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

     

    Underproduction

    • Congenital
      • Wiskott-Aldrich syndrome
      • Thrombocytopenia with absent radii
      • Fanconi Anemia
      • May-Hegglin Anomaly
      • Bernard-Soulier Syndrome
    • Nutritional Deficiencies
      • Vitamin B12
      • Folate (rarely Iron)
    • Infectious
      • Viral: HIV, Parvovirus B19
      • Hep C
      • EBV
      • Rubella, Mumps, Varicella
      • Mycobacterial: TB
      • Malaria, Leishmaniasis
    • Autoimmune:
      • Aplastic Anemia
      • Amegakaryocytic thrombocytopenia
    • Toxins:
      • Alcohol
      • Chemotherapy
    • Radiation
    • Portal HTN
    • Malignancy
      • CML, CLL, Hodghkins, NHL
      • Hairy Cell Leukemia, Myelofibrosis
    • Granulomatous: Sarcoid

    Destruction:

    • Immune Mediated
      • ITP
      • Post-Transfusion Purpura
      • Drugs: (heparin, quinine,
        quinidine, β-lactam antibiotics,
        sulfa-containing drugs,
        valproic acid)
      • Antiphospholipid syndrome
    • Non-Immune Mediated
      • DIC
      • TTP/HUS
      • HELLP
      • Gestational Thrombocytopenia
      • Mechanical Destruction
        (LVAD, CABG)
      • Localized intravascular
        coagulopathy: giant cavernous
      • hemangioma, aortic dissection

     

    Splenic Sequestration

    • ANY cause for splenomegaly

     

    • 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).
    •  

     

    Approach

    • Establish Cause!
    • Look at history of platelet counts, family hx, etc..
    • Drugs, herbals, eating/drinking (i.e. tonic water has quinine), HIV, EBV etc..
    • Physical Exam:
      • Lymphadenopathy (lymphoproliferative/myeloproliferative)
      • Hepatic
      • Skin Exam (mucocutaneous bleeding? petechiae, ecchymosis?)
        • Wet purpura are petechiae in oral mucosa = high risk of spontaneous intra-cranial hemorr. 
    • Labs:
      • CBC, Diff  
        • (Anemia leukopenia --> bone marrow disease, leukocytosis --> acute/chronic leukemia)
      • Peripheral Smear**
        • Platelet Clumping?  causes pseudothrombocytopenia.
          • Sometimes clump in EDTA in purple-top tubes, laboratory artifact.  Counter does not detect as many platelets).
          • If suspect pseudo: Send blood in heparin or citrated tube, or blood film!!!
        • Schistocytes: microangiopathic process?
      • Liver Chemistry, Creat, TSH, Electrolytes, B12, Folate, PT, aPTT, fibrinogen, D-Dimer
      • Bone Marrow
        • Bone Marrow biopsy is NOT routine, only indicated if:
          • 1.  Multiple cell lines affected
          • 2.  Myelodysplasia/leukemia consideration
          • 3.  If therapy for ITP is usuccessful

    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

     

     

    Disseminated Intravascular Coagulation (DIC)

    • Begins with abnormal thrombin generation --> rapid consumption of clotting factors, platelets, accelerated fibrinolysis.
      • Hemorrhage can result from low factors.
      • Histopathology --> fibrino clot in microvasculature.
      • Thrombotic microangiopathy can also occur (Schistocytes - only in 30%, not absolute)
    • Conditions that cause DIC:
     

    Obstetric complications

    Eclampsia

    Retained products

    Fetal demise

    Amniotic fluid embolus

    Placental abruption

    Infection

    Gram-negative bacteria

    Gram-positive bacteria

    Rickettsial organisms

    Fungi

    Viruses (hemorrhagic fevers such 

    as dengue, Ebola, in particular)

    Tissue injury

    Crush injuries

    Severe burns

    Brain injury

    Tumors

    Solid tumors

    Acute leukemias (especially 

        acute promyelocytic leukemia)

    Venoms

    Snake bites

    Brown recluse spider bites

     

    • Diagnostic Features:

      1. Low Platelets
      2. Prolonged: PTT, PT
      3. Low or decreasing Fibrinogen
      4. High D-Dimer

      Schistocytes - only in 30%, only if angiopathy is present.

     

    • Treatment:
      • Treat underlying disorder
      • Supportive Transfusions If Bleeding: Plasma, Cryoprecipitate (esp if fibrinogen low), platelets.
        • Know that consumption of transfused products can make microvascular thrombosis worse
        • Transfuse platelets only if bleeding
    • Source: MKSAP 16/ACP

     

     

    Thrombotic Thrombocytopenic Purpura (TTP)

    • Grouped with HUS and atypical HUS because present and treated similarly (plasmapheresis)
    • TTP:  Thought to have an immune cause. (most have sporatic form).
    • Pathophysiology:
      • Protein called ADAMTS13 (protease that cleaves high-molecular weight multimers of vWF).
        • vWF is a sticky protein that is usually in multimers (higher molecular weight multimers are stickier)
        • ADAMTS13 breaks down the multimers to less sticky molecules.
      • Acquired/Sporatic Form:
        • Autoantibodies against ADAMTS13 --> causing more sticky vWF to accumulate --> deposition of fibrin.
          • Fibrin causes fragmentation of RBCs --> Schistocytes
      • Congenital:
        • Born with low or absent levels of ADAMTS13
    • Triggers:
      • Drugs (Quinine, Ticlopidine, Mitomycin C, Cyclosporine, Gemcitabine)
        • [Secondary to endothelial damage, doesn't cause antibodies]
      • Pregnancy
      • HIV/AIDs
      • Transplant (solid organ or bone marrow)
    • Symptoms: (pentad)
      • 1.  Fever
      • 2.  Mental Status Change (headache, confusion --> progress to seizures, coma)
      • 3.  Acute Renal Failure
      • 4.  Thrombocytopenia
      • 5.  MAHA (Schistocytes in blood film)
    • Diagnosis:
      • Suspect in patients with MAHA (Schistocytes, thrombocytopenia, high LDH).
      • Lab Coagulation Tests (PT, PTT) are NORMAL!! (distinguishes it from DIC)
      • **Peripheral Smear**  --> Scistocytes, Nucleated RBCs, Low platelets
      • ADAMTS13 Activity --> Used for prognosis only
    • Treatment:
      • LIFE THREATENING!
        • 20% can die in first 24hrs. (almost always fatal if untreated)
      • Plasma Exchange emergently if high suspicion - even before results (once daily, sometimes BID for 3-7d)
        • Superior to simple plasma transfusion in RCT
          • Plasma exchange decreases a 90% mortality to 10%
        • Plasma Exchange gives intact ADAMTS13, and removing damaged one.
        • FFP transfusion is inferior, but can do it if plasma exchange unavailable (better than nothing)
        • keep going until platelet count is > 150,000 x2 days, and LDH normalizes.
      • DO NOT transfuse platelets, UNLESS bleeding
        • Plts can cause sudden death (by causing more microvascular occlusion)
      • Corticosteroids
        • Almost always used, but no RCTs showing benefit.

    Hemolytic Uremic Syndrome (HUS)

    • Occurs in children, very rare
    • Due to E.coli O157H7.
    • Hallmark is Complement activation
    • Characterized by more renal manifestations, and fewer neurologic sequelae
      • Often preceeded by infectious diarrheal illness.
    • Typical HUS (Infection-Related)
      • Preceeded by infectious diarrhea (E.coli O157H7, or shingella species)
      • Shinga toxin resembles antigens on renal endothelial cells, bind, and cause renal cell death.
    • Atypical HUS (Congenital)
      • Abnormality in complement proteins 
    • Treatment:
      • Plasma exchange
      • HUS does not respond to plasma exchange as well as TTP 

    Atypical HUS

    • Genetic cause of HUS
    • Inability to turn off C3 convertase leading to persistent complement activation
      • Factor H usually inhibits C3.  Factor H stopped by either antibody or genetically inactive. 

     

    TTP/HUS Mimics:

    • Other causes of MAHA:
      • Malignant HTN
      • HELLP
      • APLA
      • Scleroderma renal crisis

     

     

    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

     

    Acquired

    • Uremia
      • Dysfunctional platelets.
      • DDAVP (Desmopression) is first line in a bleeding uremic patient.
        • Dialysis eventually required to fix platelets.
      • Conjugated estrogens can help with mucosal bleeding (if desmopressin/dialysis not effective)
    • Myeloproliferative / Myelodysplastic syndrome
      • Platelets may be disfunctional.
      • Transfuse platelets if needed.
    • Drugs / Herbs
      • ASA irreversibly acetylates and inhibits COX in platelets, rendering them dysfunctional. 
      • NSAIDs causes platelet dysfunction, but is reversible. 
      • ADP-antagonist (clopidogrel) --> irreversible. 
    • Foods:
      • Garlic
      • Chinese black tree fungus
      • Ginseng
    • Patients with a predisposition (i.e. vWF disorder) can have more severe bleeding with these.
    Tag page (Edit tags)
    • No tags
    Pages that link here
    Page statistics
    31732 view(s), 26 edit(s) and 26559 character(s)

    Comments

    You must login to post a comment.

    Attach file

    Attachments