What are the causes of thrombocytopenia?

Causes of Thrombocytopenia

Thrombocytopenia results from four major mechanisms: decreased platelet production, increased platelet destruction, splenic sequestration, or dilution, with the most common causes being immune-mediated destruction, drug-induced thrombocytopenia, bone marrow disorders, infections, and liver disease. 1

Decreased Platelet Production

Bone marrow disorders impair megakaryocyte function and platelet production through several mechanisms 1, 2:

• Myelodysplastic syndromes, leukemias, and other malignancies directly infiltrate the bone marrow, particularly important in patients over 60 years 1, 2
• Aplastic anemia and megaloblastic anemia cause pancytopenia with reduced platelet production 1, 2
• Bone marrow fibrosis physically impairs megakaryocyte development 1

Inherited thrombocytopenias present from birth or early childhood and include 1, 2:

• Thrombocytopenia-absent radius (TAR) syndrome 1
• Wiskott-Aldrich syndrome 1, 2
• MYH9-related disease (identifiable by leukocyte inclusion bodies on peripheral smear) 1
• Bernard-Soulier syndrome and type IIB von Willebrand disease 1
• 22q11.2 deletion syndrome (characterized by large platelets and reduced platelet quality) 3

Increased Platelet Destruction

Primary Immune Thrombocytopenia (ITP)

Primary ITP is an autoimmune disorder with immunologic destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes 2, 4, 5.

Secondary Immune Thrombocytopenia

Autoimmune and immunodeficiency disorders trigger platelet destruction through cross-reactive antibodies 1, 4:

• Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (one of the most common autoimmune associations) 1, 4
• Common variable immune deficiency (CVID) can present with ITP as its initial manifestation 3, 4
• Evans syndrome (combined autoimmune hemolytic anemia and thrombocytopenia) 6

Infections cause thrombocytopenia through multiple distinct mechanisms 1, 4:

• Hepatitis C virus (HCV) operates via antibodies cross-reacting with platelet antigens, immune complexes binding to platelet Fcγ receptors, direct infection of megakaryocyte progenitor cells, decreased thrombopoietin production, and splenic sequestration from portal hypertension 4, 6
• HIV triggers thrombocytopenia through cross-reactive antibodies against platelet antigens and infection of megakaryocyte-dependent progenitor cells 1, 4, 6
• Helicobacter pylori generates antibodies that cross-react with platelet antigens 4, 6

Lymphoproliferative disorders including chronic lymphocytic leukemia and large granular T-lymphocyte leukemia 1, 6

Post-vaccination and viral infections in children can cause sudden severe thrombocytopenia after measles-mumps-rubella vaccination or natural infections with Epstein-Barr virus, cytomegalovirus, or varicella zoster virus 1, 6

Drug-Induced Thrombocytopenia

Medications trigger immune thrombocytopenia through drug-dependent antibodies that demonstrate drug-dependence, immunoglobulin binding to platelets, and platelet specificity 1, 4. Common culprits include prescription and non-prescription drugs, quinine (found in tonic water), and environmental toxins 1.

Heparin-Induced Thrombocytopenia (HIT)

HIT is a serious antibody-mediated reaction presenting with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation 3, 4, 7. The condition results from antibodies to platelet Factor 4-heparin complexes that induce platelet aggregation and can progress to life-threatening thrombosis 7. Evaluate using the 4T score based on degree of thrombocytopenia, timing, presence of thrombosis, and absence of other causes 3, 4.

Thrombotic Microangiopathies

Conditions causing both thrombocytopenia and thrombosis include 3, 8:

• Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (identifiable by schistocytes on peripheral smear) 1
• Antiphospholipid syndrome 3
• Disseminated intravascular coagulation (DIC) 3, 9

Pregnancy-Related Causes

Gestational thrombocytopenia is the most common cause in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70,000/μL) 3. Other pregnancy-related causes include preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) 3, 8.

Splenic Sequestration

Liver disease causes thrombocytopenia through portal hypertension leading to splenomegaly and platelet sequestration, combined with decreased thrombopoietin production 1, 9. Alcoholic liver cirrhosis represents a multifactorial cause involving both sequestration and direct bone marrow suppression 1, 9.

Other Important Causes

Post-transfusion purpura occurs after recent transfusions 1

Cyanotic congenital heart disease causes thrombocytopenia through polycythemia and hyperviscosity triggering platelet consumption, with platelet counts inversely correlating with hematocrit levels 3

Critical Diagnostic Red Flags

Physical examination findings that suggest alternative diagnoses to primary ITP include 1, 4:

• Moderate or massive splenomegaly (mild splenomegaly acceptable in younger patients) 1
• Hepatomegaly or lymphadenopathy 1, 4
• Constitutional symptoms including fever, weight loss, or bone pain 1, 4
• Non-petechial rash 3

Laboratory abnormalities beyond isolated thrombocytopenia mandate investigation for alternative diagnoses 1:

• Anemia disproportionate to bleeding 1
• Abnormal white blood cell count or morphology 1, 3
• Schistocytes suggesting thrombotic microangiopathy 1
• Leukocyte inclusion bodies indicating MYH9-related disease 1
• Excessive numbers of giant or small platelets suggesting inherited thrombocytopenia 1

Essential Initial Diagnostic Steps

First, exclude pseudothrombocytopenia by collecting blood in heparin or sodium citrate and examining the peripheral smear for EDTA-dependent platelet agglutination 1, 8. This laboratory artifact can falsely lower platelet counts 3.

Peripheral blood smear examination by a qualified hematologist or pathologist is paramount and non-negotiable 1, 2, 3.

Mandatory screening tests in adults with suspected ITP include 2, 3, 4:

• HIV testing 2, 3, 4
• Hepatitis C virus testing 2, 3, 4
• Helicobacter pylori screening 3, 4
• Immunoglobulin measurement to exclude CVID 3, 4

Bone marrow examination is indicated in patients over 60 years (to exclude myelodysplastic syndromes and leukemias), those with systemic symptoms or abnormal signs, when splenectomy is considered, or when abnormalities exist beyond isolated thrombocytopenia 1, 2, 3.