USMLE - Hematology/Oncology Part 2

Sickled cells are crescent shaped RBCs
Crew cut on skull XR due to marrow expansion from erythropoiesis (also in thalassemias)
Hydroxyurea (↑ HbF) and bone marrow transplant

Aplastic crisis (due to parvovirus B19)
Autosplenectomy (Howell-Jolly Bodies) --> ↑ risk of infections with encapsulated organisms; Functional splenic dysfunction in early childhood
Splenic sequestration crisis
Salmonella Osteomyelitis
Painful crisis (vaso-occlusive): Dactylitis, actue chest syndrome, avascular necrosis
Renal Papillary Necrosis (due to low O2 in papilla)
Microhematuria (medullary infarcts)

Extrinsic Hemolytic Normocytic Anemia
Warm and Cold Agglutinin
Coomb's Positive

Direct: anti-Ig Ab added to pt's serum --> RBCs agglutinate if coated with Ig
Indirect: Normal RBCs added to pt's serum agglutinate if serum has anti-RBC surface Ig

"Warm weather is Great"
IgG
Chronic
SLE, CLL, drugs (metyldopa)

"Cold ice cream is yuMMM"
IgM
Acute anemia triggered by cold
CLL, Mycoplasma pneumonia infections, infectious Mononucleosis

Extrinsic Hemolytic Normocytic Anemia
RBCs damaged when passing through obstructed or narrowed vessel lumina
DIC, TTP/HUS, SLE, Malignant HTN
Schistocytes

Extrinsic Hemolytic Normocytic Anemia
Prosthetic heart valve and aortic stenosis damage RBCs
Schistocytes

Extrinsic Hemolytic Normocytic Anemia

| Malaria, Babesia

↓ (primary)
↑
↓
↓↓

↓
↓
↑ (primary)
No change

↑ (primary)
↓
↑
↑↑

No change
↑ (primary)
No change
↓

Ferrochelatats and ALA Dehydratase
Protoporphyrin and δALA in blood
Microcytic anemia, GI and Kidney disease
Children: lead paint --> mental retardation
Adults: battery, ammunition, radiator factory --> Headache, Memory loss, Demyelination

Porphobilinogen daminase
Porphobilinogen, δALA, uroporphyrin (urine)
Painful abdomen, Port wine colored urine, Polyneuropathy, Psychological disturbances, Precipitated by drugs
Glucose and heme inhibit ALA synthase

Uroporphyrinogen decarboxylase
Uroporphyrin (tea colored urine)
Blistering cutaneous photosensitivity
Most common porphyria

Mito:
Glycine + Succinyl-CoA --> [δALA synthase + B6] --> δALA
Cyto:
δALA --> [δALA dehydratase] --> Porphobilinogen --> [Porphobilinogen deaminase] --> Hydroxymetylbilane --> Uroporphyrinogen III --> [Uroporphyrinogen decarboxylase] --> Coproporphyrinogen III
Mito:
Coproporphyrinogen III --> Protoporphyrin
Protoporphyrin + Fe --> [Ferrochelatase] --> Heme

δALA synthase

| Inhibited by Glucose and Heme

Extrinsic and Common pathways

| I, II, V, VII, X

Intrinsic and Common pathways

| all factors except VII, XIII

No change in PT

↑ PTT

Intrinsic coagulation defect

A: VIII

B: IX

Macrohemorrhage: Hemarthrosis, Easy bruising

↑ PT
↑ PTT
↓ synthesis of II, VII, IX, X, C, S

Microhemorrhage: Mucus membrane bleeding, Epistaxis, Petechiae, Purpura, ↑ bleeding time, possible ↓ platelet count

↓ PC
↑ BT
↓ GpIb --> defect in platelet to vWF adhesion

No change in PC
↑ BT
↓ GpIIb/IIIa --> defect platelet-to-platelet aggregation
No platelet clotting on blood smear

↓ PC
↑ BT
Anti-GpIIb/IIIa Ab --> splenic macrophage consumption of platelet/Ab complex --> ↓ platelet survival
↑ megakaryocytes

↓ PC
↑ BT
Deficiency in ADAMTS13 (vWF metalloprotease) --> ↓ degradation of vWF multimers
↑ vWF multimers --> ↑ platelet aggregation and thrombosis
↓ platelet survival
Schistiocytes, ↑ LDH
Neurologic and renal symptoms, Fever, Thrombocytopenia, and Microangiopathic hemolytic anemia

No change in PC
↑ BT
No change in PT
No change or ↑ PTT

Intrinsic pathway defect: ↓ vWF --> normal or ↑ PTT because vWF protects VIII
↓ vWF --> defect in platelet-to-vWF adhesion
Most common inherited bleeding disorder
Mild
AD
Ristocetin cofactor assay
Desmopressin releases vWF from endothelium

↓ PC
↑ BT
↑ PT
↑ PTT

Widespread activation of clotting leds to deficiency in clotting factors leading to bleeding
"STOP Making New Thrombi"
Sepsis (gram neg), Trauma, Obstetric complication, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion
Schistocytes, ↑ Fibrin split products (D-dimer), ↓ fibrinogen, ↓ factor V and VIII

Mutant V resistant to degradation by C --> hypercoagulability
Most common cause of inherited hypercoagulability in whites

Mutation in 3' UTR --> ↑ production of prothrombin --> ↑ plasma levels and venous clots --> hypercoagulability

Inherited deficiency of antithrombin --> hypercoagulability

| ↑ PTT is blunted after heparin administration

↓ ability to inactivate V and VIII --> hypercoagulability

| ↑ risk of thrombotic skin necrosis with hemorrhage following administration of warfarin

↑ Hb and O2 carrying capacity

| Acute blood loss, severe anemia

Increase platelet count

| Stop significant bleeding (Thrombocytopenia, Qualitative platelet dysfunction)

↑ Coagulation factor levels

| DIC, Cirrhosis, Warfarin OD

Contains Fibrinogen, VIII, XIII, vWF, and Fibronectin

| Treats coagulation factor deficiencies involving fibrinogen and VIII

Infection, Transfusion reaction, Iron Overload, HypoCa (citrate is a Ca chelator), HyperK (RBC lysis)

Lymphoid or Myeloid neoplasm with widespread involvement of bone marrow
Tumor cells are usually found in peripheral blood

Discrete tumor masses arising form lymph nodes

| Presentations blur definitions

Acute inflammatory response to infection
↑ WBC count with ↑ neutrophils and bands
↑ Leukocyte ALP
In CML, ↓ Leukocyte ALP

Localized, single group of nodes; extra nodal involvement rare. Contiguous spread
Stage is strongest predictor of prognosis
Reed-Sternberg cells
Bimodal distribution: young adulthood and over 55. More common in men except for nodular sclerosing type
EBV
Fever, night sweats, wt loss

Multiple, peripheral nodes. Extra nodal involvement common. Noncontiguous spread
Majority involve B cells (except for lymphoblastic T cell origin)
20-40
HIV and immunosuppression
Few constitutional signs/symptoms

Giant cell. Binucleate, bilobed w/ 2 halves as mirror images (owl eyes)
Hodgkin's Lymphoma
CD30, CD15
B cell origin
Necessary but not sufficient for diagnosis
Best prognosis with strong stromal or lymphocytic reaction against RS cells
RS rich has best prognosis

Most common

| Affects women and men equally

Lymphocyte mixed or depleted forms

Non-Hodgkin's Lymphoma

Neoplasm of mature B cells

Adolescents or young adults

t[8 (cmyc), 14 (heavy-chain Ig)]

Starry sky appearance: sheets of lymphocytes with interspersed macs

EBV

Jaw lesion in endemic forms in Africa

Pelvis or abdominal in sporadic form

Non-Hodgkin's Lymphoma

Neoplasm of mature B cells

Older adults but 20% in children

Most common adult NHL

20% mature T cell origin

Non-Hodgkin's Lymphoma

Neoplasm of mature B cells

Older males

t[11 (cyclin D1), 14 (heavy-chain Ig)]

Poor

CD5

Non-Hodgkin's Lymphoma

Neoplasm of mature B cells

Adults

t[14 (heavy-chain Ig), 18 (bcl2)]

Difficult to cure, indolent course

bcl2 inhibits apoptosis

Non-Hodgkin's Lymphoma

Neoplasm of mature T cells

Adults

Caused by HTLV1

Cutaneous lesions

Japan, West Africa, Caribbean

Aggressive

Sezary Syndrome

Non-Hodgkin's Lymphoma

Neoplasm of mature T cells

Adults

Cutaneous patches/nodules

CD4

Indolent course

Monoclonal Plasma Cell cancer (fried egg appearance). Clock face chromatin and intracytoplasmic inclusions w/ immunoglobulins

Arises in the marrow

Most common primary tumor of bone in those over 50

IgG (55%) and IgA (25%)

Susceptibility to infection, Amyloidosis
Punched out lytic bone lesions
M spike on protein electrophoresis
Ig Light Chains in urine (Bence Jones Protein)
Rouleaux formation (RBCs staked like poker chips)
"CRAB"
hyperCa, Renal insufficiency, Anemia, Bone lytic lesions/Back pain

Both have an M spike but WM doesn't have lytic bone lesions

Spike in γ on protein electrophoresis

| Multiple Myeloma, Waldenstrom's Macroglobulinemia, MGUS

Monoclonal Gammopathy of Undetermined Significance

Monoclonal expansion of plasma cells

M spike

Asymptomatic

Precursor to multiple myeloma

Unregulated growth of leukocytes in bone marrow
↑ or ↓ # of circulating leukocytes in blood and marrow --> anemia (↓RBCs), infections (↓ mature WBCs), and hemorrhage (↓ platelets)
Leukemic cells infiltrate liver, spleen, and lymph nodes

Lymphoid Neoplasm
Under 15
T cell ALL presents with mediastinal mass (leukemic infiltration of the thymus). Peripheral blood and bone marrow have ↑ lymphoblasts
TdT+ (marker for pre-T and pre-B cells), CALLA
Most response to therapy
CNS and testes
t(12;21) --> best prognosis

Lymphoid neoplasm

Over 60

Often asymptomatic. Smudge cells in peripheral blood smear. Autoimmune hemolytic anemia

CLL has ↑ peripheral blood lymphocytosis or bone marrow involvement

Lymphoid neoplasm
Adults
Mature B cell tumor in the elderly
Filamentous hair like projections. Stains TRAP+
Cladribine (adenosine analog resistant to ADA)

Myeloid Neoplasm
Median age of onset is 65
Auer Rods
↑↑↑ circulating myeloblasts on peripheral smear
t(15;17) --> M3 AML subtype which responds to all trans Retinoic acid inducing differentiation of myeloblasts
DIC is a common presentation in M3 AML

Myeloid Neoplasm
30-60
Philadelphia chromosome t(9;22) bcr-abl
Myeloid stem cell proliferation
↑ Neutrophils, Metamyelocytes, Basophils, Splenomegaly
May accelerate and transform into AML or ALL (blast crisis)
Low Leukocyte ALP from immature granulocytes (vs leukemoid reaction - mature cells)
Imatinib

Peroxidase+ Cytoplasmic inclusions in granulocytes and myeloblasts
Acute polymyelocytic Leukemia (M3)
Treatment of M3 AML can release Auer rods and produce DIC

t(9;22) bcr-abl hybrid

| CML

Burkitt's Lymphoma (c-myc activation)

Mantle Cell Lymphoma (cyclin D1 activation)

Folliclar Lymphoma (bcl2 activation)

M3 AML

| Responsive to all trans retinoic acid

Proliferative disorder of dendiritic cells from monocyte lineage
Child w/ lytic bone lesions and skin rash
Functionally immature and do not efficiently stimulate T lymphocytes via Ag presentation
S100 (neural crest cell origin) and CD1a
Birbeck granules (tennis rackets) on EM

Polycythemia Vera

What kind of disorder

RBCs

WBCs

Platelets

Philadelphia Chromosome

JAK2 mutation

Essential Thrombocytosis

What kind of disorder

RBCs

WBCs

Platelets

Philadelphia Chromosome

JAK2 mutation

Chronic Myeloproliferative Disorder

↓

Variable

Variable

-

+ (30-50%)

Chronic Myeloproliferative Disorder

↓

↑

↑

+

-

Abnormal clone of hematopoietic stem cell with constitutively active JAK2 receptor that proliferate w/o EPO
Itching after a hot shower

Similar to Polycythemia Vera but specific for megakaryocytes

Fibrotic obliteration of bone marrow
Teardrop cell
"bone marrow is crying because it is fibrosed"

↓
No change
No change

No change
↑
↓
Lung disease, Congenital Heart Disease, High Altitude

No change

↑

No change

Renal Cell Carcinoma, Wilm's Tumor, Cyst, Hepatocellular Carcinoma, Hydronephrosis,

Ectopic EPO

↑

↑↑

No change

Activates antithrombin leading to ↓ thrombin and ↓ X

Short half-life

PE, Acute Coronary Syndrome, MI, DVT

Can be used during pregnancy: does not cross placenta

Follow PTT

Bleeding, Thrombocytopenia (HIT), Osteoporosis, Drug-drug interactions

Protamine sulfate

Acts more on X, better bioavailability, and 2-4 times longer half-life
Can be administered subcutaneously and without laboratory monitoring
Not easily reversible

Development of IgG Abs against heparin bound to platelet factor 4
Ab-Heparin-PF4 --> platelets --> thrombosis --> thrombocytopenia

Derivative of Hirudin
Leeches
Anticoagulant that inhibits thrombin
Alternative to heparin in pts with HIT

"The EX-PresidenT went to WARfarin"

Coumadin

Interferes with γ-carboxylation of VitK dependent clotting factors II, VII, IX, X, C, and S

CytP450

Affects extrinsic pathway and ↑ PT

Long half life

Chronic anticoagulant (after STEMI, Venous Thromboembolism, Stroke prevention after Afib)
Do not use in pregnant women (crosses placenta)
Follow PT/INR
Bleeding, Teratogenic, Skin/Tissue necrosis, Drug-drug interactions
VitK. For rapid reversal fresh frozen plasma

Heparin

Structure

Route of Administration

Site of action

Onset

Duration

Only Heparin does

Small lipid soluble molecule

Oral

Liver

Slow

Days

Alteplase (tPA), Reteplase (rPA), Tenecteplase (TNK-tPA)

--> Plasmin

↑ PT, ↑ PTT, No change in platelet count

Early MI, Early Stroke, PE

Bleeding, Reperfusion arrhythmias

Active bleeding, Intracranial bleeding, Recent surgery, known bleeding diatheses, HTN

Aminocaproic acid

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Irreversibly blocks ADP receptor. Inhibits fibrinogen binding by preventing glycoprotein IIb/IIIa from bind fibrinogen
Acute Coronary Syndrome; Coronary Stenting; ↓incidence or recurrence of thrombotic stroke
Aspirin
Ticlopidine: Neutropenia, oral ulcers, fever

Phosphodiesterase III inhibitor. ↑cAMP in platelets thus inhibiting platelet aggregation; Vasodilator
Claudication, Coronary Vasodilation, Prevention of stroke or TIA, Angina Prophylaxis
Nausea, Headache, Facial Flushing, Hypotension, Abdominal Pain

Abciximab, Eptifibatide, Tirofiban
A is made from monoclonal Ab Fab fragment
Inhibits platelet aggregation by binding GP IIb/IIIa receptor on activated platelets
Acute coronary Syndromes, Percutaneous Transluminal Coronary Angioplasty
Bleeding, Thrombocytopenia

Antimetabolite
Folic Acid analog that inhibits DHF Reductase
↓ dTMP --> ↓ DNA and ↓ Protein synthesis
Leukemias, Lymphomas, Choriocarcinoma, Sarcomas, Abortion, Ectopic Pregnancy, RA, Psoriasis
Myelosuppression (reversible w/ leucovorin), Macrovesicular fatty change in liver, Mucositis, Teratogenic

Antimetabolite
Pyrimidine analog. Bioactivated to 5F-dUMP, which covalentaly complexes folic acid. The complex inhibits Thymidylate synthase leading to ↓ dTMP --> ↓ DNA and ↓ Protein synthesis
Colon cancer, Basal cell carcinoma (topical)
Myelosuppression (irreversible w/ leucovorin), Photosensitivity
OD treat with Thymidine

Arabinofuranosyl Cytidine

Antimetabolite

Pyrimidine analog inhibits DNA pol

Leukemias, Lymphomas

Leukopenia, Thrombocytopenia, Megaloblastic Anemia