Idiopathic thrombocytopenic purpura

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Immune thrombocytopenia(ITP) is autoimmune condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic)^[1]. The major of cases appear to be related to antibodies against platelets. Historically, it is has also been known as immune thrombocytopenic purpura or idiopathic thrombocytopenia purpura^[2] Although most cases are asymptomatic, very low platelet counts can lead to a bleeding diathesis and purpura.

• Primary ITP – immune thrombocytopenia as a result for autoimmune antibodies and not related to another identifiable cause/condition of thrombocytopenia^[3]. Based on international consensus, it is preferred to avoid the term “idiopathic” and use the term immune to denote this is an antibody-mediated cause^[1]. It is also preferred to avoid the use of purpura as the vast majority of cases occur without bleeding/bruising symptoms^[1].
• Secondary ITP – immune thrombocytopenia contributed or induced by an associated conditions, such as systemic lupus erythematosus (SLE), autoimmune thrombocytopenia (Evans syndrome), Human Immunodeficiency Virus (HIV), or drug/treatment^[3].

Conditions that cause secondary ITP[3]

Systemic lupus erythematosus (SLE),

autoimmune thrombocytopenia (Evans syndrome)

Human immunodeficiency virus (HIV)

Hepatitis C virus (HCV)

Helicobacter Pylori

Varicella Zoster

Antiphospholipid Syndrome

Drug-induced immune thrombocytopenia

In addition to the above classification, ITP can be further characterized by the both the timing of diagnosis and degree of severity^[1]:

• Timing criteria:
  • Newly diagnosed – Applies to cases within 3 months since diagnosis.
  • Persistent – Applies to cases three to 12 months since diagnosis.
  • Chronic – Applies to cases more than 12 months since diagnosis.

• Severity:
  • Severe ITP – Denotes the presence of any bleeding symptoms which mandate treatment or bleeding which requires additional treatment or change in current treatment (e.g. change in dose) in patient who has previously been stabilized.

The exact mechanism of ITP is still not completely understood. However, platelet destruction by antibodies and T-cells as well as impaired megakaryocyte (MK) function seem to play an important role ^[4].

The antibody mediated destruction of platelets is through the loss of immunological tolerance to the cell surface receptors on platelets. The production of autoantibodies, mainly IgG, target cell surface receptors, mainly GPIIbIIIa and GP Ib/IX, on platelets. These cell surface receptors are also expressed by megakaryocytes which are also impaired in patients with ITP. Targeting by autoantibodies leads to increased phagocytosis of platelets by macrophages in the spleen. The phagocytosis and destruction of platelets leads to a potential increase in cell surface targets by the immune system ^{[5] [6]}. This leads to an impairment in thrombopoiesis and a decrease in thrombocyte production. The role of autoantibody production explains the potential benefit of using rituximab, a monoclonal antibody against CD20 antigen on B-cells, in patients who do not respond to initial therapy. However, only 60% of patients with ITP have detectable levels of autoantibodies, suggesting other pathways play an important role in presentation of patients ^{[5] [7]} .

Patients with primary ITP tend to have increased levels of IFN-γ and IL-2 with decreased numbers of peripheral Th2+ and Tregs (T-regulatory cells)^{[5] [8]}. The specific T-regulatory cells decreased in ITP include [CD8+ Tregs; CD4+ Tregs; CD4+CD25+FoxP3^[9]. In addition to T-regulatory cells, B-regulatory cells (Bregs) are also shown to be decreased in number and function particularly in refractory ITP patients^{[9] [10]}.

Increases in Th17 and Th22, which contribute to proinflammatory responses, have been also been identified in patients with ITP. (30015642, 25621490, 19734430) The effect that ITP has on cytokines and T cells may lead to further increases in B cell activation^{[4] [11]}. Additional toxicity toward megakaryocytes may involve cytotoxic T cells in a study showing an increased number of Tcell expressed in the bone marrow of patients with ITP ^{[5] [12]}.

The underlying pathophysiology of ITP involves both

(1) Decreased production of platelets.

(2) Increased destruction of platelets.

Regarding the latter mechanism, this is thought to be due to B cells producing IgG, which binds to GPIIb/IIIa (fibrinogen receptor) on the platelet surface. The reason for the development of anti-GPIIb/IIIa antibodies is not very clear but is thought to related to immune or infectious phenomena. Immune etiologies involves loss of self-tolerance, whereby the body produces antibodies against its own cells. Immunosuppressive hematological conditions can precipitate this. These include CLL, APLS, SLE, and Evan’s syndrome. Infectious agents that can lead to development of anti-platelet antibodies include HIV, hepatitis C and H. pylori. Molecular mimicry between infectious agents and platelets leads to the development of the antibodies. It is important to evaluate for these etiologies in patients with suspected ITP.

Lack of data collection outside of Europe prevents accurate estimates of incidence worldwide. Over 80% of adult ITP have primary ITP while the other 20% have secondary ITP ^[4]. The age-adjusted estimated prevalence of ITP in the United States is around 9.5/100,000 persons ^[13]. Adult incidence in ITP is 3.3/100,000-person years and in children incidence estimates vary from 2.4-5.3/100,000-person years ^[14]. A nationwide study in Korea involving 10,814 patients showed an incidence in female children under 15 to be 3.8 per 100,000-person years and 1.3 per 100,000-person years in males ^[15].

• Gender – Studies have shown that adult women have a higher risk than adult men aged 30-60. ^{[16] [17]}

• Infection – Recent specific viral or bacterial infections may increase risk in pediatric patients. ^{[18] [19] [20]}

• Genetics – Some research has shown a link between genetic polymorphisms in cytokines and chemokines in the development of ITP. ^{[3] [21] [22] [23]}

Essential components to diagnosis of ITP^[24]:

• Physician examination
  • Evidence of thrombocytopenia (i.e. Signs of bleeding, petechiae, bruising)

• Complete Blood Count (CBC)
  • Results for this test should be normal and used to rule out other etiologies of thrombocytopenia
• Peripheral blood smear
  • Allows for the evaluation of platelet size and shape (morphology) which is important to rule out other etiologies of thrombocytopenia.

To rule out the causes of thrombocytopenia the following tests may be beneficial for specific patients:

• Bone morrow examination
  • Recommended for patients who have failed first-line therapies or present with systemic symptoms, in children with newly diagnosed ITP with additional abnormalities from blood work, patients >60 years of age, and in a cases who are candidates for splenectomy.
• Helicobacter Pylori testing
• Hepatitis C Virus and Human Immunodeficiency Virus testing
• Baseline immunoglobulin testing
• Direct antiglobulin testing (DAT)
• Blood group testing Rh(D)

Remission occurs spontaneously in up to 10% of adults with ITP in the first 6 months with increasing platelet counts documented over years ^{[25] [26] [16]}. The rate of successful first-line remission varies but may be as high as 60% ^[16]. Over 12% of adult patients may require a splenectomy as a treatment option due to failing first line therapy. ^[16].

A retrospective cohort in the US from 2008-2012 showed 57% of adults with ITP experienced >1 bleeding event with intracranial hemorrhage making up less than 1% of events. The most common bleeding that occurred during these events were gastrointestinal hemorrhage, hematuria, ecchymosis, and epistaxis

Acute ITP resolves in over 80% of children regardless of treatment approach. Eight of ten of the remaining children who have chronic ITP and undergo a splenectomy will be in remission with few having a relapse^[27]. However, one study in hospitalized pediatric patients in the United States showed that in 2009 there were 4499 ITP patients discharged from hospitalization. These pediatric patients ranged from 6 months to 17 years of age, with 686 having bleeding events. The mortality rate of patients with any bleeding was 1.5%. Pediatric patients with ICH (Intercranial Hemorrhage) had a mortality rate of 20.8%. However, of the 686/4499 pediatric patients with bleeding the incidence of two events were 15.2% and 3.9%, respectively^[28].

Though patients are at increased risk of bleeding, many other studies have shown either no increase in mortality or only slightly higher than the population average ^{[16] [29] [25][30][26]}. Based on the rates of remission for adults and children, and proper treatment options, most patients should live a normal lifespan.

Many patients with ITP may be asymptomatic.

If a patient presents with symptoms, they may experience the following^[31]:

• Bleeding (e.g. gastrointestinal hemorrhage, hematuria, ecchymosis, blood in the stool, blood in urine, increased bleeding during menarche)
• Bruising
• Purpura
• Petechiae
• Epistaxis
• Severe intracranial hemorrhage

Risk of bleeding in adults based on a retrospective cohort including 6651 patients with primary ITP in the US from (2008-2012)

Bleeding Event	Percent of patients with event
Hemorrhage of GI tract, unspecified	6%
Hemorrhage of rectum and anus	5%
Blood in stool	4%
Hematuria, unspecified	6%
Hematuria	1%
Spontaneous ecchymosis	6%
Epistaxis	5%

Bleeding estimates in 4499 hospitalized pediatric patients (aged 6 months – 17 years) in the US in 2009 ^[28]:

Bleeding Event	Percent of Patients with Event	Mortality of Patients with Event
Nonbleeding	85%	0.07%
All Bleeding	15.2%	1.5%
ICH	0.6%	20.8%
Upper or lower GI bleeding	0.4%	0.0%
Other GI bleeding	1.6%	1.95%
Hematuria	1.3%	2.65%

A bone marrow examination may be performed on patients over the age of 60 and people who do not respond to treatment, or when the diagnosis is in doubt. The bone marrow biopsy in ITP can show increased (thought not always) megakaryocytes, bizarre giant platelets and platelet fragments. (Large platelets are often seen in the peripheral blood smear though this can be seen in other diseases.) When the spleen is removed it may show increased lymphatic nodularity.

Recommended first line treatment in adults^[24][32] :

Medication	Time to Response	Complications
Corticosteroids
Prednisolone 0.5 – 2 mg/kg/d for 2-4 weeks	Up to several weeks	Vary based on dose and length of treatment: weight gain, fluid retention, hypertension, iatrogenic Cushing syndrome, hyperglycemia, immunosuppression, cataracts, GI distress, ulcers, mood swings
Methylprednisolone 30mg/kg/d for 7 days	Up to several weeks
Dexamethasone 40mg daily for 4 days every 2-4 wk for 1-4 cycles	Typically, within one week
IV anti-D*
IV anti-D 50-75 μg/kg for one dose	4-5 days	Hemolytic anemia, fever/chills** Rare but serious complications: renal failure, intravascular hemolysis, intravascular coagulation, death
Immunoglobulin
IVIG 0.4g/kg/d for 5 d or Infusion of 1g/kg/d for 1-2 d	Typically, within 5 days, may see a response within 24hrs	Headache, flushing, fever, chills, fatigue, tachycardia, thrombosis, renal insufficiency, nausea

*Required testing of blood group with a positive Rhesus Antigen (RH+), direct antiglobulin test (DAT), and a reticulocyte count before administration. ^[24][33]

**Premedication with APAP or corticosteroids are recommended to reduce the risk of chills and fever with the 75 μg/kg dose. ^[24]

Splenic radiation (RT) is usually given for steroid-resistant ITP. One to six weeks of 75-1370 cGy with or without concomittant post-RT steroids. Patients can respond for >1 year. It is a safe alternative for patients too old for splenectomy.

The causes and risk factors are unknown, except in children when it may be related to a viral infection. Prevention methods are unknown.

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increased platelet destructionEditor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Auto-immune thrombocytopenic purpura is described by the increased platelet destruction due to production of auto-reactive antibodies against host platelets and suppression of platelet production in the bone marrow.

Acute ITP: Mainly affects children and usually follows a viral or bacterial infection

• Antigenic mimicry – Similar molecular structures on both host cells and infectious agents, inducing a self immune response which cross reacts with the host antigens.
  • In acute ITP – anti-viral or anti-bacterial antibodies cross reacts against the patient’s platelets.
• Mostly acute ITP is self resolving as infectious agents and antibodies are cleared from the body, causing the loss of anti-platelet reactivity.
• T cells are not involved in the parthenogenesis of acute ITP

Chronic ITP: (platelet counts < 150,000 x 10⁹ per liter x 6 months) usually in adults

• Increased platelet destruction:
  • Autoantibody‐induced platelet destruction
    • Abnormal IgG auto-antibody recognizes glyco-protein IIb/IIIa, glyco-protein Ib/IX complex, GP Ia/IIa, and GP VI etc^[1]
    • Predominantly IgG auto-antibodies constitute the majority of antibodies but IgM and IgA antibodies can also be found in some of ITP patients.^[2]
    • Auto-antibodies binds to the circulating platelet membranes through glyco-proteins
    • Auto-antibody-coated platelets induce Fcγ receptors and bind to antigen-presenting cells (Splenic macrophages or dendritic cells) in the reticulo-endothelial system^[3][4]
    • The auto-antibody-coated platelets undergo phagocytosis by splenic macrophages and peripheral blood neutrophils.^[5]
  • Autoreactive T lymphocyte‐mediated platelet lysis
    • Abnormal cytotoxic T cells defect leads to differentiation of direct autoreactive B cells further leading to secretion of IgG auto-antibodies^[6]
    • Abnormal T cells includes cytotoxic T-lymphocyte (CD8+) and natural killer cells (CD3- CD16+ CD56+)^[7]
    • CD4-positive helper T cells react with platelet surface glycoproteins, through co-stimulation involving CD40:CD40L
    • T cells act directly on the megakaryocytes in the bone marrow
• Autoantibody‐mediated suppression of platelet production:
  • Decreased platelet turnover^[8]
  • Abnormal thrombopoiesis
  • Autoantibody‐induced suppression of megakaryocytopoiesis^[9]
  • Megakaryocitic nuclei and cytoplasm shows degenrative changes^[10]

Conditions associated with

On gross pathology, characteristic findings of itp include:

• Acute
• Chronic

On microscopic histopathological analysis, characteristic findings of itp include:

• Acute
• Chronic

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The cause of ITP is thought to be related to chronic infections such as HIV, hepatitis C and H. Pylori.

• antiphospholipid syndrome
• von Willebrand factor deficiency

• leukemia
• Medications (e.g. quinine, heparin)
• lupus erythematosus
• cirrhosis, HIV
• hepatitis C

can be classified as Primary and secondary

idiopathic

Absence of other cause or disorders .

Is immune- mediated thrombocytopenia with an underlying cause, including drug- induced, or systemic illness ( SLE,HIV ).^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The incidence of ITP is 5-10 new cases per 100,000 per year, with children accounting for half of that amount. The male:female ratio in the adult group is 1:1.2–1.7 (for children it is 1:1) and the median age of adults at the diagnosis is 56–60.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

More than 70% of the cases in children end up in remission within 6 months whether treated or not.^[1][2][3] Moreover, a third of the remaining chronic cases remitted during the follow-up observation, and another third ended up with only mild thrombocytopenia (>50,000 platelets per μL).^[1]

Subarachnoid, intracerebral hemorrhage or other internal bleeding are very serious possible complications of this disease. Fortunately, these are unlikely in patients with the platelets count above 20,000.

With treatment, the chance of remission (a symptom-free period) is good. Rarely, ITP may become a long-term condition in adults and reappear, even after a symptom-free period.

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