Heme Flashcards
What causes eosinophilia? “CANADA-P”
Connective tissue diseases (ex dermatomyositis), atopic disease, neoplasm, adrenal insufficiency, drugs (NSAIDs, abx), acute interstitial nephritis, parasites
Most important to know - neoplasms, allergies, atopic disease, connective tissue disease, parasites
What do basophils participate in?
Allergic reactions (heparin, histamine, LT secretion)
What cell types express CD40? What is it’s function?
All APC (macrophages, dendritic cells, and B cells) T cells bind to increase Ag presentation
The intrinsic pathway activates what in addition to the clotting cascade?
Plasmin and bradykinin (anticoagulation and inflammation are directly associated with coagulation)
What is the Ristocein assay used to diagnose? What does it do?
vonWillebrand disease
Activates vWF to bind Gp1b (no increase in agglutination)
What 3 things decrease ESR?
Polycythemia, sickle cell anemia, CHF
What 2 pathologies are associated with acanthocytes (spur cell)?
Liver disease, abetalipoproteinemia
What triggers bite cell formation in G6PD deficiency?
“Spleen Purges Nasty Inclusions From Damaged Cells”
Sulfonamides, primaquine (malaria), nitrofurantoin, isoniazid, fava beans, dapsone, chloroquine (malaria)
Where are ring sideroblasts found in sideroblastic anemia?
What distinguishes them from normal physiology?
Bone marrow, NOT periphery
Sideroblasts are normal RBC precursors, ring sideroblasts are pathological because accumulation of Fe in the mitochondria cause them to crowd the nucleus in a ring formation
How is an echinoctyte (burr cell) different than an acanthocyte (spur cell)? What pathology is associated with echinocytes?
Echinocytes have uniform spikes in the PM (acanthocyte spikes are non-uniform)
Uremia
What 4 pathologies are associated with target cells?
HbC/HbS, thalassemia - decreased RBC cytosol volume (dehydration, decreased Hb)
Liver disease - impaired cholesterol excretion, accumulates in RBC PMs to increase SA
Asplenia
What 2 pathologies are associated with Heinz bodies?
G6PD deficiency and a-thalassemia (HbH B -globin tetramers)
How would gastrectomy with preservation of the duodenum lead to Fe deficiency anemia?
Fe can only be absorbed in the 2+ state. Acid maintains the Fe2+ needed for absorption, so removal of the stomach results in more Fe3+ that cannot be absorbed
What does early vs late Fe deficiency anemia and anemia of chronic disease look like?
Early - normocytic anemia (make fewer to maintain normal RBC Hb concentration)
Late - microcytic hypochromatic anemia
What psychological condition is associated with Fe deficiency anemia?
Pica
What enzyme is deficient in sideroblastic anemia?
ALA Synthase
What are the 3 causes of acquired sideroblastic anemia?
Alcohol - mitochondrial poison, location of Fe binding to protoporphyrin
Lead poisoning - ALAD and ferrochelatase inhibition decreases protoporphyrin for Fe binding
Vitamin B6 deficiency (ALAS cofactor) - isoniazid
What does Ferritin and serum Fe content look like in sideroblastic anemia?
Both are high - Fe accumulates in sideroblasts, generates ROS causing cell death, Fe leaks out into blood and is picked up by macrophage Fe storage cells (high storage and high blood Fe) = ultimately Fe overloaded state because cannot be loaded onto protoporphyrin
What are Thalassemia carriers protected against?
Plasmodium falciparum
What is the genetic cause of a-thalassemia? B-thalassemia?
a-thalassemia = gene deletion B-thalassemia = gene mutations
In a-thalassemia with deletion of 2 a genes:
Is cis or trans deletion worse and why?
What ethnicity is this more common in?
Cis - more likely for offspring to have serious a-thalassemia (if other parent is a 1- or 2-deletion carrier)
Asian
What disorder produces HbH and what is it? Hb Barts?
HbH = a-thalassemia with 3 gene deletions, tetramer of B-globins
Hb Barts = a-thalassemia with 4 gene deletions, tetramer of gamma-globins in the fetus
What pathology is associated with an isolated increased HbA2?
B-thalassemia minor
What two enzymes are blocked in Lead poisoning?
ALA dehydratase (ALAD) and ferrochelatase
What 2 unique findings are associated with lead poisoning?
Lead lines (gingival and bones) and foot/wrist drop (peripheral neuropathy)
What lab finding distinguishes vitB12 deficiency from folate deficiency?
Elevated methylmalonic acid (vitB12 needed to convert it to succinyl-CoA)
What medications cause folate deficiency?
Methotrexate, trimethoprim, phenytoin
Infection with what organism causes vitB12 deficiency?
Diphyllobothrium datum (fish tapeworm)
What pathology is associated with megaloblastic anemia not cured by folate/vitB12 supplementation?
Orotic aciduria - defective UMP synthase stops pyrimidine synthesis (orotic acid accumulates)
What clinical feature distinguished Orotic Aciduria from Ornithine Transcarbamolase deficiency?
No hyperNH3
Why are reticulocytes blue-ish?
Still have mRNA in their cytoplasm
Corrected reticulocyte count
reticulocyte count x (Hct/45)
What is a normal reticulocyte percentage? What does that mean?
> 3% of RBCs
Bone marrow is responding appropriately
What anemias have increased RDW?
Fe deficiency anemia, anemia of chronic disease, hereditary spherocytosis (PM blebs continuously removed)`
What cellular process underlies splenomegaly in Hereditary Spherocytosis?
Work hypertrophy (caused by increased consumption of spherocytes)
What lab test is used to diagnose Hereditary Spherocytosis and why?
Osmotic fragility test - spherocytes do not have the central extra PM available to accommodate swelling, thus they burst sooners
What is used as therapy for Sickle Cell anemia?
Hydroxyurea - increases HbF
What is the primary location of hemolysis in Sickle Cell anemia and why? (extra or intravascular)
Extra-vascular = each time RBC passes through microcirculation it sickles and polymerized HbS pokes holes in the membrane. With time this makes the RBC less flexible and gets stuck in the spleen where it is hemolysed.
What is the clinical presentation of Sickle Cell anemia?
> 6 month-old infant with dactylitis (swollen fingers/toes)
Why does asplenia lead to increased risk of infection with encapsulated organisms?
Spleen is the major source of antibodies, which is the primary defense against encapsulated organisms
What is the precipitating factor for acute chest syndrome in Sickle Cell anemia patients?
Pneumonia - causes vasodilation of pulmonary arteries (inflammatory-mediated) which worsens RBC dehydration and hypoxia
What is the most common cause of death in kids with Sickle Cell? Adults?
Kids - infection with encapsulated organism
Adults - acute chest syndrome
What is the one manifestation of sickle cell disease in patients with Sickle Cell Trait and why?
Renal damage (decreased ability to concentrate urine) - need > 50% HbS to sickle EXCEPT in the renal medulla (hugely concentrated, RBCs become much more dehydrated)
Glutamic acid at AA6 is changed to what AA in sickle cell? HbC?
Sickle cell - valine (hydrophobic)
HbC disease - lysine (positive charge = rhomboid crystals)
How would you look for Paroxysmal Nocturnal Hemoglobinuria days after the most recent incident?
Hemoglobinuria only occurs during the RBC hemolysis. But as Hb passes through the glomerulus, tubular epithelial cells pick up hemosiderin and are sloughed of days later. Presence of hemosiderin-laiden epithelial cells days after the hemoglobinuria would suggest PNH
What test is used to diagnose PNH?
Ham’s test - introduce acidosis (by giving surcrose) to activate complement (PNH will have hemolysis)
What is the main cause of death in PNH?
Thrombosis (hepatic/portal or cerebral) - platelets also lack GPI and are susceptible to lysis, platelet fragments activate the coagulation cascade
What type of leukemia can PNH progress to?
AML (10%)
What 2 pathologies are associated with IgG autoimmune hemolytic anemia?
SLE and CLL (naive B cell neoplasm, both IgG and IgM)
What 2 infectious causes are associated with IgM autoimmune hemolytic anemia?
Mycoplasma pneumoniae and infectious mononucleosis (heterophile antibodies)
Encephalopathy + colicky abdominal pain + renal failure + foot drop + microcytic anemia
Lead poisoning (also basophilic stippling and lead lines)
Abdominal pain + polyneuropathy + psychosis + wine-colored urine
Acute intermittent porphyria (neuropathic pain + psychosis)
What enzyme is deficient in acute intermittent porphyria?
Porphobilinogen deaminase
What is the presentation of Porphyria cuteness trade? (stereotypical homeless man)
Blistering cutaneous photosensitivity, hypertrichosis (beard), facial hyperpigmentation (out in the sun), alcoholism
What enzyme is deficient in porphyria cuteness tarda?
Uroporphyrinogen decarboxylase
What platelet R is defective in Bernard-Soulier syndrome?
Gp1b (plt-vWF)
What platelet R is defective in Glanzmann Thrombasthenia?
GpIIb/IIIa (plt-plt)
What is the first step in hemostasis?
Vasoconstriction (damaged endothelial cells release endothelin-1)
Where does vWF come from?
Endothelial cells (weibel-palade bodies) and platelets (alpha granules)
What is stored in endothelial cell weibel-palade bodies?
vWF and P-selectin
What is the feared complication of severe thrombocytopenia?
Intracranial bleeding
What is splenectomy used to treat in immune thrombocytopenia?
The spleen is the source of the auto-antibodies and the location of platelet-antibody destruction, so splenectomy removes two steps in the pathogenesis
What tissue is predominantly affected in TTP? HUS?
TTP - CNS
HUS - kidneys
How does TTP and HUS affect PT and PTT?
PT/PTT are normal - no activation of the coagulation cascade
Which qualitative platelet disorder has enlarged platelets and mild thrombocytopenia?
Bernard-Soulier - “Big Suckers”
What is the treatment for Von WIllebrand disease?
DDAVP (desmopressin) - increases vWF release from Weibel-palade stores in endothelial cells
What is the antidote for thrombolytics?
Aminocaproic acid
Does more Reed-Sternberg cells in Hodgkin lymphoma indicated a good or poor prognosis?
Poor prognosis
What translocation is associated with Burkitt Lymphoma?
What gene is activated?
t(8;14)
c-Myc oncogene
What is the most common lymphoma in kids? Adults?
Lymphoblastic lymphoma
Diffuse large B cell lymphoma
Which lymphomas are associated with t(14;18)?
Follicular lymphoma and Diffuse large B cell lymphoma (transformed follicular lymphoma)
What histology is associated with Burkitt lymphoma?
Starry sky appearance
What translocation is associated with Mantle cell lymphoma?
What gene is activated?
t(11;14) Cyclin D (enters S phase)
What condition is associated with Intestinal T cell lymphoma?
Celiac disease
What form of leukemia is associated with bone pain?
ALL
What is the Philadelphia chromosome?
What drug targets it’s gene product?
t(9;22) = bcr-abl constitutively active tyrosine kinase
Imatinib
What form of leukemia is most commonly associated with the Philadelphia chromosome? What 2 other may also be associated?
CML “Philadelphia CreaM cheese”
Also ALL and rarely AML
What forms of leukemia are Down Syndrome patients predisposed to?
ALL and AML (due to t(8;21))
What marker is positive in ALL?
TdT
What age are lymphoid leukemias seen? Myeloid leukemias?
Lymphoid - extremes of age (ALL kids, CLL elderly)
Myelogenous - “Middle age”
What form of leukemia have risk factors including radiation, alkylating agents, and myeloproliferative disorders?
AML
What does the CBC look like in someone with and acute leukemia? Chronic leukemia?
Acute - pancytopenia
Chronic - high WBCs
What type of leukemia is associated with smudge cells?
CLL
What other hematologic finding may be present with CLL?
Autoimmune hemolytic anemia (IgG or IgM)
What serious complication could cause imminent death in a patient with CML?
Progression to AML
What gene translocation is associated with Acute proMyelocytic Leukemia?
What unique feature is found in these neoplastic cells?
What can be used to treat?
t(15;17)
Auer rods
All-trans retinoic acid
What is Pseudo-Pelger Huet anomaly?
What is it associated with?
Bilobed PMNs that look like glasses Myelodysplastic syndromes (pre-leukemia)
What genetic mutation is associated with myeloproliferative disorders?
JAK2 gene mutation
What pathology is associated with fat infiltration of the bone marrow? Fibrous replacement of the bone marrow?
Fat infiltration - aplastic anemia
Fibrous replacement - myelofibrosis (a myeloproliferative disorder)
How does Multiple Myeloma present?
HyperCa + renal insufficiency + anemia + back pain (lytic lesions)
“CRAB”
How is Waldenstrom macroglobulinemia different than multiple myeloma?
M spike is IgM and no lytic bone lesions
What is an extra medullary plasmacytoma?
Where is it most commonly found?
Solid tumor of B cells
Nose
Increased levels of what type of WBC is seen in CML?
Basophils
What are Auer rods composed of?
What do they predispose to?
MPO (peroxidase +)
DIC
Child with lytic bone lesions + skin rash with increased S-100 and CD1a + cells
Langerhans cell histrocytosis - birbeck granules
What complication occurs just after starting Warfarin and why?
What is give to prevent this?
Skin necrosis - warfarin inhibits Protein C and S much sooner than Factors 2, 7, 9, and 10 so there is a brief period of hyper coagulability. This can cause clotting in the dermis and skin necrosis.
Heparin given simultaneously
What is the mechanism of action of clopidogrel, prasugrel, ticagrelor, and ticlodipine?
ADP R inhibitors (no GPIIb/IIIa)
What is the mechanism of action of abciximab and eptifibatide?
GPIIb/IIIa inhibitors (directly bind and inhibit)
Spooned nails + dysphagia
Fe deficiency anemia in the context of Plummer-Vinson syndrome
What are 3 uses for MTX?
What are 3 side effects?
Cancers (hematologic - tumor lysis syndrome), uterine pathologies (ectopic pregnancy), and immune-suppression (RA)
Myelosuppression (reverse with leucovorin), lung fibrosis, and mucositis
What are the 2 most common uses for 5FU?
Basal cell CA and actinic keratosis
Given with what cancer drug and what does it prevent: Leucovorin Uridine Mesna Dexrazoxane
Leucovorin - MTX, myelosuppression
Uridine - 5FU, myelosuppression
Mesna - cyclophosphamide, hemorrhagic cystitis
Dexrazoxane - doxo/dauno-rubicin, dilated cardiomyopathy
What is 6-thioguanine?
6MP that is NOT metabolized by xanthine oxidase, thus safe with allopurinol
Mechanism of cytarabine
Pyrimidine analog that inhibits DNApol
CyTarabine = pyrimidine Cytosin and Thymidine
What is the mechanism of cyclophosphamide?
What are 3 non-cancer uses?
Alkylating agent
Lupus nephritis, polyarteritis nodosa, and granulomatosis with polyangiitis (Wegeners)
What is the major side effect of cyclophosphamide?
What causes it and what can prevent it?
Hemorrhagic cystitis (increases risk for transition cell CA) Acrolein causes is, meson prevents it
What organ must be functioning for cyclophosphamide to work?
Liver - require activation
What is the use for -mustine drugs?
Brain tumors (nitrosoureas - alkylating agents that cross BBB)
What 3 chemo drugs cause pulmonary fibrosis?
Busulfan (alkylating agent), bleomycin (generates free radicals), and MTX
What is the mechanism of anthracyclines (doco/dauno-rubicin)?
- Generates free radicals
2. Intercalates DNA
What is the mechanism of Dactinomycin?
What are 3 uses?
Intercalates DNA
Wilms tumor, ewing sarcoma, and rhabdomyosarcoma
“dACTinomycin = kids ACT out = treats childhood tumors”
What is the use for Bleomycin?
“Lance armstrong”
Testicular cancer
“Lance armstrong - stopped Bleomycin for his testicular CA in fear that the pulmonary fibrosis would put is bicycling career in jeopardy”
3 uses for Cisplatin
Testicular/ovarian CA and bladder CA
What 4 drugs are nephrotoxic and ototoxic?
Vancomycin, aminoglycosides, loop diuretics, and cisplatin
Which topoisomerase is inhibited by:
Etoposide
-tecan (irinotecan)
Etoposide = topoisomerase 2 Irinotecan = topoisomerase 1 "Etoposide = Entire strand break = dsDNA breaks" "irinoTecan = Teeny strand break = ssDNA breaks"
What is used to treat testicular cancer?
“Eradicate Ball Cancer”
Etoposide, bleomycin (or ifosfamide), and cisplatin
What is the effect on MTs:
Vincristine, vinblastine
Paclitaxel
Vincristine, vinblastine - prevents polymerization
Paclitaxel - stabilizes polymerization
“Taxes stabilize society”
Side effect of vincristine? Vinblastine?
Vincristine - peripheral neuritis
Vinblastine - bone marrow suppression
“vinBLASTine = BLASTs bone marrow”
What 5 drugs target MTs?
Vincristine/vinblastine, paclitaxel, mebendazole/albendazole (anti-helminth), griseofulvin (antifungal), and colchicine (gout)
What chemo drugs are used for chorioCA?
MTX and vincristine
What chemo drugs are used for Wilms tumor or ewing sarcoma?
Dactinomycin and vincristine
“dACTinomycin = kids ACT out”
What type of cancers can be treated with prednisone?
Lymphoid tumors (part of the mechanism for immunosuppression is causing lymphoid apop)
What SERM increases risk for endometrial CA but can also be used to treat it?
Tamoxifen (estrogen PA in endometrium)
What is Trastuzumab?
What is the side effect?
HER2+ breast cancers
Cardiotoxic “HER2 HERts the HEaRt”
What is the mechanism of bevacizumab?
What are 2 side effects?
antiVEGF
Hemorrhage and impaired wound healing
Fetus of a G0P1 mother is found to have hemolysis, why?
First pregnancy - mother must be blood type O while fetus is A or B.
A or B type mothers and anti-B or anti-A Abs as IgM that cannot cross the placenta, BUT O type others have antiA and antiB Abs that are IgG.
Cannot be Rh Abs because that can only occur with subsequent pregnancies.
What can cause DIC?
“STOP Making Thrombi”
Sepsis, trauma, obstetrics, pancreatitis, malignancy, and transfusion
What 6 drugs cause agranulocytosis?
Clozapine (atypical antipsychotic) Carbamazepine (seizures) Colchicine (gout) PTU/methimazole (antithyroid) Dapsone (Leprosy)
What is the mechanism of cyclosporine?
Tracolimus?
Sirolimus?
Cyclosporine-cyclophilin inhibits calcineurin to prevent IL2 transcription
Tracolimus-FKBP inhibits calcineurin to prevent IL2 transcription
Sirolimus-FKBP inhibits mTOR to prevent T cell response to IL2
Which drug is non-nephrotoxic: cyclosporine, tracolimus, or sirolimus?
Sirolimus
What are infliximab/adalimumab used to treat (TNFa inhibitors)?
Seronegative spondyloarthropathies + RA
IL12R deficiency increases susceptibility to what infection?
Mycobacterial and fungal infections (macrophages cannot stimulate T cell maturation into Th1 cells)
Recurrent bacterial infection starting at 6 mo age in a boy
Bruton agammaglobulinemia (X-linked tyrosine kinase mutation = no Igs, protected by mom for first 6 mo)
Recurrent airway/GI infections throughout life + eczema or asthma + anaphylaxis following blood transdfusion
Selective IgA deficiency
Severe recurrent infections (including PCP) + chronic diarrhea + failure to thrive
SCID (absent thymic shadow)
Ataxia/poor smooth pursuit + low IgA + elevated AFP
Ataxia-telangectasia
What causes ataxia-telangectasia?
Impaired Non-homologous end joining DNA repair mechanisms (avoid X-rays, increased risk for leukemias)
“ATAXIA = Ataxia Telangectasia, Acute leukemias, Xray sensitivity, Iga deficiency, Afp”
Little boy with eczema on trunk + purport + recurrent pyogenic infections
Wiscott-Aldrich (X-linked, eczema normally on flexural surfaces)
“WATER = Wiscott Aldrich, Thrombocytopenia, Eczema, Recurrent infections”
How does wiscott-aldrich affect Ig levels?
High IgA and low IgM
IgM is most effective against bacteria with capsules = recurrent pyogenic infections
Recurrent infections with Staph aureus and Aspergillis
Chronic granulomatous disease
Which 4 Immunodeficiencies are X-linked?
Bruton agammaglobulinemia (B cell), wiscott-aldrich (B and T cell), hyper IgM syndrome (B or T cell), and CGD (PMN)
Large phagosome vesicles in PMNs + partial albinism + recurrent respiratory/skin infections + neurological disorders
Chediak-Higashi syndrome
What causes Chediak-Higashi syndrome?
LYST gene mutation = impaired trafficking of lysosomal enzymes = giant cytoplasmic granules in PMNs (un-digested endocytosed material)
Eczema + cold abscesses + coarse facial features + retained primary teeth
Hyper-IgE/Job syndrome (IgE and Eosinophils are elevated, but PMN recruitment is the main pathology)
Delayed separation of the umbilical cord
Leukocyte adhesion deficiency
