Hematology Flashcards
Anemia definition?
Low hemoglobin (M: <130g/L, F: <120g/L), normal MCV 80-100fL
What are the symptoms of anemia?
Symptoms of anemia: fatigue, headache, SOB, light-headedness, malaise, weakness, decreased exercise tolerance, dyspnea, palpitations, dizziness, tinnitus, and syncope
What should be your physical exam for anemia?
o HEENT: pallor in mucous membranes and conjunctiva at Hb <90g/L (<9g/dL), ocular bruits at Hb <55 g/L (<5.5 g/dL), angular cheilitis, jaundice
o Cardiac: tachycardia, orthostatic hypotension, systolic flow murmur, wide pulse pressure, signs of CHF
o Dermatologic: ecchymosis, petechiae, pallor in palmar skin creases at Hb <75 g/L, jaundice (if due to hemolysis), nail changes (spooning - koilonychia), and glossitis
o Splenomegaly, lymphadenopathy
What should be asked on history for anemia?
o Acute vs. chronic, bleeding, systemic illness, diet (Fe, B12 sources), alcohol, and family history
o Menstrual history: menorrhagia, menometrorrhagia
o Rule out pancytopenia (recurrent infection, mucosal bleeding, easy bruising)
Define microcytic anemia
If MCV <80
Clinical features of microcytic anemia
Iron deficiency may cause fatigue before clinical anemia develops
Signs/symptoms of anemia
Brittle hair, nail changes (brittle, koilonychia)
Pica (appetite for non-food substances e.g. ice, paint, and dirt)
Restless leg syndrome
Ddx of microcytic anemia
TAILS: thalassemia, anemia or chronic disease, iron deficiency*, lead poisoning, sideroblastic anemia
Lab results of iron deficiency anemia
low serum iron, high TIBC and low ferritin. High RDW
Etiology of iron deficiency anemia?
Increased demand
Increased physiological need for iron in the body (e.g. pregnancy)
Decreased supply: dietary deficiencies - Cow’s milk (infant diet), “tea and toast” diet (elderly), absorption imbalances, post-gastrectomy, malabsorption (IBD of duodenum, celiac disease, autoimmune atrophic gastritis, and H.pylori infection)
Increased losses
Hemorrhage - menorrhagia, abnormal uterine bleeding, and frank GI bleed. Occult: peptic ulcer disease, GI cancer
Hemolysis - Chronic intravascular hemolysis (e.g. PNH, cardiac valve RBC fragmentation)
Sequence of iron deficiency
Decrease in iron – increase TIBC – decrease Hb – decrease MCV - hypochromia
What is anemia of chronic disease
Hepatic hepcidin production is increased in inflammatory processes, trapping iron in enterocytes and macrophages (via ferroportin inhibition).
Lab results of anemia of chronic disease
Low serum iron, low TIBC and high/normal ferritin. Inflammatory markers (CRP)
Etiology of anemia of chronic disease
o Infection, malignancy, inflammatory, and rheumatologic disease
o Chronic renal and liver disease
o Endocrine disorders (e.g. DM, hypothyroidism, hypogonadism, and hypopituitarism)
Lab results of thalassemia
Normal iron, high RBC, very low MCV, historically low MCV
What is thalassemia?
Condition characterized by ineffective synthesis of globin chains due to inherited mutations in the alpha or beta globin genes; alpha or beta thalassemia depending on which chain is affected;
If 4/4 alpha globing genes deleted?
Incompatible with life
What is thalassemia trait?
Thalassemia trait→ carrier state, mild anemia with microcytosis
Beta thalassemia disease treatment?
Severe transfusion dependent anemia
Diagnostic hallmark of sideroblastic anemia?
Ringed sideroblasts
Etiology of sideroblastic anemia?
o Hereditary (rare): X-linked; median survival 10yr o Idiopathic (acquired) - Refractory anemia with ringed sideroblasts: a subtype of MDS - Preleukemic phenomenon (1-2% transform to AML) o Reversible: drugs (isoniazid, chloramphenicol), alcohol, lead, copper deficiency, zinc toxicity, and hypothyroidism
What is sideroblastic anemia?
Erythrocytes with iron- containing (basophilic) granules in the cytoplasm
Explain the “ring” - The hallmark of sideroblastic anemia
“ring”: iron deposits in mitochondria, forming large, abnormal granules that surround the nucleus
Lab results of sideroblastic anemia?
Increased serum Fe2+, normal TIBC, increased ferritin
Treatment of sideroblastic anemia?
o X-linked: high dose pyridoxine (vitamin B6) in some cases
o Acquired: EPO and G-CSF
o Reversible: remove precipitating cause
Distinguishing features between Iron deficiency and thalassemia?
RDW red cells in thalassemia tend to have a narrower distribution than in iron deficiency
MCV red cells in thalassemia tend to be smaller than in iron deficiency
RBC high or normal if thalassemia but tend to decrease proportionally to Hb in iron deficiency
THALASSEMIA INDEX MCV/RBC. Suggests thalassemia if <13 and iron deficiency if >13
Basic lab investigations for microcytic anemia?
CBCD, peripheral smear, reticulocyte count, serum iron, serum ferritin, TIBC (transferrin), % sat, Hb electrophoresis (thalassemia), fecal occult blood (if suspect GI bleed), CRP (anemia of inflammation)
Who should receive endoscopy (gastroscopy and/or colonoscopy) for microcytic anemia?
Symptoms in any man or post-menopausal woman with iron deficiency or in anyone with suspected GI bleeding
IV iron indications
o Intolerant of oral iron
o Inflammatory bowel disease
o Chronic kidney disease on hemodialysis
Treatment of iron deficiency anemia?
Iron deficiency (iron gluconate 300 mg PO TID - It may take up to 6 weeks to correct anemia and 6 months to replete iron stores. Oral iron should be taken with citrus juice (vitamin C) to enhance absorption
Definition of normocytic anemia?
Definition: If MCV 80-100
Clinical features of normocytic anemia?
Can present acutely or insidiously
Symptoms of anemia
Thrombocytopenia and/or infection
Splenomegaly and lymphadenopathy
Ddx of normocytic anemia with increased RBC loss or destruction?
- Bleeding: GI, GU, pelvis/abdomen, skin, CNS
- Hemolysis
Acquired:
Immune-mediated: autoimmune hemolytic anemia (warm agglutinins, cold agglutinins), drug induced hemolytic anemia, alloimmune hemolytic anemia (acute hemolytic reaction)
Microangiopathic (MAHA): TTP, HUS, DIC, pre-eclampsia, eclampsia, malignant hypertension, prosthetic valves
Infection: Malaria, babesiosis, Clostridium infections
Hereditary:
Enzymopathies - G6PD deficiency, pyruvate kinase deficiency
Membranopathies – hereditary spherocytosis, elliptocytosis
Hemoglobinopathies – thalassemia and sickle cell disease
What is myelofibrosis?
Bone marrow replaced with collagenous deposition–scarring of bone marrow
Ddx of normocytic anemia with decreased RBC production?
- Primary causes: Marrow hypoplasia, myelopathies, myeloproliferative diseases, red cell aplasia
- Secondary causes: chronic renal failure, liver disease, anemia of chronic disease
Basic lab investigations for normocytic anemia?
CBCD, peripheral smear, reticulocyte count, iron, ferritin, TIBC, % sat, Cr, TSH, AST, ALT, ALP, bilirubin, INR, PTT, haptoglobin, LDH, direct and indirect Coombs test, serum protein electrophoresis (MM), fecal occult blood (if suspect GI bleed)
What is included in a hemolytic workup?
- LDH (enzyme found in RBCs, released when broken up)
- Bilirubin (Hb released from RBCs metabolized to bilirubin), unconjugated bilirubin – liver is overwhelmed and is unable to keep up
- Haptoglobin (present in blood to mop up toxic free Hb) – so it will decrease rapidly
- Blood film (changed RBC shape)
- DAT (direct antiglobulin test/Coomb’s test: look for antibodies bound to red cell surface supporting immune cause of hemolysis) DAT positivity suggests immune rather than non-immune causes of hemolysis
What is intravascular hemolysis?
Severe damage to RBC membrane such that immediate lysis occurs in the circulation - schistocytes
What is extravascular hemolysis?
RBCs are destroyed outside of the vessels - membrane alterations by the macrophages of the spleen and liver
What are the findings of intravascular hemolysis?
Schistocytes. Low haptoglobin and hemoglobinuria - pink or brown serum and dark urine
Diagnosis of immune-mediated hemolytic anemia?
Antibodies to red blood cell surface antigens. Diagnosis: Spherocytes and positive DAT
Ddx of normocytic anemia with overexpansion of plasma volume?
Pregnancy, Overhydration
What is warm antibody hemolytic anemia?
Polyclonal IgG bind to protein Ag on RBC surface at 37C
Etiology of autoimmune hemolytic anemia?
Etiology: Most cases are idiopathic, lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, non-Hodgkin’s lymphoma), antibiotics (penicillin, sulfa drugs, cephalosporins), HIV
o Warm: SLE
o Cold: Infections (M. pneumonia, EBV mono),
What is cold antibody hemolytic anemia?
IgM bind to polysaccharide Ag on RBC surface at <37C
Treatment of warm antibody hemolytic anemia?
Warm: RBC transfusions (test for co-existing allo-antibodies), reduce Ab production (prednisone), supportive therapy (folic acid, bisphosphonates, Ca and vit D replacement), treat underlying cause (malignancy, rheumatological condition, d/c offending medication)
Treatment of cold antibody hemolytic anemia?
Cold: usually supportive (does not respond to steroids or splenectomy). If transfusion needed (warm prior to infusion), avoidance of cold, treatment of underlying malignancy if present
What is the most severe alloimmune hemolytic anemia?
ABO incompatibility
What are examples of microangiopathic hemolytic anemia (MAHA)?
TTP, HUS, DIC, pre-eclampsia, eclampsia, malignant hypertension, prosthetic valves
How to diagnosis microangiopathic hemolytic anemia (MAHA)?
Schistocytes
What are the events that can causes hemolysis in G6PD deficiency?
Hemolytic events caused by infections, drugs, ingestion of fava beans
Diagnosis of hereditary spherocytosis?
Spherocytosis noted on peripheral smear, a family history (in 75 percent of cases), and a negative DAT
Treatment of hereditary spherocytosis?
Treatment: splenectomy
What is sickle cell disease?
Autosomal recessive sickling disorders arise due to a mutant globin chain, most commonly caused by a Glu - Val substitution at position 6 (chromosome 11) resulting in HbS variant
Pathophysiology of sickle cell disease?
At low pO2, deoxy HbS polymerizes leading to rigid crystal-like rods that distort membranes → ‘sickles’
Clinical features of HbAS (sickle cell trait)?
Patient will be asymptomatic except during extreme hypoxia or infection - increased risk of renal medullary carcinoma
Clinical features of HbAS (sickle cell trait)?
Patient will be asymptomatic except during extreme hypoxia or infection - increased risk of renal medullary carcinoma
Clinical features of SCD-SS (HbSS)?
Chronic hemolytic anemia, jaundice in the first year of life, retarded growth and development ± skeletal changes, splenomegaly in childhood; splenic atrophy in adulthood
Investigations for sickle cell disease?
- Sickle cell prep (detects sickling of RBCs under the microscope in response to O2 lowering agent): determines the presence of a HbS allele, but does not distinguish HbAS from HbSS
- Hb electrophoresis distinguishes HbAS, HbSS, HbSC, and other variants
Treatment of vaso-occlusive crisis in sickle cell disease?
Supportive care: oxygen, hydration (reduces viscosity), correct acidosis, analgesics/opiates
Treatment of sickle cell disease?
- Folic acid to prevent folate deficiency
* Hydroxyurea to enhance production of HbF
Prevention of crises of sickle cell disease?
- Establish diagnosis
- Avoid conditions that promote sickling (hypoxia, acidosis, dehydration, fever)
- Vaccination in childhood (pneumococcus, meningococcus, H. influenzae b)
- Prophylactic penicillin (age 3 mo-5 yr)
- Good hygiene, nutrition, and social support
Definition of macrocytic anemia?
Definition: If MCV >100→ macrocytic anemia
Ddx of macrocytic anemia?
BF HARM - vit B12 or folate deficiency*, hypothyroidism, EtOH/liver disease, reticulocytosis (blood loss, hemolysis), myelodysplasia
Investigations for macrocytic anemia?
CBCD, peripheral blood smear, reticulocyte count, vitamin B12, RBC folate, TSH, AST, ALT, ALP, bilirubin, INR, PTT
Why a peripheral blood smear for macrocytic anemia?
Blood smear to determine if megaloblastic or non-megaloblastic
What is megaloblastic anemia?
Megaloblastic is due to impaired DNA synthesis during RBC synthesis leading to continued cell growth without division. Pancytopenia, hypersegmented neutrophils
Examples of megaloblastic anemia?
Due to Vit B12 deficiency and folate deficiency
What does vitamin B12 bind to?
Binds to intrinsic factor (IF) secreted by gastric parietal cells
Where is vitamin B12 absorbed?
Terminal ileum
What is pernicious anemia?
IgA targets intrinsic factor or parietal cell and therefore vit B12 can’t be absorbed.
Etiology of vitamin B12 deficiency?
- Diet - Strict vegan
- Gastric - Mucosal atrophy (Gastritis, autoimmune), Pernicious anemia, Post-gastrectomy
- Intestinal absorption – Malabsorption (Crohn’s, celiac sprue, pancreatic insufficiency, H. pylori), Stagnant bowel, Resection of ileum
Clinical features of vitamin B12 deficiency?
o Peripheral neuropathy (variable reversibility) - usually symmetrical, affecting lower limbs more than upper limbs
o Cord (irreversible damage) - subacute combined degeneration
Posterior columns: decreased vibration sense, proprioception, 2-point discrimination, and paresthesia
Pyramidal tracts: spastic weakness, ataxia
o Cerebral (common, reversible with B12 therapy) - confusion, delirium, and dementia
o Cranial nerves (rare) - optic atrophy
Treatment of vitamin B12 deficiency?
B12 1000 mcg IM: daily x 7d then weekly x 4 weeks then monthly. B12 1000 mcg PO daily (monitor for hypokalemia)
Etiology of folate deficiency?
Dietary (neglected elderly, EtOH), malabsorption (celiac, enteritis, short bowel syndrome), increased requirements (hemolysis, pregnancy), drugs (methotrexate, phenytoin)
Clinical features of folate deficiency?
Clinical Features: anemia, mild jaundice, glossitis, diarrhea, confusion, pallor
Treatment of folate deficiency?
Folate 5 mg PO
What is non-megaloblastic anemia?
Reflects membrane abnormality with abnormal cholesterol metabolism increased RBC cell membrane size, no DNA replication problems
Examples of non-megaloblastic anemia?
Due to liver disease, chronic alcohol intake, hypothyroidism, drugs, myelodysplasia
Treatment of pernicious anemia?
Transfuse fewer units and transfuse each unit slowly over 3 h since an expanded intravascular volume puts patients at risk for transfusion induced pulmonary edema.
Definition of localized lymphadenopathy?
Localized lymphadenopathy is specific to 1 lymph node region
Definition of generalized lymphadenopathy?
Generalized lymphadenopathy involves > 2 noncontiguous lymph node regions
Reassuring features of lymphadenopathy?
Reassuring: a few small (<1cm), localized, mobile, tender LNs with acute onset, associated with infectious symptoms, and no changes to overlying skin.
Worrisome features of lymphadenopathy?
Worrisome: generalized, subacute or chronic lymphadenopathy with fixed, non-tender nodes, changes to overlying skin, and associated fever, weight loss, night sweats, joint or bone pain, splenomegaly
Causes of localized lymphadenopathy?
- Infection (bacterial more common)
- Neoplasm - Metastatic disease
- Local inflammation
- Local reaction (insect bite)
Causes of generalized lymphadenopathy?
Reactive
- Bacterial (TB, Lyme, brucellosis, cat scratch disease, and syphilis)
- Viral (EBV, CMV, HIV, rubella) – most common
- Parasitic (toxoplasmosis)
- Fungal (histoplasmosis)
Inflammatory
- Collagen disease (RA, dermatomyositis, SLE, vasculitis, and Sjögren’s)
- Drug hypersensitivity
- Sarcoidosis, amyloidosis
- Serum sickness
Neoplastic (lymphoma)
- Lymphoma – especially when you see nodes enlarged above and below the diaphragm, this is less likely a metastasis from a solid tumour and more likely lymphoma
What should be asked on history for lymphadenopathy?
- Lymph nodes – onset, duration, progression (any changes), characteristics, associated symptoms
- Recent illnesses – URTI, rash, headache, vision changes, nausea/vomiting/diarrhea
- Constitutional symptoms – fever, night sweats, weight loss (ask about changes in clothing sizes)
- Skin lesions/trauma
- Recent travel/exposures – Infectious symptoms around travel time, animal bites, ticks, cat scratch, food
- Medications: Carbamazepine, phenytoin
Physical exam for lymphadenopathy?
- LN
- H&N exam: scalp infection, oropharynx (large tonsils, inflamed gums), ears (AOM), eyes (conjunctivitis), thyroid, ROM
- Abdomen: hepatosplenomegaly, masses
- Skin: rash, erythema, petechiae, bruising and pallor
- Resp exam
Red flags for lymphadenopathy
Generalized lymphadenopathy, Size >2cm, not decreasing after 4 weeks, Firm, matted, rubbery consistency, Nontender, Supraclavicular location, Systemic symptoms
What should you comment on for lymph node exam?
Comment on: Location +(Non)Tender + Size (abnormal if >terminal phalanx of pinky) + Rubbery/Firm + Fixed/Mobile + Matting w/ Other Nodes + Drainage + Skin Changes (swelling/erythema/induration)
Investigations for lymphadenopathy
o CBC and differential, blood film
o If generalized, consider tuberculin test, HIV RNA, VDRL, Monospot/EBV serology, ANA, and imaging (CXR +/- abdomen CT)
o If localized and no symptoms suggestive of malignancy, can observe 3-4wk (if no resolution - biopsy)
Gold standard bx for lymphoproliferative disease?
Excisional biopsy is the gold standard
Most common presentation of cervical adenitis?
Acute Bilateral
History for acute bilateral cervical adenitis?
History: rhinorrhea, cough, sore throat, sick contacts
Most common etiology for acute bilateral cervical adenitis?
Viruses
Physical exam findings for acute bilateral cervical adenitis?
Physical: bilateral, small, mobile, LN, minimally tender, no erythema or overlying warmth
- Associated findings: +/- fever, pharyngitis, hepatosplenomegaly, rash
Investigations for acute bilateral cervical adenitis?
Clinical +/- swabs or serology
Treatment for acute bilateral cervical adenitis?
Treatment: supportive, self-limited
Most common etiology for acute unlateral cervical adenitis?
Usually bacterial
History for acute unlateral cervical adenitis?
History: viral prodrome
Physical exam findings for acute unilateral cervical adenitis?
Physical: tender, warm, erythematous and poorly mobile LN
- Associated findings: +/- fever, fluctuance, ill-appearing
Investigations for acute unilateral cervical adenitis?
Clinical +/- partial septic workup if febrile and ill-appearing, throat swab and cultures of draining skin lesions + US
Treatment for acute unilateral cervical adenitis?
Antibiotics
Presentation of lymphoma?
Presents with lymphadenopathy and/or splenomegaly, abdominal or mediastinal mass – can compress vessels or kidneys/ureters, cytopenia (Can cause ITP because the abnormal lymphoma cells can sometimes make wonky antibodies that for some reason can destroy platelets), B sx (weight loss, fever, night sweats), recurrent infections.
Investigations for lymphoma?
▪ CBC/diff + blood smear, lytes, liver function tests, creatinine, LDH (Can be high if the lymphoma is aggressive and has a high proliferation rate - for whatever reason when cells are turning over frequently LDH will elevate), urate (uric acid – marker of tumor lysis)
▪ Others: viral studies (HIV, hep B or C) - helpful because some of the drugs will cause reactivation of these infections if they’re positive, and must rule these out as causes of lymphadenopathy
▪ Blood culture and broad spectrum antibiotics
▪ Biopsy of LN or involved organ. Can do histology, immunophenotyped by flow cytometry, cytogenetics (karyotype), immunostaining
Classification for lymphoma?
- B-cell NHL (more common)
- Indolent e.g. Follicular
- Aggressive e.g. Diffuse large B cell lymphoma - T-cell NHL
- Indolent (causing little or no pain)
- Aggressive/very aggressive - Hodgkin
Which is more common NHL or HL?
NHL is more common than HL
Presentation of NHL?
- Bimodal – elderly
- LN – peripheral, non-contiguous spread
- Bone marrow involvement – more frequent
- Peripheral blood involvement sometimes
When treating aggressive lymphomas or lymphomas with high tumour bulk, we’ll give ______ to prevent conversion to uric acid, and keep them hydrated. ______ can break down uric acid that has already built up
Allopurinol
Rasburicase
Treatment goal with agressive NHL?
Treatment: Goal is cure. Treat immediately with chemotherapy with anti-CD20 monoclonal antibody if B cell lymphoma
Is it necessary to treat indolent NHL immediately?
Often asymptomatic, not necessary to treat immediately. When they become symptomatic, we then give them treatment to shrink the LNs to take away symptoms but still can’t cure them
Is indolent NHL or aggressive NHL more likely to result in tutor lysis syndrome?
Agressive NHL
Presentation of Hodgkin’s lymphoma?
- Bimodal – peak 20-30 and then at 70-80
- LN – central – mediastinal mass, continuous spread
- Bone marrow involvement – rare
- Peripheral blood involvement – cytopenias secondary to impaired production (as in the case of bone marrow replacement), to sequestration in the spleen, or to autoimmune destruction (by a dysfunctional immune system that makes antibodies against normal peripheral blood cells