Differentials
Pseudothrombocytopenia
SIGNS / SYMPTOMS
A spuriously low platelet count caused by agglutination when exposed to disodium ethylenediaminetetraacetate occurs in 0.1% of adults.
Prompt recognition of this benign condition avoids exposure to potentially dangerous diagnostic tests and treatments.
INVESTIGATIONS
Ex-vivo agglutination, or clumping, can lead to spuriously low platelet counts on automated counters because the machine is unable to detect and count the individual platelets that make up a clump. This may account for up to 15% to 30% of all cases of isolated thrombocytopenia.[23]
Peripheral blood smear shows platelet clumps.
Platelet satellitism, where platelets form a ring around neutrophils, may also be seen.
Congenital thrombocytopenia
SIGNS / SYMPTOMS
Positive family history of congenital thrombocytopenia.
This is a broad category, which includes MYH9 disorders and several congenital syndromes, such as Paris-Trousseau syndrome.
The bleeding may be worse than expected for the platelet count reported, as platelet function may also be impaired in addition to impaired platelet production.
Congenital disorders may have associated facial dysmorphism, heart defects, intellectual disability, skeletal abnormalities, high-tone sensorineural deafness, nephritis, and cataracts.
INVESTIGATIONS
Macrothrombocytes and Dohle body-like inclusions in leukocytes on peripheral blood smear.
A subpopulation of platelets with giant alpha granules is seen in Paris-Trousseau syndrome.
Acquired thrombocytopenia (e.g., related to liver disease or alcohol ingestion)
SIGNS / SYMPTOMS
Large amounts of alcohol consumption can directly suppress bone marrow production of platelets.[24] Thrombopoietin is produced in the liver, and so severely impaired liver synthetic function can lead to reduced stimulation of platelet production.
Physical exam may demonstrate signs of liver failure including splenomegaly, ascites, varices, spider angiomata, palmar erythema, and gynecomastia.
Massive splenomegaly from liver disease can lead to exaggerated splenic pooling and thrombocytopenia.
INVESTIGATIONS
Elevated gamma glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase.
Prolonged prothrombin time.
Decreased serum albumin.
Megaloblastic peripheral blood smear with macrocytic red blood cell (RBC), hypersegmented neutrophils, and Howell-Jolly bodies (chromosomal remnants in RBC) suggests vitamin B12 or folate deficiency.
Thrombotic thrombocytopenic purpura
SIGNS / SYMPTOMS
May demonstrate neurological changes or fever as well as signs of anemia and thrombocytopenia.
Diagnosed during pregnancy or postpartum in 12% to 25% of cases, with 75% of these cases occurring around the time of delivery.[25]
INVESTIGATIONS
CBC shows anemia and thrombocytopenia with fragmented red blood cells (schistocytes) on blood smear (microangiopathic film).
Elevated lactate dehydrogenase and low haptoglobin.
Malignant hypertension
SIGNS / SYMPTOMS
Patients have severely elevated blood pressure.
INVESTIGATIONS
CBC shows a microangiopathic picture with anemia, thrombocytopenia, and fragmented red blood cells (schistocytes) on blood smear.
Disseminated intravascular coagulation (DIC)
SIGNS / SYMPTOMS
DIC is a disorder of coagulation that occurs in the setting of other medical conditions such as sepsis, trauma, malignancy, pregnancy, and amniotic fluid embolism.
Patients are usually very ill with significant bleeding due to coagulation defects.
INVESTIGATIONS
CBC shows a microangiopathic picture with anemia, thrombocytopenia, and fragmented red blood cells (schistocytes) on blood smear.
Prolonged prothrombin time and activated partial thromboplastin time.
Elevated D-dimer.
Sepsis
SIGNS / SYMPTOMS
Patients with sepsis can develop thrombocytopenia. These patients have hypotension and other signs of sepsis. Treatment of the underlying infection should correct the thrombocytopenia.
INVESTIGATIONS
Elevated white cell count with left shift.
Peripheral blood smear may show vacuoles in the cytoplasm of neutrophils, which is highly specific for bacteremia.
Blood cultures may be positive.
Thrombocytopenia and anemia are often related to a concurrent DIC phenomenon.
Gestational thrombocytopenia
SIGNS / SYMPTOMS
In general, gestational thrombocytopenia is more common and milder than immune thrombocytopenia (ITP). It occurs in late gestation and recovers completely after delivery.
Gestational thrombocytopenia has no risk to the baby, whereas ITP in pregnancy can cause neonatal thrombocytopenia.
INVESTIGATIONS
There is no absolute test to differentiate between gestational thrombocytopenia and ITP in pregnancy. Platelet count for gestational thrombocytopenia does not usually fall below 70 × 10³/microliter.
A platelet count <100 × 10³/microliter during pregnancy may indicate another underlying cause of thrombocytopenia other than gestational thrombocytopenia, such as ITP.[26]
Myelodysplastic syndromes (MDS)
SIGNS / SYMPTOMS
MDS is a rare cause of isolated thrombocytopenia. Incidence increases with age, so bone marrow biopsy (which can differentiate immune thrombocytopenia from MDS) is recommended in the workup of patients over 60 years with isolated thrombocytopenia.
Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon but may be present.
INVESTIGATIONS
CBC usually shows a decrease in other cell lines, but isolated thrombocytopenia can occur in up to 5% of cases.[27]
Bone marrow core biopsy shows hypercellular marrow.
Bone marrow cytogenetic analysis shows chromosomal abnormalities.
Bone marrow aspirate and trephine shows single or multilineage dysplasia.
Type IIB von Willebrand disease
SIGNS / SYMPTOMS
Autosomal-dominant disorder, so may have known family history.
A gain-of-function mutation in von Willebrand factor results in binding to platelets and clearance of platelets from the circulation.
These patients have bleeding out of proportion to their platelet count.
INVESTIGATIONS
Decreased von Willebrand factor activity.
Increased ristocetin-induced platelet aggregation.
Decreased large von Willebrand factor multimers on electrophoresis.
Splenomegaly/hypersplenism
SIGNS / SYMPTOMS
Splenomegaly can lead to a reversible pooling of up to 90% of the total body platelet count, whereas hypersplenism results in early destruction of platelets in the spleen.
Patients may have palpable splenomegaly and signs of the underlying cause of splenomegaly, such as lymphadenopathy in lymphoma or jaundice and spider nevi in portal hypertension due to liver disease. Consider also a diagnosis of Gaucher disease or other metabolic storage disorders.
INVESTIGATIONS
Ultrasound and CT scan will show splenomegaly.
Drug-induced thrombocytopenia
SIGNS / SYMPTOMS
A thorough medication and herbal supplement history is important for identifying potential offending drugs.
Many drugs have been implicated, including quinidine, quinine, rifampin, and bactrim. Herbal remedies can also be implicated, including tonic water (contains quinine) and tahini (a component of hummus).[28]
Resolution of thrombocytopenia when drug ceased.
INVESTIGATIONS
Diagnosis is clinical.
Positive drug-associated antibody test (carried out in specialized laboratories).
Heparin-induced thrombocytopenia (HIT)
SIGNS / SYMPTOMS
A medication history will reveal the use of heparin or low-molecular-weight heparin.
HIT affects up to 5% of patients exposed to heparin. Thrombocytopenia usually occurs 5 to 14 days after starting heparin therapy (but can occur sooner if there has been a prior heparin exposure).
Up to 55% of patients with untreated HIT will develop thrombosis (e.g., deep vein thrombosis and/or pulmonary embolism).[29]
INVESTIGATIONS
Positive for HIT antibodies on anti-platelet factor 4-heparin enzyme-linked immunosorbent assay (ELISA); positive serotonin release assay.
Severe preeclampsia
SIGNS / SYMPTOMS
New blood pressure elevation and proteinuria after 20 weeks' gestation in pregnant women.
INVESTIGATIONS
Elevated urinary protein.
Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome
SIGNS / SYMPTOMS
Typically, occurs in pregnant women who are already being followed up for gestational hypertension or preeclampsia.
Patients are hypertensive and may complain of headache, nausea, and abdominal discomfort.
INVESTIGATIONS
Low hemoglobin, low haptoglobin, and elevated unconjugated bilirubin consistent with hemolytic anemia.
Elevated LFTs.
Low platelets.
May have abnormal coagulation studies if DIC present.
Acute fatty liver of pregnancy
SIGNS / SYMPTOMS
A coagulopathy typically precedes the thrombocytopenia.
INVESTIGATIONS
Elevated white cell count with left shift.
Total bilirubin increased to levels ≥4 mg/dL.
Hypoglycemia.
Elevated liver enzymes.
Other laboratory abnormalities may include a metabolic acidosis, elevated serum creatinine, elevated BUN, and elevated uric acid.
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