Hematology Flashcards
What clinical features are necessary to consider Thrombotic Thrombocytopenic purpura?
Microangiopathic hemolytic anemia and Thrombocytopenia
What causes Thrombotic Thrombocytopenic purpura?
Inhibition or deficiency of ADAMTS13 (cleaves vWF), leading to vWF multimers
What is the deficiency in Acute Intermittent Porphyria?
Porphobilinogen deaminase
What is the treatment for Acute Intermittent Porphyria?
Hemin- downregulates aminolevulinate synthase
What mutations are common in hereditary spherocytosis?
Scaffolding proteins- ankyrin and spectrin
What are the symptoms associated with hereditary spherocytosis?
hemolytic anemia, jaundice, and splenomegaly. Infection can trigger acute hemolytic crisis
Why can’t mature erythrocytes produce heme?
Mitochondria are required for the first and last 3 steps of heme synthesis
How does posttranscriptional silencing work?
miRNAs and siRNAs are incorporated into RNA-induced silencing complexes. If the RISC and mRNA are a perfect match, they mRNA will be cleaves. If they are a partial match, there will be translational repression, because the ribosome cannot bind
What are the major mechanisms of cell death via ionizing radiation?
DNA double strand break
Free radical formation
What is the surface marker for monocyte-macrophage lineage?
CD14
What is pure red cell aplasia? With which diseases is it associated?
Rare form of marrow failure characterized by hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis.
Associated with thymoma, lymphocytic leukemias, and parvo b19
Why is desmopressin beneficial to patients with von willebrand disease?
Increases vWF factor release from endothelial cells. Also raises circulating levels of factor VIII (hemophilia A)
What is the drug of choice in treatment of heparin-induced thrombocytopenia?
Direct thrombin inhibitor (-rudin, argatroban, dabigatran)
also, stop heparin
Which myeloproliferative disorders have a mutation in JAK2?
Essential thrombocytosis
Polycythemia vera
Primary Myelofibrosis
What is primary myelofibrosis?
Megakaryocytic hyperplasia stimulates fibroblasts, leading to replacement of marrow space with collagen. Hepatosplenomegaly is due to extramedullary hematopoiesis. Teardrop cells
Name the steps and special proteins involved in inflammatory leukocyte migration
- Margination
- Rolling: Sialylated carb groups bind to L-Selectin on neutrophils or E/P-selectin on endothelial cells
- Activation
- Tight adhesion and crawling: Neutrophilic CD 18 beta 2 integrins bind to endothelial ICAM-1
- Transmigration: Neutrophil integrin attachment to PECAM-1
What are the types of leukocyte adhesion deficiencies?
Type 1: absence of CD18, recurrent skin infections sans pus, delayed detachment of umbilical cord
Type 2: less severe
Type 3: similar to type 1
What are the symptoms associated with polycythemia vera?
aquagenic pruritis, facial plethora, splenomegaly
What causes polycythemia vera?
mutation in JAK2, a cytoplasmic (non-receptor) tyrosine kinase
What are heterophile antibodies?
Abs which react to antigens from animal erythrocytes
Which malignancies are associated with EBV?
Burkitt Lymphoma (especially endemic) Nasopharyngeal carcinoma
What are the stop codons?
UAA, UGA, UAG
What determines the prognosis of colorectal adenocarcinoma?
Tumor stage
What is the histological appearance of the spleen in SS patients after repeated infarction?
significant scarring, fibrosis, and atrophy
Why do SS patient have increased folic acid demand?
Increased erythrocyte turnover
What is a common histochemical marker for epithelial-derived tumors?
cytokeratin
What does the HER2 oncogene do?
codes for a human epidermal growth factor receptor with tyrosine kinase activity in the intracellular domain- activates epithelial growth and differentiation, reduces apoptosis.
What drug can be used for HER2 + carcinomas?
Trastuzumab
What are the steps involved in basement membrane penetration?
- detach by reducing E-cadherin expression
- Attach to BM by increasing Laminin
- Invade by releasing proteolyic enzymes
What is haptoglobin?
The thing in blood that binds to hemoglobin after hemolysis
What happens when there is a point mutation in the kozak consensus sequence of the beta globin?
ribosome does not assemble–> translation is not initiated–> beta thalassemia
What symptoms are worrisome for spinal metastases?
advanced age, progressive and persistent pain that is worse at night, not relieved by rest or analgesics, and is accompanied by systemic symptoms
Addition of what substance to a folate-deficient medium can reduce apoptosis?
Thymidine
What are the symptoms of infectious mononucleosis?
sore throat, myalgias, malaise, lymphadenopathy, splenomegaly, and fever
How does EBV infect lymphocytes?
binds to CD-21 on B-cells and infects them. Reactive (atypical) CD 8 T-cells then kill the virally infected B cells
How do reactive (atypical) T-cells look?
Larger with abundant cytoplasm, eccentrically placed nucleus, and cells membrane that conforms to border of other cells.
What stage of the cell cycle do Vinka alkaloids inhibit?
M phase by binding to beta tubulin and preventing polymerization of microtubule proteins
What are the signs and symptoms of multiple myeloma?
bone pain, fatigue, anemia, kidney dz, and hypercalcemia
What is the mechanism of action of bortezomib (boronic acid containing peptide) in MM?
In MM too much Ig is being made- bortezomib inhibits the proteasome, so there is accumulation of toxic intracellular proteins and proapoptotic proteins
Where does complement (C1) bind the Fc portion of IgG or IgM?
The Fc portion closer to the hinge region
What is a common cause for bleeding complications in neonates that do not receive normal care?
Vitamin K deficiency- need prophylactic supplementation. Vit K needed for gamma carboxylation
Which other enzyme deficiency can present similarly to G6PD deficiency?
Glutathione reductase- Along with NADPH, it is necessary for reduction of oxidized glutathione.
What is the acquired mutation in paroxysmal nocturnal hemoglobinuria?
PIGA gene that is involved in synthesis of GPI anchor that is needed for CD55 and CD59 attachment. CD55 and CD59 are need to inactivate complement and prevent MAC forming on normal cells.
What are the s/s of paroxysmal nocturnal hemoglobinuria?
hemolytic anemia, hypercoagulability (due to release of free Hgb and other prothrombotic factors from lysed red blood cells), and pancytopenia.
More hemolysis at night due to lower blood pH.
What is the effect of pyruvate kinase deficiency on RBCs?
Can’t produce ATP, so lose concentration gradients and defective maintenance of cell membrane architecture–> hemolysis.
What effect do damaged red blood cells have on the spleen?
Hyperplasia of the red pulp since reticuloendothelial cells are involved in the removal of damaged RBCs
What does integrin bind to in the ECM?
fibronectin, collagen, and laminin
What are some extrapulmonary manifestations of Mycoplasma pneumoniae?
Hemolytic anemia from cold agglutinins, SJS, joint pains, encephalitis, cardiac rhythm disturbances, bullous myringitis
What are the symptoms associated with B12 deficiency?
megaloblastic anemia, paresthesias, weakness, ataxic gait (dorsal and lateral columns)
What are some causes of aplastic anemia?
Autoimmune
Drug: Carbamazepine, chloramphenicol, sulfonamides
Infection: Parvo B19, EBV
Exposure to radiation or toxins- benzene, solvents
What is the presentation of aplastic anemia?
pancytopenia without splenomegaly
Dry tap- bone marrow is hypocellular with hematopoietic elements replaced by fat and bone marrow stroma
How does protein c restrict clot formation?
inactivates Va and VIIIa
What are the lab values associated with uremic platelet dysfunction?
Normal PT, PTT, and platelet count
Increased bleeding time
What type of anemia is seen in SLE?
Autoimmune hemolysis due to warm IgG antibodies against RBCs.
Spherocytosis, + direct coombs test, extravascular hemolysis
Can also get leukopenia and thrombocytopenia
Can lead to IC deposit and Lupus nephritis
Why does t(15;17) cause malignancy?
Leads to abnormal RARareceptor that can’t signal for myeloid differentiation at physiologic levels of retinoic acid
Discuss the steps in the activation of the mTOR pathway
- growth factor binds receptor tyrosine kinase–> autophosphorylation
- phosphotyrosine residues activate PI3K
- Phosphorylates PIP2–>PIP3
- Activation of Akt
- Activates mTOR
- Translocates to nucleus and induces genes for survival, antiapoptosis, and angiogenesis
What histologic feature indicates myeloid differentiation?
Auer rods
Stain for peroxidase
What are the clinical s/s of AML and what causes them?
anemia, thrombocytopenia, and neutropenia due to marrow replacement by leukopenic cells
Which of the most common non hodgkin lymphomas is indolent with a waxing and waning course?
follicular lymphoma- most often present with painless lymph node enlargement
What types of mutations cause beta thalassemia?
ones that result in defective transcription, processing, and translation of Beta-globin mRNA
Which symptoms are associated with platelet deficiencies versus factor deficiencies?
Platelet: Epistaxis, gingival bleeding
Factor: hemarthrosis, bruising
How does HIV become resistant to protease inhibitors, NRTIs, and NNRTI?
Pol gene mutation
What is the peau d’orange rash and what causes it?
Itchy, erythematous rash with firm and coarse skin texture- rapidly progressive
peau d’orange + breast edema=inflammatory breast cancer
The rash is caused by cancerous cells obstructing lymph drainage
What are characteristic lab abnormalities in HUS?
decreased hemoglobin and platelet count and increased bleeding time, LDH, bilirubin, BUN, and creatinine
What is Wiskott-Aldrich syndrome and what are the three cardinal findings?
XLR B cell and Tcell disorder
Eczema, recurrent infections (especially polysaccharide capsular organisms), and thrombocytopenia (petechiae, purpura, hematemesis)
What causes a right shift of the oxygen-hemoglobin dissociation curve
increased H+, 2-3BPG, Temp,
Which antiemetic drugs and receptors are useful in the treatment of chemotherapy induced nausea?
5-HT3 receptor antagonist: ondansetron- blocks vagus mediated nausea and central 5HT receptors in the area postrema
NK1 receptor antagonist: aprepitant- inhibits substance P
DA antagonist: metoclopramide
What mutation causes X-linked sideroblastic anemia? What vitamin is a cofactor for this enzyme?
ALA synthase
B6–> pyridoxal 5’ phosphate
What are the symptoms of B6 deficiency?
dermatitis, stomatitis, neuropathy, confusion, and sideroblastic anemia
What are the treatments for cyanide poisoning?
Inhaled amyl nitrate: changes hemoglobin into methemoglobin, which bind better to CN than O2.
Hydroxycobalamin and sodium thiosulfate- turn CN into relatively nontoxic metabolites
What are the symptoms of CN poisoning?
Reddish skin discoloration, tachypnea, headache, and tachycardia, often accompanied by N/V, confusion, and weakness
What happens in CCl4 poisoning?
CYP 450 metabolizes CCl4 to toxic CCl3. This form free radicals that attack the the plasma membrane via lipid peroxidation, which leads to further damage from the peroxide created in the process
Where does B cell VDJ recombination take place?
bone marrow
Where does isotype switching occur?
in germinal centers within the follicles of the lymph node
What are the skin findings in dermatomyositis?
heliotrope rash in the peri-orbital area and cheeks
Gottron’s papules- raised erythematous papules over joints and bony prominences of the hands
With which malignancies is dermatomyositis associated?
ovarian, lung, colorectal, and non-hodgkin lymphoma
What is a pathognomonic blood smear finding in AML?
Auer rods
Why does overexpression of BCL2 lead to malignancy?
inhibits apoptosis of tumor cells
What is the most common brain tumor in adults? What are the histological findings?
Glioblastoma multiforme
Gross: areas of necrosis and hemorrhage
Light microscopy: psudopalisading tumor cells and areas of necrosis
What are the markers in ALL vs. AML?
AML: peroxidase positive granules (auer rods)
ALL: TdT+ and PAS+
What are the precursor B cell markers?
CD10, CD19
What are the precursor T cell markers?
CD 1, 2, 3, 4, 5, 7, 8
What downregulates the T-cell response to tumor cells?
Binding of PD-1 to PD-1L. MABs blocking PD-1 can promote apoptosis of tumor cells
Why would erythrocytes have not net gain of ATP in glycolysis?
If they were making 2,3-BPG during a hypoxic state- detours from the step that would generate ATP
What is the treatment for carcinoid syndrome?
octreotide for symptomatic patients
surgery for liver metastases
What is the primary mechanism of iron deficiency anemia?
blood loss. In the GI tract it is most often occult blood loss
What is the product of c-myc?
a nuclear phosphoprotein that functions as a transcription activator controlling cell proliferation, differentiation, and apoptosis
What is the leukemoid reaction? What are leukocyte alkaline phosphatase levels? What is seen on peripheral smear?
Leukemoid reaction is a benign leukocytosis in response to severe infection
The leukocyte alkaline phosphatase levels are normal or increased (decreased in CML)
There are basophilic inclusions in mature neutrophils- ribosomes bound with RER
What is the action of the Rb tumor suppresor gene
Rb is active in its hypophosphorylated state and prevent the cell from moving from G1 to S
What happens with an activating mutation in a KRAS gene?
Constitutive downstream signaling in the absence of EGFR–> increased cell proliferation and growth that is resistant to anti-EGFR meds.
Which drugs cause aplastic anemia?
carbamazepine, chloramphenicol, sulfonamides
When do T cells stop expressing both CD4 and CD8?
After negative selection is complete
What causes the greenish color from a bruise after a few days?
Erythrocyte destruction–> release of iron-containing heme molecules that are degraded by heme oxygenase to biliverdin, CO2, and Fe. Biliverdin is green and is then further reduced to the yellow pigment bilirubin, whichis then transferred to the liver bound to albumin
WHy is a reticulocyte bluer than an erythrocyte?
Because it retains its basophilic, reticular network of residual rRNA
What nail changes are seen in iron deficiency?
koilonychia- spoon-shaped nails
What causes primary hemochromatosis?
HFE gene mutation- normally complexes with transferrin to sense iron stores, but mutation causes it to detect falsely low iron levels.
This causes enterocytes to increase apical expression of DMT 1, which increases iron absorption from the intestinal lumen. Hepatocytes decrease hepcidin synthesis, resulting in increased ferroportin expression on the basolateral surface of enterocytes, leading to increased iron absorption
What is the main mediator of neoplastic cachexia?
TNF-alpha:
- hypothalamus: appetite suppression
- Increases basal metabolic rate
What are the characteristic s/s/pathology of Hairy cell leukemia?
dry tap with marrow fibrosis, massive splenomegaly
lymphocytes with filamentous, hair-like cytoplasmic projections. TRAP stain
What is the treatment for hairy cell leukemia?
Cladribine and and pentostatin (adenosine analogs)
What are the classic histological findings in Burkitt’s lymphoma?
Diffuse medium-sized lymphocytes and high proliferation index represented by high Ki-67 fraction
Starry sky appearance (macrophages)
How does the ristocetin test work?
Ristocetin causes platelets to express GP1b. If platelets do not aggregate, then vWF level is decreased.
What is the the first line therapy for menorrhagia due to vWF disease?
COCs
What does the JAK2 V617F mutation do in polycythemia vera?
Makes hematopoietic cells more sensitive to growth factors
Discuss the phases of apoptosis
Initiation: Bcl-2 and Bcl-x are replaced with proapoptotic Bak, Bax, and Bim, allowing for increased permebility of the mitochondria and release of cytochrome c, which activates caspase.
Execution: Caspases cleave cellular proteins and activate DNAses
What is the most common cause of aplastic anemia in a patient with sickle cell?
Parvovirus B19
