Immune Thrombocytopenia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

Idiopathic Thrombocytopenia (ITP) was first described by a German poet Paul Werlhof, in 1735. He referred to classical signs of ITP as mucosal bleeding, black and purple spots on the patient's arm, due to this description, ITP is called Werlhof's disease.In 1881, an Italian pathologist, Guilio Bizzozero was the first to discover the role of platelet in hemostasis. In 1889, George Hayem proved the association between purpura and the development of thrombocytopenia by physically counting the patient's platelet. In 1916, a medical student Paul Kasnelson developed the idea of excessive destruction of platelets by spleen. Soon he persuaded his professor Schloffer to splectomize a patient with ITP, thereafter they found outstanding increase of platelet count following splenectomy. In 1951, Harrington experiment in Missouri proved the hypothesis that a humoral factor causes platelet destruction. He exchanged whole blood of himself and a patient with chronic purpura who had the same blood group. after the exchange, the patient platelet count remained unchanged but his platelet count which was normal prior to exchange dropped to 10 x 109 /L . In 1951, an American hematologist, Maxwell Wintrobe, showed immunosuppressive therapy with corticosteroids. In 1981, Paul Imbach in Switzerland, realized the role of Fc receptors on splenic macrophages led to first successful use of intravascular immunoglobulin. In 2009, International working group (IWG) recommended standard terminology for ITP. The term " purpura" was removed from immune thrombocytopenia as many patients don't have cutaneous bleeding but ITP as shorthand for immune thrombocytopenia was redefined by IWG.

• Idiopathic Thrombocytopenia (ITP) was first described by a German poet Paul Werlhof, in 1735. He referred to classical signs of ITP as mucosal bleeding, black and purple spots on the patient’s arm, due to this description, ITP is called Werlhof’s disease.
• In 1881, an Italian pathologist, Guilio Bizzozero was the first to discover the role of platelet in hemostasis.
• In 1889, George Hayem proved the association between purpura and the development of thrombocytopenia by physically counting the patient’s platelet.
• In 1916, a medical student Paul Kasnelson developed the idea of excessive destruction of platelets by spleen. Soon he persuaded his professor Schloffer to splectomize a patient with ITP, thereafter they found outstanding increase of platelet count following splenectomy.
• In 1951, Harrington experiment in Missouri proved the hypothesis that a humoral factor causes platelet destruction. He exchanged whole blood of himself and a patient with chronic purpura who had the same blood group. after the exchange, the patient platelet count remained unchanged but his platelet count which was normal prior to exchange dropped to 10 x 10⁹ /L .
• in 1951, an American hematologist, Maxwell Wintrobe, showed immunosuppressive therapy with corticosteroids.
• In 1981, Paul Imbach in Switzerland, realized the role of Fc receptors on splenic macrophages led to first successful use of intravascular immunoglobulin. ^[1]
• In 2009, International working group (IWG) recommended standard terminology for ITP. The term ” purpura” was removed from immune thrombocytopenia as many patients don’t have cutaneous bleeding but ITP as shorthand for immune thrombocytopenia was redefined by IWG. ^[2]

The following are a few famous cases of [disease name]:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

There is no established system for the classification of [disease name].

OR

Immune thrombocytopenia may be classified according to associated conditions into groups: primary or secondary.

OR

[Disease name] may be classified into [large number > 6] subtypes based on [classification method 1], [classification method 2], and [classification method 3]. [Disease name] may be classified into several subtypes based on [classification method 1], [classification method 2], and [classification method 3].

OR

Based on the duration of symptoms,Immune thrombocytopenia may be classified as either acute, persistent and chronic.

OR

If the staging system involves specific and characteristic findings and features: According to the [staging system + reference], there are [number] stages of [malignancy name] based on the [finding1], [finding2], and [finding3]. Each stage is assigned a [letter/number1] and a [letter/number2] that designate the [feature1] and [feature2].

OR

The staging of [malignancy name] is based on the [staging system].

OR

There is no established system for the staging of [malignancy name].

Immune thrombocytopenia may be classified according to disease phase into three groups:

• Newly diagnosed ITP (0-3 months)
• Persistent ITP (3-12 moths)
• Chronic ITP ( > 12 months)

Immune Thrombocytopenia may be classified into two subtypes based on associated disease:

• Primary ( isolated thrombocytopenia < 100 <math>\times</math><math>10^{9}</math>/L in the absence of co-existing disorder)
• Secondary ( associated to another disease such as ITP associated with common variable immune deficiency (CVID). ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that immune thrombocytopenia is caused by either destruction of platelet by macrophages in spleen, or antibody mediated underproduction. Antibodies are mostly against platelet surface glycoproteins. There are also some genetic predisposition with some gene mutations such as MUC3A, mTOR signaling pathway, Fc<math>\gamma</math>R polymorphism and so on. There are some other conditions which ITP has correlation with such as, SLE, sjogren disease, CVID, AIDS and etc.

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[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

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Immune thrombocytopenia arises from platelet decrease, which are hematopoietic cells that are normally involved in hemostasis.

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The progression to [disease name] usually involves the [molecular pathway].

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The pathophysiology of [disease/malignancy] depends on the histological subtype.

• Immune thrombocytopenia arises from platelets, which are blood cells that are normally involved in hemostasis.
• It is understood that Immune thrombocytopenia is caused by destruction of one’s own platelets and megakaryocytes.
• The progression to immune thrombocytopenia usually involves the genetic predisposition, immune dysregulation and environmental factors which lead to autoimmunity.
• Molecular mimicry between foreign antigens and autologous platelet antigens leads to activation of cross-reactive B and T cell, starting autoimmune response.^[1]
• In immune thrombocytopenia , the balance between platelet production and destruction is impaired. Therefore, platelet destruction is accelerated by macrophages in spleen, and moderately impaired platelet production by anti platelet antibody or cytotoxic T-cells.
• Anti platelet antibodies ( anti platelet surface glycoproteins) includes:
  • anti GP<math>\Pi</math>b/<math>\Pi\Iota</math>a antibody
  • anti GP<math>\Iota</math>b/<math>\Iota</math>X antibody

• Abnormal T-cells:
  • Increase Th17 and IL-17 level.
  • Increase oligoclonal T-cells.
  • Presence of cytotoxic T-cells again autologous platelets.^[2]

[Disease name] is transmitted in [mode of genetic transmission] pattern.

OR

Genes involved in the pathogenesis of immune thrombocytopenia include:

• Transmembrane mucin, MUC3A. (missense mutation)
• Secretory mucin, MUC5B. ( missense mutation)
• Secretory mucin, MUC6. (missense mutation) ^[3]
• Fc<math>\gamma</math>R polymorphism.^[4]
• IKZF1 haploinsufficiency ( hematopoietic zinc finger transcription factor which directly binds to DNA. presents in familial immune thrombocytopenia.)^[5]
• HIF1 signaling pathway.
• mTOR signaling pathway.
• PI3K/Akt signaling pathway.^[6]

OR

The development of [disease name] is the result of multiple genetic mutations such as:

• [Mutation 1]
• [Mutation 2]
• [Mutation 3]

Conditions associated with immune thrombocytopenia include:

• SLE
• Primary Sjogren Syndrome
• AIDS^[7]
• CVID ^[8]
• autoimmune thrombocytopenia (Evans syndrome)
• Vaccination side effect
• Bone marrow transplant associated side effect
• Lymphoproliferative disorder ^[9]

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

Disease name] may be caused by [cause1], [cause2], or [cause3].

OR

Immune thrombocytopenia has been classified to two groups; Primary or Secondary. Common causes of secondary ITP include SLE, antiphospholipid syndrome, infectious disease and thyroid disease. There are also some less common cause which include Evans syndrome and lymphoproliferative disease.

OR

The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

OR

The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

• Immune thrombocytopenia include primary and secondary.
• The cause of Primary immune thrombocytopenia is unknown. It occurs by autoantibodies binding to platelet surface then captured and destructed by macrophages in spleen and liver.

Common causes of secondary immune thrombocytopenia may include:

• systemic lupus erythematous
• antiphospholipid syndrome
• Thyroid disease ( hypothyroidism, hyperthyroidism, immune Thyroid disease)
• Drug induced thrombocytopenia ( such as Heparin induced thrombocytopenia)
• Infectious disease (HIV, HCV, Helicobacter pylori )

Less common causes of [disease name] include:

• Evans syndrome (immune anemia , immune thrombocytopenia and immune neutropenia)
• Posttransfusion purpura ( In caucasian woman within 7 days of blood product transfusion due to developing antibody against HPA1b epitope.)
• Lymphoproliferative disease ( CLL (difficult to distinguish from marrow infiltration and splenomegaly), Large granular lymphocytic leukemia (clonal sequestration of megakaryocytic.) and Hodgkin lymphoma.)^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [differential dx1], [differential dx2], and [differential dx3].

OR

As [disease name] manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. [Subtype name 1] must be differentiated from other diseases that cause [clinical feature 1], such as [differential dx1] and [differential dx2]. In contrast, [subtype name 2] must be differentiated from other diseases that cause [clinical feature 2], such as [differential dx3] and [differential dx4].

On the basis [symptom 1], [symptom 2], and [symptom 3], [disease name] must be differentiated from [disease 1], [disease 2], [disease 3], [disease 4], [disease 5], and [disease 6].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

The incidence of Immune thrombocytopenia is approximately 1.6- 3.9 per 100,000 adult individuals worldwide and 1.1- 5.8 per 100,000 individuals among children. Patients of all age groups may develop Immune thrombocytopenia. The Prevalence of chronic Immune thrombocytopenia increases with age. Black and non-hispanic individuals are less likely to develop ITP.

• The incidence of Immune thrombocytopenia is approximately 1.6- 3.9 per 100,000 adult individuals worldwide and 1.1- 5.8 per 100,000 individuals among children. The overall incidence rate was higher in women (4.4 per 100,000 person year) than men ( 3.4 per 100,000 person year).Women are more commonly affected by Immune thrombocytopenia than men.
• In year 2014, the incidence of Immune thrombocytopenia among French people is approximately 2.9/ 100,000 person years with higher incidence among women. The incidence has bimodal distribution with first peak among male children among 1-5 years and men over 75 years of age. However the distribution for women is constant.^{[1] [2]}

• The prevalence of chronic immune thrombocytopenia ( lasting longer than 12 months) is approximately 9.5-11.2 per 100,000 individuals in the United States.
• In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
• The prevalence of [disease/malignancy] is estimated to be [number] cases annually.

• In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate/mortality rate of [number range]%.
• The case-fatality rate/mortality rate of [disease name] is approximately [number range].

• Patients of all age groups may develop Immune thrombocytopenia.
• The Prevalence of chronic Immune thrombocytopenia increases with age; the childhood ITP remits spontaneously.
• Immune thrombocytopenia commonly affects individuals younger than 5 years of age.
• [Chronic disease name] is usually first diagnosed among [age group].
• [Acute disease name] commonly affects [age group].

• There is no racial predilection to [disease name].
• Black and non-hispanic individuals are less likely to develop ITP, thereafter, the providers should suspect alternative diagnosis or secondary ITP in these races.^[3]

• [Disease name] affects men and women equally.
• Women are more commonly affected by Immune thrombocytopenia than men.

• The majority of Immune thrombocytopenia cases are reported in January and the minority in summer in all age group probably due to viral infection..^{[1] [2]}

• [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of ITP is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of ITP include environmental, genetic and viral. Genetic risk factors includes mutations in single nucleotide polymorphism and variety of interleukins. The most common viral and environmental risk factors include infection with HIV and Helicobacter pylori.

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Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

• Common risk factors in the development of Immune thrombocytopenia may be environmental, genetic, and viral.
• Genetic risk factors include:
  • • association between ITP and single nucleotide polymorphism (SNP)
    • Polymorphism in genes of Interleukin-1, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-<math>\alpha</math>, TNF-<math>\beta</math> and INF-<math>\gamma</math>. ^[1]
• Environmental and viral risk factors include exposure with HIV, Helicobacter pylori, HCV, CMV, and EBV.
• Common non-modifiable risk factors in the development of Immune thrombocytopenia in children include:
  • older age
  • less thrombocytopenia at the initial diagnosis
  • gradual onset of symptoms
  • lack of platelet count recovery at four weeks
  • lack of proceeding infection or vaccination as a trigger.^[2]

• Less common risk factors in the development of [disease name] include:
  • [Risk factor 1]
  • [Risk factor 2]
  • [Risk factor 3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with:

• [Condition 1]
• [Condition 2]
• [Condition 3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Barkhordarian, M.D.[2]

The symptoms of chronic immune thrombocytopenia usually develop in the any decade of life, many patients are asymptomatic however about two third of patients start with symptoms such as mucocutaneous , gastrointestinal and genitourinary bleeding. Prognosis is generally excellent/good/poor, and the 5-10-year mortality rate of patients with ITP is approximately 22-34% respectfully.

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

• The symptoms of chronic immune thrombocytopenia usually develop in the any decade of life, many patients are asymptomatic however about two third of patients start with symptoms such as mucocutaneous , gastrointestinal and genitourinary bleeding.^[1][2]
• The symptoms of (disease name) typically develop ___ years after exposure to ___.
• If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

• Common complications of immune thrombocytopenia include:
  • Thromboembolic risk ( the risk of thromboembolism, in ITP is twice higher than general population.)
  • Infection ( due to splenectomy or immunosuppressive medications)
  • [Complication 3]

• Prognosis is generally excellent/good/poor, and the 5-10-year mortality rate of patients with ITP is approximately 22-34% respectfully.^[3]
• Depending on the extent of the [tumor/disease progression] at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor/good/excellent.
• The presence of [characteristic of disease] is associated with a particularly [good/poor] prognosis among patients with [disease/malignancy].
• [Subtype of disease/malignancy] is associated with the most favorable prognosis.
• The prognosis varies with the [characteristic] of tumor; [subtype of disease/malignancy] have the most favorable prognosis.

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