Thrombocytopenia

Thrombocytopenia simply means having a lower-than-normal number of platelets circulating in the blood (typically defined as <150,000/µL or <150 x 10⁹/L). Platelets are our tiny “first responders” for stopping bleeding, so when their numbers drop, the primary risk is bleeding

Just like with anemia, thrombocytopenia isn’t a disease itself but a sign of an underlying issue. We need to figure out why the platelet count is low. The causes fall nicely into non-immune and immune categories

Non-Immune Thrombocytopenia: When Antibodies Aren’t the Main Culprit

These causes involve problems with platelet production, non-antibody-mediated destruction or consumption, or platelets getting stuck somewhere

Pathophysiology (How it Happens)

• Decreased Platelet Production: The bone marrow “factory” isn’t making enough platelets
  • Bone Marrow Failure/Suppression
    • Aplastic Anemia: Failure of the marrow to produce all cell lines, including megakaryocytes (platelet precursors)
    • Leukemia, Lymphoma, Myelodysplastic Syndromes (MDS): Malignant cells infiltrate and crowd out normal marrow elements, including megakaryocytes
    • Metastatic Cancer: Cancer cells from elsewhere invade the marrow
    • Chemotherapy/Radiation Therapy: These treatments damage rapidly dividing cells, including hematopoietic stem cells and megakaryocytes
    • Certain Viral Infections: (e.g., HIV, Hepatitis C, CMV, EBV) can directly suppress marrow production
    • Alcohol Toxicity: Chronic heavy alcohol use suppresses marrow function
  • Nutritional Deficiencies: Severe Vitamin B12 or Folate deficiency can impair DNA synthesis, affecting megakaryocyte maturation and platelet production (often part of pancytopenia in megaloblastic anemia)
  • Inherited Syndromes: Rare genetic conditions affect megakaryocyte development (e.g., Congenital Amegakaryocytic Thrombocytopenia - CAMT, Thrombocytopenia Absent Radii - TAR syndrome)
• Increased Platelet Destruction or Consumption (Non-Immune): Platelets are being used up or destroyed too quickly by mechanisms not primarily involving anti-platelet antibodies
  • Disseminated Intravascular Coagulation (DIC): Widespread, uncontrolled activation of both coagulation and fibrinolysis. Platelets are consumed rapidly in the formation of microthrombi throughout the circulation
  • Thrombotic Microangiopathies (TMAs): Conditions characterized by platelet aggregation in small blood vessels, leading to consumption and organ damage
    • Thrombotic Thrombocytopenic Purpura (TTP): Usually due to deficiency (often autoimmune) of the enzyme ADAMTS13, which normally cleaves large von Willebrand Factor (vWF) multimers. Uncleaved large vWF multimers cause spontaneous platelet aggregation in the microvasculature
    • Hemolytic Uremic Syndrome (HUS): Often triggered by Shiga toxin-producing bacteria (like E. coli O157:H7). Toxin damages endothelial cells, leading to platelet activation and microthrombi formation, particularly affecting the kidneys
  • Mechanical Destruction: Physical shearing forces damage platelets (e.g., malfunctioning prosthetic heart valves, extracorporeal circuits like ECMO or cardiopulmonary bypass)
  • Giant Hemangiomas (Kasabach-Merritt Syndrome): Platelets become trapped and consumed within large vascular tumors
• Sequestration: Platelets get pooled or trapped, reducing the number in active circulation
  • Hypersplenism: An enlarged spleen (due to various causes like liver cirrhosis, portal hypertension, lymphoma, infections) traps an excessive proportion of platelets (normally holds ~1/3, can hold up to 90% when enlarged)

Detection (Finding the Cause)

• Clinical Assessment: History (meds, alcohol, infections, bleeding pattern, family history), physical exam (petechiae, purpura, ecchymoses, splenomegaly, signs of underlying disease)
• Laboratory Tests
  • Complete Blood Count (CBC) with Differential & Platelet Count: Confirms thrombocytopenia. Check WBC and RBC lines for other cytopenias (pancytopenia suggests marrow failure)
  • Peripheral Blood Smear Review: ESSENTIAL!
    • Confirms low platelet count (visual estimate)
    • Rules out pseudothrombocytopenia (platelet clumping, usually EDTA-dependent artifact - redraw in sodium citrate tube!)
    • Assesses platelet morphology: Giant platelets (inherited syndromes like Bernard-Soulier, ITP), platelet fragments?
    • Looks for associated findings: Schistocytes (fragmented RBCs - hallmark of TTP/HUS/DIC), blasts (leukemia), teardrop cells (marrow infiltration), hypersegmented neutrophils (B12/folate deficiency)
  • Coagulation Studies (PT, aPTT, Fibrinogen, D-dimer): Crucial if DIC is suspected (prolonged PT/aPTT, low fibrinogen, high D-dimer)
  • Liver Function Tests / Renal Function Tests: Assess for underlying organ disease
  • Bone Marrow Aspirate/Biopsy: Indicated if decreased production is suspected or the cause remains unclear. Assesses cellularity, presence/morphology of megakaryocytes, infiltrative processes
  • ADAMTS13 Activity: Specific test for TTP (activity usually <10%)
  • Infectious Disease Testing: (HIV, HCV, etc., if suspected)

Treatment

Treatment MUST address the underlying cause:

• Decreased Production: Treat the underlying condition (e.g., leukemia chemo, B12/folate replacement, stop offending drug/alcohol). Thrombopoietin Receptor Agonists (TPO-RAs like Romiplostim, Eltrombopag) can stimulate platelet production in some settings (e.g., aplastic anemia, chemo-induced). Stem cell transplant for aplastic anemia/leukemia
• Increased Destruction/Consumption
  • DIC: Treat underlying trigger (sepsis, trauma), supportive care with blood components (FFP, Cryo, Platelets)
  • TTP: Plasma Exchange (PEX) is life-saving! Removes autoantibodies and large vWF multimers, replenishes ADAMTS13. Immunosuppression often added
  • HUS: Primarily supportive care (especially renal support). PEX less effective than in TTP. Eculizumab (anti-C5 antibody) for atypical HUS
• Sequestration: Treat underlying cause of splenomegaly if possible. Splenectomy is rarely done just for sequestration but may improve counts if done for another reason
• Platelet Transfusion: Key supportive measure when counts are critically low (<10-20,000/µL for prophylaxis against spontaneous bleeding) or if the patient has active, significant bleeding. Transfusion treats the symptom (low count/bleeding), not the cause

Immune Thrombocytopenia: When the Immune System Attacks Platelets

Here, antibodies are the primary drivers of platelet destruction

Pathophysiology (How it Happens)

• Immune Thrombocytopenia (ITP): (Formerly Idiopathic Thrombocytopenic Purpura)
  • Mechanism: Autoantibodies (usually IgG) are produced against platelet surface glycoproteins (most commonly GPIIb/IIIa or GPIb/IX). These antibody-coated platelets are recognized by Fc receptors on macrophages, primarily in the spleen, leading to premature clearance (opsonization and phagocytosis). Some antibodies may also impair megakaryocyte function, contributing to reduced production
  • Types
    • Primary ITP: No identifiable underlying cause
    • Secondary ITP: Associated with other conditions (e.g., SLE, HIV, HCV, CLL, certain drugs)
• Alloimmune Thrombocytopenia: Antibodies against non-self platelet antigens
  • Neonatal Alloimmune Thrombocytopenia (NAIT): Mother lacks a specific Human Platelet Antigen (HPA, most commonly HPA-1a) that the fetus inherits from the father. Mother produces IgG alloantibodies against the fetal HPA during pregnancy. These antibodies cross the placenta and destroy fetal/neonatal platelets. Can cause severe thrombocytopenia and risk of intracranial hemorrhage in the fetus/newborn. Analogous to HDFN, but for platelets
  • Post-Transfusion Purpura (PTP): Rare but serious. Occurs ~1-2 weeks after transfusion. Patients (usually multiparous women negative for HPA-1a) develop high-titer anti-HPA-1a (or other HPA antibodies). Paradoxically, these antibodies destroy both transfused antigen-positive platelets and the patient’s own antigen-negative platelets (mechanism unclear, possibly bystander destruction or immune complex formation). Results in sudden, severe thrombocytopenia
• Drug-Induced Immune Thrombocytopenia (DITP): (Excluding HIT)
  • Mechanism: Similar to DIHA. Drugs can act as haptens, trigger immune complex formation, or induce drug-dependent antibodies that bind platelet glycoproteins only when the drug is present. Leads to antibody-mediated platelet clearance
  • Common culprits: Quinine, Quinidine, Sulfonamides, Vancomycin, Rifampin, some NSAIDs
• Heparin-Induced Thrombocytopenia (HIT): (CRITICAL TO RECOGNIZE!)
  • Mechanism: A specific, dangerous form of DITP. Occurs 5-10 days after heparin exposure (or sooner if prior exposure). Patients develop IgG antibodies against complexes of Platelet Factor 4 (PF4) (a protein released from platelet alpha granules) and heparin
  • The Paradox: These PF4-heparin-IgG immune complexes bind to Fc receptors (FcγRIIa) on platelet surfaces, causing massive platelet activation, aggregation, and degranulation. This leads to:
    1. Prothrombotic State Release of procoagulant microparticles and further platelet consumption -> high risk of venous and arterial thrombosis (DVT, PE, limb ischemia, stroke, MI)
    2. Thrombocytopenia Activated platelets are rapidly cleared from circulation by the MPS
  • Key Feature: HIT is primarily a prothrombotic disorder where thrombocytopenia is a marker, not necessarily the main clinical problem

Detection (Finding the Immune Cause)

• Clinical Assessment: History is paramount! (New drugs? Heparin exposure? Recent transfusion/pregnancy? Autoimmune symptoms?). Bleeding pattern (ITP, NAIT, PTP, DITP) vs. Thrombosis (HIT)
• Laboratory Tests
  • CBC/Smear: Confirm thrombocytopenia. Rule out pseudothrombocytopenia. Giant platelets common in ITP. Schistocytes should NOT be prominent (if present, consider TTP/HUS/DIC instead or concurrently)
  • ITP Diagnosis: Primarily a diagnosis of exclusion. Platelet autoantibody testing is generally not recommended due to poor sensitivity and specificity
  • NAIT Diagnosis: Test maternal serum for HPA antibodies; HPA genotype mother, father, and infant (if possible)
  • PTP Diagnosis: Test patient serum for HPA antibodies (usually anti-HPA-1a)
  • DITP Diagnosis: Requires high clinical suspicion and temporal association with drug initiation. Drug withdrawal leads to recovery. Specialized testing for drug-dependent antibodies is complex and not widely available
  • HIT Diagnosis: Requires BOTH clinical suspicion (using scoring systems like the “4Ts”) AND laboratory confirmation:
    • Immunoassays: Detect antibodies binding to PF4/heparin complexes (e.g., ELISA). High sensitivity but moderate specificity (can be positive without clinical HIT)
    • Functional Assays: Detect platelet activation by patient serum in the presence of heparin (e.g., Serotonin Release Assay - SRA, Heparin-Induced Platelet Aggregation - HIPA). High specificity but technically demanding. Considered gold standard

Treatment

• ITP
  • Goal: Raise platelet count to a safe level (prevent major bleeding), not necessarily normalize it
  • First-line: Corticosteroids (suppress antibody production/clearance), Intravenous Immune Globulin (IVIg - rapidly blocks Fc receptors on macrophages, temporary effect)
  • Second-line: Rituximab (anti-CD20, depletes B cells), TPO-RAs, Splenectomy (removes primary site of destruction and some antibody production), other immunosuppressants
  • Platelet Transfusion: Generally reserved for life-threatening bleeding, as transfused platelets are rapidly destroyed
• NAIT
  • Antenatal: If diagnosed prenatally in high-risk cases: Maternal IVIg +/- steroids
  • Postnatal: HPA-matched platelets (e.g., HPA-1a negative platelets if mother has anti-HPA-1a) are ideal but often unavailable emergently. Washed, irradiated maternal platelets are an alternative. IVIg for the infant. Exchange transfusion rarely needed
• PTP
  • First-line: IVIg. Plasma exchange may be considered
  • Platelet Transfusion: Generally avoided unless life-threatening bleeding. If needed, HPA-matched platelets (e.g., HPA-1a negative) are required
• DITP
  • STOP THE OFFENDING DRUG!: Platelet count usually recovers within days to weeks
  • Supportive care, platelet transfusion only if severe bleeding
• HIT
  • STOP ALL HEPARIN EXPOSURE IMMEDIATELY: (including flushes, coated catheters)!
  • Initiate a non-heparin anticoagulant: (e.g., Direct Thrombin Inhibitors like Argatroban or Bivalirudin; Fondaparinux in some cases) even if thrombosis is not yet evident
  • DO NOT TRANSFUSE PLATELETS routinely,: as this may “fuel the fire” and increase thrombotic risk. Only consider for life-threatening hemorrhage

Key Terms

• Thrombocytopenia: Low platelet count (<150,000/µL)
• Megakaryocyte: Large bone marrow cell from which platelets bud off
• Pseudothrombocytopenia: Artificially low platelet count on automated analyzers due to in vitro platelet clumping (usually EDTA-dependent)
• Petechiae: Pinpoint skin hemorrhages characteristic of low platelets
• Purpura: Larger bruises/skin hemorrhages
• Sequestration: Trapping of platelets, typically in an enlarged spleen (hypersplenism)
• Disseminated Intravascular Coagulation (DIC): Pathological widespread activation of clotting and fibrinolysis, consuming platelets and factors
• Thrombotic Thrombocytopenic Purpura (TTP): TMA usually due to ADAMTS13 deficiency, causing microthrombi
• Hemolytic Uremic Syndrome (HUS): TMA often toxin-induced, causing microthrombi, primarily affecting kidneys
• Immune Thrombocytopenia (ITP): Autoimmune disorder with antibodies targeting platelet glycoproteins
• Neonatal Alloimmune Thrombocytopenia (NAIT): Alloimmune disorder where maternal IgG antibodies target fetal platelet antigens
• Post-Transfusion Purpura (PTP): Alloimmune disorder where antibodies develop post-transfusion, destroying transfused and autologous platelets
• Heparin-Induced Thrombocytopenia (HIT): Prothrombotic disorder caused by antibodies to PF4/heparin complexes, leading to platelet activation and consumption
• Human Platelet Antigens (HPAs): Polymorphic antigens expressed on platelet glycoproteins, targets in NAIT/PTP
• Platelet Factor 4 (PF4): Protein released from platelet alpha granules, target antigen in HIT
• Plasma Exchange (PEX): Therapeutic procedure to remove patient plasma and replace it with donor plasma or albumin
• Intravenous Immune Globulin (IVIg): Concentrated human IgG used to treat various immune cytopenias
• Thrombopoietin Receptor Agonists (TPO-RAs): Drugs that stimulate platelet production by mimicking thrombopoietin