PLT Functions & Disorders

These tiny, anucleated cell fragments are the unsung heroes of hemostasis, the body’s process for stopping bleeding. They’re the first responders at the site of vascular injury, quickly forming a temporary plug and providing a crucial surface for the coagulation cascade to build upon

Understanding how platelets normally function and what happens when their numbers are low or their function is impaired is absolutely critical for diagnosing bleeding disorders and managing patients, especially when considering platelet transfusions

Normal Platelet Function: The Steps to Plugging the Hole

When a blood vessel is injured, the normally smooth endothelial lining is disrupted, exposing underlying structures like collagen. This triggers a rapid sequence of events involving platelets:

1. Adhesion: Sticking to the Site
   • Trigger: Exposure of subendothelial collagen and the release of von Willebrand Factor (vWF) from damaged endothelial cells and platelets themselves. vWF rapidly binds to the exposed collagen
   • Mechanism: Platelets initially tether and roll along the injured surface. This is mediated primarily by the platelet surface receptor complex Glycoprotein Ib/IX/V (GPIb/IX/V) binding to the immobilized vWF. Think of vWF as the molecular glue bridging the platelet to the damaged vessel wall. Direct binding to collagen via other receptors (like GPVI) also occurs and provides stronger adhesion
2. Activation: Getting Fired Up
   • Adhesion itself, plus exposure to various agonists (substances that trigger activation) released at the injury site (like collagen, thrombin generated by the coagulation cascade, ADP released from damaged cells and other platelets, and Thromboxane A2 (TXA2) synthesized by activated platelets), causes platelets to undergo dramatic changes:
     • Shape Change: They transform from smooth discs into spiny spheres with extending pseudopods. This dramatically increases their surface area for interaction
     • Granule Release (Secretion): Activated platelets release the contents of their internal storage granules:
       • Dense Granules: Contain potent platelet agonists like ADP, ATP, Calcium (Ca++) (essential for coagulation), and serotonin (vasoconstrictor)
       • Alpha Granules: Contain adhesive proteins (vWF, fibrinogen, fibronectin), coagulation factors (Factor V, Factor XI), growth factors (PDGF), and platelet-specific proteins (like Platelet Factor 4 - PF4)
       • Purpose: The released substances (especially ADP and TXA2) recruit and activate more platelets to the site, amplifying the response
     • Thromboxane A2 (TXA2) Synthesis: Activation triggers the platelet’s internal enzymatic machinery (via cyclooxygenase - COX enzyme) to produce TXA2, a potent vasoconstrictor and powerful platelet activator/aggregator
     • Membrane Changes
       • GPIIb/IIIa Activation: The most abundant platelet receptor, Glycoprotein IIb/IIIa (GPIIb/IIIa), undergoes a conformational change, enabling it to bind fibrinogen (and vWF)
       • Phospholipid Exposure: Negatively charged phospholipids (like phosphatidylserine) flip to the outer surface of the platelet membrane. This creates the essential binding surface (“platelet phospholipid”) for coagulation factor complexes (tenase and prothrombinase), localizing and accelerating clot formation
3. Aggregation: Sticking Together
   • Mechanism: Activated GPIIb/IIIa receptors on one platelet bind to fibrinogen, which then bridges to activated GPIIb/IIIa receptors on other platelets
   • Result: Platelets stick firmly to each other, building up layer upon layer to form the primary platelet plug. This plug is initially unstable but effectively seals small breaches and provides the scaffold for the coagulation cascade
   • Stabilization: The primary plug is later reinforced by the fibrin mesh generated by the coagulation cascade, forming a stable secondary hemostatic plug (a true clot)

Platelet Disorders (Pathophysiology): When the Plug Fails

Problems with platelets can be broadly categorized into two types: not enough platelets (quantitative) or platelets that don’t work properly (qualitative)

Quantitative Disorders: Thrombocytopenia (Low Platelet Count)

• Definition: Platelet count below the lower limit of the reference range (typically < 150,000/µL or 150 x 10⁹/L)
• Causes: Diverse, falling into three main categories:
  • Decreased Production: Problems in the bone marrow prevent sufficient platelet production (e.g., Aplastic anemia, leukemia, chemotherapy, radiation, certain viral infections, nutritional deficiencies like B12/folate)
  • Increased Destruction/Consumption: Platelets are destroyed or used up faster than they can be made:
    • Immune Mediated: Antibodies target platelets (e.g., Immune Thrombocytopenia - ITP, Heparin-Induced Thrombocytopenia - HIT, Neonatal Alloimmune Thrombocytopenia - NAIT, Post-Transfusion Purpura - PTP, drug-induced)
    • Non-Immune: Platelets are consumed in clotting processes or damaged mechanically (e.g., Disseminated Intravascular Coagulation - DIC, Thrombotic Thrombocytopenic Purpura - TTP, Hemolytic Uremic Syndrome - HUS, mechanical heart valves)
  • Sequestration: An enlarged spleen (hypersplenism) traps a larger-than-normal proportion of platelets, lowering the circulating count
• Clinical Features: Risk of bleeding increases as the count drops. Characteristic mucocutaneous bleeding:
  • Petechiae (pinpoint hemorrhages)
  • Purpura (larger bruises)
  • Epistaxis (nosebleeds)
  • Gingival (gum) bleeding
  • Menorrhagia (heavy menstrual bleeding)
  • Severe internal bleeding (GI, intracranial) can occur at very low counts (<10-20,000/µL)

Qualitative Disorders: Thrombocytopathy (Platelet Dysfunction)

• Definition: Platelet count may be normal (or sometimes mildly decreased), but the platelets do not function correctly in one or more steps (adhesion, activation, aggregation, secretion)
• Causes: Can be inherited or acquired
  • Inherited Platelet Function Disorders: Relatively rare genetic conditions affecting specific platelet components:
    • Disorders of Adhesion
      • Bernard-Soulier Syndrome: Deficiency or dysfunction of the GPIb/IX/V complex. Platelets cannot bind vWF effectively. Characterized by giant platelets and moderate/severe thrombocytopenia
    • Disorders of Aggregation
      • Glanzmann Thrombasthenia: Deficiency or dysfunction of GPIIb/IIIa. Platelets cannot bind fibrinogen and therefore cannot aggregate
    • Disorders of Secretion (Storage Pool Disease): Deficiency in dense granules or alpha granules, or defects in the release mechanism. Leads to impaired activation/aggregation amplification
    • Disorders of Signal Transduction/Activation: Defects in pathways leading to TXA2 synthesis or response to agonists
  • Acquired Platelet Function Disorders: More common than inherited disorders:
    • Drugs: Very common cause!
      • Aspirin: Irreversibly inhibits the COX-1 enzyme, blocking TXA2 synthesis for the life of the platelet (~7-10 days)
      • NSAIDs (e.g., Ibuprofen): Reversibly inhibit COX-1
      • ADP Receptor Inhibitors (e.g., Clopidogrel, Ticagrelor): Block platelet activation by ADP
      • GPIIb/IIIa Inhibitors (e.g., Abciximab, Tirofiban): Directly block fibrinogen binding and aggregation (used therapeutically in cardiology)
      • Other: High-dose penicillin, SSRIs, etc
    • Systemic Conditions
      • Uremia (Kidney Failure): Circulating toxins impair multiple aspects of platelet function
      • Myeloproliferative Neoplasms / Myelodysplastic Syndromes: Abnormal platelet production can lead to dysfunctional platelets
      • Cardiopulmonary Bypass: Mechanical stress and activation during surgery can lead to temporary dysfunction
      • Paraproteinemias (e.g., Multiple Myeloma): Abnormal proteins can coat platelets and interfere with function
• Clinical Features: Similar to thrombocytopenia (mucocutaneous bleeding), but the platelet count is normal or near normal. Severity varies greatly

Laboratory Evaluation

• Platelet Count: Measured as part of a Complete Blood Count (CBC)
• Platelet Function Tests
  • Platelet Function Analyzer (PFA-100/PFA-200): Automated screening test simulating primary hemostasis in vitro. Measures closure time under high shear stress using collagen/epinephrine and collagen/ADP cartridges. Prolonged closure times suggest platelet dysfunction or low vWF. Sensitive to Aspirin, vWD, severe platelet defects
  • Platelet Aggregometry: Gold standard. Measures the change in light transmission through platelet-rich plasma as platelets aggregate in response to various added agonists (ADP, collagen, epinephrine, ristocetin, arachidonic acid). Specific patterns of aggregation help diagnose different types of platelet dysfunction (e.g., absent aggregation with most agonists in Glanzmann; absent aggregation only with ristocetin in Bernard-Soulier)
  • Bleeding Time (Historical): Largely replaced by PFA due to poor standardization and reproducibility

Blood Bank Relevance

• Platelet Transfusion: Primary treatment for severe thrombocytopenia or bleeding due to platelet dysfunction. Platelets are collected by apheresis or pooled from whole blood donations
• Platelet Refractoriness: Some patients fail to achieve the expected increase in platelet count after transfusion. Causes can be:
  • Non-Immune: Fever, sepsis, splenomegaly, DIC, medications (e.g., Amphotericin B) - most common
  • Immune: Antibodies against HLA Class I antigens or, less commonly, Human Platelet Antigens (HPAs). Requires HLA-matched or crossmatched platelets
• NAIT/PTP: Specific alloimmune conditions requiring HPA-compatible platelets and specialized management

Key Terms

• Platelet (Thrombocyte): Anucleated cell fragment derived from megakaryocytes, essential for primary hemostasis
• Hemostasis: The process of stopping bleeding
• Adhesion: The process of platelets sticking to a non-platelet surface (like exposed collagen via vWF)
• Activation: The process by which platelets undergo shape change, granule release, and membrane alterations after stimulation
• Aggregation: The process of platelets sticking to each other, mediated primarily by fibrinogen binding to GPIIb/IIIa
• von Willebrand Factor (vWF): Adhesive plasma protein crucial for platelet adhesion to collagen and carrier for Factor VIII
• Glycoprotein Ib/IX/V (GPIb/IX/V): Platelet receptor complex that binds vWF for adhesion
• Glycoprotein IIb/IIIa (GPIIb/IIIa): Platelet receptor (integrin αIIbβ3) that binds fibrinogen (and vWF) for aggregation
• Dense Granules: Platelet storage organelles containing ADP, Ca++, serotonin
• Alpha Granules: Platelet storage organelles containing vWF, fibrinogen, Factor V, PF4
• Thromboxane A2 (TXA2): Potent platelet activator and vasoconstrictor synthesized by platelets via the COX enzyme
• Primary Platelet Plug: The initial aggregate of platelets formed at the site of injury
• Thrombocytopenia: Low platelet count
• Thrombocytopathy: Abnormal platelet function (qualitative defect)
• Petechiae: Pinpoint, non-blanching capillary hemorrhages in the skin
• Purpura: Larger areas of bruising/bleeding under the skin
• Bernard-Soulier Syndrome: Inherited adhesion disorder due to GPIb/IX/V defect
• Glanzmann Thrombasthenia: Inherited aggregation disorder due to GPIIb/IIIa defect
• Storage Pool Disease: Inherited secretion disorder due to granule deficiency
• Platelet Refractoriness: Poor increment in platelet count following transfusion