Differentials
Common
Leukemia
History
chills, fatigue, weakness, frequent infections, anorexia, night sweats, shortness of breath, bony tenderness, epistaxis, bleeding gums
Exam
fever, lymphadenopathy, hepatosplenomegaly, petechiae, pallor
1st investigation
- CBC with differential:
low platelets; low Hb; low, normal, or high WBCs; left-shifted granulopoiesis
- peripheral blood smear:
blasts
- metabolic panel:
elevated LDH and uric acid in acute myelogenous leukemia
Other investigations
- bone marrow aspirate:
>20% blasts
More
Metastatic malignancy
History
previous known malignancy (e.g., breast, prostate, lung)
Exam
breast lump, enlarged prostate gland, anorexia, lymphadenopathy
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
leukoerythroblastic changes
- chest x-ray:
mass or nodule in lung cancer
More - CT abdomen:
mass in visceral organ
Other investigations
Hodgkin lymphoma
History
fever, night sweats, weight loss
Exam
adenopathy, hepatosplenomegaly, skin infiltration
1st investigation
Other investigations
Non-Hodgkin lymphoma
History
fever, night sweats, weight loss, fatigue/malaise
Exam
adenopathy, hepatosplenomegaly, skin infiltration
1st investigation
- lymph node biopsy:
positive
- CT scan:
lymphadenopathy or hepatosplenomegaly
More - CBC with differential:
low platelet count
- peripheral blood smear:
low platelet count; no abnormal cells
Other investigations
- flow cytometry:
tumor surface markers determined
Miliary tuberculosis
History
fever, night sweats, weight loss, hemoptysis
Exam
temporal wasting
1st investigation
- CBC with differential:
normal or pancytopenia
- peripheral smear:
nucleated red blood cells may be seen
- chest x-ray:
consolidation, pulmonary infiltrates, mediastinal or hilar lymphadenopathy, upper zone fibrosis
More - sputum acid-fast bacilli smear and culture:
presence of acid-fast bacilli (Ziehl-Neelsen stain) in specimen. Testing of 3 specimens (minimum 8 hours apart, including an early morning specimen) is recommended in many countries; consult local guidance.[38]
More - nucleic acid amplification tests (NAAT):
positive for M tuberculosis
More
Other investigations
- lateral flow urine lipoarabinomannan (LF-LAM) assay:
positive
More
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Disseminated intravascular coagulation (DIC)
History
fever, cough, dyspnea, confusion, epistaxis, bleeding gums; possible history of sepsis, obstetric complications such as abruptio placentae, snake bite, malignancy (e.g., acute promyelocytic leukemia), or tissue trauma (e.g., surgery)
Exam
petechiae, ecchymosis gangrene, GI or GU tract bleeding, hypotension, tachycardia, pleural friction rub
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
thrombotic microangiopathy (schistocytes)
- serum PT and activated PTT:
elevated
- serum fibrinogen:
low
- D-dimer:
elevated
Other investigations
Post-transfusion
History
often occurs in ICU setting, recent blood transfusion, symptoms 7 to 10 days post-transfusion
Exam
bleeding at sites of intravascular lines, dialysis catheters, extracorporeal oxygenation devices, chest tubes, mediastinal or pericardial tubes; lymphadenopathy or hepatosplenomegaly
1st investigation
Other investigations
Hemolysis, elevated liver enzymes, low platelet count (HELLP)
History
end of third trimester
Exam
hypertension, jaundice
1st investigation
- CBC with differential:
low platelet count
- liver function tests:
elevated aminotransferases
- peripheral blood smear:
may be normal or have mild degree of microangiopathy
Other investigations
Cardiopulmonary bypass
History
recent open heart surgery
Exam
no specific findings on examination
1st investigation
- CBC with differential:
low platelet count
More
Other investigations
Immune thrombocytopenia (ITP)
History
typically a young woman, usually rapid onset of bleeding, sometimes postviral or postvaccination
Exam
petechiae, ecchymoses, buccal mucosal hemorrhages
1st investigation
- CBC with differential:
low platelet count
- peripheral smear:
isolated low platelets; otherwise normal
- serum PT and activated PTT:
normal
- serum fibrinogen:
normal
Other investigations
- bone marrow biopsy:
increased megakaryocytes
More
Systemic lupus erythematosus (SLE)
History
fatigue, fever, and weight loss; peripheral lymphadenopathy, rash, alopecia, arthralgia, Raynaud phenomenon; anterior chest pain, dyspnea; oral ulcers; female patient of reproductive age
Exam
swollen joints, malar rash, discoid rash, fever, oral ulcers, peripheral lymphadenopathy, pleural effusion, pericardial friction rub, cranial nerve abnormalities, hypertension may indicate renal involvement
1st investigation
- CBC with differential:
low platelet count, lymphopenia, anemia; rarely pancytopenia
- peripheral blood smear:
microangiopathy (in severe form)
- serum antinuclear antibodies (ANA):
positive
More - anti-double stranded DNA (anti-dsDNA) antibodies:
positive
More - anti-Smith antibodies:
positive
More - ESR:
elevated
- serum urea and creatinine:
elevated if there is renal involvement
- urinalysis:
may show hematuria, casts (red cell, granular, tubular, or mixed), or proteinuria if there is renal involvement
Rheumatoid arthritis
History
arthralgia, joint swelling (usually symmetrical swelling of the small joints of the hands and feet), morning stiffness
Exam
tender swollen joint; ulnar deviation of metacarpophalangeal joints occurs in advanced disease
1st investigation
- CBC with differential:
low platelet count; WBC count may be normal or elevated
- peripheral blood smear:
low platelet count; otherwise normal
- rheumatoid factor:
usually positive
- ESR:
elevated
Other investigations
- anti-cyclic citrullinated peptide (anti-CCP) antibody:
positive
More
Antiphospholipid syndrome
History
recurrent miscarriages; history of venous, arterial, or small-vessel thrombosis in any tissue or organ
Exam
digital ischemia, swollen extremities from venous thrombosis; livedo reticularis
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
low platelet count; otherwise normal
- serum anticardiolipin antibodies:
positive
- lupus anticoagulant assays:
positive
- anti-beta2-glycoprotein I antibodies:
positive
Other investigations
HIV/AIDS
History
early: fever, cough, shortness of breath, diarrhea, weight loss; late: night sweats, shaking chills, chronic diarrhea, headaches, blurred vision, fatigue, rash, epistaxis
Exam
early: lymphadenopathy; late: white spots on tongue, petechiae, ecchymosis, GI or GU tract bleeding, splenomegaly
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
low platelet count
- HIV antibody test:
positive
- CD4 count:
<200 cells/mm³
More
Other investigations
- bone marrow aspirate:
variable megakaryocytes; fungi or mycobacteria
More
Malaria
History
travel to endemic region, chills, fever, sweats, headache, arthralgias, malaise, fatigue, nausea and vomiting
Exam
muscle weakness, splenomegaly, jaundice, hepatomegaly
1st investigation
- CBC with differential:
low platelet count and Hb
- malaria blood smear:
erythrocytic parasites, Schuffner dots (Plasmodium vivax and P ovale)
More
Other investigations
- serum bilirubin:
elevated
- serum AST:
elevated
- serum ALT:
elevated
- urine albumin:
elevated
- urinalysis:
RBC casts
- rapid diagnostic tests:
detection of parasite antigen or enzymes
More
Dengue fever
History
acute febrile syndrome with headache, retro-orbital pain, nausea, vomiting, diarrhea, myalgia, arthralgia, upper respiratory tract symptoms; recent travel to endemic region
Exam
abdominal tenderness, hepatomegaly, mucosal bleeding, skin flushing, rash
1st investigation
Other investigations
- non-structural protein 1 detection:
positive
More
Zika virus infection
History
often asymptomatic; however, may present with mild self-limited illness, acute onset of low-grade fever, arthralgia, gastrointestinal symptoms, retro-orbital pain, lower limb edema; recent travel to endemic region
Exam
maculopapular pruritic rash, non-purulent conjunctivitis
1st investigation
Other investigations
Cytomegalovirus (CMV)
History
fever, diarrhea, visual changes, solid organ transplant recipient on immune-modulating drugs
Exam
petechiae or ecchymoses, retinal changes
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
low platelet count; otherwise normal
- CMV serology:
positive
More - CMV DNA nucleic acid amplification test:
positive
Other investigations
Infectious mononucleosis
History
adolescents or young adults with fever, pharyngitis
Exam
posterior cervical lymphadenopathy, pharyngitis, soft palate petechiae may be present, possible splenomegaly
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
atypical lymphocytes
- heterophil antibody agglutination test:
positive for Epstein-Barr virus
- antibodies to Epstein-Barr virus (EBV) viral capsid antigen, early antigen, and nuclear antigen:
positive
Other investigations
COVID-19
History
fever, cough, dyspnea, altered sense of taste or smell
Exam
fever, tachypnea, tachycardia, cyanosis, crackles/rales on auscultation, bronchial breath sounds if there is pneumonia
1st investigation
- CBC with differential:
low platelet count; leukopenia, lymphopenia or lymphocytosis, decreased eosinophils, decreased hemoglobin
More - real-time reverse transcription polymerase chain reaction (RT-PCR):
positive for SARS-CoV-2 RNA
Other investigations
Parvovirus B19
History
rash, arthralgia/arthritis, may be history of low-grade fever or coryzal symptoms before rash onset
Exam
characteristic "slapped cheek" rash, reticular rash on extremities and torso
1st investigation
- CBC with differential:
usually pure red cell aplasia, but neutropenia and thrombocytopenia can occur
- reticulocyte count:
decreased
- serology:
positive IgM antibodies for parvovirus B19
Other investigations
Sepsis
History
symptoms of localized infection, non-specific symptoms include fever or shivering, dizziness, nausea and vomiting, muscle pain, feeling confused or disoriented; may be history of risk factors (e.g., immunosuppression, pregnancy or postpartum period, frailty, recent surgery or invasive procedures, intravenous drug use or breach of skin integrity)
Exam
tachycardia, tachypnea, hypotension, fever (>38℃) or hypothermia (<36℃), prolonged capillary refill, mottled or ashen skin, cyanosis, low oxygen saturation, newly altered mental state, reduced urine output
1st investigation
- blood cultures:
May be positive for organism
More - serum lactate:
may be elevated; levels >18 mg/dL (>2 mmol/L) associated with adverse prognosis; even worse prognosis with levels ≥36 mg/dL (≥4 mmol/L) elevated
More - CBC with differential:
WBC count >12×10⁹/L (12,000/microliter) (leukocytosis); WBC count <4×10⁹/L (4000/microliter) (leukopenia); or a normal WBC count with >10% immature forms; low platelets
More - C-reactive protein:
elevated
- blood urea and serum electrolytes:
serum electrolytes may be deranged; blood urea may be elevated
- serum creatinine:
may be elevated
More - liver function tests:
may show elevated bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase
More
Other investigations
- ECG:
may show evidence of ischemia, atrial fibrillation, or other arrhythmia; may be normal
More - chest x-ray:
may show consolidation; demonstrates position of central venous catheter and tracheal tube
- urine microscopy and culture:
may be positive for nitrites, protein or blood; elevated leukocyte count; positive culture for organism
- sputum culture:
may be positive for organism
- lumbar puncture:
may be elevated WBC count, presence of organism on microscopy and positive culture
More
Heparin-induced thrombocytopenia (HIT)
History
recent exposure to heparin
Exam
possible signs of deep venous thrombosis or arterial clotting (e.g., cord, edema, pallor, pulselessness)
1st investigation
Other investigations
- serotonin release assay:
positive
- IgG-specific chemiluminescent assay:
positive
- particle gel immunoassay:
positive
- lateral flow immunoassay:
positive
- polyspecific enzyme-linked immunosorbent assay (ELISA):
positive
- polyspecific chemiluminescent immunoassay (CLIA):
positive
- Warkentin (4Ts) probability scale:
score of 6-8 indicates high clinical suspicion for HIT; score of 4-5 indicates intermediate clinical suspicion for HIT; score of 0-3 indicates low clinical suspicion for HIT
More
Antimalarials, antiseizure drugs, antibiotics, or chemotherapies
History
recent drug ingestion or use
Exam
bruises, petechiae
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
low platelet count; eosinophilia if allergic component
Other investigations
- drug/antibody assays:
unreliable, mostly used in research
Alcohol ingestion
History
history of alcohol misuse
Exam
may have signs of chronic liver disease (e.g., palmar erythema, telangiectasia on upper torso, splenomegaly)
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
macrocytosis without reticulocytosis
- LFTs:
elevated
- serum PT and activated PTT:
elevated
Other investigations
- hepatic ultrasound:
may show hepatomegaly, fatty liver, liver cirrhosis, liver mass, splenomegaly, ascites, evidence of portal hypertension
B12 deficiency
History
weakness, paresthesias
Exam
pale, sallow color; decreased vibratory sensation, dementia
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
macrocytic anemia; thrombocytopenia; hypersegmented polymorphonuclear cells
- serum B12 level:
low
Other investigations
Folate deficiency
History
malabsorption symptoms (e.g., weight loss, diarrhea)
Exam
pale, sallow color
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
macrocytic anemia; thrombocytopenia; hypersegmented polymorphonuclear cells
- serum folate level:
low
Other investigations
Gestational thrombocytopenia
Cirrhosis
History
alcohol misuse, LUQ abdominal pain or history of pancreatitis, early satiety, pruritus, fatigue, easy bruising, frequent infections, confusion, epistaxis, weight loss
Exam
splenomegaly, spider telangiectasias (chest), palmar erythema, ascites (fluid wave), pedal edema, jaundice, spider angiomas, muscle wasting
1st investigation
- CBC with differential:
low Hb and platelet count
- peripheral blood smear:
low platelet count
- serum AST:
elevated
- serum ALT:
elevated
- serum PT and activated PTT:
elevated
- serum LDH:
elevated
- serum bilirubin:
elevated
- serum albumin:
low
Other investigations
- hepatitis C virus serology:
positive in chronic hepatitis C infection
- hepatitis B surface antigen:
positive in hepatitis B infection
- serum ANA:
positive (autoimmune hepatitis)
- serum antimitochondrial antibody:
positive (primary biliary cholangitis)
- serum ferritin:
elevated (hemochromatosis)
- serum iron:
elevated (hemochromatosis)
- serum ceruloplasmin:
low (Wilson disease)
More - CT of abdomen:
portal hypertension
More - ultrasound abdomen/pelvis:
decreased hepatic size, nodules
More - paracentesis:
normal or fluid
- liver biopsy:
features of cirrhosis
Uncommon
Multiple myeloma
History
night sweats, excessive thirst and urination, constipation, nausea, anorexia, weight loss, confusion, fatigue, bone pain, history of bone fractures and of repeated infections (i.e., UTIs, pneumonia)
Exam
bony tenderness (back or ribs), bone fractures, weakness, or leg numbness
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
rouleaux formation
- serum protein electrophoresis:
M proteins or M spike
- urine protein electrophoresis:
Bence Jones proteins
- serum free light chain assay:
increased concentrations of free light chain in serum
More - serum calcium:
may be elevated
Other investigations
- serum beta-2-microglobulin:
positive
More - bone marrow aspirate and biopsy:
>60% plasma cells
- bone marrow cytogenetic analysis:
del13, del17p, t(4;14), t(14;16), chromosomal trisomies or monosomies
More - skeletal survey (x-rays of skull, long bones, spine):
diffuse osteopenia or lytic lesions or fractures
More - whole-body low dose computed tomography:
osteolytic lesions or fractures
Bone marrow fibrosis
History
weight loss, early satiety, low-grade fever, cachexia, fatigue, pruritus
Exam
hepatosplenomegaly
1st investigation
- CBC with differential:
pancytopenia
- peripheral smear:
tear drop red cells and leukoerythroblastic changes
More
Other investigations
- bone marrow:
marrow fibrosis
- CT scan:
hepatosplenomegaly
Thrombotic thrombocytopenic purpura (TTP)
History
fatigue, confusion, visual changes, pregnant, easy bruising, epistaxis, fever, numbness and tingling sensation
Exam
petechiae, arthralgias, prolonged bleeding from lacerations, buccal mucosal bleeding, GI or GU tract bleeding, seizures, decreased sensation (rare), irregular pulse, jaundice
1st investigation
- CBC with differential:
low platelet count, Hb <10 g/dL, low WBC count
- peripheral blood smear:
thrombotic microangiopathy (schistocytes)
- serum LDH:
elevated
- serum reticulocyte count:
elevated
- serum indirect bilirubin:
elevated
- serum PT and activated PTT:
normal
- serum fibrinogen:
normal
- D-dimer:
normal
- pregnancy test:
positive or negative
More - serum creatinine:
normal or elevated
- CT scan brain:
intracranial bleed (rare)
More
Other investigations
- bone marrow biopsy:
hyaline thrombi
Hemolytic uremic syndrome (HUS)
History
recent diarrheal illness in child; recent solid organ recipient on cyclosporine; and recent use of gemcitabine in patients with cancer
Exam
no specific findings on examination
1st investigation
- CBC with differential:
low Hb and platelet count
- peripheral smear:
thrombotic microangiopathy (schistocytes)
- reticulocyte:
elevated reticulocyte count
- serum creatinine:
elevated
- serum electrolytes:
abnormalities may include hyperkalemia, hyponatremia, hypernatremia, acidosis (due to bicarbonate loss), hyperphosphatemia
More
Other investigations
- stool culture:
Shiga toxin-producing E coli cannot ferment sorbitol and appears as white colonies on sorbitol-MacConkey agar
- polymerase chain reaction to detect Shiga toxins 1 and 2:
positive
Sarcoidosis
History
often in young African-American women, dyspnea, cough, uveitis, fever, fatigue, weight loss, arthralgia, rash
Exam
rarely neck lymphadenopathy; otherwise, wheezing/rhonchi if airway involvement, erythema nodosum or lupus pernio, may be normal
1st investigation
- CBC with differential:
low platelet count; WBC count may be normal, decreased, or elevated; may be anemia
- peripheral blood smear:
low platelet count
- chest x-ray:
bihilar adenopathy
Other investigations
- serum calcium:
may be elevated
- liver function tests:
aminotransferases may be elevated
- serum urea and creatinine:
elevated in renal involvement
- ECG:
conduction defects in cardiac involvement
- pulmonary function tests:
obstructive or restrictive pattern
- skin testing with purified protein derivative of tuberculin (PPD):
anergy
Cyclic thrombocytopenia
History
episodic bleeding every 21 to 35 days, may be associated with menstruation
Exam
petechiae that occur then disappear on their own
1st investigation
- CBC with differential:
platelets low periodically
- peripheral blood smear:
normal or low platelet count
Other investigations
Wiskott-Aldrich syndrome
History
male, more common in children, bruising, bleeding, atopy
Exam
poor development, signs of atopy (e.g., rash, ecchymoses, adenopathy, hepatosplenomegaly)
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
small platelets
- flow cytometry for quantitative abnormalities of Wiskott-Aldrich syndrome protein (WASP):
decreased
- WASP gene mutation analysis:
Confirms WASP gene mutation
Other investigations
MYH9-related disorders, including May-Hegglin anomaly
History
lifelong bruising, recurrent epistaxis, menorrhagia
Exam
ecchymoses, petechiae, cataracts, high-frequency hearing loss
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
large platelets, Döhle bodies in polymorphonuclear cells
More
Other investigations
- single gene sequencing to establish MYH9 mutations:
positive
- next generation sequencing panel that includes MYH9 gene:
positive
Bernard-Soulier syndrome
History
white European ancestry, lifelong bruising, recurrent epistaxis, menorrhagia
Exam
ecchymoses, petechiae
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
large platelets
- platelet flow cytometry:
low expression of glycoprotein IB/IX
Other investigations
- platelet aggregation studies:
significantly reduced or absent platelet aggregation in the presence of ristocetin and low dose thrombin
Gaucher disease
History
bone pain, Ashkenazi Jewish background (although can be any ethnic group)
Exam
hepatosplenomegaly
1st investigation
- CBC with differential:
low WBC count, low platelet count
- peripheral blood smear:
low WBC count, low platelet count
- glucocerebroside assay:
reduced activity
Other investigations
Hashimoto thyroiditis
History
symptoms of hypothyroidism (weight gain, fatigue, hair loss, constipation, dry skin)
Exam
peripheral edema, hair loss, bradycardia, hypothyroid facies, enlarged thyroid gland, delayed return of deep tendon reflexes
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
low platelet count; otherwise normal
- antimicrosomal antibodies:
positive
- TFTs:
elevated TSH, low T4
Other investigations
Aplastic anemia
History
fevers, weakness, bruising, epistaxis
Exam
furuncles, ecchymoses, petechiae, pallor, tachycardia
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
pancytopenia
Other investigations
- bone marrow biopsy:
severe hypocellularity
Vaccinations
History
history of recent vaccination (e.g., measles, mumps, and rubella)
Exam
ecchymoses, petechiae
1st investigation
- CBC with differential:
pancytopenia
- peripheral blood smear:
pancytopenia
Other investigations
Paroxysmal nocturnal hemoglobinuria (PNH)
History
gradual onset weakness; can have thrombotic presentation such as abdominal distention due to Budd-Chiari syndrome
Exam
bruises, pallor
1st investigation
- CBC with differential:
anemia or pancytopenia
- peripheral blood smear:
pancytopenia
- LDH:
elevated
- reticulocyte count:
elevated
- unconjugated bilirubin:
elevated
- PNH flow cytometry:
elevated CD59-positive RBCs and granulocytes
- urinanalysis:
hemoglobinuria
- urine microscopy:
hemosiderinuria
Other investigations
Pseudothrombocytopenia
History
no bleeding history, history of low platelets
Exam
normal
1st investigation
- CBC with differential:
low platelet count
- peripheral blood smear:
clumped platelets
- serum platelet count in EDTA tube:
low
- serum platelet count in or heparin tube:
normal
- peripheral smear from fingerstick sample:
normal platelet count
- manual platelet count on a sample without anticoagulants:
normal platelet count
Other investigations
Familial platelet disorder with germline RUNX1 mutation
History
mild to moderate bleeding tendency
Exam
normal
1st investigation
- CBC with differential:
low platelet count
- platelet aggregation studies:
impaired with collagen and epinephrine
- Sanger sequencing:
RUNX1 mutation
Other investigations
- next generation sequencing:
RUNX1 mutation
- skin fibroblast culture:
RUNX1 mutation
More
Thrombocytopenia due to germline ANKRD26 mutation
History
mild bleeding tendency
Exam
normal
1st investigation
- CBC with differential:
low platelet count
- platelet aggregation studies:
normal
- PCR testing for ANKRD26 mutation:
positive
Other investigations
- skin fibroblast culture:
ANKRD26 mutation present
More
Thrombocytopenia due to germline ETV6 mutation
History
mild to moderate bleeding tendency
Exam
normal
1st investigation
- CBC with differential:
low platelet count
- platelet aggregation studies:
normal
- next generation sequencing:
ETV6 mutation
Other investigations
- skin fibroblast culture:
ETV6 mutation present
More
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