspirin; DAPT after ACS/PCI; long-term secondary prevention after non-cardioembolic stroke/TIA

Prasugrel

MOA: Irreversible, potent P2Y12 blockade

Key Adverse effects: major bleeding; increased risk in older or low-weight patients

When to give: ACS when PCI is planned; DO NOT GIVE WITH PRIOR STROEK/TIA

Ticagrelor

MOA: reversible P2Y12 blockade

Key Adverse effects: bleeding, dyspnea, bradyarrhythmias; CYP3A interactions

When to give: ACS and selected acute ischemic stroke/TIA protocols; use with aspirin <= 100 mg/day

Eptifibatide

MOA: Reversible GP2b/3a blockade —> prevents fibrinogen cross-linking

Key Adverse effects: bleeding, thrombocytopenia; accumulation with renal impairment

When to give: selective cat-lab bailout or high thrombus burden during PCI

Abciximab

MOA: near - irreversible GP2b/3a blockade

Key Adverse effects: bleeding, acute immune thrombocytopenia, hypersensitivity

When to give: selective high-risk PCI; not routine upstream therapy

Dipyridamole

MOA: inhibits adenosine uptake and PDE activity —> increase camp/cgmp

Key Adverse effects: headache, dizziness, hypotension, angina

When to give: with aspirin as extended-release dipyridamole for secondary prevention after non-cardioembolic stroke/TIA

Cilostazol

MOA: PDE-3 inhibition —> increase platelet cAMP and vasodilation

Key Adverse effects: headache, diarrhea, palpitations, tachycardia

When to give: intemrittent claudification; CI IN HF

Alteplase

MOA: fibrin-bound tpa converts plasminogen —> plasmin —> fibrin degradation

Key Adverse effects: major bleeding, intracranial hemorrhage, orolingual angioedema

When to give: eligible acute ischemic stroek, STEMI when indicated, or massive PE with instability

Tenecteplase

MOA: modified, longer-acting, more fibrin-specific tPA; converts plasminogen—> plasmin

Key Adverse effects: bleeding, intracranial hemorrhage, orolingual angioedema

When to give: eligible acute ischemic stroke or STEMI; adminstered as a single IV bolus

Urokinase

MOA: Directly converts plasminogen—> plasmin; non-fibrin specific

Key Adverse effects: bleeding, including intracranial hemorrhage

When to give: selected PE or catheter-directed thrombolysis

Streptokinase

MOA: forms a complex with plasminogen —> systemic plasmin generation

Key Adverse effects: bleeding, hypersensitivity; antigenic

When to give: historical STEMI/PE/DVT use; not currently marketed in the US

Unfractionated heparin

MOA: activates antithrombin —> inhibits thrombin and Xa

Key Adverse effects: bleeding, HIT

When to give: acute VTE, ACS, procedural anticoagulation; reverse with protamine

LMWH

MOA: activates antithrombin; preferentially inhbits Xa

Key Adverse effects: bleeding, HIT risk lower than UFH

When to give: VTE treatment or prophylaxis; protamine gives incomplete reversal

Warfarin

MOA: inhibits vitamin K epoxide reductase —> decrease factors 2, 7, 9, 10 and proteins C/S

Key Adverse effects: Bleeding, skin necrosis, teratogenicity

When to give: Long-term anticoagulation; reverse with vitamin K plus 4-factor PCC for major bleeding

Dabigatran

MOA: Direct thrombin/2a inhibitor

Key Adverse effects: Bleeding, dyspepsia

When to give: AF-related stroke prevention or VTE; revers with idarucizumab

Apixaban, rivaroxaban, edoxaban

MOA: Direct factor Xa inhibition

Key Adverse effects: Bleeding

When to give: AF-related stroke prevention or VTE; reversal may use factor Xa-specific therapy where available or PCC-based strategies

Fondaparinux

MOA: indirect Xa inhibition through antithrombin

Key Adverse effects: Bleeding

When to give: VTE treatment or prophylaxis; no specific antidote

UFH

Reversal Agent: Protamine, near-complete survival

LMWH

Reversal Agent: Protamine, partial reversal

Fondaparinux

Reversal Agent: no specific antidote

Warfarin

Reversal Agent: 4 factor PCC + vitamin K

Dabigatran

Reversal Agent: Idarucizumab

Apixaban/rivaroxban/edoxaban

Reversal Agent: 4-factor PCC or institution specific factor Xa reversal strategy

Argatroban/bivalirudin

Reversal Agent: stop infusion; no specific antidote

Quinidine, Procainamide, Disopyramide

MOA: Class 1A - Na+ & K+ block

Use: For atrial and ventricular arrthymias

AEs: QT prolongation —> TdP, lupus-like (procainaminde), anticholinergic (disopyramide), hypotension (qunidine)

Lidocaine

MOA: Class 1b - Na+ block

Use: Acute VT/VF post-MI

AEs: CNS toxicity (seizures, tremor), bradycardia

Flecainide, Propafenone

MOA: Class 1 C - strong Na+ block

Use: Supraventricular arrhythmia (AF in healthy heart)

AEs: Proarrhythmia, blurred vision, dizziness, taste disturbances (propafenone)

Amiodarone, dronedarone, Sotalol, Ibutilide, Dofetilide

MOA: Class 3 - K+ blockers

Use: broad-spectrum (AF, VT, VF). Amiodarone has all in one action of antiarrhythmics

AEs: Amiodarone: pulmonary fibrosis, hepatotoxicity, thyroid dysfunction (dronedarone has no thyroid adv effect), corneal deposits. Sotalol/Dofetilide: TdP (AT prolongation)

Atropine

MOA: Muscarinic blocker

Use: Acute bradyarrhythmias, AV block

AEs: anticholinergic: dry mouth, urinary retention, delirium

Adenosine

MOA: AV node inhibitor via A1 receptor

Use: first line for paroxysmal SVT

AEs: flushing, chest pain, transient aystole, bronchospasm, metallic taste