section name header

Info


A. Types

  1. Childhood Form of ITP
    1. Typically following a viral illness
    2. High spontaneous remission rate (>80%)
    3. Strongly associated with parvovirus B19 infection
    4. Boys and girls are affected nearly equally (~5 cases per 100,000 per year)
    5. Treatment quite different from adult form (see below)
  2. Adult Form
    1. Usually without preceeding viral syndrome
    2. ~70% of patients are women; of these, ~70% are <40 years old
    3. Spontaneous remissions in <10%
    4. Platelet autoantibodies against glycoproteins (GP) IIb/IIIa and/or Ib/IX or Ia/IIa
    5. Platelet glycoprotein IIb/IIIa is most abundant on platelet
    6. Incidence is ~5 per 100,000 per year (about 20,000 cases in USA currently)
    7. Diagnosis of exclusion requires ruling out other causes of thrombocytopenia
  3. Other Common Causes of Antibody Associated Thrombocytopenia
    1. Systemic Lupus - often with positive ANA
    2. Antiphospholipid Syndrome
    3. Associated with lymphoma, leukemia, or myelodysplasia
    4. Drugs - procainamide, quinidine, heparin, cimetidine, ticlopidine, gold, penicillamine [12]
    5. Parvovirus B19 infection
    6. HIV - risk factors should be assessed and patients tested as indicated
    7. Hepatitis C Virus (HCV)
    8. Platelet associated antibodies specific for GPIIb/IIIa, Ib/IX, or others found in 30% of cases of critically ill patients with thrombocytopenia [7]
  4. Splenomegaly
    1. Not part of typical ITP
    2. Often present in persons with cirrhosis
    3. May be a manifestation of myelodysplastic syndrome, lymphoma, or leukemia

B. Pathophysiology [1,5]

  1. Autoimmune disease against platelet GPs
  2. Most commonly directed against platelet GP IIb/IIIa
  3. T-dependent antigens
    1. Autoreactive B lymphocytes are oligoclonal
    2. Require T cell help
    3. Poor association with specific histocompatibility subtypes
  4. Likely that activated macrophages present antigen to T lymphocytes
    1. T cell activation requires specific antigen + accessory stimulatory molecules
    2. CD40 on presenting cell and CD40L (CD154) on T cell is key interaction
    3. Activated T cells stimulate autoreactive B lymphocytes
  5. Drugs such as quinidine, vancomycin can stimulate an autoimmune thrombocytopenia [21]

C. Diagnosis

  1. Clinical History
    1. Mucosal (gum) bleeding and nose bleeding
    2. Easy bruising
    3. Heavy menstruation
    4. In pregnant women, blood pressure is important to rule out pre-eclampsia
  2. Physical Exam
    1. Most common: petechiae and purpura; echymoses rarer
    2. Hematuria and gastrointestinal bleeding are less common
    3. Intracerebral hemorrhage is very uncommon, even in patients with platelets <10K/µL
    4. Palpable spleen is evidence against ITP (abdominal ultrasound study should be done)
  3. Laboratory
    1. Other hematologic cell lineages usually normal
    2. Evaluation of peripheral smear - platelet size, clumping, other abnormal cells
    3. Giant platelets are evidence of increased bone marrow production
    4. Neutropenia or leukopenia often accompany virus associated thrombocytopenia, not ITP
    5. Hemolytic anemia is uncommon (combination with ITP is called Evan's Syndrome)
    6. Platelet kinetic studies may be useful for clarifying etiology [19]
    7. Some patients with "ITP" have reduced production of platelets
    8. Therefore, anti-platelet autoantibodies can affect production of platelets as well as increase their destruction [19]
  4. Bone Marrow
    1. Indicated to establish diagnosis in patients over 60 and pre-splenectomy
    2. Also indicated in patients who fail to respond to glucocorticoids
    3. Some physicians will perform bone marrow prior to initiating glucocorticoids at all
    4. Bone marrow shows presence/appearance or absence of megakaryocytes
    5. Some anti-platelet antibodies are specific for megakaryocytes and reduce their numbers
    6. Many patients have inappropriately low megakaryocyte numbers for their platelet counts
    7. Rule out infiltrative bone marrow disease and myelodysplastic syndrome
  5. Bleeding Risk
    1. Normal Activity and most Surgeries: Platelets >50K/µL desired
    2. Restricted Activity, Precautions Taken: Platelets <20K/µL
    3. Gum Bleeding occurs at ~20-50K/µL
    4. Intracranial Bleed: increased risk at <10-15K/µL
    5. Overall increased risk with dysfunctional platelets (aspirin use, renal failure, others)
    6. Patients with platelets >50K/µL can safely undergo invasive procedures
    7. Older patients (>65 years) appear to be at higher risk for serious bleeding than younger patients with equivalent platelet counts

D. Initial Treatment of Adults [13]

  1. Indications for Treatment
    1. Platelet count <50K/µL with significant bleeding or purpura or risk factors for bleeding
    2. Platelet count <30K/µL in all patients
    3. Initial therapy with glucocorticoids is recommended
    4. Hospitalize patients with platelet count <20K/µL and hemorrhage
    5. Patients with <20K/µL platelet counts and hemorrhage should be treated immediately with intravenous (IV) glucocorticoids and intravenous immunoglobulin (IVIg)
    6. Splenectomy is recommended when platelet counts remain <30K/µL after 4-6 weeks of initial therapy therapy
    7. For patelet count <30K/µL without bleeding - prednisone or anti-RhD immune globulin
  2. Glucocorticoids [1,3,4]
    1. 1mg/kg/d prednisone x 5-7d then taper very slowly (months) if good response
    2. Alternative high dose methylprednisolone (Solumedrol®) 15mg/kg to 1gm maximum IV qd x 3 days then followed by prednisone 1mg/kg/d provides long-term responses [4]
    3. Dexamethasone 40mg qd x 4 days induced responses at day 10 in 85% of patients and >50K/µL platelets in 50% of patients at 6 months [6]
    4. Patients with <50K/µL platelets after initial therapy should continue on prednisone
    5. About 50% of patients will relapse at prednisone <20mg/day or less
    6. Initial complete responses occur in 25-80% of cases
    7. Goal long-term is to reduce daily prednisone to <10mg
    8. Consider splenectomy if prednisone cannot be reduced to <15mg po qd after 3-6 months
    9. High dose dexamethasone (DEX) also used in resistant ITP
  3. Splenectomy [1,3]
    1. Response rate ~70% within <10 days (usually within 3 d) of splenectomy
    2. ~10% of nonresponders (platelets <30-50K/µL) will have accessory spleens
    3. Absence of Howell-Jolly Bodies after splenectomy suggests accessory spleens
    4. Overall initial response is highest for this modality of therapy
    5. Response to high dose IVIg predicts good response to splenectomy [16]
    6. Splenectomy is reasonable on first relapse in adults after initial therapy
    7. Vaccinate with HIB, pneumococcus, meningococcus
    8. Pre-operative thyroid function testing is appropriate
    9. IVIg and/or oral glucocorticoids for elective splenectomy with platlets <20K/µL
    10. Early splenectomy rather than prolonged steroids may be preferred for patients with a good response to IVIg [16]
  4. Intravenous Gammaglobulin (IVIg) [4,16]
    1. Well tolerated in most patients
    2. Dose is 2gm total as 400mg/kg x 5d or 1gm/kg/d x 2 days or 0.7gm/kg/d x 3 days
    3. No or slightly more effective than glucocorticoids and very expensive
    4. These doses of Ig increase serum Ig ~2X and block Fc receptors in spleen [16]
    5. May be combined with platelet transfusions in acute bleeding episodes
    6. Should be followed by oral prednisone 1mg/kg to maintain responses [4]
    7. May be preferred in pregnant women and patients at risk for steroid side effects
  5. Anti-RhD Immune Globulin [3,11]
    1. For treatment of chronic ITP in patients with intact spleen who are RhD+
    2. Adults have platelet increase of ~50K/µL, lasting about 3 weeks
    3. ~80% of children with ITP respond with platelet increases up to 200K/µL
    4. Hemolysis occurs and can be severe in some patients
    5. Dose is 75µg/kg IV daily x 2 days
    6. Overall, about as effective as IVIg and somewhat less costly
  6. Danazol [10]
    1. Androgenic compound with mild to moderate efficacy and few side effects
    2. Dose 400mg/day can be increased to 800mg/d and tapered to 200mg/d
    3. Side effects mild include acne, hirsuitism
    4. May be effective in ITP associated with SLE or anti-phospholipid syndrome
    5. Does not appear to reduce anti-platelet antibody titers
    6. 67% response (complete + partial) in chronic ITP after splenecomy or glucocorticoids
  7. Platelet transfusions
    1. Indicated only for active (severe) bleeding
    2. Usually destroyed within 12-24 hours of transfusion
    3. Addition of IVIg may improve lifespan [1,4]
  8. Treatment of ITP in Pregnancy
    1. Main initial concern is other causes of low platelets, especially pre-eclampsia
    2. Incidence of fetal thrombocytopenia is ~10%
    3. Major concern is risk to infant during vaginal delivery
    4. Cesarean section may be considered, especially for fetal platelet count <50K/µL
    5. Prednisone treatment of mother is generally safe during pregnancy
    6. IVIg therapy is also apparently safe and may be used until delivery is completed
    7. Splenectomy may be required

D. Treatment of Adults with Refractory Chronic ITP [14]

  1. Refractory chronic ITP occurs if platelet counts are <30K/µL after splenectomy
  2. Indications for Treatment of Adults with Refractory ITP
    1. All adults (age >16 years) with platelet counts <10K/µL should be treated
    2. Adults with platelet counts <30K/µL strongly consider treatment
    3. Splenectomy leads to chronic platelet counts >30K/µL in >70% of adults
    4. Medical literature supporting post-splenectomy treatment is difficult to interpret [14]
  3. Consider the following initially in treatment of refractory chronic ITP:
    1. Accessory splenectomy (diagnosis required)
    2. Glucocorticoids - high doses for induction (acute/subacute) therapy
    3. Rituximab (Rituxan®) - monocloncal antibody given intravenously (IV)
    4. Danazol (see above)
    5. Dapsone
    6. Chronic glucocorticoids with glucocorticoid sparing agent
  4. Anti-CD20 Antibody (rituximab, Rituxan®) [8,9,20]
    1. Chimeric monoclonal antibody binds CD20 mainly found on B cells
    2. Weekly infusion 375mg/m2 IV for 4 weeks led to depletion of circulating B cells
    3. Clearly active in severe refractory ITP with 50-60% overall response rates [8,18]
    4. Review showed 44% of relapsed patients with platelets >150K/µL after 4 week course [8]
    5. Concern over 2.9% associated mortality rate in rituximab treated adult ITP [8]
    6. Activity in chronic graft-versus-host associated thrombocytopenia [9,20]
    7. Rituximab is overall well tolerated and may be considered in refractory ITP
  5. High Dose Glucocorticoids
    1. Prednisone 1mg/kg po with slow tapering ± glucocorticoid sparing agents
    2. DEX 40mg po qd for 4 days every 28d for 6 cycles (also for initial therapy)
    3. Cycled DEX may provide ~75% response and maintenance rates
    4. If high doses of glucocorticoids are required for prolonged periods, add sparing agents
  6. Glucocorticoid "Sparing" Agents
    1. In refractory patients or with concommitant disease requiring chronic glucocorticoids
    2. Mycophenolate mofitel (CellCept®) 1gm bid; generally well tolerated but limited efficacy data
    3. Azathioprine initially 1mg/kg/d then 2mg/kg/d - response within 4 months; follow WBC, HCT; maximum 4mg/kg/day
    4. Cyclophosphamide 2mg/kg/d po (maximum 150mg/d) - response within 1-2 months; follow WBC
  7. Dapsone
    1. Dose is 75-100mg/d po
    2. Responses in 4-8 weeks in up to 40% response in refractory patients
    3. Do not use in G6PD deficiency
  8. Thrombopoietins [3,17]
    1. Thrombopoietins are growth factors that stimulate platelet production
    2. PEG-conjugated megakaryocyte growth and development factor stimulates platelet counts in ~80% of chronic ITP but can induce anti-MGDF antibodies
    3. These anti-MGDF antibodies can cause severe, persistent thrombocytopenia
    4. Romiplostim (AMG 531) - novel MGDF stimulating domain linked to immunoglobulin Fc protein
    5. Romiplostim given weekly x 6 as subcutaneous injections in chronic ITP patients lead to target platelet levels in 10 of 16 patients without any major adverse events [17]
    6. Romiplostim given weekly x 24 weeks induced durable (>50K/µL) platelet counts in 38% of splenectomized relapsed ITP patients versus 0% in placebo treated patients [24]
    7. Romiplostim given weekly x 24 weeks induced durable (>50K/µL) platelet counts in 88% of non-splenectomized relapsed ITP patients versus 14% in placebo treated patients [24]
    8. Romiplostim did not induce autoantibodies
  9. Eltrombopag
    1. Orally active TPO receptor agonist
    2. Stimulates platelet counts, even in chronic disease settings
    3. Good activity in thrombocytopenia associated with hepatitis C viral cirrhosis [22]
    4. In adults with chronic refractory ITP with platelet counts <30K/µL, ~80% of patients given 75mg qd achieved platelet counts >50K/µL after 6 weeks versus 11% on placebo [23]
    5. Side effects similar to placebo
  10. Severe Disease with Symptoms
    1. High-dose cyclophosphamide (1.0-1.5gm/m2 surface area) IV monthly - stem cell support
    2. Pulse cyclophosphamide therapy - very toxic with limited efficacy
    3. Peripheral Stem Cell Transplantation has been used in severe cases [15]
    4. Combination chemotherapy such as cyclophosphamide, prednisone, etoposide [10,14]
    5. Plasmapheresis may be beneficial in severe thrombocytopenia
    6. Interferon alpha
    7. Vincristine, Vinblastine sometimes effective - decrease Fc receptors
  11. Colchicine and Protein A immunoabsorption have shown no real efficacy

E. ITP in Pregnancy [1]

  1. Incidence is 0.1-0.2% of pregnancies
  2. Thrombocytopenia in Pregnancy: Differential Diagnosis
    1. HELLP Syndrome
    2. Benign thrombocytopenia of pregnancy (gestational thrombocytopenia)
  3. Treatment
    1. Generally for symptomatic disease or platelets <20K/µL
    2. Glucocorticoids avoided if possible (gestational diabetes, hypertension)
    3. IVIg is currently treatment of choice in pregnant women
  4. Epidural anesthesia is contraindicated for platelets <50-100K/µL
  5. Monitor newborn platelet levels which are often reduced

F. Prognosis in Adults

  1. Benign in most patients; ~10% will remit spontaneously
  2. Overall, ~30% of patients with ITP can be "cured" (in 12 year followup study)
  3. Prednisone gives ~65% initial response, but only ~20% have sustained response off drug
  4. Steroid "sparing" agents generally produced transient, not permanent, remissions
  5. Overall, mortality is about 4% from disease and/or current treatment [14]

G. Treatment of Children with ITP [1]

  1. Decision to treat is controversial
  2. Treatment usually driven by
    1. Concern for intracranial hemorrhage
    2. Restrictions on physical activity
  3. Intracranial Hemorrhage
    1. Nearly always occurs with platelets <20K/µL
    2. Most cases (not related to trauma) with platelets <10K/µL
  4. Most ITP in children resolves within weeks
  5. Treatment Choices
    1. Usually for platelets <20K/µL
    2. IVIg 0.8gm/kg for 1 days OR
    3. Anti-RhD immune globulin 75µg/kg for 2 days
    4. Generally avoid glucocorticoids if possible
    5. If required, prednisone 1-2mg/kg qd up to 4mg/kg qd x 4 days
    6. ~25% of children relapse after treatment
  6. Acute hemorrhage requires urgent treatment
    1. Methylprednisolone 30mg/kg/d to maximum 1gm/d
    2. IVIg 1gm/kg qd x 2-5 days (may be given with platelet infusions)
    3. Splenectomy
    4. Vincristine
    5. Plasmapheresis of limited benefit
    6. E-Aminocaproic Acid for mucosal bleeding
    7. Activated Factor VII
  7. Refractory ITP
    1. Attempt to maintain platelets >30K/µL with IVIg or anti-RhD immune globulin
    2. Low dose prednisone may also be tried
    3. Azathioprine recommended 2-3mg/kg qd (may be used with prednisone)
    4. Vincristine or vinblastine
    5. Pulse cyclophosphamide 1.5gm/m2 at 4 week intervals

References

  1. Cines DB and Blanchette VS. 2002. NEJM. 346(13):995 abstract
  2. Karpatkin S. 1997. Lancet. 349:1531 abstract
  3. Bromberg ME. 2006. NEJM. 355(16):1643 abstract
  4. Godeau B, Chevret S, Varet B, et al. 2002. Lancet. 359(9300):23 abstract
  5. Cooper N and Bussel J. 2006. Br J Haematol. 133:364 abstract
  6. Cheng Y, Wong RSM, Soo YO, et al. 2003. NEJM. 349(9):831 abstract
  7. Stephan F, Cheffi MA, Kaplan C, et al. 2000. Am J Med. 108(7):554 abstract
  8. Arnold DM, Dentali F, Crowther MA, et al. 2007. Ann Intern Med. 146(1):25 abstract
  9. Ratanatharathorn V, Carson E, Reynolds C, et al. 2000. Ann Intern Med. 133(4):275 abstract
  10. Maloisel F, Andres E, Zimmer J, et al. 2004. Am J Med. 116(9):590 abstract
  11. Anti-RhD Immune Globulin. 1996. Med Let. 38(966):6 abstract
  12. Aster RH and Bougie DW. 2007. NEJM. 357(6):614
  13. Amer. Soc. Hematology ITP Practice Guideline Panel. 1997. Ann Intern Med. 126(4):319 abstract
  14. Vesely SK, Perdue JJ, Rizvi MA, et al. 2004. Ann Intern Med. 140(2):112 abstract
  15. Lim SH, Kell J, Al-Sabah A, et al. 1997. Lancet. 349:475 abstract
  16. Law C, Marcaccio M, Tam P, et al. 1997. NEJM. 336(21):1494 abstract
  17. Bussel JB, Kuter DJ, George JN, et al. 2006. NEJM. 355(16):1672 abstract
  18. Saleh MN, Gutheil J, Moore M, et al. 2000. Blood. 96:252a
  19. Louwes H, Lathori OAZ, Vellenga E, de Wolf JTM. 1999. Am J Med. 106(4):430 abstract
  20. Saleh MN, Gutheil J, Moore M, et al. 2000. Semin Oncol. 27(supp12):99 abstract
  21. Von Drygalski A, Curtis BR, Bougie DW, et al. 2007. NEJM. 356(9):904 abstract
  22. McHutchison JG, Dusheiko G, Shiffman ML, et al. 2007. NEJM. 357(22):2227 abstract
  23. Bussel JB, Cheng G, Saleh MN, et al. 2007. NEJM. 357(22):2237 abstract
  24. Kuter DJ, Bussel JB, Lyons RM, et al. 2008. Lancet. 371(9610):395 abstract