Hem/Onc Flashcards
Source of energy for erythrocytes
Glucose (90% glycolysis, 10% HMP)
RBC transporter that allows RBCs to export bicarb and transport CO2 from periphery to lungs
Cl-/HCO3- antiporter
ANisocytosis
Varying sizes of RBC
Pikilocytosis
Varying shapes of RBC
Life span of plts
8-10 d
Dense granule of plts contents
ADP, Ca2, Serotonin
Alpha granule of plts contents
vWF, fibrinogen, fibronectin
Storage of plt pool
1/3 in spleen
Low platelets/plt fxn –>
Petiechiae
vWF receptor
GpIb (attach)
Fibrinogen receptor
GIIb/IIIa (aggregate)
Blue color in retics…
Residual rRNA
Neutrophil specific granule contents
Leuk Alk PHos, collagenase, lysozyme, lactoferrin
Azurophilic granule contents
In neuts – proteinases, acid phos, MPO, b-glucuronidase
Hypersegmented neuts in
Vit B12/folate def
More band cells means
More myeloid proliferation (CML, bacterial infxn)
Neutrophil chemotactic agents
C5a, IL8, LTB4, kallikrein, PAF
Activates macs
Gamma interferon
Lipid A binds…
From bacteria LPS binds CD14 on macs –> septic shock
Eosinophils produce
Histaminase, MBP (helminthotoxin), eosinphil peroxidase, eosinophil cationic protein, eosinophil derived neurotoxin
Causes of eosinophilia
Neoplasia, Asthma, Allergic process, Chronic adrenal insufficiency, Parasites
Basophil granules contain
Heparin (anticoag), histamine (vasodilator)
Basophils can synthesize
Leukotrienes – not preformed!
Basophilia can mean
Myeloproliferative disease, like CML
Mast cell from same precursor as
Basophils
Mast cell releases
Histamine, heparin, tryptase, and eosinophil chemotactic factors
Drug that prevents mast cell degranulation and use
Cromolyn sodium – asthma prophylaxis
B cell markers
CD19, CD20,CD21
T cell markers
Tc: CD3, CD8
Th: CD3, CD4
T reg: CD3, CD28
Majority of circulating lymphs are…
T cells (80%)
Plasma cell cancer
Multiple myeloma
Fetal erythropoesis
Yolk sac (3-8wks) Liver (6wk-birth) Spleen (10-28 wks) Bone marrow (18wk-adult) Young Liver Synthesizes Blood
Embryonic globins
L and E
Fetal hemoglobin
a2gamma2
Adult hemoglobin
a2b2
Why does HbF have a higher affinity of O2?
Less avid binding of 23 BPG –> can extract oxygen from maternal hemoglobin across placenta
HbA2
a2d2 – small amounts in adult
ABO abs are
IgM
Rh abs are
IgG
Presentation of ABO hemolytic disease in newborn (rare)
Mild jaundice in neonate w/in 24 hrs of birth – tx phototherapy or exchange transfusion
Order of furthest migration on a gel for hemoglobins
A (normal hemoglobin B chain – HbA)
F (normal hg gamma chain – HbF)
S (sickle cell hemoglobin B chain – HbS)
C (Hemoglobin C B chain – HbC)
Intrinsic (contact activation) pathway
Collagen/basement membrane/activated platelets –> 12>11>9 and 8…
Tissue factor (extrinsic) pathway
7>…
Combined pathway
X & V>2>1> cross linking via 13
Require calcium/phospholipid
9 to 9a, 9a+8a to X-->Xa, 7-->7a-->+cofactor to catalyze X-->Xa Xa+Va to catalyze II-->IIa 13 to crosslink
Kinin cascade
HMWK > activates 12
via kallikrien–>bradykinin –> vasodilation, permeability and pain
Inhibited by Warfarin
2,7,9,10 C,S
Hemophilia A def
Factor 8 – XR
Hemophilia B
Factor 9 – XR
Hemophilia C
Factor 11 –AR
Vit K in coagulation
Reduced via epoxide reductase to become cofators in gamma glutamyl carboxylation to make mature/active coag cascade components
VIt K def
Low fact II, 7, 9, 10, pC, pS
vWF carries/protects
Factor 8
Protein C cleave and inactivates
Va and 8a w/ help of pS
Antithrombin inhibits activated
2,7,9,10,11,12; principal targets are thrombin and Xa
Heparin acts by
Enhancing activity of antithrombin
Factor V leiden mutation
Factor V that cannot be inhibited by protein C –> hypercoagulability
Plasminogen–>
via tPA to plasmin –> fibrinolysis – cleavage of fibrin mesh, destruction of coag factors
Platelet plug formation
Endothelial damage –> transient vasoconstriction (neural stim reflex and endothelin released) –> vWF binds exposed collagen (from Weibel Palade bodies of endothelial cells and a granules of plts –> plts bind vWF via GpIb and undergo conformational change –> release ADP (helps plts adhere, binds P2Y12 receptor to induce GpIIbIIIa expresion on plt), Ca, and TXA2 –> Fibrinogen binds GpIIb/IIIa receptors to link platelets
Proaggregation factors
TXA2 from plts, slower blood flow, increased platelet agg
Antiaggregation factors
PGI2 and NO from endothelial cells, faster blood flow, less platelet aggregation
How does aspirin cause anticoag?
Irreversible inhib of COX in plts –> no TXA2 synthesis
These inhibit GpIIb/IIIa direction
Abiciximab, eptifibatide, tirofiban
Action of ristocetin
Activates vWF to bind GpIb – failure of assay with vWD and Bernard Soulier syndrome
Inhibit P2Y12 receptor
Clopidogrel, prasugrel, ticlodipine
Deficiency of GpIb on plt –>
Bernard-Soulier syndrome
Def of vWF
vWD
Inside endothelial cells
vWF and factor 8, thromboplastin, tPA, PGI2
Acanthocytes seen in
Liver disease, abetalipoproteinemia (states of cholesterol dysregulation)
Basophilic stippling seen in
Lead poisoning, sideroblastic anemias, myelodysplastic syndromes
Basophilic stippling sample
Periperal smear
Ringed sideroblast sample
Bone marrow
Basophilic stippling is
Aggregation of residual ribosomes
Dacrocyte aka
Teardrop cell
Acanthocytes aka
Spur cell
Dacrocyte seen in
Bone marrow infilitration (myelofibrosis) – due to mechanical squeezing out of its home
Degmacyte aka
Bite cell
Degmacyte seen in
G6PD def
Echinocyte aka
Burr cell
Echinocyte seen in
ESRD, liver disease, PK def
Ddx from acanthocyte to echinocyte
Echinocyte has more uniform and smaller projections
Elliptocyte seen in
Mereditary elliptocytosis, usually asymptomatic – caused by mutations in genes encoding RBC membrane proteins (spectrin)
Macroovalocytes seen in
Megaloblastin anemia (w/ hypeseg PMNs)
Ringed sideroblast seen in
Sideroblastic anemia, excess iron in mitochondria
Schistocyte seen in
Microangiopathic hemolytic anemias (DIC,TTP/HUS, HELLP), mechanical hemolysis
Schitocyte is a
Fragmented RBC, eg helmet cell
Sickle cell seen in/caused by
Sickle cell anemia – occurs w/ dehydration, deoxygenation, and high altitudes
Spherocytes seen in
Hereditary spherocytosis, drug/infxn induced hemolytic anemia
Target cells seen in
HbC disease, Asplenia, Liver disease, Thalassemia (HALT)
Heinz bodies seen in
G6PD def (precipitated hemoglobin due to SH grp reduction to S-S – phagocytes eat leading to bite cells
Howell Jolly bodies seen in
Fxnal hyposplenia or asplenia
HJ bodies are made up of
Basophilic nuclear remnants in RBCs –normally removed by splenic macrophages
Causes microcytic anemia
Sideroblastic anemia (cause be caused by Cu def) ACD Lead poisoning Thalassemias Iron def (late) SALTI
Causes megaloblatic macrocytic anemia
Folate def
B12 def
Orotic aciduria
Causes nonmegaloblastic macrocytic anemia
Liver disease
Alcoholism
Diamond-BLackfan anemia
Causes nonhemolytic normocytic anemia (normal or low retic)
Iron def (early)
ACD
Aplastic anemia
CKD
Causes intrinsic hemolytic normocytic anemia
RBC membrane defect (hereditary spherocytosis), RBC enzyme def (G6PD, pyruvate kinase), HbC disease, Paroxysmal nocturnal hemoglobinuria, Sickle cell anemia
Causes extrinsic hemolytic normocytic anemia
Autoimmune, microangiopathic, macroangiopathic, infxns
Iron def causes
Chronic bleeding (GI loss, mnorrhagia), malnutrition, absorption disrders, GI surg, increased demand (e.g. preg), –> lowers the final step in heme synth
Labs in iron def anemia
Low iron, high TIBC, low ferritin, high free erythrocyte protophyrin; microcytosis, hypochromasia (central pallor)
Sx of IDA
Fatigue, conjunctival pallor, pica, spoon nails (koilonychia); glossitis, cheliosis
Plummer Vinson
IDA, esophageal webs, dysphagia
Alpha thalassemia caused by
Alpha globin deletions –> less alpha synthesis
Alpha thalassemia genetics
Cis – Asian pops
Trans – African pops
4 allele deletion –> no alpha globin, excess gamma globin –> Hb Barts (gamma4) –> hydrops fetalis
3 allele delition –> HbH disease – very little alpha globin –> excess b globin makes HbH
2 allele deletion –> less clinically severe anemia
1 allele deletion –> no anemia (clinically silent)
HbH disease sx
Hemolytic anemia, jaundice (hyperBR), high LDH, low hapto
B thalassemia genetics
Point mutations in splice sites and promoter sequences –> less B globin synthesis (esp in Mediterranean pops)
B thalassemia minor
Heterozygote – less B change produced, usually asymptomatic – diagnosis by high HbA2 (>3.5%) on EP
B thalassemia major
Homozygote – no B chain –> severe mycrocytic hypochromic anemia w/ target cells and increased anisopoikilocytosis req blood transfusion (2o hemochromatosis) –>
a. marrow expansion (crew cut on xray) –> skeletal deformities, chipmunk facies,
b. extramedullary hematopoesis -_> hepatosplenomegaly, higher risk of parvo aplastic crisis
High HbF (alpha2g2) – protective in infant so only symptomatic after 6 mths when fetal hb declines
HbS/B thalassemia heterozygote
Mild-mod sickle cell depending on amt of B globin prodxn
Lead poisoning inhibs
Ferrochetalase and ALA DHase –> less heme synth and increased RBC protophyrin;
also inhib rRNA degradation –> retaining aggregates of rRNA –> basophilic stippling
Sx of lead poisoning (and Tx)
Lead lines on gingivae (Burton lines) and metaphyses of long bones on Xray
Encephalopathy and Erythrocyte basophilic stippling
Abdominal colic and sideroblastic Anermia
Drops – wrist/food; Dimercaprol and EDTA are 1st line tx
In kids tx
Succimer
Siderblastic anemia causes
Genetics (x linked defect in ALA synthase), acquired (myelodyslastic syndromes), reversible (EtOH, lead, B6 def, Cu def, isoniazid)
Labs in sideroblastic anemia
Increased iron, normal or low TIBC, high ferritin; ringed sideroblasts w/ iron laden Prussian blue stained mitochondria in bone marrow; peripheral smear –> basophilic stippling of RbCs
Tx of sideroblastic anemia
Pyridoxine (B6 – cofactor for ALA synthase)
Megaloblastic anemia
Impaired DNA synth –> maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm
See RBC macrocytosis, hyperseg neuts, glossitis
Folate deficiency causes
Malnutrition (alcoholics), malabsorption, drugs (methotrexate, TMP, phenytoin), increased req (e.g. hemolytic anemia, preggers)
Labs in folate def
High homocystein, normal MMA; NO NEURO SYMPTOMS
Vitamin B12 def causes
Insufficient intake (veganism), malabsoprtion (Crohns), pernicious anemia, Diphyllobothrium latum (fish tapeworm), gastrectomy
Vit B12 def labs
High homocysteine, high MMA
Vit B12 sx
NEURO! REversible dementia, SCD due to involvement in fatty acid pathways and myelin synth –> spinocerebellar tract, LCST, dorsal column
Schilling test
Dietary vs malabsorption
Liver can store folate or B12 longer
B12 – takes several years
Orotic aciduria mechanism
Inability to convert orotic acid to UMP (de novo pyrimidine synth pathway) due to defect in UMP synthase
Orotic aciduria genetics
AR
Orotic aciduria presentation
In children – failure to trive, developmental delay, megaloblastic anemia refractory to folate and B12
NO HYPERAMMONEMIA! (vs OTC def!)
Orotic aciduria lab
Orotic acid in urine
Tx of orotic aciduria
Uridine triacetate to bypass mutated enzyme
Nonmegaloblastic anemia
Macrocytic anemia where DNA synth is unimpaired –> RBC macrocytosis w/o hyperseg neuts
Nonmegaloblastic anemia causes
EtOH, liver disease
Diamond Blackfan anemia mechanism
Rapid onset anemia w/in first year of life due to intrinsic defect in erythroid progenitor cells (build up–> disrupt bone formation)
Diamond blackfan labs
High %HbF, but low total Hb
Diamond blackfan presentation
Short stature, craniofacial abnormalities, upper extremity malformations (triphalangeal thumbs)
Intravascular hemolysis findings
Low hapto, high schistocytes, hemoglobinuria, hemosiderinuria, urobilinogen in urine, high unconj bili
Causes of intravascular hemolysis
Mechanical, paroxysmal nocturanl hemoglobinuria, microangiopathic hemolytic anemia
Extravascular hemolysis findings
Macs in spleen clear RBCs – spherocytes in peripheral smear; no hemoglobinuria or hemosiderinura but may have urobilinogen in urine
Most common causes of extravascular hemolysis
Hereditary spherocytosis and autoimmune hemolytic anemia
Anemia of chronic disease mechanism
Inflamm –> high hepcidin (binds ferroportin on intestine cells and macs to inhib iron transport –> less release of iron from macs and less iron absorption in gut
ACD assc
SLE, RA, neoplastic disorders, CKD
ACD findings
Low iron, low TIBC, high ferritin
Tx of ACD
Address underling cause, can consider transfusion or stimulation
Aplastic anemia causes
Failure/destruction of myeloid stem cells due to
Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites)
Viral agents (parvovirus B19, EBC, HIV, hepatitis)
Fanconi anemia (DNA repair defects –> bone marrow failure, macrocytosis may be seen on CBC, also short statures, high incidence of tumors/leukemia, cafe au lait spots, thumb/radial defects
Idiopathic
Findings in aplastic anemia
Low retic, high EPO; pancytopenia w/ severe anemia, leukopenia, thrombocytopenia; normal cell morph but hypocellular bone marrow w/ fatty infiltration
DRY BONE MARROW TAP!
Sx of aplastic anemia
Fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infxn
Tx of aplastic anemia
W.drawal of offending agent, immunosuppressive regiments (antithymocyte globulin, cyclosporine), bone marrow allograft, RBC/plt transfusion, bone marrow stim (GM-CSF)
Hereditary spherocytosis
A type of intrinsic hemolytic anemia – extravascular hemolysis due to defect in proteins interacting w/ RBC membrane skeleton and plasma membrane (anykyrin band 3, protein 4.2, spectrin) –> small, round RBCs w/ less surface area and no central pallor (high MCHC)–>premature removal by spleen
Hereditary spherocytosis genetics
AD
Sx and labs in hereditary spherocytosis
Sx: splenomegaly, aplastic crisis (parvoB19 infxn)
Labs: Osmotic fragility test pos (put in saline), NL/low MCV w/ abundance of cells
Tx of hereditary spherocytosis
Splenectomy
Most common enzymatic disorder of RBCs
G6PD def
Genetics of G6PD def
XLr
G6PD def mechanism
Extravascular and intravascular hemolysis due to defect in G6PD –> low glutathione -> high RBC susceptibility to oxidant stress -> hemolytic anemia under that stress (sulfa drugs, antimalarials, infxns, fava beans)
Sx of G6PD def
Back pain, hemoglobinuria a few days after oxidant stress
Labs in G6PD def
Heinz bodies and bite cells on blood smear
Pyruvate kinase
PEP–> Pyruvate and ATP
Pyruvate kinase def genetics
Ar
Pyruvate kinase def mechanism
Less PKase–> less ATP –> rigid RBCs–>extravascular hemolysis
Increases levels of 23 BPG–>lower Hb affinity for O2
Presentation of pyruvate kinase def
Hemolytic anemia in a newborn
Paroxysmal nocturnal hemoglobinuria pathophys and associations
Compliment mediated intravascularRBC lysis due to impaired synth of GPI anchor for DAF (protects RBC membrane from compliment)
Is an acquired mutation in hematopoetic stem cell
–> increased incidence of acute leukemias, assc w/ aplastic anemia
PNH fx
Red or pink urine (hemoglobinuria), Coombs neg hemolytic anemia, pancytopenia, venous thrombosis
PNH labs
CD55/59 neg RBCs on flow cyto
PNH tx
Eculizumab (terminal compliment inhibitor)
Sickle cell anemia mutation
HbS point mutation –> single amino acid replacement in beta chain (glutamic acid –> valine)
Type of hemolysis in sickle cell
Intra and extravascular
