Thrombocytopenic Purpura Immune

Article Author:
Angel Justiz Vaillant
Article Editor:
Nagendra Gupta
Updated:
6/18/2019 7:08:12 PM
PubMed Link:
Thrombocytopenic Purpura Immune

Introduction

Immune thrombocytopenic purpura (ITP) is an autoimmune pathology characterized by a low platelet count, purpura and hemorrhagic episodes caused by antiplatelet autoantibodies. The diagnosis is typically made by the exclusion of the known causes of thrombocytopenia. IgG autoantibodies sensitize the circulating platelets. It leads to accelerated removal of these cells by antigen-presenting cells (macrophages) of the spleen, and sometimes the liver or other components of the monocyte-macrophage system. Bone marrow compensates the platelet destruction by increasing platelet production. ITP most often occurs in healthy children and young adults within a few weeks following a viral infection. ITP is usually manageable with immunosuppressive therapy.[1][2] An identical form of autoimmune thrombocytopenia can also be associated with chronic lymphocytic leukemia, lymphomas, SLE, infectious mononucleosis and other bacterial and viral infections. Certain drugs can also cause immune thrombocytopenia indistinguishable from ITP. Most children have spontaneous remission within a few weeks or months, and splenectomy is rarely needed. However young adults rarely have spontaneous remissions necessitating splenectomy within the first few months after diagnosis.

Etiology

ITP can occur with infections (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] Somehow in these diseases, there is a formation of anti-platelet antibodies leading to platelet destruction. Drugs may also cause autoimmune thrombocytopenia, for example, acetazolamide, aspirin, aminosalicylic acid, carbamazepine, cephalothin, digitoxin, phenytoin, meprobamate, methyldopa, quinidine, rifampin, and sulfamethazine. 

Epidemiology

ITP can be divided into two classifications; acute and chronic. The acute form presents in childhood, affects both sexes and may be prefaced by a viral infection. Most children (85%) have a benign course and do not require treatment. They can spontaneously recover within three months. The chronic form affects individuals between ages 20-50 years; there is a female/male ratio of 3:1 and It is usually not preceded by a viral infection. It may present with episodes of bleeding by months or years, during that time the platelet counts are close to normal. Fewer than 10% of children develop chronic ITP.

HIV-associated disease is now the most common cause of thrombocytopenic purpura, especially in males between 20 and 50 years of age. Testing for HIV antibodies is a critical part of the assessment of ITP.[4][5]

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 other platelet antigens.[6]

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).[7] 

Childhood immune thrombocytopenic purpura often occurs within a few weeks following a viral infection, suggesting a possible cross-immunization between viral and platelet antigens, the absorption of immune complexes, or a hapten mechanism.

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

Histopathology

Histopathology of immune thrombocytopenic purpura can often reveal the finding of increased production of megakaryocytes in the bone marrow.[8] This finding suggests that the thrombocytopenia is secondary to increased platelet destruction rather than decreased platelet formation. Harrington and coworkers first showed in 1951 that the plasma from a patient with immune thrombocytopenic purpura caused thrombocytopenia when transfused into a healthy subject.

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, and hematuria. More commonly the illness is gradual in onset but chronic in the course.

The chronic ITP may be characterized by insidious onset or suddenly becomes acute. It is seen more common in females and presents with scattered petechiae, epistasis and menorrhagia, episodes of bleeding separated by a long period and occasionally these clinical findings can be due to HIV-related illness.

Evaluation

The laboratory tests will show:

  • Low platelet count, usually <40x10^9/L for over three months.
  • Blood film: It shows large platelets and tiny platelet fragments.
  • Bone marrow examination: It shows an 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. 
  • Various other tests can be used to detect anti-platelet antibodies including lymphocyte activation by autologous platelets, lymphocyte activation by platelet-antibody immune complexes, phagocytosis of platelet-associated IgG by competitive binding assays, radiolabeled Coombs antiglobulin test, fluorescein-labeled Coombs antiglobulin, and ELISA. 

Testing for systemic lupus erythematosus (presenting with ITP):

  • 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[9][1][10]

  • 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. In severe cases, the treatment of choice is intravenous immunoglobulin (IV IgG). A 5-day course of 400 mg/kg/d is given. Responses occur in more than 70% in 1-4 days, but only for a short period many patients respond, and repeated courses may be necessary.  
  • 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. Therefore, splenectomy is the treatment of choice for adult patients with ITP who have persistent symptomatic thrombocytopenia.
  • In adults patients with ITP, the corticosteroid preferred is prednisone 1-2 mg/kg/d.  
  • It reserves 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 was transferred during birth.  
  • Vincristine seems to be a valuable drug in adult patients that do not respond to splenectomy.
  • Zidovudine is effective in raising platelet counts in individuals with HIV-associated immune thrombocytopenic purpura.

Differential Diagnosis

One should consider thrombocytopenias due to increased platelet destruction and those due to platelet production.[1][11][12]

Thrombocytopenias due to increased platelet destruction include:

Immune thrombocytopenia

  • Idiopathic thrombocytopenic purpura
  • Secondary autoimmune thrombocytopenias
  • Drug-induced immune thrombocytopenias
  • Posttransfusion purpura
  • Neonatal immune thrombocytopenias
  • Thrombocytopenias due to use of factor VIII concentrate
  • HIV infection

Consumptive thrombocytopenias

  • Thrombotic thrombocytopenic purpura 
  • Disseminated intravascular coagulation (DIC)
  • Hemolytic-uremic syndrome
  • Vasculitis
  • Sepsis 

Hypersplenism

Thrombocytopenias due to decreased platelet production

  • Bone marrow suppression by drugs, alcohol, toxins, and infections 
  • Aplastic anemia 
  • Leukemias and other bone marrow cancers   
  • Megaloblastic anemia   
  • Refractory anemias, preleukemia, and hematopoietic dysplasia 

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. Vincristine is used in adult patients that do not respond to splenectomy.

Complications

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

Deterrence and Patient Education

The general practitioner can assess the bleeding and make recommendations about the management, and also a 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 the patient with ITP. The clinician and nursing staff may monitor subjects with a less severe disease if it does not involve important organ systems. The clinician should refer patients with complications to a hematologist, which can coordinate closely with the patient's clinician to maximize management and progress. The pharmacist should be involved in the coordination of drug therapy and monitoring for complications.


References

[1] Matzdorff A,Wörmann B, [Diagnosis and Therapy of Immune thrombocytopenia]. Deutsche medizinische Wochenschrift (1946). 2018 Aug     [PubMed PMID: 30060276]
[2] Swinkels M,Rijkers M,Voorberg J,Vidarsson G,Leebeek FWG,Jansen AJG, Emerging Concepts in Immune Thrombocytopenia. Frontiers in immunology. 2018     [PubMed PMID: 29760702]
[3] 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 coagulation     [PubMed PMID: 30036278]
[4] Ponzetto A,Figura N,Fiorini G, Immune thrombocytopenic purpura and infections. Internal and emergency medicine. 2018 Oct;     [PubMed PMID: 30030700]
[5] Okazaki M,Nakamura M,Imai A,Asagiri T,Takeuchi S, Sequential occurrence of Graves' disease and immune thrombocytopenic purpura as manifestations of immune reconstitution inflammatory syndrome in an HIV-infected patient. International journal of STD     [PubMed PMID: 29361886]
[6] 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. 2018 Nov 29     [PubMed PMID: 30488955]
[7] 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     [PubMed PMID: 29863943]
[8] Vrbensky JR,Nazy I,Toltl LJ,Ross C,Ivetic N,Smith JW,Kelton JG,Arnold DM, Megakaryocyte apoptosis in immune thrombocytopenia. Platelets. 2018 Nov     [PubMed PMID: 29787328]
[9] 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{sup}®{/sup} 10% DIF) in patients with immune thrombocytopenic purpura. Immunotherapy. 2018 Nov 30     [PubMed PMID: 30499734]
[10] George JN, Sequence of treatments for adults with primary immune thrombocytopenia. American journal of hematology. 2012 May     [PubMed PMID: 22389032]
[11] Lee AC, Isolated thrombocytopenia in childhood: what if it is not immune thrombocytopenia? Singapore medical journal. 2018 Jul     [PubMed PMID: 30109354]
[12] Sundin M,Marits P,Nierkens S,Kolios AGA,Nilsson J,     [PubMed PMID: 29620681]