Heme/Onc Flashcards
How does Factor V Leiden cause hypercoagulable state?
Usually activated protein C proteolytically inactivates Va (and VIIIa). Va Leiden doesn’t get cleaved as well. Furthermore, Va helps prothrombin - >thrombin.
How prevent tumor lysis syndrome?
Hydration and hypouricemic agents like allopurinol (xanthinse oxidase inhibitor) or rasburicase (urate oxidase which makes uric acid into allantoin)
Hydroxyurea tx for sickle cell?
Increases Hb F synthesis by unknown mechanism. Use for those w/ freq. pain crisis.
HUS
Microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency. Typically after EHEC O157:H7 -> hemorrhagic diarrhea and cramping, undercooked beef/unpasteurized milk. Endothelial injury > isolated activation of PLT = micro thrombi -> schistocytes w/o coagulation system activation (DIC).
HbC?
Glutamic acid -> Lysine (Neg to POS). Less movt non electrophoresis.
FFP vs. Cryoprecipitate
FFP contains all coagulation factors. Cryo only contains cold-soluble proteins (VIII, fibrinogen, vWF, vitronectin, XIII). Cold F-Eight von Vitronectin!
High dose ADH affects coagulation how?
Increases factor VIII activity in pts with Hemophilia A and von Willebrand disease.
Von willebrand Disease
AD with variable penetrance. vWF is mediator of platelet adhesion. Absence leads to function factor VIII and pot deficiency = inc. PTT and inc. bleeding time.
Where does 2,3-DPG bind?
To the two beta subunits of HbA after Hgb is deoxygenated. HbF (2 alpha, 2 gamma) does NOT bind to 2,3-DPG as well, so binds to O2 with HIGHER affinity (usu. bad, except helpful for HbF).
Polycythemia vera
Plethoric face, splenomegaly, peptic ulceration, itching, gouty arthritis. Mutation in JAK2 = non-receptor tyrosine kinase associated with EPO receptor. Constiutive kinase activation -> inc. production of blood cells.
Vincristine, bleomycin, doxorubicin, cyclophosphamide side effects
Vincristine - neurotoxicity. Bleomycin - pulmonary fibrosis and flagellate skin discoloration, doxo - CHF, cyclo - hemorrhagic cystitis.
Precursor B-ALL vs T-ALL immunophenotypes
TdT+, CD10+, CD19+ vs. all T-cell (CD2,3,4,5,7,8), TdT, and CD1a
Mature B-cell leukemia immunophenotypes
CD19 and co-express CD5 (T-cell)
Hemophilia A vs. B
VIII vs. IX. Both have isolated PTT elongation.
Desmopressin acetate effect on clotting?
Releases vWF and VIII (think Hemophilia A) from the endothelium.
Plummer-Vinson/Patterson Kelly Syndrome
Formation of esophageal webs 2/2 to Fe-deficiency anemia -> dsyphagia. Disfigured fingernails are also specific for Fe-deficiency anemia. Atrophic glossitis
How do parasethesias occur after pRBC transfer?
Citrate in transfusions can chelate Ca+ –> hypocalcemia. Requires massive transfusions (5-6L/24h)
Reticulocyte characteristic
Immature RBC that is slightly LARGER and BLUER (2/2 ribosomal RNA). Lacks cell nucleus.
BCR-ABL
CML (chromosome 9 to chromosome 22). Imatinib.
t(8;14)
Burkitt lymphoma
Acute promyelocytic leukemia
Subset of AML. Can present with persistent infection and COAGULOPATHY -> hemorrhagic signs and symptoms. Biopsy with promyelocytes with intracytoplasmia AUER rods. t(15;17) -> alpha RETINOIC acid receptor w/ PML.
Histopath of follicular lymphoma?
LN biopsy shows aggregates of packed follicles. Mostly centrocytes > centroblasts (larger). T(14;18) w/ BCL-2 over-expression.
ITP vs. DIC?
ITP has ISOLATED thrombocytopenia (dec. plt count and increased bleeding time). DIC has throbocytopenia, INC PT, PTT, DEC plasma fibrinogen, and RBC fragmentation.
TTP vs. HUS?
Disease spectrum w/ pentad of fever, neuro, ARF, thrombocytopenia, microangiopathic hemolytic anemia. TTP adults w/ neuro. HUS children with renal. NO COAG involvement.
Osmotic fragility test
Spherocytes are more susceptible to hypertonic saline. Sickle cells are NOT.
Complications of hereditary spherocytosis?
Pigment gallstones, asplastic crises 2/2 parvovirus B19
What are the important platelet receptors?
GpIb for vWF receptor. GpIIb/IIIa for fibrinogen receptor.
What granules do platelets carry?
Dense granules (ADP and Ca2). Alpha granules (vWF, fibrinogen)
Hypersegmented polys?
Vitamin B12/folate deficiency
Surface marker for macrophages?
CD13, CD14, CD15, CD64
Causes of eosinophilia?
NAACP = Neoplasia, Asthma, Allergic processes, Connective tissue diseases, Parasites
Basophil function?
Mediates allergic reaction. Basophilic granules contain heparin, histamine, leukotrienes (SRS-A: “slow reacting substance of anaphylaxis”)
What drug prevents mast cell degranulation?
Cromolyn sodium
B lymphocyte CD’s?
CD 19, CD20.
Treatment to prevent hemolytic disease of the newborn?
Rho(D) immune globulin. Which is IgG (there CAN cross placenta but doesn’t cause disease b/c it is in low levels….) Apparently IgG > IgM, so that’s why they use IgG.
Roles of bradykinin
Vasodilation, increased permeability, and increased pain. Produced by cleavage of HMWK by kallikrein
Fibrin vs. Plasmin?
Fibrin is used for making clots. Plasmin is used to break said clots.
What coagulation factors does IIa activate?
Factors VIII, V, and XIII.
Extrinsic pathway key?
TF:VIIa
At what point do the intrinsic and extrinsic pathways coalesce?
In activating factor X. Because factor X (w/ Ca, PL, and Va) activates II.
Factor V Leiden mutation?
Produces a factor V that is RESISTANT to CLEAVAGE by Protein C.
Protein C pathway?
Activated via thrombin-thrombomodulin complex, then with Protein S, cleaves and inactivates Va and VIIIa. “Chad Ocho Cinco.”
What factors does anti-thrombin inhibits?
1972 + XI and XII.
Walk me through platelet plug formation.
Exposed collagen. vWF binds to it. Attracts PLT via GpIb receptor inducing release of ADP and Ca2+. ADP induces GpIIb/IIIa receptor expression, which attracts fibrinogen to LINK platelets. Now it’s a fight between TXA2 and PGI2/NO.
Ristocetin
Activates Gp1B-vWF interaction.
Drugs inhibiting ADP induction of GpIIb/IIIa receptor expression
Clopidogrel, ticlopidine, prasugrel, ticagrelor
Glanzmann thrombasthenia
Deficiency in GpIIb/IIIa
Bernard-Soulier syndrome
Deficiency in Gp1B
Causes of decreased ESR?
Polycythemia, sickle cell anemia, CHF, microcytosis, hypofibrinogenemia.
Acanthocyte
Spiny, “spur cell.” Liver disease, abetalipoproteinemia
Basophilic stippling
Anemia of chronic disease, alcohol abuse, lead poisoning, thalassemias
Schistocyte
“Helmet” cell. DIC, TTP/HUS, traumatic hemolysis (e.g. mechanical heart valve)
Teardrop cell
Bone marrow infiltration
Target cell
HbC disease, Asplenia, Liver disease, Thalassemia
Heinz bodies
Seen in G6PD w/ crystal violet stin.
Howell-Jolley bodies
Basophilic nuclear remnants usu. removed by functioning splenic macrophages. May be sign of hyposplenia/asplenia
Etiological differences between alpha and beta-thalassemias?
Alpha thalassemias are due to the deletion of the four alpha globin genes. Beta thalamssemias are often due to mutations of splicing/promoting problems that decrease the amount of Beta-globin synthesis. Alpha not seen on electrophoresis but Beta does.
Lead poisoning physical findings and lab findings?
Burton lines (Gingivae) and lead lines on long-bones. Wrist/foot drop. Sideroblastic microcytic anemia. Accumulated protoporhyrin and d-ALA
Lead poisoning mech and treatment?
Mech - inhibits ferrochelatase and ALA dehydratase -> decreased heme synthesis and increased RBC protoporphyrin. Tx = EDTA and dimercaprol.
Causes of sideroblastic anemia?
EtOH (mitochondrial damage), vitamin B6 deficiency/INH (ALA synthase problem), X-linked defect in ALA synthase gene, lead poisoning. Tx = pyridoxine
Lab differences between B9 and B12 deficiency?
B12 involved in making methionine from homocysteine and well as in making methylmalonic acid into succinyl-CoA. Therefore, B12 deficiency will have increased homocysteine and methylmalonic acid. B9 deficiency will have increased homocysteine (because folate needed to make methionine) but NORMAL methylmalonic acid.
Mechanisms of anemia of chronic disease?
Increased ferritin b/c of storage of Fe away from blood to prevent bacterial growth. TIBC/transferrin low. Low Fe.
Labs for hereditary spherocytosis
Positive osmotic fragility test. Eosin-5-maleiimide binding test.
Labs for paroxysmal noctural hemoglobunuria?
Commbs NEG hemolytic anemia, pancytopenia, CD55 [decay-accerlerating factor] and CD59 [MAC inhibitory protein] NEG RBC’s on flow cytometry.
Paroxysmal nocturnal hemoglobunuria?
INTRAvascular hemolytic anemia. Complement mediated lysis (b/c of impaired synthesis of GPI anchor for membrane protecting factor). Acquired mutation in hematopoietic stem cell that increases incidence of acute leukemias.
Warm vs. cold agglutinin autoimmune hemolytic anemias?
Cold are IgM. Acute anemia triggered by cold seen in CLL, mycoplasma or mono infectious. Warm are IgG and seen in SLE, CLL or methyldopa.
Direct Coomb’s vs. Indirect Coomb’s
Direct look for stuff on RBC’s. So anti-Ig Ab for Ig’s on RBCs. Indirect adds normal RBC’s to serum to see if there’s anti-RBC surface Ig’s.
Causes of neutropenia?
Sepsis, drugs (chemo), aplastic anemia, SLE, radiation
Causes of lymphopenia?
HIV, DiGeorge, SCID, SLE, steroids, radiation, sepsis, post-op
HbC disease?
Glutamic acid-to-lysine in Beta-globin. Leads to a hemolytic normocytic anemia.
Acute intermittent porphyria
HMB synthase = porphoilinogen deaminase deficiency. 5 P’s - painful abdomen, port wine-colored urine, polyneuropathy, psychological disturbances, precipitated by drugs, EtOh, and starvation. Tx = glucose and heme which inhibits ALA synthase. Build-up of porphobilinogen, d-ALA, and coporphobilinogen (urine)
Porphyria cutanea tarda
Uroporphyrinogen decarboxylase deficiency. Most common. Uroporphyrin build-up in urine (tea-colored). Blistering cutaneous photosensitivity.
Treatment for paroxysmal nocturnal hemoglobinuria?
Eculizumab - Ab against complement
Warfarin mechanism?
Inhibits vitamin K dependent carboxylation of glutamic acid residues of clotting factors 1972.
Heparin mechanism?
Increases effect of naturally occurring anticoagulant antithrombin-III by binding to it -> conformational change -> increased antithrombin binding and neutralization of THROMBIN (II) and Xa. Unfractionated heparin has greater inactivating of thrombin than LMWH b/c of longer pentasaccharide chain.
Defects in what factors only lead to increased PT and not increased PTT?
VII, then the common pathway = X, V, II, I. B/c PTT is intrinsic while PT is extrinsic (add TF with Ca2+)
Platelet abnormality symptoms
Mucous membrane bleeding, epistaxis, petechiae, purpura, inc. bleeding time, possibly a decreased platelet count
Bernard-Soulier vs. Glanzmann thrombasthenia labs?
GpIb vs. GpIIb/IIIa defect. Thrombocytopenia in B-S but not in Glanzmann. Both will have increased bleeding times. No change in PT or PTT. Glanzmann will show poor PLT clumping on blood smear.
Etio of thrombotic thrombocytopenic purpura?
Inhibition or deficiency in ADAMTS13 = vWF metalloprotease that degrades vWF multimers. Large multimers -> increased PLT adhesion and thrombosis but DEC. PLT survival
TTP labs?
Schistocytes, increased LDH. Dec. PLT count. Inc. Bleeding time.
How do you diagnose von Willebrand disease?
Ristocetin cofactor assay. Ristocetin activates GpIb-vWF interaction. So vWF disease patients will have DCREASED agglutination.
Treatment for von Willebrands?
DDAVP which releases vWF stored in endothelium. (Desmopressin acetate)
Etios of DIC
STOP Making New Thrombi = Sepsis (gram neg), Trauma, OB comps, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion
DIC labs
decreased PLT count. Inc. BT, PT, PTT. Inc. fibrin-split product (D-dimers), dec. fibrinogen, dec. factors V and VIII.
Skin and subcutaneous tissue NECROSIS after warfarin?
Protein C deficiency. (Unable to inactivate V and VIII) -> thrombotic skin necrosis
Antithrombin deficiency etios
Genetic. Renal failure/nephrotic syndrome can lead to antithrombin loss in the urine leading to increased factors II and X.
Hodgkin’s lymphoma vs. Non-Hodgkin’s Lymphoma
Localized single group of nodes vs. multiple, peripheral nodes w/ extra nodal involvement. Reed-Sternberg vs. B-cell. Bimodal vs. Peak at 20-40. EBV association vs. ?HIV + immunosuppression. B signs (wt loss, fever, night sweats) vs. fewer constitutional symptoms
Reed-Sternberg CD?
CD 15 and CD30.
What subtypes of Hodgkins’ lymphoma have the best prognosis?
Lymphocyte-rich. Lymphocyte-mixed or depleted have poorest prognosis.
Burkitt lymphoma
Adolescent/young adults. c-myc (8) + heavy-chain Ig (14). Histo is “Starry sky” = sheets of lymphocytes with interspersed macrophages. EBV. Jaw lesion endemic in Africa. FAST-growing tumor. Decent prog.
Diffuse large b-cell lymphoma
Usually in older adults. t(14;18) = BCL2. Histo - large nuclei with open chromatin and prominent nucleoli. CD19, CD20. EBV, HHV-8. Rapidly enlarging often symptomatic mass at single nodal or extra nodal site. Decent prog.
Mantle cell lymphoma
Older men. t(11;14) = cyclin D1 to heavy-chain Ig. Incurable. Fatigue, lymphadenopathy found to have generalized disease.
Follicular lymphoma
Indolent course w/ remissions and recurrences. Fluctuating painless LN enlargement (waxing and waning). Abdominal mass. t(14;18) leading to over expression of BCL-2 (inhibits apoptosis). Centrocytes (cleaved nuclear outline) mixed with centroblasts. (large nucleoli)
Adult T-cell lymphoma
Caused by HTLV-1. In adults. Cutaneous lesions, lytic bone lesions, hyperCa. Southern Japan and Carribbean. Extremely aggressive.
Mycosis fungoides/Sezary syndrome
Cd4+ T-cells. Plaques/tumors. Sezary cells are the circulating cells. Incurable but indolent.
Multiple Myeloma acronym
CRAB = hyperCalcemia, Renal insufficiency, Anemia, Bone lytic lesions/Back pain
Multiple Myeloma findings
Infections, primary amyloidis, “punched-out” lytic lesions, M-spike on serum, Ig light chains in urine (not all MM’s secrete heavy chains found in serum electrophoresis), Rouleaux formation on smear, plasma cells w/ “clock face” chromatin and intracytoplasmic inclusions.
Monoclonal gammopathy of undetermined significance
MGUS. A monoclonal expansion of plasma cells leading to a M spike < 3g/dL and BM with < 10% monoclonal plasma cells. 1-2% MM rate per year
Waldenstrom macroglobulinemia
Unlike MM, the M-spike is due to IgM -> hyperviscosity but NO bone lesions
Pseudo-Pelger-Huet anomaly
After chemo, sometimes you will see bilobed neutrophils that a thin piece of chromatin connecting the lobes
ALL
Acute lymphoblastic leukemia/lymphoma. Within 3 months, fatigue, infection, bleeding, bone pain, splenomegaly, hepatomegaly, CNS. TdT, CD10+ (b-cells). Responsive to therapy. t(12;21) has better prognosis. T-cell ALL is more likely to present as a MEDIASTINAL mass -> resp, dysphagia, SVC syndrome. Down syndrome has 10-20x increased risk.
Hairy cell leukemia
Indolent B-cell leukemia with hairlike cytoplasmic projections. CD19, CD20. CD11c and CD103. Older men. Stains TRAP. Marrow FIBROSIS = dry tap. Tx with caldribine (2-DA), which is an adenosine analog that is resistant to adenine deaminase. Excellent prognosis
Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL)
Different names for extent of peripheral involvement. Often asymptomatic or nonspecific symptoms. Infectioins. Autoimmune hemolytic anemia. Older age. CD20+, Cd5+ B-cell neoplasm. Often asymptomatic. SMUDGE cells in peripheral blood
Acute myelogenous leukemia (AML)
Older. Myeloblasts on peripheral smear. RFs include chemo, radiation, myeloproliferative disorder. Promyelocytic leukemia responsive to vitamin A b/c it induces terminal differentiation and also has AUER rods.
Chronic myelongenous leukemia (CML)
Adults. Philadelphia chromosome of t(9;22) BCR-ABL responding to imatinib. Can accelerate into a blast crisis (AML or ALL). Very low leukocyte alk phos (whereas HIGH leukocyte all phosphate in a leukomoid reaction)
t(11;14)
Mantle cell
t(14;18)
Follicular lymphoma
Langerhans cell histiocytosis
Proliferative disorder of dendritic cells. Lytic bone lesions, skin rash, recurrent otitis media with mass in mastoid. S-100 and Cd1a. Birbeck granules on EM (“tennis rackets”)
Myelofibrosis
Fibrotic obliteration of BM. TEARDROP RBC’s (dacrocytes) and immature myeloid cells.
Heparin-induced thrombocytopenia (HIT)
IgG Ab’s against heparin-PLT factor 4 = complexes that lead to thrombosis and thrombocytopenia. Enlarged clot or new clot.
Direct thrombin inhibitors
Argatroban, bivalirudin. Used for anti coagulating patients with HIT.
Warfarin vs. heparin
Long-lasting vs. short-lasting. Not for pregnant women vs. doesn’t cross placenta. PT vs. PTT. P450 vs. not P450. Vitamin K/FFP vs. Protamine.
Direct factor Xa inhibitors names and usage
Apixaban, rivaroxaban. Used for DVT/PE tx and ppx and stroke ppx in Afib patients. No monitoring for oral agents.
Phosphodiesterase-3 (NOT 5) inhibitors
Cilostazol and dipyridamole. Increase cAMP in platelets and inhibit platelet aggregation. Used for claudication, coronary vasodilation, prevention of stroke or TIA a/ ASA, and angina ppx.
G2 phase chemo drugs
Bleomycin and etoposide
S phase chemo drugs
Etoposide and antimetabolites
M phase chemo drugs
Vinca alkaloids and taxols
Etoposide mechanism
Inhibits topoisomerase II
Doxorubicin mechanism
DNA intercalator
Cisplatin mechanism
Cross-links DNA
Vinca alkaloids mechanism
Inhibit microtubule formation by binding Veta-tubulin. Vincristine and vinblastine.
Paclitaxel mechanism
Inhibit MT disassembly by hyper stabilizing MT’s in M-phase. No Anaphase.
MTX usage
Leukemias, lymphomas, chorioca, sarcoma. Abortion, ectopic pregnancy, RA, psoriasis, IBD.
MTX toxicity
Myelosuppression reversible w/ lecuovorin (folinic acid). Maccrovesicular fatty change. Mucositis. Teratogenic.
5-FU mechanism
Inhibits thymidylate synthase
5-FU usage and tox
Colon ca, pancreatic ca, basal cell ca. Myelosuppresion (NOT reversible with leucovorin). Photosensitivity.
Cytarabine mech, usage, and tox
Pyrimidine analog. Leuk/lymphomas. Leukopenia, thrombocytopenia, megaloblastic anemia.
6-MP mech
PRPP glutamyl amidotransferase (first step in committed purine synthesis).
6-MP usage and tox
Preventing organ rejection, RA, SLE, leukemia, IBD. Tox - BM, GI, liver. Increased toxicity with allopurinol b/c it is metabolized via xanthine oxidase.
Dactinomycin
DNA intercalator. Wilms, ewing, rhabdo. Tox = myelosuppression
Doxorubicin = Adriamycin
Intercalates DNA leading to breaks. Generates free radicals. SOLID tumors, leuekmias,lymphomas. Tox dilated cardiomyopathy, myelosuppresion, alopecia. Dexrazoxane (Fe chelator) used to prevent cardiotoxicity
Bleomycin
Free radical formation causing DNA breaks. Testicular cancer, Hodgkin’s. Tox - pulmonary fibrosis, skin, mucositis.
Names of alkylating agents?
Cyclophosphamide, ifosfamide, nitrosureas, busulfan
Cyclophosphamide
Covalently binds DNA. Requires liver activation. Solid tumors, leuekemias, lymphomas, some brain ca. Myelosuppresion, hemorrhagic cystitis (mesna prevention)
Nitrosureas
Carmustine, lomustine, semustine, streptozocin. Cross-link DNA. BRAIN tumors. CNS tox.
Busulfan
CML or ablation before BM transplantation. Tox - severe myelosuppression, pulmonary fibrosis, hyperpigmentation.
Vinca alkaloids usage and tox
Solid tumors, L/L. Vincristine has neurotox. Vinblastine has myelosuppresion.
Paclitaxel and other taxol usage and tox
Ovarian and breast ca. Myelosuppresion, alopecia, hypersensitivity.
Platin usages and tox.
Cis/carboplatin. Testicular, bladder, ovary, and lung. Nephro and acoustic nerve damage. Amifostine (free radical scavenger) and cl- diuresis to preotect kidneys.
Etoposide usage and tox
Solid tumors, L/L. Tox - myelosuppresion, GI, alopecia
Irinotecan, topotecan
Inhibits topoisomerase I to prevent DNA unwinding and replication.
Hydroxyurea
Inhibits ribonucleotide reductase (s-phase). Melanoma, CML, sickle cell. BM suppresion and GI.
Rituximab
Monoclonal Ab against CD20 (B-cell). Used for Non-hodgkin lymphoma, RA w/ MTX, ITP. Risk of PML
Vemurafenib
Small molecule inhibitor of B-RAF kinase. Used for metastatic melanoma.
Bevacizumab
Anti-VEGF monoclonal Ab. Used for solid tumors.
Etios of aplastic anemia
Hep C. Chloramphenicol, indomethicin. Parvovirus. Radiation. Phenylbutozone, thyroid drugs.
Main mediator of paraneoplastic cachexia?
TNF-alpha. Cytokine causing necrosis of tumors. Also involved with producing fever in a bacterial infection and releasing acute-phase reactants. Suppresses appetite, inhibits lipoprotein lipase, increases insulin resistance.
TGF-beta vs. TNF-alpha?
TGF-beta’s role is the INHIBITION of inflammatory response. TGF-beta promotes inflammatory response.
Carcinoid syndrome etiologies?
Intestinal carcinoid tumors that haven’t metastasizes will have their products degraded by the liver. Therefore, a metastatic tumor (liver, lung) will need to symptoms: flushing, dizziness, diarrhea, wheezing, R-sided valvular disease.
Pure red cell aplasia
Rare form of BM failure. Severe hypoplasia of erythroid elements but NOT other elements. Associated with thymoma, B19 infection, lymphocytic leukemias.
Thrombin time
Add thrombin to blood and see how long it takes for blood to clot. TT is prolonged with agents that directly or indirectly inhibit thrombin (e.g. heparin)
