Hematopoietic & Lymphoreticular Flashcards
t(9;22)
Chronic myelogenous leukemia (CML)
t(12;21)
B-cell acute lymhocytic leukemia (ALL)
t(14;18)
Follicular lymphoma
t(15;17)
Acute promyelocytic leukemia (APL)
Translocation of retinoic acid receptor alpha gene (chromosome 17) and promyelocytic leukemia gene (chromosome 15)
Auer rods (see picture)
Tx: all-trans retinoic acid
Composition of platelet granules
Dense granules: ADP, calcium
α granules: vWF, fibrinogen
Bernard-Soulier syndrome
Deficiency of GpIb decreases platelet-to-vWF adhesion
von Willebrand disease
AD deficiency in von Willebrand factor prevents platelet adhesion and inhibits intrinsic pathway (vWF carries/protects factor VIII)
Dx: negative ristocetin test, increased BT and PTT
Tx: DDAVP (releases stored vWF from endothelial cells)
Glanzmann’s thromboasthenia
Deficiency of GpIIb/IIIa prevents platelet-to-platelet aggregation
Ticlopidine
Clopidogrel
Prasugrel
Ticalgrelor
Inhibits ADP-induced expression of GpIIb/IIIa inhibiting platelet aggregation
Indicated for ACS, coronary stending
SA: neutropenia (ticlopidine), TTP/HUS
Abciximab
Eptifibatide
Tirofiban
Inhibits GpIIb/IIIa directly preventing platelet aggregation
Indicated for unstable angina, angioplasty
SA: bleeding, thrombocytopenia
Vitamin K associated factors
II, VII, IX, X, C, S
Factor V Leiden
Mutant factor V is resistant to degradation by activated protein C → pro-thrombotic
β-thalassemia
Decreased synthesis of β globin chain due to point mutation in splice sites and promoter sequences (normally 2 genes on chromosome 11)
β-thalassemia minor (heterozygote): can be asymptomatic
β-thalassemia major (homozygote): severe anemia, HbA2, HbF, marrow expansion, extramedullary hematopoiesis
α-thalassemia
Decreased synthesis of α globin chain due to gene deletion (normally 4 genes on chromosome 16)
cis deletion in Asian populations (more severe disease in offspring)
Trans mutation in African populations
4 deletions: Hb Barts (γ2γ2), fetal hydrops
3 deletions: HbH (β2β2)
1-2 deletions: asymptomatic
Paroxysmal nocturnal hemoglobinuria
Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI) anchoring protein → inability to bind DAF allows complement-mediated damage to RBCs, WBCs, and platelets
Hemolysis occurs at night when shallow breathing → acidosis → complement activation
Triad: Coombs - hemolytic anemia, pancytopenia, venous thrombosis
Labs: lack of CD55/59 (DAF)
Tx: eculizumab
A/w acute leukemias
G6PD deficiency
X-linked recessive disorder characterized by decreased half-life of glucose-6-phosphate dehydrogenase → reduced production of NADPH → reduced glutathione regeneration → RBCs become susceptible to oxidative stress
Findings: Heinz bodies, bite cells
Hereditary spherocytosis
Inherited defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectrin, band 3.1, protein 4.2)
Autoimmune hemolytic anemia
Warm agglutinin (IgG): SLE, CLL, drugs
Cold agglutinin (IgM): CLL, Mycoplasma pneumonia, infectious mononucleosis
Immune thrombocytopenic purpura (ITP)
Autoantibody mediated destruction of platelets (typically IgG directed against GPIb or GPIIb/IIIa)
Increased megakaryocytes on bone marrow biopsy
Thrombotic Thrombocytopenic Purpura (TTP)
Deficiency of ADAMTS13 → reduced degradation of vWF multimers → accumulation of multimers promotes platelet activation and aggregation → microthrombi
Characterized by neurologic and renal symptoms, fever, thrombocytopenia, and microangiopathic hemolytic anemia
Tx: exchange transfusion and steroids
Disseminated intravascular coagulation (DIC)
Widespread activation of clotting leads to deficiency in clotting factors
Causes: sepsis (gram -), trauma, obstetric complications, acute pancreatitis, malignancy, nephrotic syndrome, transfusion
Labs: increased BT, PT, PTT, and fibrin split products (D-dimer), decreased platelets, fibrinogen, factors V and VIII
Hemophilia
Hemophilia A: defect in factor VIII
Hemophilia B: defect in factor IX
Both increase PTT and cause hemarthroses, easy bruising
Protein C or S deficiency
Reduced ability to inactivate factors V and VIII
Increased risk of thrombotic skin necrosis with hemorrhage following administration of warfarin
Which coagulation factors are activated by FVIIa?
IX, X
Which coagulation factors are activated by FIIa (thrombin)?
XI, VIII, V, XIII, activates platelets
Which coagulation factors require Vitamin K?
II (thrombin), VII, IX, X (2-7-9-10), protein C, and protein S
Which coagulation factors are found in cryoprecipitate?
I (fibrinogen), VIII, XIII, vWF, fibronectin
Which coagulation factor is produced outside of the liver in addition to within the liver?
Factor VIII is produced by endothelial cells
Which coagulation factors are inhibited by antithrombin III?
Inhibits thrombin and serine protease inhibitors (serpins) Potentiated by heparin XII, XI, IX, X, II (thrombin) 9-10-11-12 + 2 (thrombin)
Which coagulation factors are inactivated by the protein C and S complex?
Factors Va and VIIIa
What is Bernard-Soulier syndrome?
Bleeding disorder caused by genetic deficiency of GPIb –> prevents platelet adhesion
What is Glanzmann thrombasthenia?
Bleeding disorder caused by genetic deficiency of GPIIb/IIIa –> prevents platelet aggregation
What is HbH?
α-Thalassemia (three gene deletion) β2β2 hemoglobin
What is HbF?
Fetal hemoglobin α2γ2
What is HbA?
Normal adult hemoglobin α2β2
What is Hb Barts?
α-Thalassemia (four gene deletion) γ2γ2
What is HbA2?
Increased in β-thalassemia α2δ2
How many genes encode hemoglobin α chains and on which chromosome are they?
4 genes on chromosome 16
How many genes encode hemoglobin β chains and on which chromosome are they?
2 genes on chromosome 11
Which anemias results in extramedullary hematopoiesis (e.g. hematopoiesis moves into skull –> crew-cut x-ray, facial bones –> chimpmunk facies, liver, spleen –> hepatosplenomegaly)?
β-thalassemia major Sickle cell anemia
How do you diagnose specific thalassemias?
Gel electrophoresis α-thalassemia: HbH (β2β2) or Hb Barts (γ2γ2) β-thalassemia minor: reduced HbA (α2β2), increased HbA2 (α2δ2), increased HbF (α2γ2) β-thalassemia major: no HbA (α2β2), increased HbA2 (α2δ2), increased HbF (α2γ2)
Where is iron, folate, and vitamin B12 absorbed?
Duodenum, jejunum, and ileum, respectively
What is anisocytosis?
Variations in the size of RBCs
What is poikilocytosis?
Variations in the shape of RBCs
What are Howell-Jolly bodies?
Fragments of DNA left in RBCs that are usually removed by the spleen Associated with hereditary spherocytosis (treated with splenectomy), sickle cell anemia (autosplenectomy)
What is the difference in the gene mutation for sickle cell anemia and hemoglobin C?
A glutamic acid residue is replaced by valine in sickle cell anemia and lysine in hemoglobin C
What is CD55?
CD55 is decay accelerating factor (DAF) which is absent in paroxysmal nocturnal hemoglobinuria
What is a Heinz body?
Precipitated hemoglobin due to oxidative stress
G6PD deficiency
Heinz bodies are removed by splenic macrophages resulting in bite cells
Which diseases are associated with target cells?
Thalassemias
Hemoglobinopathies (sickle cell, HbC)
Which neoplasia is associated with t(12;21)?
B-cell acute lymphoblastic leukemia (B-ALL)
Good prognosis, more common in children
Which neoplasia is associated with t(9;22)?
Philadelphia chromosome –> BCR-ABL fusion protein –> increased tyrosine kinase activity –> treat with imantinib
B-cell acute lymphoblastic leukemia (B-ALL); poor prognosis, more common in adults
Chronic myeloid leukemia (CML)
Which neoplasia is associated with t(15;17)?
Acute promyelocytic leukemia
The retinoic acid receptor (RAR) on chromosome 17 is translocated to chromosome 15
RAR disruption blocks maturation and promyelocytes accumulate (Auer rods)
Treat with all-trans-retinoic acid (ATRA) –> vitamin A derivative
Which neoplasia is associated with t(14;18)?
Follicular lymphoma
Diffuse large B-cell lymphoma (most common type of NHL)
BCL2 on chromosome 18 translocates to the Ig heavy chain locus –> overexpression of Bcl2 (inhibits apoptosis)
Which neoplasia is associated with t(11;14)?
Mantle cell lymphoma
Cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus –> overexpression of cyclin D1 –> promotes G1/S cell cycle transition –> neoplastic proliferation
CD5+
Which neoplasia is associated with t(8;14)?
Burkitt lymphoma (B cells CD20+)
C-MYC on chromosome 8 translocates to Ig heavy chain locus –> overexpression of c-myc oncogene
Associated with EBV
African form → jaw
Sporadic form → abdomen, pelvis
Histology: “starry-sky”
Which neoplasias are associated with lytic bone lesions?
Adult T-cell lymphoma
Multiple myeloma
Which neoplasias are CD5+ and CD20+
CLL/SLL Mantle cell lymphoma
Langerhans cell histiocytosis
What diseases are associated with ineffective hematopoiesis?
Megaloblastic anemia
Hemolytic anemia
β-Thalassemia
What diseases are associated with tear-drop RBCs?
Extramedullary hematopoiesis (β-Thalassemia, sickle cell anemia)
Myelophthisic process
Myelofibrosis
What does tissue factor pathway inhibitor inhibit?
TF-VIIa complex and Xa
How do endothelial cells inhibit platelet activation and aggregation?
PGI2, NO, ecto-ADPase
Melphalan
Nitrogen mustard derivative bifunctional alkylating agent Alkylates DNA resulting in breaks and cross-linking
Chlorambucil
Nitrogen mustard derivative bifunctional alkylating agent Alkylates DNA resulting in breaks and cross-linking
Cyclophosphamide
Ifosfamide
Nitrogen mustard derivative bifunctional alkylating agent
Alkylates DNA resulting in cross-linking at guanine N-7
Must be activated by the liver
Side effects: hemorrhagic cystitis, myocardial necrosis, myelosuppression
Partially prevented with mesna
Carmustine
Nitrosurea alkylating agent
Alkylates DNA resulting in breaks and cross-linking
Can penetrate CNS
Can be used as implantable wafer
Lomustine
Nitrosurea alkylating agent
Alkylates DNA resulting in breaks and cross-linking
Can penetrate CNS
Cisplatin
Platinum alkylating agent
Cross-links DNA
Side effects: nephrotoxicity (prevent with amifostine and chloride diuresis), ototoxicity
Oxaliplatin
Platinum alkylating agent Cross-links DNA Side effects: neurotoxicity Treats colorectal cancer
Carboplatin
Platinum alkylating agent
Cross-links DNA
Procarbazine
Nonspecific alkylating agent Treats non-Hodgkin lymphoma Side effects: MAOI (eat less tyramine)
Vincristine
Binds to tubulin, prevents polymerization into microtubules, arrests cells in M-phase
Side effects: neurotoxicity (areflexia, peripherla neuritis), paralystic ileus
Vinblastine
Binds to tubulin, prevents polymerization into microtubules, arrests cells in M-phase
Side effects: neurotoxicity, mucositis, myelosuppression
Paclitaxel
Promotes polymerization and stability of microtubules and inhibits disassembly (prevents anaphase)
Side effects: neutropenia, mucositis, alopecia
Docetaxel
Promotes polymerization and stability of microtubules and inhibits disassembly Affect G2/M-phase Side effects: neutropenia, mucositis
Ixabepilone
Binds β-tubulin and promotes polymerization and stability of microtubules and inhibits disassembly Affect G2/M-phase Side effects: neutropenia, cardiotoxicity, peripheral neuropathy
Etoposide
Inhibits topoisomerase II and increases DNA degradation
Affects G2/S-phase
Side effects: myelosuppression
Teniposide
Inhibits topoisomerase II and increases DNA degradation
Affects G2/S-phase
Side effects: myelosuppression
Irinotecan
Inhibits topoisomerase I and prevents DNA unwinding and replication
Affects S-phase
Side effects: neutropenia, diarrhea
Topotecan
Inhibits topoisomerase I and prevents DNA unwinding and replication
Affects S-phase
Side effects: neutropenia, diarrhea
Daunorubicin
Anthracycline antibiotic: 1) intercalates in DNA inhibiting DNA and RNA polymerase 2) induces free radical formation which breaks DNA 3) inhibits DNA topoisomerase II
Side effects: cardiotoxicity (dilated cardiomyopathy from free radical damage), myelosuppression, alopecia
Dexrazoxane (iron chelator) may reduce cardiac damage
Doxorubicin
Anthracycline antibiotic: 1) intercalates in DNA inhibiting DNA and RNA polymerase 2) induces free radical formation which breaks DNA 3) inhibits DNA topoisomerase II
Side effects: cardiotoxicity (dilated cardiomyopathy from free radical damage), myelosuppression, alopecia
Dexrazoxane (iron chelator) may reduce cardiac damage
Dexrazoxane
Iron chelator inhibits free radical formation and reduces cardiac damage associated with daunorubicin and doxorubicin (anthracycline antibiotics)
Affects G2-phase
Bleomycin
Forms DNA-bleomycin-Fe complex that is oxidized –> free radicals break DNA
Affects G2-phase
Side effects: pulmonary fibrosis, hyperpigmentation of hands, mucositis
Methotrexate
Competitively inhibits dihydrofolate reductase: 1) prevents formation of dTMP 2) decreases synthesis of purine ring structure
Affects S-phase
Side effects: myelosuppression, mucositis, hepatotoxicity (high dose), abortifacient
Can use leucovorin (folinic acid) to reverse side effects
5-fluorouracil
Pyrimidine analogue converted to 5-FdUMP which inhibits thymidylate synthase; 5-FdUTP incorporated into RNA resulting in defective transcripts
Side effects: myelosuppression, photosensitivity
Rescue with uridine
Capecitabine
5-FU prodrug whose final set of activation is catalyzed by thymidine phosphorylase, and enzyme elevated in tumor cells
Cytarabine
Cytidine analogue converted to Ara CTP which inhibits DNA polymerase and causes DNA chain termination when incorporated
Causes pancytopenia
Gemcitabine
Cytidine analogue inhibits DNA polymerase and ribonucleotide reductase
Azacitidine
Pyrimidine nucleoside analog gets incorporated into RNA and inhibits processing and function Treats myelodysplastic syndrome
6-mercaptopurine
Purine analogue: 1) inhibits de novo purine synthesis 2) competitively inhibits biosynthetic reactions 3) incorporated into DNA and RNA
Side effects: myelosuppression, hepatotoxicity, increased toxicity with allopurinal (metabolized by xanthine oxidase)
6-thioguanine
Purine analogue: 1) inhibits de novo purine synthesis 2) competitively inhibits biosynthetic reactions 3) incorporated into DNA and RNA
Side effects: myelosuppression, hepatotoxicity
Asparaginase
Catalyzes conversion of asparagine to aspartate to inhibit protein synthesis (asparagine levels are low in tumor cells) Side effects: reduced protein synthesis (clotting factors, insulin, albumin), hypersensitivity reactions, hepatotoxicity
Imatinib mesylate
Competitively blocks ATP-binding side of c-abl tyrosine kinase Inhibits c-kit and PDGF-associated tyrosine kinases Treats CML and Ph+ ALL Side effects: myelosuppression and CHF
Erlotinib
Inhibits EGF receptor-associated tyrosine kinase Side effects: CHF
Gefitinib
Inhibits EGF receptor-associated tyrosine kinase Side effects: CHF
Vemurafenib
Inhibits B-raf serine-threonine kinase with V600E mutation
Treats melanoma
Cetuximab
Antibody against EGF receptor
Trastuzumab (Herceptin)
Inhibitor of HER2 tyrosine kinase receptor (extracellular domain)
SA: cardiotoxicity
Bevacizumab
Antibody against VEGF –> inhibits angiogenesis
Rituximab
Anti-CD20 antibody that promotes complement-mediated lysis of malignant B cells
May cause reactivation of HBV, increases risk of progressive multifocal leukoencephalopathy (a/w JC virus)
Ipilimumab
Antibody against CTLA-4 that blocks inhibitory activity Treats malignant melanoma
Pembrolizumab
Bind to PD-1 receptor on T cells
Gamtuzumab ozogamicin
Antibody against CD33 (myeloid surface antigen)
Bortezomib
Proteasome inhibitor Treats multiple myeloma and mantle cell lymphoma
all-trans-retinoic acid
Treats promyelocytic leukemia by causing blasts to mature
Heparin
Anticoagulant
Activates antithrombin –> inactivates thrombin and factor Xa
Indicated for PE, ACS, MI, DVT; safe during pregnancy (highly water soluble so doesn’t cross the placenta)
Monitor with PTT
Can reverse with protamine sulfate
Can cause heparin-induce thrombocytopenia –> IgG develops against heparin bound to platelet factor 4 –> activates platelets –> thrombosis and thrombocytopenia
Warfarin (Coumadin)
Inactivates vitamin K epoxide reductase –> reduced gamma-carboxylation of factors II, VII, IX, X, proteins C and S
Monitor with PT/INR
Contraindicated in pregnancy (highly lipophilic and crosses placenta)
May cause tissue necrosis
Give vitamin K or FFP for reversal
Smudge cells
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
TRAP +
Hairy cell leukemia
Enoxaparin
Low-molecular weight heparin (acts more on factor Xa)
Better bioavailability, 2-4 times longer half-life, can be administed subcutaneously and without laboratory monitoring
Dalteparin
Low-molecular weight heparin (acts more on factor Xa)
Better bioavailability, 2-4 times longer half-life, can be administed subcutaneously and without laboratory monitoring
Argatroban
Inhibits thrombin directly (derived from leeches)
Indicated for anticoagulation in patients with HIT
Bivalirudin
Inhibits thrombin directly (derived from leeches)
Indicated for anticoagulation in patients with HIT
Apixaban
Directly inhibits Xa
Indicated for stroke prophylaxis in patients with afib
Don’t require coagulation monitorng
Rivaroxaban
Directly inhibits Xa
Indicated for stroke prophylaxis in patients with afib, treatment and prophylaxis for DVT and PE
Don’t require coagulation monitorng
Alteplase (tPA)
Reteplase (rPA)
Tenecteplase (TNK-tPA)
Aids conversion of plasminogen to plasmin which cleaves thrombin and fibrin clots (↑ PT and PTT)
Indicated for early MI, stroke, severe PE
SA: bleeding
Treat toxicity with aminocaproic acid (fibrinolytic inhibitor), FFP, cryoprecipitate
Azathioprine
Purine analogue: 1) inhibits de novo purine synthesis 2) competitively inhibits biosynthetic reactions 3) incorporated into DNA and RNA
Side effects: myelosuppression, hepatotoxicity, increased toxicity with allopurinal (metabolized by xanthine oxidase)
Dactinomycin
Intercalates in DNA
SA: myelosupression
Hydroxyurea
Inhibits ribonucleotide reductase to decrease DNA synthesis
Imantinib
Tyrosine kinase inhibitor of brc-abl (Philadephia chromosome fusion gene in CML) and c-kit
Indicated for CMG, GI stromal tumors
SA: fluid retention
Common chemotoxicities
Rasburicase
Recombinant version of urate oxidase, and enzyme that converts uric acid into more soluble metabolites to prevent hyperuricemia from tumor lysis syndrome
Pure reb cell aplasia
Associated with parvovirus B19 infection, thymomas, or lymphocytic leukemias
