Thrombocytopenia Flashcards Preview

Heme/Onc > Thrombocytopenia > Flashcards

Flashcards in Thrombocytopenia Deck (14):

Describe normal platelet physiology, especially the role of megakaryocytes and thrombopoietin.

  • Produced by megakaryocytes
    • Large multinucleated cells located in bone marrow
    • Numbers regulated by a number of growth factors
      • GMCSF (granulocyte stimulating factor)
      • Interleukins (IL) 3, IL-6, IL-11
      • lineage specific thrombopoiten
    • Platelet life span ~9-10 days
    • Approximately 15,000-45,000 platelets/mL are needed to be produced each day to maintain steady state
    • Normal platelet level: 140-390,000
    • Up to ~1/3 sequestered in spleen at any given time
  • Thrombopoiten (TPO)
    • Most important regulatory protein in platelet production
    • Main production of TPO is in the liver
      • Also produced to lesser extent in kidneys and marrow stroma
    • TPO levels are regulated by platelet and megakaryocyte counts (feedback inhibition)
      • Levels increase with low platelet mass and megakaryocyte count
      • Levels decrease as platelet count increases
    • TPO half life is approximately 20-30 hours
    • Target receptor: cMPL
      • These receptors are present on both megakaryocytes and platelets
      • Important in production of both megakaryocytes & platelets


What are the most common causes of decreased platelet production?

  • Marrow suppression/damage
    • Medications
      • Cytotoxic chemotherapy
      • Antibiotics
  • Myelophthisic processes: replacement of normal marrow stroma
  • Malignancy
    • Metastatic solid tumors (causing a myelophthisic process)
    • Primary hematologic malignancies: eg, leukemia: marrow producing leukemia cells, but not platelets
    • Myelofibrosis: reticulin replaces normal marrow
  • Radiation therapy: destruction of stem cells
  • Aplastic anemia
    • Also destruction of stem cells
    • Several potential causes, including drugs, viruses, or idiopathic (autoimmune)
  • Ineffective production:
    • Deficiencies of B12/folate
    • Myelodysplastic syndrome (covered elsewhere in this course)
  • Congenital defectsvery rare. You will not be tested on these processes, these are listed here to be complete.
    • Amegakaryocytic aplasia
    • Fanconi’s anemia
    • TAR syndrome: Congenital hypoplastic thrombocytopenia with absent radii
    • Wiskott Aldrich syndrome
    • May Hegglin anomaly


What are some common causes of platelet sequesteration?

  • Splenomegaly
    • Normally ~1/3 of platelet mass sequestered in the spleen
    • The percentage of platelets sequestered in the spleen can increase significantly with increased spleen size
    • Common causes:
      • Liver disease
      • Myeloproliferative disease/myelofibrosis


What are some common causes of platelet destruction?

  • Immune mediated causes
    • Autoimmune/idiopathic thrombocytopenic pururpa (ITP)
    • Heparin-induced thrombocytopenia/HIT
    • Systemic lupus erythromatosis/SLE
    • Other drug induced: eg, antibiotics
  • Nonimmune mediated
    • DIC
    • HUS/TTP (also immune mediated)
    • HELLP syndrome


What is the etiology of Idiopathic/immune Thrombocytopenic Purpura (ITP)?

  • Immune mediated clearance of physiologically normal platelets
    • IgG, IgM, IgA, complement to platelet surfaces
      • IgG felt to be most pathogenic
    • Multitude of platelet antigen targets:
      • Glycoprotein GP-Ib, IIb, -IIIa, and GP IIb-IIIa complex
      • The antibody responsible for clearance typically does not interfere with platelet activity (ie, typically causes a quantitative, but not qualitative, platelet problem)
  • Trigger unclear
    • Children: viral illness often precedes ITP
      • Often no need for treatment (varies by case)
      • Process often self-limited
    • Adults: appears to be true autoimmune- that is, not necessarily virally triggered
      • Often is a chronic condition with varying severity
      • Relapsing/remitting courses common


What is the clinical presentation of ITP?

  • Varies by degree of thrombocytopenia, but can include
    • Mucosal bleeding
    • Petechiae
    • Increased bruising
  • With increase use of automated CBC, it is now very often picked up on routine lab draws


What is the diagnosis of ITP?

  • Clinical Diagnosis/Diagnosis of exclusion
    • Patients often have normal white blood count, hemoglobin
    • There is no other explanation of thrombocytopenia present
  • Lab testing for anti-platelet antibodies:
    • Variable sensitivity and specificity: high false +/- rate
    • Currently little utility in checking for presence of anti-platelet antibodies due to the poor specificity/sensitivity
  • Peripheral blood smear
    • Nonspecific, often bland findings in ITP
    • Will see low platelet numbers, & can often see large/giant platelets
  • Bone marrow biopsy
    • Nonspecific findings, but there is often lack of other bone marrow pathology (that is, no evidence of myelofibrosis, myelodysplastic syndrome, etc.)
    • Can see increased numbers of megakaryocytes
    • Bone marrow biopsies are typically only done in certain patients, for example:
      • If there is abnormal hemoglobin and/or wbc
      • In patients >60 years old to rule out another marrow process, since frequency of diseases such as myelodysplastic syndrome increase with age


What are the common treatment options for ITP?

  • Treatment varies from provider to provider, patient to patient
  • Often reserved for severe thrombocytopenia (platelets <20-30K)
  • Will treat if <50K and bleeding/high risk of bleeding
  • Corticosteroids
    • Typical first line treatment
    • Mechanism of action:
      • Decrease antibody production
      • Decrease reticuloendothelial platelet clearance
    • Options:
      • Prednisone 1mg/kg/day to start, with a slow taper thereafter
      • Pulse dose dexamethasone: 40 mg/d x4 days, no taper
      • High response rate: >80%
      • >60% complete remission
  • Intravenous immunoglobulins (IVIG, gammaglobulin)
    • Fast acting: increases platelet counts within 1-2 days
    • Downsides: expensive, and allergic reactions are common
    • Often transient response with early relapses
  • Anti-Rh factor (Rh factor is a red blood cell antigen)
    • Very similar to IVIG in fast onset of action, mechanism of action, and also often transient responses
    • Need to monitor patients for significant hemolysis
    • Cannot give if patient is Rh negative
    • Cannot give if patient had prior splenectomy
  • Rituximab
    • Chimeric anti-CD20 monoclonal antibody developed for lymphoma
    • Growing interest for use in autoimmune disorders
    • Current data for its use in ITP is mainly case series/case reports (ie, there are no large randomized controlled trials published yet)
    • In a meta-analysis of available reports, there is a ~60% response rate, but there is variable follow up, with unclear long term benefits or complications
  • Splenectomy
    • Currently, the only known curative option
    • ~2/3 response rate
    • Need to be inoculated against encapsulated bacterial organisms (strep pneumonia, haemophilus influenza, neisseria meningiditis)
  • Thrombopoiten receptor agonists
    • Stimulate cMpl receptor on megakaryocytes to produce more platelets, megakaryocyte maturation
    • Romiplostim and Eltombopag
  • Other immunosuppression: there have been a number of other medications used in other clinical scenarios to suppress the immune system, with some benefit in ITP (including azathioprine, cyclosporine)


What is the role of Romiplostim and Eltombopag in the treatment of ITP?

  • Romiplostim
    • Peptide mimetic that is bound to IgG
    • Given as once-weekly subcutaneous injection
    • Shown in randomized trials to increase platelet levels in refractory ITP, decrease need for other therapies such as corticosteroids
    • Side effect: unwanted increase in bone marrow reticulin in small % of patients
  • Eltombopag
    • Non-peptide mimetic, also binds to cMpl receptor
    • Oral,once daily
    • Also increases platelet counts in patients with refractory ITP


What are the potential mechanisms of drugs that can lead to drug induced thrombocytopenia?

  • Various potential mechanisms depending on the drug
  • Drug-induced myelosuppression (eg, seen with chemotherapeutics)
  • Drug-induced platelet antibodies (primarily seen with certain antibiotics)
    • Idiosyncratic reaction in a minority of patients exposed to the drug.
    • Antibody specificity
      • Drug-antibody complex bind to platelet glycoproteins
      • Drug-antibody complex results in complement activation; the platelet is subsequently damaged.
    • Severity
      • Most patients have mild thrombocytopenia which resolves 7-10 days after drug discontinuation
      • Can have profound thrombocytopenia with bleeding
      • Severe cases may require treatment with corticosteroids and/or platelet transfusion


What is the mechanism of heparin induced thrombocytopenia?

  • Autoantibody formation against heparin-platelet factor 4 (PF4) complex
    • PF4: platelet-specific chemokine
      • Stored in α granules
      • Released on heparin exposure
      • Interacts with heparin, and this causes a neoepitope formation that is the target for a new antibody formation
    • Antibodies
      • Form in response to new epitopes on PF4
      • Only imimunoglobulin IgG thought to be pathogenic
      • Bind to FcγIIa receptors on platelets → activation of platelets
      • Unfractionated heparin causes formation of antibodies much more than low molecular weight heparins
    • Overall process seen in HIT causes excessive thrombin formation, and greatly increases risk for arterial and venous blood clots
      • Mechanism is mainly from platelet microparticle formation after antibody (Ab) activation of platelets
      • Ab can target PF4/endothelial glycosoaminoglycans → tissue factor (TF) expression → thrombin formation
      • Monocytes may also be activated → TF expression → thrombin formation


What is the clinical presentation of heparin induced thrombocytopenia?

  • Thrombocytopenia from platelet activation and premature clearance
    • ≥50% drop from baseline
    • Usually mild (average ~60,000)
    • Not associated with bleeding
  • Thrombosis (approximately 50% of patients have clot at diagnosis, & another 50% after heparin is removed if no alternative anticoagulation used)
  • Serologic evidence of anti-PF4 Ab
    • ELISA PF4 test
    • Serotonin release assay (functional test of platelet activation)
      • This is considered the gold standard in diagnosis
      • It is a functional assay to see if the patient has antibodies that can activate donor platelets in the presence of heparin
      • It is time consuming and often takes a long time to return


What is the treatment of heparin induced thrombocytopenia?

  • Cessation of heparin is extremely important
  • Due to high rates of clot formation, institution of alternative anticoagulant is also necessary
    • Not low molecular weight heparin due to cross-reactivity; pathologic process will continue
    • Direct thrombin inhibitor: Argatroban or Lepirudin
  • Unclear duration of anticoagulation if no thrombosis present at diagnosis; usually done at least until platelet recovery


What are some common marrow failure syndromes?

  • Rare, often associated with megakaryocyte hypoplasia
    • Fanconi’s anemia
    • Amegakaryocytic aplasia
    • TAR syndrome
  • Wiskott Aldrich syndrome
    • X-linked
    • Eczema, immune deficiency in addition to thrombocytopenia
  • May Hegglin anomaly
    • Atypical platelet morphology
    • Dohle bodies seen in white blood cells: basophilic inclusions
    • Mild-moderate thrombocytopenia with variable bleeding risks.
  • Aplastic Anemia