Thrombocytopenia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Farbod Zahedi Tajrishi, M.D. [2]

Overview

Thrombocytopenia has a broad range of potential causes. While a good history and physical examination can be helpful to diagnose some of these causes such as drug-induced thrombocytopenia, they usually don't suffice and further evaluation is often needed. There are also some useful points that may guide the physician to an appropriate diagnosis. For example, asymptomatic, isolated thrombocytopenia most probably suggests ITP, while thrombocytopenia in critically ill, hospitalized patients is usually suggestive of iatrogenic causes (eg. dilution), platelet consumption, bone marrow suppression from infection/sepsis, or even drug-induced thrombocytopenia. One should consider however, that a wide variety of other conditions such as autoimmune disorders, nutrient deficiencies, thrombotic microangiopathies could all as well cause thrombocytopenia.

Thrombocytopenia Differential Diagnosis

Differentiating the diseases that can cause thrombocytopenia:

Category	Condition		Etiology	Mechanism			Inherited	Acquried	Clinical manifestations									Para−clinical findings								Gold standard	Associated findings
									Demography	History	Symptoms			Signs
																		Lab Findings
											Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other	CBC			PBS	Bone marrow exam	PT	PTT	UA
				Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen												Plt	HB	WBC
Hematology	Bone marrow disorders	Myelodysplastic syndromes	Unknown Mutation	+	−	−	±	+	Elderly	Exposure to Chemotherapy Radiation therapy Tobacco smoke	+	Petechiae, purpura, diffuse erythematous rash	+	Nl	+	+	Shortness of breath Fatigue Pallor	↓	↓	↓	Ovalomacrocytosis Basophilic stippling Howell-Jolly body Dysplastic neutrophils	Impaired myeloid maturation Dyserythropoiesis Dysgranulopoiesis Dysmegakaryocytopoiesis Hypercellular bone marrow Fibrosis	Nl	Nl	Nl	Bone marrow examination + clinical manifestation	Might transformed to acute leukemia
		Aplastic anemia	Unknown secondary to radiation, drugs and chemicals, pregnancy, PNH and viral or autoimmune causes	+	−	−	±	±	Biphasic (the young and the elderly)	Exposure to chemicals Radiation History of prior drug use Viral infection Positive family history of aplastic anemia	−	−	+	Nl	−	−	Shortness of breath Fatigue Pallor	↓	↓	↓	Large RBCs Low platelets and granulocytes	Hypocellular bone marrow replacement of bone marrow by fat	↑	↑	Nl	Bone marrow examination + laboratory findings	Fanconi Anemia Dyskeratosis congenita Schwachman-Diamond syndrome Preleukemia
		Acute leukemia	Immune mediated Chromosomal abnormalities	+	+	−	±	±	AML in adults	Exposure to chemicals Radiation Pre-existent blood disorders	±	Petechiae	+	Nl	±	−	Weakness	↓	↓	↓	Pancytopenia	Blast cells	↑	↑	Hemoglobinuria	Bone marrow examination	Tumor lysis syndrome Infection CNS involvement DIC
		Paroxysmal nocturnal hemoglobinuria (PNH)	Deficiency of complement regulatory proteins Mutations	+	+	−	−	+	Any age (usually younger adults)	Sudden nocturnal hemoglobinuria with partial clearing during the day	−	−	−	Nl	−	−	Thrombosis Smooth muscle dystonia	↓/Nl	↓	↓/Nl	Pancytopenia	Cellular marrow Erythroid hyperplasia dyserythropoiesis Hypocellular marrow in certain stages of the disease	Nl	Nl	Hemoglobinuria	Flow cytometry	Chronic renal failure Pulmonary hypertension Aplastic anemia
	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
	Thrombotic microangiopathy (TMA)	Thrombotic thrombocytopenic purpura (TTP)	Deficiency of, or antibodies to, the metalloprotease ADAMTS13	−	+	−	±	+	Any age	Neurologic manifestations Fatigue due to anemia	+	Petechiae	Not common	Nl or ↑	−	+	Neurologic findings Signs of renal impairment	↓	↓	Nl or ↑	Fragmented RBCs	NA	Nl	Nl	Hemoglobinuria	Laboratory findings	Hemolysis Microvascular thrombosis
		Hemolytic uremic syndrome (HUS)	Escherichia coli O157:H7 Genetic defects	−	+	−	±	+	Children	Exposure to contaminated water or milk Consuming undercooked ground beef	+	Petechiae	−	↓	−	+	Abdominal tenderness Diarrhea	↓	↓	Nl or ↑	Fragmented RBCs	NA	Nl	Nl	Hemoglobinuria	Laboratory findings	Acute renal failure Hemolysis Microvascular thrombosis
		DIC	Overstimulation of the coagulation system	+	+	−	−	+	Any age	History of trauma, sepsis, malignancy, vasculitis or exogenous toxins	+	+	+	↓	−	+	Neurologic findings Signs of renal impairment	↓	↓↓	↑	Schistocytes Helmet cells	Low platelets Low RBCs	↑↑	↑	Hemoglobinuria	Clinical manifestation + laboratory findings	Hemolysis Microangiopathy Multi-organ dysfunction
	Nutrient deficiencies	Folate, vitamin B12, copper deficiencies	Decreased platelet production	+	−	−	−	+	Any age	Malnutrition Alcohol use	−	−	−	Nl	−	−	Fatigue Weakness	↓	↓	Nl	Low platelets Low RBCs	Low platelets Low RBCs	Nl	Nl	Nl	Laboratory findings	Megaloblastic anemia
	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
	Congenital platelet disorders	MYH9-related disorders	Cytoskeletal defects in megakaryocytes Mutation	+	−	−	+	−	Any age, very rare	Positive family history	−	Petechiae	+	Nl	−	−	Hearing loss Renal impairment Cataract	↓	↓	Nl	Large platelets Döhle body-like inclusions in peripheral blood neutrophils	NA	Nl	Nl	Nl	Genetic study	Autosomal dominant
		Bernard-Soulier syndrome	Absence of Gp Ib-IX-V	+	−	−	+	−	Children, rare	Positive family history	−	−	+	Nl	−	−	−	↓	Nl	Nl	Large platelets	Large platelets	Nl	Nl	Nl	Flow cytometry	Autosomal recessive Increased bleeding time
		Gray platelet syndrome	Reduction or absence of alpha-granules in blood platelets	+	−	−	+	−	Rare	Positive family history	−	Petechiae	+ Mucocutaneous	Nl	+	−	Epistaxis	↓	Nl	Nl	Large platelets and lack of granulation	Myelofibrosis	Nl	Nl	Nl	Genetic study	Autosomal recessive
		Wiskott-Aldrich syndrome	Mutation in GATA-1	+	−	−	+	−	Rare	Positive family history	−	Eczema	+	Nl	−	−	Bloody diarrhea	↓	Nl	Nl	Small but low platelets	Small but low platelets	Nl	Nl	Nl	Genetic study	Recurrent infections autoimmune disorders Malignancy
		Thrombocytopenia with absent radius (TAR) syndrome	1q21.1 deletion and bone marrow failure	+	−	−	+	−	Children	Positive family history	−	+	+	Nl	−	−	Bilateral radial aplasia	↓	Nl	Nl or ↑	Normal size platelets	Normal or hypercellular bone marrow Decreased, absent, or immature megakaryocytes Small, basophilic, vacuolated megakaryocytes Erythroid hyperplasia	Nl	Nl	Nl	Evidence of absent radius + Laboratory findings	Cow's milk allergy Various other anomalies
		Fechtner syndrome	Mutation of chromosome 22q11-13	+	−	−	+	−	Children	Positive family history	−	Ecchymoses and petechia	+ Mucocutaneous	Nl	−	−	Hearing loss Eye abnormalities	↓	Nl	Nl or ↑	Large platelets Granulocytic inclusions	NA	Nl	Nl	Microscopic hematuria Pyuria Red cell casts Cylindrical casts Proteinuria	Clinical manifestation + genetic study	Autosomal dominant variant of Alport syndrome Renal failure Hypoalbuminemia
		Von Willebrand disease	VWF deficiency/dysfunction	+	−	−	+	Rarely	More common with O blood type	Positive family history	−	−	+	−	−	−	−	Nl/ ↓	Nl/↓	Nl	Large platelets	NA	Nl	Nl or ↑	Hematuria	Laboratory findings	Lifelong bleeding disorder
Category	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
Rheumatologic/autoimmune disorders	ITP		Immune-mediated platelet destruction Inhibition of platelet release from the megakaryocyte	+	+	−	−	+	Any age	−	−	Ecchymoses and petechia	+ Mucocutaneous	Nl	−	−	−	↓↓↓	Nl	Nl	Nl	Large platelets, otherwise normal	Nl	Nl	Nl	Diagnosis of exclusion	Spontaneous remission
	Systemic lupus erythematosus		Immune-mediated platelet destruction	−	+	−	−	+	Young women, more prevalent in Africans and Asians	Medication use History of weight changes Other rheumatologic and autoimmune diseases Family history of rheumatologic diseases	+	Malar rash, generalized maculopapular rash, discoid rash	+ Hemoptysis	Nl or ↑	+	+	Mucosal ulcers Lymphadenopathy Crackles Chest tenderness Murmur Hepatomegaly Cognitive impairment	↓	↓	↓	Pancytopenia	Pancytopenia	↑	↑	Hematuria Pyuria Proteinuria Cellular casts	Clinical manifestation + serology	TTP Multiorgan dysfunction Infections Atherosclerosis Malignancies Poor prognosis with lupus nephritis
	Antiphospholipid syndrome		Autoantibody-mediated syndrome	−	+	−	+	+	Middle aged women, more in African American and Hispanic population	Abortion Other rheumatologic and autoimmune diseases Family history of rheumatologic diseases	−	−	−	Nl	−	−	DVT	↓	Nl	↓	Reduced platelets and WBC	Reduced platelets and WBC	Nl	↑	Hematuria	Clinical manifestation + repeated positive tests of aPL	Recurrent thrombosis Stroke
	Felty's syndrome		Autoantibody-mediated syndrome Splenomegaly	−	+	+	±	+	Rare, young women	Arthritis Family history of RA	−	Necrotizing skin lesions Rheumatoid nodule	−	Nl	+	−	Lymphadenopathy	↓	Nl	↓	Reduced platelets and WBC	Reduced platelets and WBC	Nl	Nl	Nl	Clinical manifestation	Rheumatoid arthritis Positive RF and anti-citrullinated peptide antibodies Episcleritis Pleuropericarditis
Category	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
Infection-induced	Bacterial infections	Sepsis	Direct bone marrow suppression	+	+	−	−	+	Any	Bacterial infection	+	Petechiae Purpura Erythema Ulceration	±	Nl to ↓	−	±	Malaise Lymphadenopathy	↓/↑	Nl	↑↑	Reduced platelets	NA	↑	↑	+ Depends on the etiology	Clinical manifestation + culture	Associated with ↑ mortality
		Helicobacter pylori	Immune thrombocytopenia	−	+	−	−	+	Any	−	−	−	−	Nl	−	−	Epigastric tenderness Heartburn	↓	Nl	Nl	Reduced platelets	NA	Nl	Nl	Nl	Clinical manifestation + culture	GERD
		Tick-borne infection	Immune thrombocytopenia	−	+	−	−	+	Endemic area like China, Japan, and Korea	Being bitten by a tick	+	Petechiae Purpura Erythema Ulceration	±	Nl to ↓	±	±	Encephalitis Hemorrhagic fever	↓	Nl	↓	Reduced platelets	NA	Nl	Nl	Proteinuria	PCR	Elevated ALT and AST Multiple organ failure Lymphadenopathy
	Viral infections	HIV	Immune thrombocytopenia	+	+	+	−	+	Any	High risk behaviors Close contact	+	Skin lesions	±	Nl to ↓	±	±	Lymphadenopathy Muscle weakness Joint swelling Focal neurological deficits	↓	↓	↓	Pancytopenia	Pancytopenia	↑	↑	Proteinuria	Isolation of HIV	Malignancy Severe immunodeficiency
		Other viruses such as rubella, mumps, varicella, parvovirus, hepatitis C, & Epstein-Barr virus	Immune thrombocytopenia	+	−	−	−	+	Any	High risk behaviors Close contact	+	Petechiae Purpura	−	Nl	±	±	Lymphadenopathy Muscle weakness Joint swelling Focal neurological deficits Depends on etiology	↓	↓	↓	Pancytopenia	Pancytopenia	Nl	Nl	Hematuria	Clinical manifestation + lab tests	Depends on etiology Encephalomyelitis
	Parasitic infections	Malaria	Unknown Immune thrombocytopenia	+	−	−	−	+	Endemic area	Being bitten by a mosquito	+	−	±	Nl to ↓	±	±	Headache Weakness Night sweats Joint pain Muscle pain	↓	↓	↓	Pancytopenia	Pancytopenia	Nl	Nl	Hematuria	Clinical manifestation + microscopic examination of blood smear	Life-threatening disease Multiple organ failure
		Babesiosis	Unknown Immune thrombocytopenia	+	−	−	−	+	Rare	Being bitten by a tick Immunodeficiency	+	−	±	Nl to ↓	±	±	Fatigue Chills Sweats Headache	↓	↓	↓	Pancytopenia	Pancytopenia	Nl	Nl	Hematuria	Clinical manifestation + microscopic examination of blood smear	Severe hemolytic anemia DIC Multiple organ failure
Category	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
Medication/toxicity	Antibiotics/ Antiepileptic	Quinine Sulfonamides Carbamazepine Phenytoin	Occurrence of drug-dependent, platelet-reactive antibodies	+	+	−	−	+	Any	Drug ingestion or injection	−	Ecchymoses Petechia	−	Nl	−	−	−	↓↓	↓	Nl	Reduced platelets	NA	Nl	Nl	Nl	Clinical manifestation + exclusion of the other causes	NA
	Heparin-induced thrombocytopenia		Anti-heparin/PF4 antibody	−	+	−	−	+	Any	Heparin injection	−	Necrotic skin lesions	−	Nl	−	−	−	↓	Nl	Nl	Reduced platelets	NA	Nl	Nl	Nl	ELISA	Early or delayed-onset Thrombosis
	Cytotoxic chemotherapy		Bone marrow suppression	+	−	−	−	+	Patients with malignancy	Drug ingestion or injection Cancer	−	Ecchymoses Petechia	−	Nl	−	−	−	↓	↓	↓	Reduced platelets	Megakaryocytic hypoplasia or aplasia	↑	↑	Hematuria	Clinical manifestation + exclusion of the other causes	Thrombosis
	Radiation therapy		Predictable, dose-dependent myelosuppression	+	−	−	−	+	Patients with malignancy	Radiation Cancer	−	Purpura Petechiae	+	Nl	−	−	−	↓	↓	↓	Reduced platelets	Megakaryocytic hypoplasia or aplasia	↑	↑	Hematuria	Clinical manifestation + exclusion of the other causes	Thrombosis
GI	Chronic liver disease		Bone marrow suppression	+	−	−	−	+	Any	Cirrhosis Alcohol use	−	Purpura Petechiae	+	↓	+	+	−	↓	↓	Nl	Reduced platelets	NA	↑	↑	Nl	Biopsy	Portal vein thrombosis Hepatorenal syndrome Variceal hemorrhage Hepatic hydrothorax Spontaneous bacterial peritonitis
	Portal hypertension		Bone marrow suppression	+	−	−	−	+	Any	Cirrhosis Alcohol use	−	Purpura Petechiae	+	↓	+	+	−	↓	↓	Nl	Reduced platelets	NA	↑	↑	Nl	Clinical manifestation	Portal vein thrombosis Ascites
Category	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings
Vascular	Giant capillary hemangioma (Kasabach-Merritt syndrome)		Platelet destruction	−	+	−	+	−	Infants	Rare but serious infantile coagulopathy	−	Multiple purple hemangioma	Intralesional bleeding	Nl	−	−	Visceral hemangiomas	↓↓	↓↓	Nl	Normocytic normochromic erythrocytes and markedly reduced platelets	Normal erythropoiesis, myelopoiesis, and megakaryocytic hyperplasia	↑	↑	Hematuria	Biopsy	Kaposiform hemangioendothelioma Tufted angioma
	Cardiopulmonary bypass		Platelet destruction	−	+	−	−	+	Elderly	Coronary artery disease	−	Purpura Petechiae	+	Nl or ↑	−	−	−	↓	↓	Nl	Normocytic normochromic erythrocytes and markedly reduced platelets	NA	↑	↑	Hematuria	Clinical manifestation	Coagulopathy Hypofibrinogenemia
Other	Alcohol		Platelet production suppression	+	−	+	−	+	Any	History of alcohol use	−	−	−	Nl	+	+	Hepatomegaly	↓	↓	↓	Cytopenia, macrocytosis	Cytopenia, macrocytosis	↑	↑	Nl	Clinical manifestation	Chronic liver disease
	Post-transfusion purpura		Platelet destruction by anti-platelet antibodies	−	+	−	−	+	Women	History of blood transfusion or pregnancy	−	Purpura Petechiae	+	↓	−	−	−	↓↓↓	↓	Nl	Nl	NA	Nl	Nl	Nl	Positive circulating alloantibody to a common platelet antigen	Severe but rare reaction
	Gestational thrombocytopenia		Might be physiologic adaptation of pregnancy	−	−	−	−	+	Pregnant women	Positive history of mild thrombocytopenia	−	−	−	Nl	−	−	−	↓	Nl	Nl	Nl	NA	Nl	Nl	Nl	Diagnosis of exclusion	Self-limited condition
	HELLP syndrome		Unknown	−	+	−	−	+	Pregnant > 25 years	History of preeclampsia	−	−	+	↑	−	+	Abdominal tenderness Ascites	↓	↓	Nl	Schistocytes	NA	Nl	Nl	Proteinuria	Lab abnormalities	Elevated liver enzymes and bilirubin Multiorgan dysfunction
	Idiopathic cyclic thrombocytopenia		Unknown Might be autoimmune platelet destruction	+	+	−	−	+	Females with the median age of onset 35 years	Misdiagnosed as ITP with uniformly poor responses	−	Purpura Petechiae	Minor mucocutaneous bleeding	Nl	−	−	−	↓	Nl	Nl	Reduced platelets and megakaryocytes	Megakaryocytic hypoplasia or aplasia	Nl	Nl	Nl	Diagnosis of exclusion	Rebound thrombocytosis Myeloproliferative diseases Myelodysplastic syndrome
	Pseudothrombocytopenia		Platelet clumping due to EDTA	−	−	−	−	+	Rare	Collected sample in EDTA anticoagulant	−	−	−	Nl	−	−	−	↓	Nl	Nl	Low platelet count and platelet clumps	Low platelet count and platelet clumps	Nl	Nl	Nl	Repeat collecting sample in a heparin tube	Nl
Category	Condition		Etiology	Decreased platelet production	Platelet destruction in blood	Platelet destruction in spleen	Inherited	Acquried	Demography	History	Fever	Rash	Bleeding	BP	Splenomegaly	Jaundice	Other signs	Plt	HB	WBC	PBS	Bone marrow exam	PT	PTT	UA	Gold standard	Associated findings