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Thrombocytopenic Purpura Immune

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Last Update: January 29, 2019.

Introduction

Immune thrombocytopenic purpura is an autoimmune pathology characterized by a low platelet count and hemorrhagic episodes caused by antiplatelet autoantibodies. The diagnosis is typically made by the exclusion of the known causes of thrombocytopenia.

ITP may affect children and adults of any age and is usually manageable with immunosuppressive therapy.[1][2]

Etiology

ITP can occur with many drugs, infection (e.g., human immunodeficiency virus), malignancy (e.g., adenocarcinoma and lymphoma), and common variable immunodeficiency and autoimmune diseases (e.g., systemic lupus erythematosus, autoimmune hepatitis, and thyroid disease).[3]

Epidemiology

ITP divides into two classifications; acute and chronic. The acute form presents in childhood, affects both sexes and may be preceded by an infection. Most children (85%) have a benign course, do not require treatment and recover spontaneously within three months. The chronic form affects individuals between ages 20-50 years; there is a female/male ratio of 3:1 and there is no infectious disease association. It may present with episodes of bleeding by months or years, during that time the platelet counts are normal. Fewer than 10% of children develop chronic ITP.

Pathophysiology

The spleen is an essential site of autoantibody production. Sequestration of anti-platelet IgG antibodies takes place in the spleen's red pulp, where sensitized platelet removal occurs by phagocytosis. Research showed that radiolabeled-IgG sensitized platelets removal occurs in few hours compared with a normal platelet half-life of 8-9 days.[2]

Neonatal alloimmune thrombocytopenia may occur in pregnant women who are negative for the platelet antigen PL a1 but were sensitized in prior pregnancies by infants who were PL a1 positive or by blood transfusion. The condition has also involved to other platelet antigens.[4]

In drug-induced ITP, the drug absorbs on the platelet cell membrane. The immune system makes antibodies to the target drug-platelet complex, which results in the removal of the sensitized platelet by phagocytes residing in spleen and liver. The activation of the complement system by the classical pathway is another effector mechanism of platelet cell damage (thrombocytopenia).[5] 

Many other platelet antigens are a target of autoantibodies, including GPIIb/IIIA and GP V (after chickenpox).

Histopathology

ITP histopathology will reveal a finding of an increased number of megakaryocytes in the bone marrow.[6] This finding suggests that the thrombocytopenia is secondary to increased platelet destruction rather than decreased production.

History and Physical

There may be a history of drugs use, a viral infection or immunization. The acute ITP can be characterized by:

  • Generalized purpura in a previously healthy child or less commonly in an adult
  • Bruises following minor trauma
  • The presence of oral hemorrhagic bullae
  • Epistaxis
  • Gastrointestinal bleeding
  • Conjunctival hemorrhage   
  • Hematuria 

The chronic ITP may be characterized by:

  • Insidious onset
  • More common in females
  • Scattered petechiae
  • Epistasis and menorrhagia
  • Episodes of bleeding separated by long period
  • Occasionally these clinical findings can be due to HIV-related illness

Evaluation

The laboratory test will show:

  • Low platelet count, usually <40x10^9/L for over three months.
  • Blood film: Large platelets and tiny platelet fragments.
  • Bone marrow examination: Increased number of megakaryocytes.
  • Platelet Coomb's test: Detects anti-platelet antibodies fixed on the patient's platelets.
  • Indirect test: Uses a pool of normal donor platelets to detect free serum antibodies against platelets, usually anti-glycoprotein IIb/IIIa antibodies. 

Testing for systemic lupus erythematosus:

  • Antinuclear antibodies (ANA), can be performed using indirect immunofluorescence. Most cases of SLE show positive ANA results. 
  • Testing for auto-antibodies: This includes testing for anti-double-stranded DNA (anti-dsDNA), anti-Smith, ENA, anti-cardiolipin, and anti-beta2 GP-I antibodies. A high serum level of anti-dsDNA and anti-Smith antibodies suggests SLE.   
  • Additionally, detection of C3 and C4, immunoglobulins (IgM, IgG, and IgA), serum protein electrophoresis, and cryoglobulins (if Raynaud's is present) may be performed.
  • Biopsies (lupus band test): Shows deposits of IgG and C3/C4 along the dermo-epidermal junction in a lumpy-bumpy distribution. Renal biopsy may be helpful. It shows deposition of immunocomplexes in the glomeruli. 

Treatment / Management

The management of ITP involves the following[7][1][8]:

  • Aim to bring the platelet count to be normal.
  • Indication for active therapy is only when there is acute bleeding.
  • The vast majority of children recover spontaneously without sequelae.
  • Adults require treatment if platelet count is below 40x10^9/L.
  • Patients (children and adults) with active bleeding require corticosteroids to stop further destruction of platelets (about 60% of patients respond well within two weeks).
  • Patients who do not respond adequately and have active bleeding after a month of being treated with corticosteroids may need splenectomy, after using intravenous immunoglobulins to raise the platelet count.
  • One may use cytotoxic drugs in adults if the previous management fails.
  • Reserve plasmapheresis for cases of fulminant ITP.
  • Neonatal thrombocytopenia is treatable with intravenous immunoglobulin which raises the platelet count. 
  • Platelets increase after three months in untreated ITP neonates, due to the catabolism of maternal anti-platelet antibody that were transferred during birth.

Differential Diagnosis

One should consider the following diseases in the differential diagnosis of ITP:

  • Thrombotic thrombocytopenic purpura (TTP)
  • Disseminated intravascular coagulation (DIC)
  • Autoimmune disorders (e.g., SLE), infections (e.g., HIV)
  • Use of drugs (e.g., quinine and heparin)
  • Inherited bone marrow failures (e.g., congenital amegakaryocytic thrombocytopenia)[1][9][10]

These disorders may be ruled out by the history, clinical presentation (signs and symptoms), histology and laboratory investigations.

Prognosis

Prognosis is good for acute ITP since most patients make a spontaneous recovery. Patients with chronic ITP almost always require treatment and relapse commonly occurs. Complete response to the first-line steroid can occur about 20% of the patients, and about 60% have a partial response.

Complications

The most severe complication of ITP is hemorrhage, especially bleeding into the brain that may prove fatal. 

Deterrence and Patient Education

Children should receive counseling, regarding the need for rapid communication of any manifestation of bleeding to the parents of the affected child or other members of the family. The general practitioner can assess the bleeding and make recommendations about the management, and also referral to a specialist (hematologist). Adults should remain compliant with medications. 

Pearls and Other Issues

  • The definition of thrombocytopenia is when the blood platelet count is < 150x10^9/L. It may not be symptomatic until the platelet count falls below 10x10^9/L.  
  • ITP can be idiopathic, although it is often autoimmune-related.   
  • ITP can be secondary to SLE, HIV, and drugs (e.g., quinine).   
  • The antibody involved is not temperature dependent and always directed against platelet-specific antigens.    
  • Corticosteroids work by decreasing phagocytosis of antibody-coated platelet by phagocytes in both spleen and liver.   
  • Splenectomy removes the sites of autoantibody production and phagocytosis and is successful in most patients.    
  • In refractory patients, one can successfully use intravenous immunoglobulins. The IgG blocks Fc-receptors on macrophages and reduces platelet binding to autoantibodies.

Enhancing Healthcare Team Outcomes

An interdisciplinary team should manage patient with ITP. The family physician may monitor subjects with a less severe disease if it does not involve important organ systems. The family physician should refer patients with complications to a hematologist, which can coordinate closely with the patient's family physician to maximize management and progress.  

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Matzdorff A, Wörmann B. [Diagnosis and Therapy of Immune thrombocytopenia]. Dtsch. Med. Wochenschr. 2018 Aug;143(15):1076-1081. [PubMed: 30060276]
2.
Karakurt N, Uslu İ, Albayrak C, Tomak L, Ozyazici E, Albayrak D, Aygun C. Neonates born to mothers with immune thrombocytopenia: 11 years experience of a single academic center. Blood Coagul. Fibrinolysis. 2018 Sep;29(6):546-550. [PubMed: 30036278]
3.
Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG. Emerging Concepts in Immune Thrombocytopenia. Front Immunol. 2018;9:880. [PMC free article: PMC5937051] [PubMed: 29760702]
4.
Poles A, Lucas G, Green F, Walser P, Davey S, Ridgwell K, Wylie P. Neonatal alloimmune thrombocytopenia due to a new alloantigen Bl(a) defined by an Asp458Gly substitution in GPIIIa. Transfusion. 2019 Jan;59(1):396-404. [PubMed: 30488955]
5.
Alzahrani M, Alrumaih I, Alhamad F, Abdel Warith A. Rapid onset severe thrombocytopenia following reexposure to piperacillin-tazobactam: report of two cases and review of the literature. Platelets. 2018 Sep;29(6):628-631. [PubMed: 29863943]
6.
Vrbensky JR, Nazy I, Toltl LJ, Ross C, Ivetic N, Smith JW, Kelton JG, Arnold DM. Megakaryocyte apoptosis in immune thrombocytopenia. Platelets. 2018 Nov;29(7):729-732. [PubMed: 29787328]
7.
Apte S, Navarro-Puerto J, Damodar S, Ramanan V, John J, Kato G, Ross C, Shah C, Torres M, Fu C', Rucker K, Pinciaro P, Barrera G, Aragonés ME, Ayguasanosa J. Safety and efficacy of intravenous immunoglobulin (Flebogamma® 10% DIF) in patients with immune thrombocytopenic purpura. Immunotherapy. 2018 Nov 30; [PubMed: 30499734]
8.
George JN. Sequence of treatments for adults with primary immune thrombocytopenia. Am. J. Hematol. 2012 May;87 Suppl 1:S12-5. [PubMed: 22389032]
9.
Lee AC. Isolated thrombocytopenia in childhood: what if it is not immune thrombocytopenia? Singapore Med J. 2018 Jul;59(7):390-393. [PMC free article: PMC6056371] [PubMed: 30109354]
10.
Sundin M, Marits P, Nierkens S, Kolios AGA, Nilsson J. "Immune" Thrombocytopenia as Key Feature of a Novel ADA2 Deficiency Variant: Implication on Differential Diagnostics of ITP in Children. J. Pediatr. Hematol. Oncol. 2018 Apr 03; [PubMed: 29620681]
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Bookshelf ID: NBK537240PMID: 30725925

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