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Flashcards in Thrombocytopenia Deck (14):
1

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

2

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

3

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

4

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

5

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

6

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

7

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

8

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)

9

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

10

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

11

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

12

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

13

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

14

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