Platelets

Introduction

• Sticky cells, made in bone marrow from megakaryocytes.
• TPO drives production of platelets (along with cytokines like IL-11)
• Normal lifespan 7-10 days (1/10th replace daily).
• Normal: 150,000-400,000
• Symptoms of Platelet Dysfunction:
  • Mucocutaneous bleeding (primary hemostasis)
• Important Points:
  • Do not transfuse platelets in HIT and TTP
  • Avoid transfusing platelets in DIC (consider if bleeding)

Thrombocytopenia

• Defined as Platelet Count < 150,000
• Isolated thrombocytopenia is not due to bone marrow syndromes!
• Causes
  • Underproduction:
    • Vitamin B12, Folate deficiencies (often causes pancytopenia)
  • Peripheral Destruction
  • Splenic Sequestration
• Causes:

Causes of Thrombocytopenia

• Often detected incidentally.
• Platelet Counts:
  • 100,000-150,000  --> No increase in bleeding risk;
  • 50,000-100,000 --> NOT significant bleeding risk
  • <50,000 --> Mucocutaneous bleeding
  • <10,000 --> Increased risk of spontaneous ICH (RARE! even with low plts).
•  

Immune Thrombocytopenic Purpura

• Auto-antibodies against platelet surface --> platelet destruction
  • ALSO Decreased platelet production (NEW studies), new drugs target production.
• Common, Children > Adults  (often self-limited in children)
• Symptoms:
  • Mild-to-Severe bleeding
  • New onset thrombocytopenia, wet purpura, hemorrhagic symptoms.
• Diagnosis:
  • Diagnosis of exclusion
    • Supportive findings: otherwise normal CBC (or anemia from bleeding), absence of organ dysfunction, normal blood smear.
• Labs:
  • Normal CBC (or anemia from bleeding)
  • No organ dysfunction
  • Blood smear normal (can see larger platelets, just released from BM)
    • Usually new platelets more effective = less bleeding than expected
    • Hence: often patients asymptomatic

• ITP causes:
  • Drug-Induced
  • Autoimmune (Lupus, HIV, lymphoproliferative CLL, etc..)
• Treatment
  • Not all patients require treatment (often plts 30-40, no bleeding, 15% risk of more severe ITP)
    • Follow: CBC q2weeks or so

  • Indications for treating ITP      1.  Platelets < 30,000-40,000      2.  Active Bleeding

  • if plts < 30-40 or if bleeding.
  • 1st Line: Corticosteroids is mainstay or therapy, but can taken time to take effect.
    • Prednisone or Methylprednisolone (1-2mg/kg/day)
      • Some suggest high-dose dexamethasone, for lower relapse rate. (not tested)
      • Initial response: 75-80% of pts, relapses common
  • If don't respond to steroids and continue to bleed:
    • Can use adjunctive IVIG or (anti-D Ig, esp in pregnant) - especially if bleeding or plts < 10.
      • More quick than steroids, often in actively bleeding (rare), or requiring surgery.
        • IVIG quickly elevates platelet count while steroids are taking effect.
      • Anti-D Immune globulin can be alternative if spleen intact and Rh-positive blood.
        • Anti-D IgG attacks RBCs with Rh+ receptor, and its immune-mediated clearance saturates the Fc-gamma receptors in spleen, minimizing removal of ITP-antibody-coated platelets.
    • Other Drugs: Rituximab, or Mycophenylate Mofetil
  • Splenectomy
    • For refractory ITP.
    • Effective in 75%,  However rituximab replaced splenectomy in many places
  • NEW: Etrombopag (PO), Romiplostim (IV) (Thrombopoietin receptor mimetic)
    • Approved for refractory ITP (often need special prescribing privileges)
    • Can increase platelet counts in patients with ITP

Drug-Induced Thrombocytopenia

• Many drugs can do this, but mostly:
  • Antibiotics (B-lactams, cephalosporins, sulfa, vancomycin)
  • Quinine (off market)
    •  Still exists in tonic water
  • GpIIBIIIA inhibitors
• Treatment:
  • Discontinue offending blood, platelets should recover.

Heparin Induced Thrombocytopenia (HIT)

• 1-3% of patients treated with Unfractionated Heparin
  • UFH has a 7-fold higher risk than LMWH.
  • More likely post-CV or post-Ortho surgeries compared to medical pts.
  • In Renal Failure: HIT is uncommon
• 5-10d after exposure to heparin, >50% decrease in platelet count.
  • Some develop HIT rapidly in 1-2 days, but RARE. (esp if already received before).
• High risk of clotting - (24-fold increased risk)
• Pathophysiology:
  • Platelet Factor 4 (in alpha-granules) binds heparin, develop antibodies to that complex.
  • Fc portion of the antibody binds to platelets --> plt activation --> degranulate --> more PF 4 release --> etc.
  • Antibodies bind glycosaminoglycans (heparin-like compounds) on endothelial cell surface, causing endothelial damage --> THROMBOSIS
• Presentation:
  • Low platelets 
  • Arterial or Venous thrombotic events (despite thrombocytopenia)
• Diagnosis:
  • Screen: Pre-Test Probability based on 4-T Score:  (has very high NEGATIVE Predictive value)
    • Prospectively validated tool

    • 4-T Score of HIT (For Pre-Test probability)      2 points - T - Thrombocytopenia (>50% decline in plt number)    2 points - T - Timing (5-10 days after heparin administration)    2 points - T - Thrombosis (Confirmed new thrombosis)    2 points - T - Thrombocytopenia (Exclucing other causes)   Points Interpretation 0 - 3  Low Probability 4 - 5 Intermediate Probability 6 - 8  High Probabilit

  • Diagnosis:
    • Step 1:
      • ELISA (EIA): Antibody test for Anti-PF4 (sensitive, but lacks sensitivity, lots of false-positives)
    • Step 2:  (High Sensitivity + High Specificity)
      • Functional Assay: Heparin-induced platelet aggregation assay.
        • (Radiolabeled C14 serotonin release assay).
        • (incubate plts with C14 serotonin, then incubate with heparin concentrations, and check if C14 serotonin released into supernatant)
  • Caution: HIT possible <5days, thrombotic event can occur even after heparin d/c'ed.
    • Can cause skin necrosis (similar to warfarin)
• Treatment:
  • STOP heparins (lines, heparin-impregnated catheters)
  • Anticoagulate (24-fold increased risk)
    • Options:
      • Leparudin (from medicinal leech, CAUTION in renal impairment)
      • Argatroban to treat hypercoagulable state (REQUIRED) - FDA approved
      • Other: (Not FDA approved HIT treatments)
        • Bivalirudin (Only for HIT + PCI in heart disease)
        • Fondaparinux also has been used b/c easy single daily injection (evidence not as good, but still used in US+Europe for HIT).
      • DO NOT USE WARFARIN IN ACUTE STATE => risk of limb gangrene based on one study. (use it later)
      • DO NOT TRANSFUSE PLATELETS!!!

Microangiopathic Hemolytic Anemia (MAHA)

• Abnormal activation of platelets and endothelial cells --> deposition of fibrin in peripheral vasculature.
  • Leading to peripheral destruction of erythrocytes and decreased platelets. 
• Clinical Features:

1. Thrombocytopenia
2. Schistocytes on blood smear
3. Increased LDH

Thrombocytopenias due to Underproduction

• Inadequate megakaryocyte in BM.
• Any BM failure syndrome:
  • Aplastic Anemia, Myelodysplasia, Vit B12, Folate deficiency, Fanconi Anemia.
  • Invasion of marrow by: leukemia, granulomatous disease
  • Also: inonizing radiation, infection, drugs (esp EtOH)
• Platelet transfusions typically effective for preventing bleeding

Platelet Function Disorders

• Platelet count is OK but platelets aren't working.
• NOTE: NO routine recommendation to screen coagulation preoperatively. 
• Guidelines: Screening for platelet dysfunction recommended ONLY for personal or family hx of mucocutaneous bleeding.
• Labs:
  • "Bleeding Time Tests" - No longer performed (not reliable)
  • PFA-100 (Platelet Factor Analyzer Assay - new "bleeding time"), screens for primary hemostasis
    • Recommended for pts with personal or family hx of mucocutaneous or post-surgical bleeding.
    • Whole citrated blood aspirated to an aperture in a cartrige.  Membrane of aperture activates platelets, which clump and eventually block aperture, halting flow of blood.
      • Closure time is recorded (prolonged in severe platelet dysfunction). 
      • Prolonged in vWF, or platelet dysfunction syndromes, but may be normal if mild.
  • Platelet Aggregation Testing:  (available only in certain centers)
    • Suspend platelets, and measure light transmission.
      • When aggregate --> increased light transmission