What causes a low platelet (thrombocytopenia) count?

Causes of Low Platelet Count (Thrombocytopenia)

Low platelet counts occur through four primary mechanisms: decreased bone marrow production, increased destruction (immune or non-immune), splenic sequestration, or dilution/clumping—with the specific cause determining both prognosis and treatment approach. 1, 2

Major Mechanisms and Causes

Decreased Platelet Production

• Bone marrow disorders including myelodysplastic syndromes, leukemias, aplastic anemia, and bone marrow fibrosis directly impair megakaryocyte function and platelet production 1, 2
• Viral infections (HIV, hepatitis C, EBV) suppress bone marrow platelet production and may precede other symptoms by years 1, 2
• Medications and toxins including chemotherapy agents, chronic alcohol use, and certain antivirals cause myeloid toxicity 3, 1
• Nutritional deficiencies such as vitamin B12 or folate deficiency lead to megaloblastic anemia with associated thrombocytopenia 2
• Inherited thrombocytopenias including thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome affect platelet production from birth 1, 2

Increased Platelet Destruction

Immune-mediated destruction:

• Primary immune thrombocytopenia (ITP) is an autoimmune disorder with antibody-mediated destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes 3, 1, 2
• Secondary immune thrombocytopenia occurs with HIV, hepatitis C, H. pylori infection, autoimmune diseases (lupus, antiphospholipid syndrome), lymphoproliferative disorders, common variable immune deficiency, and as a side effect of certain vaccinations or bone marrow transplantation 1, 2
• Drug-induced thrombocytopenia can result from heparin, quinine, sulfonamides, vancomycin, cefazolin, clindamycin, and many other medications 1

Non-immune destruction:

• Heparin-induced thrombocytopenia (HIT) typically presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation, paradoxically causing thrombosis rather than bleeding 3, 1
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and atypical HUS cause platelet consumption through microvascular thrombosis 1, 4
• Disseminated intravascular coagulation (DIC) causes consumption of platelets and coagulation factors through widespread fibrin and platelet deposition, typically in the setting of sepsis or malignancy 1, 4
• Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding 3, 1

Splenic Sequestration

• Hypersplenism from portal hypertension in cirrhosis causes intra-splenic platelet sequestration, with thrombocytopenia being the most common hematological manifestation 3
• The origin is multifactorial, linked to portal hypertension, myeloid toxicity, anti-platelet antibodies, and low thrombopoietin levels 3
• Cyanotic congenital heart disease produces mild thrombocytopenia (100,000-150,000/μL) due to polycythemia and hyperviscosity triggering platelet consumption, with platelet counts inversely correlating with hematocrit levels 1

Pregnancy-Related Causes

• Gestational thrombocytopenia is the most common cause in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70,000/μL) 1
• Preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) can cause severe thrombocytopenia requiring emergency intervention 1, 5

Critical Diagnostic Algorithm

Step 1: Exclude Pseudothrombocytopenia

• Collect blood in heparin or sodium citrate tube and repeat platelet count, as EDTA-dependent platelet clumping can falsely lower automated counts 1, 5
• Request manual peripheral blood smear examination by a qualified hematologist or pathologist to identify platelet clumping definitively 1

Step 2: Confirm Isolated Thrombocytopenia vs. Pancytopenia

• Complete blood count with differential determines whether thrombocytopenia is isolated or part of pancytopenia, which suggests bone marrow failure or infiltrative disease 1, 2
• Peripheral blood smear review identifies schistocytes (suggesting TMA), giant platelets (suggesting inherited thrombocytopenia), immature white cells (suggesting leukemia), or other abnormalities 1, 2

Step 3: Distinguish Acute from Chronic

• Review previous platelet counts to determine if thrombocytopenia is new (acute) or longstanding (chronic) 5
• Acute thrombocytopenia may require hospitalization, especially if associated with bleeding, systemic illness, or platelet count <10 × 10⁹/L 5

Step 4: Identify Red Flags Requiring Emergency Evaluation

• Fever, systemic symptoms, or altered mental status suggest TTP, sepsis with DIC, or acute leukemia 1
• Schistocytes on smear indicate thrombotic microangiopathy requiring urgent plasma exchange 1
• Recent heparin exposure with thrombosis suggests HIT requiring immediate heparin cessation and alternative anticoagulation 3, 1
• Pregnancy with hypertension raises concern for preeclampsia/HELLP syndrome 1
• Splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for lymphoproliferative disorders, chronic liver disease, or infections 1, 2

Step 5: Mandatory Testing to Exclude Secondary Causes

• HIV and hepatitis C testing should be performed in all adults with suspected ITP, regardless of risk factors, as these infections may be clinically indistinguishable from primary ITP 1, 2
• H. pylori testing should be considered, as eradication therapy can resolve thrombocytopenia in H. pylori-associated ITP 1
• Comprehensive medication review including over-the-counter medications and herbal supplements to identify drug-induced causes 1
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) if DIC is suspected 1

Step 6: Determine Need for Bone Marrow Examination

Bone marrow examination is NOT necessary in patients with typical ITP features: isolated thrombocytopenia, normal physical exam except bleeding manifestations, normal-sized or slightly enlarged platelets on smear, and no systemic symptoms 3, 1

Bone marrow examination IS mandatory in the following situations 1:

• Age ≥60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies)
• Systemic symptoms present (fever, weight loss, bone pain)
• Abnormal blood count parameters beyond thrombocytopenia (anemia, leukopenia, leukocytosis)
• Atypical peripheral smear findings (schistocytes, immature white cells, giant platelets approaching red blood cell size)
• Splenomegaly, hepatomegaly, or lymphadenopathy on physical exam
• Minimal or no response to first-line ITP therapies
• Before splenectomy in patients with persistent disease

Common Diagnostic Pitfalls to Avoid

• Missing pseudothrombocytopenia by relying solely on automated counts without peripheral smear review can lead to unnecessary workup and treatment 1
• Failing to test for HIV and HCV in adults with suspected ITP, as these infections can precede other symptoms by years and require different treatment approaches 1, 2
• Not recognizing HIT in patients on heparin who develop thrombosis despite thrombocytopenia, as this requires immediate heparin cessation 3, 1
• Overlooking inherited thrombocytopenias by not reviewing family history or noting giant platelets on smear 1
• Assuming low platelets always cause bleeding, when conditions like HIT, antiphospholipid syndrome, and TMA paradoxically cause thrombosis 3, 1, 4
• Delaying bone marrow examination in patients over 60 years or those with atypical features, as missing malignancy has catastrophic mortality implications 1

Clinical Context: When Platelets Cause Bleeding

• Platelet counts >50 × 10⁹/L are generally asymptomatic with minimal bleeding risk 5
• Platelet counts 20-50 × 10⁹/L may cause mild skin manifestations (petechiae, purpura, ecchymosis) 5
• Platelet counts <10 × 10⁹/L carry high risk of serious spontaneous bleeding including intracranial hemorrhage 5
• However, in cirrhosis, low platelet count per se does not predict bleeding risk, as both pro- and anti-coagulant factors are affected 3