Hematology Flashcards
Fever of unknown origin
- body temp >38.3 on >1 occasion
- duration >3wk
- no dx after 3d inpatient eval or 3 outpt apt
Hyperpyrexia
excessive fever >41.5 caused by increase in body’s thermal set point
Hyperthermia
increase in body temperature beyond the body’s thermal set point
Exogenous pyrogens
- substances (microbial cell wall components, Lipopolysaccharides on bacteria) that induce formation of endogenous pyrogens from host cells (macrophages)
Pyrogenic cytokines
cytokines (IL-6) that act on hypothalamus to increase body temperature by releasing PGE2
Antipyretics mechanism of action
Inhibit synthesis of PGE2
Corticosteroids mechanism of action
Inhibit phospholipase A2
ASA and NSAID mechanism of action
Inhibit cyclooxyrgenase
Cell-mediated immunity
- composed of T lymphocytes, macrophages, and NK cells
- major defence against intracellular pathogens
- cytotoxic T cells directly attack and lyse host cells expressing foreign antigens
- helper T cells stimulate B cell proliferation and production of immunoglobulin (Ab)
- reticuloendothelial system = monocyte-derived phagocytes in liver, spleen, LN, lung that clear circulating microorganisms
defects predispose to intracellular pathogen infection - bacteria, fungi, parasitic, viral (various species)
vs. hypogammaglobulinemia and asplenia predispose to infection with encapsulated bacteria (S. pneumonia, H. influenza, N. meningitidis)
Humoral immune system
- Ab, complement system, phagocytes
- defends against extracellular pathogens (encapsulated bacteria)
- Ab produced by mature B cells that recognize and bind foreign antigens
- proteins of complement system can act as opsonins, ‘tagging’ pathogens for destruction by phagocytes - terminal complement proteins can directly kill some pathogens via membranes attack complex
Neutrophils re: immunity
- engulf and destroy pathogenic microbes
- circulating neutrophils localize sites of infection via adhesion molecules expressed by endothelial cells
- diapedesis into extravascular space and further localize via chemokine and chemoattractants
Vaccinations in asplenic patients
S. pneumo
HiB
N. meningitides
Influenza
T cells
- primary mediators of CMI
- Ab production requires intact T-cell number and function (stimulation of B cell proliferation by IL2)
Leukocytosis
high WBC count
Leukopenia
low WBC count
Neutrophils and what are derived from the same common progenitor?
erythrocytes, megakaryocytic, monocytes
proliferation from common progenitor via IL-3 and GM-CSF
later differentiation via granulocyte colony-stimulating factor
Migration of neutrophils
To sites of infection or inflammation via paracellular and transcellular routes through endothelial cell layers
Are polymorphonuclear leukocytes (PML) granules toxic?
Yes
Neutropenia
- ANC <1.5 x1^9/L
- decreased production (primary marrow disorder, B12/folate deficiency, infection/sepsis, drugs)
- increased destruction (autoimmune disease, drugs)
- sequestration (splenomegaly)
- constitutional/normal variant (African descent)
Neutrophilia
- ANC >7.5 x10^9/L
- increased production (reactive, myeloproliferative disease)
- decreased destruction (hyposlenism, asplenism)
- decreased margination (drugs, vigorous physical exertion, stress)
Lymphocytosis
> 4 x10^9/L
- infection (often viral, pertussis, toxoplasmosis)
- hypersensitivity (drug induced, serum sickness)
- neoplastic (ALL, CLL, lymphoma)
- stress (cardiac, trauma, status epileptics, post-splenectomy)
- autoimmune (RA, malignant thymoma)
Leukemoid reaction
- persistent neutrophilic with ABC 30,000-50,000/ microL; circulating neutrophils tend to be mature, not globally derived (vs. leukaemia)
- often with septicaemia and severe bacterial infections (shigellosis, salmonellosis, meningococcemia)
- if 12% all cells immature then LEFT SHIFT (rapid release of cells from bone marrow)
- may see increased band forms
- higher degree of left shift = more immature neutrophil precursors = serious bacterial infection, trauma, burns, surgery, acute hemolysis, hemorrhage
BCR-ABL
aka Philadelphia chromosome
CML
Primary hemostasis
- platelets and vWF
- endpoint = platelet plug formation
bleeding - mucocutaneous (epistaxis, gingival, menorrhagia, petechia/ecchymoses) - immediate onset of bleeding after injury
Secondary hemostasis
- coagulation cascade
- result in fibrin cross linking = reinforcement and stabilization of platelet plug
bleeding - deep tissue (hemarthrosis, intramuscular hematoma) - delayed onset of bleeding after injury
Intrinsic coagulation pathway
collagen (injured vessel) = XII -> XIIa XIIa = XI -> XIa XIa = IX -> IXa platelet phospholipids, calcium, VIIIa to common pathway
Extrinsic coagulation pathway
Tissue factor = VII -> VIIa
platelet phospholipids, calcium
to common pathway
Common coagulation pathway
IXa + VIIa = X -> Xa platelet phospholipids, calcium, Va = II -> IIa (thrombin) -> XIII IIa = fibrinogen -> fibrin XIIIa = fibrin -> cross linked fibrin
Tests for hemostasis
primary
- platelet count, platelet function test
secondary
- PTT: intrinsic pathway factors (VII, IX, XI, XII), monitors heparin tx
- PT/INR: extrinsic pathway factor (VII), monitors warfarin tx
- TT (thrombin time): measures fibrinogen deficiency or reduced prothrombin activation
PTT 1:1 dilution
- if PTT corrects with 1:1 dilution = absolute deficiency in factor level
- if PTT remains high = factor inhibitor present
Ddx hypercoagulable state
inherited - thrombopilia
- antithrombin deficiency
- protein c & s deficiency
- factor V Leiden
- prothrombin 20210 mutation
acquired
- cellular elements (hypercoagulability) - malignancy, pregnancy, OCP, HRT, HIT, DIC, TTP, other
- vascular endothelium - surgery, trauma
- circulatory - pregnancy, immobilization, a. fib
HIT with subsequent thrombosis
- patient has Ab to PF4-heparin complex
- reduction in platelet count and 30-fold increase risk of thrombosis
- d/c heparin and cannot replace with LMWH (cross reactivity) or warfarin (skin necrosis)
- switch to direct thrombin inhibitor or heparinoid anticoagulation
Diagnostic testing re: VTE/ hypercoagulable
- compression U/S gold standard veins above calf
- V/Q scan if PE (not if parenchymal lung disease present)
- spiral CT if PE (not if reduced renal function or pregnancy)
- pulmonary angiography is fold standard for PE (rarely used - CI if compromised renal function)
Ddx splenomegaly
Increased splenic function demand
- clearance of abnormal RBC (thalassemia major, abnormal RBC shape)
- infection (bacterial, viral, fungal, parasitic)
- autoimmune (RA - Felty syndrome, SLE, collagen vascular disease, drug rxn)
Altered splenic circulation
- cirrhosis, portal HTN, protein vein obstruction, hepatic vein obstruction, splenic vein obstruction, CHF
Splenic infiltration
- Myeloproliferative disorders, malignancy, amyloidosis, sarcoidosis, storage disease
Major causes splenomegaly acronym
ICE MASS
- infectious
- congestive splenomegaly
- chronic liver disease
- extra medullary hematopoesis
- malignancy
- amlyoidosis
- sarcoidosis, storage disease
Castell sign
- percussion in 8-9 intercostal space in left anterior axillary line of supine patient elicits resonant note throughout respiratory cycle if spleen normal
- > castell sign = percussion on full inspiration produces dull note (splenic enlargement)
Anemia
- decrease in number of circulating RBC
- result from reduced production, increased destruction, or blood loss
- MCV must be taken into account
B12 (cobalamin) absorption
- cobalamin-protein complex from diet enters stomach -> stomach acid release cobalamin from protein
- cobalamin + R proteins (parietal cells)
- pancreatic enzymes in stomach release cobalamin from R-protein
- cobalamin binds intrinsic factor -> to terminal ileum
- cobalamin-IF complex binds cubuilin (R on mucosal cells in ileum) = endocytosis
- cobalamin binds transport proteins -> TCII-cobalamin complex endocytose; cobalamin released and converted to coenzymes
B12 deficiency causes
Decreased intake - vegans
Altered metabolism
- pernicious anemia (antibodies to parietal cells or IF)
- achlorhydria (acid needed to release cobalamin from protein)
- H2 blockers (decrease IF secretion)
- postgastrectomy
- pancreatic insufficiency (can’t digest R-binders off)
Decreased absorption
- ileal disease
- celiac disease
- pancreatic insufficiency
Neuro sx B12 deficiency
dementia peripheral neuropathy (esp. lower limbs) subacute combined degeneration - cortocospinal tract (spasticity, hyperreflexia) and dorsal column (decreased proprioception and vibration sense)
Fe-deficiency labs
- ferritin = ++ decreased
- serum iron = decreased/normal
- TIBC = increased/high normal
- % saturation = ++decreased
Ddx microcytic anemia
MCV <80fL
- iron deficiency
- thalassemia
- anemia of chronic disease
- lead poisoning
- siberoblastic anemia
Ddx normocytic anemia
MCV 80-100fL Low/normal reticulocytes - anemia of chronic disease - renal failure - combined iron and B12/folate deficiency - marrow infiltration - aplastic anemia
High reticulocytes
- acute blood loss
- hemolysis
- splenic sequestration
Ddx microcytic anemia
MCV >100fL
- megaloblastic (B12/folate deficiency, drugs)
- liver disease
- EtOH
- MDS
- hypothyroidism
- reticulocytosis (response to hemorrhage or hemolysis)
Polycythemia
Increase in hemoglobin (increase RBC mass or decrease plasma volume)
- primary = polycythemia vera
- secondary = increased EPO
Ratio of RBC mass to plasma volume
Hemoglobin and hematocrit
- sensitive to changes in either RBC mass or plasma volume
Polycythemia vera characteristics
- absolute increase of RBC mass and decreased EPO
- median age dx 60
- venous and arterial thrombosis in unusual sites
- headache
- blurry vision
- erythromelagia
- gouty arthritis
- pruritus
- splenomegaly
- easy bleeding (GI bleed, epistaxis)
Polycythemia vera dx
Dx requires both major criteria and one minor criterion OR first major criterion and two minor criteria:
Major criteria
- elevated hemoglobin (>185 males, >165 females)
- JAK2 mutation
Minor criteria
- hyper cellular bone marrow with trilineage myeloproliferation (panmyelosis)
- decreased serum EPO
- endogenous erythroid colony growth in vitro
EPO stimulation, production, action
Stimulation - reduced oxygenation of blood
Production - peritubular kidney cells
Action - bone marrow, increase RBC production
Lymphadenopathy and ddx
LN >1cm = abnormal
- LN have cortex and medulla (germinal enters in cortex)
DDx
- infectious - viral, bacterial, fungal, parasitic
- malignancy - lymphoma, leukaemia, metastatic CA
- immunologic/ inflammatory - serum sickness, collagen vascular disease, drug hypersensitivity
- other - sarcoidosis, amyloidosis, endocrine (hyperthyroidism), storage disease
Lymphatic system constituents
LN and vessels
Thymus
Spleen
Peyer patches in gut
Activation of adaptive immunity
Recognition stage
- antigens recognized by lymphocytes and macrophages
Proliferation stage
- dominant lymphocytes proliferate and differentiate into cytotoxic (killer) T cells or B cells
Response stage
- cytotoxic T and B cells perform cellular and hum oral functions
Effector stage
- antigens destroyed or neutralized through action of antibodies, complement, macrophages, and cytotoxic T cells
LN characteristics (normal, inflammation, lymphoma, metastatic)
normal - soft, discrete, mobile
inflammation - tender, mobile
lymphoma - large, rubbery, non-tender, mobile
metastatic cancer - hard,non-tender, matted, non-mobile
