Thrombocytopenia

Question 1

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

Answer 1

• 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

Question 2

What are the most common causes of decreased platelet production?

Answer 2

• 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 defects: very 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

Question 3

What are some common causes of platelet sequesteration?

Answer 3

• 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

Question 4

What are some common causes of platelet destruction?

Answer 4

• 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

Question 5

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

Answer 5

• 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

Question 6

What is the clinical presentation of ITP?

Answer 6

• 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

Question 7

What is the diagnosis of ITP?

Answer 7

• 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

Question 8

What are the common treatment options for ITP?

Answer 8

• 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)

Question 9

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

Answer 9

• 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

Question 10

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

Answer 10

• 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

Question 11

What is the mechanism of heparin induced thrombocytopenia?

Answer 11

• 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

Question 12

What is the clinical presentation of heparin induced thrombocytopenia?

Answer 12

• 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

Question 13

What is the treatment of heparin induced thrombocytopenia?

Answer 13

• 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

Question 14

What are some common marrow failure syndromes?

Answer 14

• 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