Immune thrombocytopenic purpura

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Immune thrombocytopenia
)
Not to be confused with autoimmune thrombotic thrombocytopenic purpura.
Immune thrombocytopenic purpura
Other namesIdiopathic thrombocytopenic purpura, idiopathic immune thrombocytopenia, primary immune thrombocytopenia, idiopathic thrombocytopenic purpura, primary immune thrombocytopenic purpura, autoimmune thrombocytopenic purpura
Petechiae, or small bruise-like markings, may occur in ITP
SpecialtyHematology
Frequency50–100 per million (12-month risk)

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of

low platelet count in the absence of other causes, and accompanied by a red-purple rash called purpura.[1][2] It leads to an increased risk of bleeding.[1] ITP manifests in two distinct clinical syndromes
: an acute form observed in children, and chronic conditions observed in adults. The acute form often follows an infection and typically resolves within two months, while chronic immune thrombocytopenia persists for longer than six months and its specific cause is unknown.

ITP is considered an

antigens
) can be detected.

Diagnosis of ITP involves identifying a low platelet count through a

bone marrow biopsy
, may be necessary in certain cases.

For mild cases, careful observation may be sufficient. However, in instances of very low platelet counts or significant bleeding, treatment options may include

immunosuppressive medications. Refractory ITP, which does not respond to conventional treatment or shows constant relapse after splenectomy, requires treatment to reduce the risk of significant bleeding.[3] Platelet transfusions may be used in severe cases with extremely low platelet counts in individuals experiencing bleeding. In some cases, the body may compensate by producing abnormally large platelets
.

Signs and symptoms

Signs of ITP include the spontaneous formation of bruises (

abrasions is usually prolonged.[citation needed
]

In cases where platelet counts drop to extremely low levels (<5,000 per μl), serious and potentially fatal complications may arise. These complications include

blunt abdominal trauma, such as in a motor vehicle crash. These complications are unlikely to occur when the platelet count is less than 20,000 per μl.[5]

  • Petechiae on the lower extremities
    Petechiae on the lower extremities
  • Oral petechiae/purpura - lower lip
    Oral petechiae/purpura - lower lip
  • Petechia on the tongue in a person with platelets of 3 due to ITP
    Petechia on the tongue in a person with platelets of 3 due to ITP
  • Petechia of the lower leg in a person with platelets of 3 due to ITP
    Petechia of the lower leg in a person with platelets of 3 due to ITP

Pathogenesis

In approximately 60 percent of cases,

Ib-IX, and are of the immunoglobulin G (IgG) type. The Harrington–Hollingsworth experiment established the immune pathogenesis of ITP.[7]

The coating of platelets with IgG renders them susceptible to

opsonization and phagocytosis by splenic macrophages, as well by Kupffer cells in the liver. The IgG autoantibodies are also thought to damage megakaryocytes, the precursor cells to platelets, although this is believed to contribute only slightly to the decrease in platelet numbers. Recent research now indicates that impaired production of the glycoprotein hormone, thrombopoietin, which is the stimulant for platelet production, may be a contributing factor to the reduction in circulating platelets. This observation has led to the development of a class of ITP-targeted medications referred to as thrombopoietin receptor agonists.[5]

The stimulus for auto-antibody production in ITP is probably abnormal T cell activity.[8][9][10] Preliminary findings suggest that these T cells can be influenced by medications that target B cells, such as rituximab.[11]

Diagnosis

Blood film showing giant platelets - arrows – in a person with ITP (Giemsa stain)

The diagnosis of ITP is a process of exclusion. First, it has to be determined that there are no blood abnormalities other than a low platelet count, and no physical signs other than bleeding. Then, secondary causes (5–10 percent of suspected ITP cases) should be excluded. Such secondary causes include leukemia, medications (e.g., quinine, heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency, onyalai and others.[4][12] All patients with presumed ITP should be tested for HIV and hepatitis C virus, as platelet counts may be corrected by treating the underlying disease. In approximately 2.7 to 5 percent of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome.[13][14]

Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead to a search for other possible causes for the thrombocytopenia. Bleeding time is usually prolonged in ITP patients. However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines[15] and a normal bleeding time does not exclude a platelet disorder.[16]

Bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt.[12] On examination of the marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP. An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80 percent specificity of this test is sufficient to be clinically useful.[12]

Treatment

With rare exceptions, there is usually no need to treat based on platelet counts. Many older recommendations suggested a certain platelet count threshold (usually somewhere below 20.0/µl) as an indication for hospitalization or treatment. Current guidelines recommend treatment only in cases of significant bleeding. Treatment recommendations sometimes differ for adult and pediatric ITP.[17]

Steroids

Initial treatment usually consists of the administration of

diabetes and cataracts.[19]

Anti-D

Another option, suitable for

platelets. There are two anti-D products indicated for use in patients with ITP: WinRho SDF and Rhophylac. The most common adverse reactions are headache (15%), nausea/vomiting (12%) chills (<2%) and fever (1%).[citation needed
]

Steroid-sparing agents

There is increasing use of

immunosuppressants such as mycophenolate mofetil and azathioprine because of their effectiveness. In chronic refractory cases, where immune pathogenesis has been confirmed,[20] the off-label use of the vinca alkaloid[21][22][23] and chemotherapy agent vincristine may be attempted.[24][25] However, vincristine has significant side effects[26]
and its use in treating ITP must be approached with caution, especially in children.

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) may be infused in some cases in order to decrease the rate at which macrophages consume antibody-tagged platelets. However, while sometimes effective, it is costly and produces improvement that generally lasts less than a month. Nevertheless, in the case of an ITP patient already scheduled for surgery who has a dangerously low platelet count and has experienced a poor response to other treatments, IVIg can rapidly increase platelet counts, and can also help reduce the risk of major bleeding by transiently increasing platelet counts.[27]

Thrombopoietin receptor agonists

Main article: Thrombopoietic agent

Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction.[28] Two such products are currently available:

  • Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.[31]
  • GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.[33]

Thrombopoietin receptor agonists exhibited the greatest success so far in treating patients with refractory ITP.[34]

Side effects of thrombopoietin receptor agonists include headache, joint or muscle pain, dizziness, nausea or vomiting, and an increased risk of blood clots.[28]

Surgery

Fc receptors), and so removal of the spleen reduces platelet destruction. The procedure is potentially risky in ITP cases due to the increased possibility of significant bleeding during surgery. Durable remission following splenectomy is achieved in 60 - 80 percent of ITP cases.[35] Even though there is a consensus regarding the short-term efficacy of splenectomy, findings on its long-term efficacy and side-effects are controversial.[34][36] After splenectomy, 11.6 - 75 percent of ITP cases relapsed, and 8.7 - 40 percent of ITP cases had no response to splenectomy.[34][37][38][39] The use of splenectomy to treat ITP has diminished since the development of steroid therapy and other pharmaceutical remedies.[40]

Platelet transfusion

Platelet transfusion alone is normally not recommended except in an emergency and is usually unsuccessful in producing a long-term platelet count increase. This is because the underlying autoimmune mechanism that is destroying the patient's platelets will also destroy donor platelets, and so platelet transfusions are not considered a long-term treatment option.[41]

H. pylori eradication

In adults, particularly those living in areas with a high prevalence of

peptic ulcers), identification and treatment of this infection has been shown to improve platelet counts in a third of patients. In a fifth, the platelet count normalized completely; this response rate is similar to that found in treatment with rituximab, which is more expensive and less safe.[42] In children, this approach is not supported by evidence, except in high prevalence areas. Urea breath testing and stool antigen testing perform better than serology-based tests; moreover, serology may be false-positive after treatment with IVIG.[43]

Other agents

  • Dapsone (also called diphenylsulfone, DDS, or avlosulfon) is an anti-infective sulfone medication. Dapsone may also be helpful in treating lupus, rheumatoid arthritis, and as a second-line treatment for ITP. The mechanism by which dapsone assists in ITP is unclear but an increased platelet count is seen in 40–60 percent of recipients.[44][45]
  • The off-label use of
    randomized controlled trials are inconclusive.[46]

Prognosis

In general patients with acute ITP will only rarely have life-threatening bleeding.[47] most of the patients ultimately have stable but lower platelet counts which is hemostatic for a person. Unlike in pediatric patients who can be cured, most of the adults will run a chronic course even after splenectomy.[48]

Epidemiology

A normal platelet count is considered to be in the range of 150,000–450,000 per microlitre (μl) of blood for most healthy individuals. Hence one may be considered thrombocytopenic below that range, although the threshold for a diagnosis of ITP is not tied to any specific number.[49]

The incidence of ITP is estimated at 50–100 new cases per million per year, with children accounting for half of that number. At least 70 percent of childhood cases will end up in remission within six months, even without treatment.[50][51][52] Moreover, a third of the remaining chronic cases will usually remit during follow-up observation, and another third will end up with only mild thrombocytopenia (defined as a platelet count above 50,000).[50] A number of immune related genes and polymorphisms have been identified as influencing predisposition to ITP, with FCGR3a-V158 allele and KIRDS2/DL2 increasing susceptibility and KIR2DS5 shown to be protective.[53][54]

ITP is usually chronic in adults

orphan disease.[56]

The

elderly. Ninety-six percent of reported ITP-related deaths were individuals 45 years or older. No significant difference was noted in the rate of survival between males and females.[57]

Pregnancy

The incidence of ITP in pregnancy is not well known. It may occur during any trimester of pregnancy. It is the most common cause of significant thrombocytopenia (platelets less than 100,000) in the second trimester, and it is a common cause of significant thrombocytopenia in the first and third trimesters.

drug induced thrombocytopenia, hereditary thrombocytopenia and pseudothrombocytopenia should also be ruled out.[58] ITP can be difficult to distinguish from gestational thrombocytopenia (which is by far the most common cause of thrombocytopenia in pregnancy). Unlike ITP, the platelet count in gestational thrombocytopenia rarely goes below 100,000, and a platelet count below 80,000 is even more rare (seen in less than 0.1% of cases of gestational thrombocytopenia). Also unlike ITP, gestational thrombocytopenia is not a cause of neonatal or maternal bleeding, or neonatal thrombocytopenia.[58]

Women with ITP often have a decrease in their platelet counts when they become pregnant, often requiring treatment.

blood clots observed. Further, in those with ITP, platelet counts usually return to pre-pregnancy levels after delivery.[58]

Anti-platelet autoantibodies in a pregnant woman with ITP will attack the patient's own platelets and will also cross the placenta and react against fetal platelets leading to thrombocytopenia. Thrombopoietin levels are also increased during pregnancy (which is thought to be due to placental production of estradiol) and this estradiol leads to decreased megakaryocyte activity and therefore decreased platelet production.[58] Therefore, ITP is a significant cause of fetal and neonatal immune thrombocytopenia. Approximately 10% of newborns affected by ITP will have platelet counts <50,000/uL and 1% to 2% will have a risk of intracerebral hemorrhage, comparable to that of infants with neonatal alloimmune thrombocytopenia (NAIT).[59][60]

No lab test can reliably predict if neonatal thrombocytopenia will occur. The risk of neonatal thrombocytopenia is increased with:[61]

  • Mothers with a history of splenectomy for ITP
  • Mothers who had a previous infant affected with ITP
  • Gestational (maternal) platelet count less than 100,000/uL

It is recommended that pregnant women with thrombocytopenia or a previous diagnosis of ITP be tested for serum antiplatelet antibodies. Indications for treatment of pregnant people with ITP include the presence of bleeding, platelet counts less than 20-30,000, planned procedures (such as an

MRI are also recommended for severely thrombocytopenic infants to rule out a brain bleed.[58]

History

After initial reports by the Portuguese physician

Amato Lusitano in 1556 and Lazarus de la Rivière (physician to the King of France) in 1658, it was the German physician and poet Paul Gottlieb Werlhof who in 1735 wrote the most complete initial report of the purpura of ITP. Platelets were unknown at the time.[62] The name "Werlhof's disease" was used more widely before the current descriptive name became more popular.[62][63] Platelets were described in the early 19th century, and in the 1880s several investigators linked the purpura with abnormalities in the platelet count.[62][64] The first report of a successful therapy for ITP was in 1916, when a young Polish medical student, Paul Kaznelson, described a female patient's response to a splenectomy.[62] Splenectomy remained a first-line remedy until the introduction of steroid therapy in the 1950s.[62]

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External links

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