Introduction

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura, is an autoimmune disorder whereby antibodies are produced against the body’s own platelets. It is a type of bleeding disorder. The presentation is different between children and adults. For the purpose of this article, the focus shall be on ITP in adults. ITP occurs in 3 in 100000 adults per year. Between the age groups 30-60, the disease is more common in women than men. At the extremes of ages, ITP is equally common in men and women. In adults, ITP often have an insidious onset and have a relapsing and remitting nature. Patients may be asymptomatic most of their lives but require a few hospital admissions. The mainstay of treatment involves use of oral steroids. Surgical options such as splenectomy have traditionally been offered to steroid refractory cases.

Epidemiology

  • Incidence: 5.00 cases per 100,000 person-years
  • Peak incidence: 70+ years
  • Sex ratio: more common in females 2:1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

Below is an explanation for the aetiology of ITP:
  • It is thought that ITP is an autoimmune disorder resulting in antibodies produced to target against individual’s own platelets, leading to thrombocytopenia.
  • This in turn results in petechiae and in rarer cases more severe bleeding.

Furthermore, ITP can be primary or secondary. Primary ITP occurs when there is isolated thrombocytopenia is found with no co-existing conditions. Secondary ITP is associated with co-existing conditions. These include:
  • Rheumatological diseases
  • CLL
  • Lymphoma
  • Viral infections
  • Various pharmacological agents

Pathophysiology

ITP is an autoimmune disorder. In ITP abnormal immune system leads to destruction of own platelets . Although the precise mechanism for ITP is not completely understood, there have been several widely accepted theories:
  • In ITP, autoantibodies are produced by the patient's B cells, principally of IgG. These target against platelet membrane glycoproteins GPIIb/IIIa.
  • These platelets with autoantibodies are then engulfed by macrophages and degraded in the spleen.
  • The bone marrow compensates by producing megakaryocytes (precursor to platelets).
  • Purpura occurs as a result of increased permeability in capillary due to low platelets.
  • In some cases, it is thought that viral infections can precede development of ITP. Antibodies against viral antigens cross react with normal antigens on platelet surfaces thus producing molecular mimicry.

Clinical features

In adults, ITP can present in a number of different ways. In normal individuals, platelet counts range between 150 to 400. Thrombocytopenia, or low platelets, occurs when the count drops below 100. The onset of presentation may be within days or months. ITP can be categories depending on duration of thrombocytopenia:
  • Newly diagnosed when thrombocytopenia is present for less than 3 months;
  • Persistent ITP refers to thrombocytopenia of 3 to 12 months;
  • Chronic ITP is defined as thrombocytopenia of greater than 12 months.

Clinical Presentations:
  • Approximately 1/3 of patients are asymptomatic and have incidental discovery on blood test.
  • Approximately 2/3 of patients have bleeding. Commonly patients with ITP present to their doctors with petechiae , small red dots on the skin. Purpura , formed by petechiae joined together, can also occur.
  • Mild epistaxis is common. Continuous epistaxis requiring nasal packing or cauterisation may pose greater risks of bleeding.
  • In women, patients with ITP may have prolonged and heavy menstrual cycles.
  • Very rarely, nonetheless the most importantly, ITP can present with intracranial bleeding; this occurs in 1.4% of the cases.
  • Severe non-intracranial bleeds such as large gastrointestinal bleed occur in 9.6% of the cases.
  • Patients with ITP can present as generally unwell, i.e. feeling lethargic.
  • Occasionally, patients with ITP may present with strokes and TIA, often referred to as paradoxical thrombotic events in ITP.
ITP may be discovered incidentally. In some cases there may be associated precedent events such as a viral infection. Moreover, various medications have been associated with thrombocytopenia; these include various antibiotics, quinine, statin, calcineurin inhibitors and herbal remedies such as ginkgo plant. Hence it is important to elicit these in the history.

Investigations

There are a number of investigations to be considered in patients presenting with bleeding and in those with incidental findings of thrombocytopenia. There is no single blood marker for ITP. Rather it is a diagnosis of exclusion. Minimum investigations to be done if thrombocytopenia is found include:
  • Firstly, full blood count and blood film need to be requested. This would demonstrate isolated decrease in platelet counts, with normal counts in all other cell lineages. Additionally, there should be no evidence of fragments on the film.
  • Secondly, a virology screen including HIV, EBV, hepatitis screen.

Further investigations to be considered, as guided by history and examination findings:
  • Clotting screen including PT and APTT, especially in those with severe bleeding.
  • Thyroid function tests
  • Malarial screen
  • Myeloma screen.
  • Immunological tests including ANA is considered especially if coexisting rheumatological features are present.
  • Imaging including CT may be useful if there is a high index of suspicion for cancer.

Bone marrow biopsy is no longer a standard investigation for ITP. If there are blood count abnormalities such as anaemia, leucopenia or other unexplained haematological findings, a bone marrow biopsy is warranted. In cases where ITP is not responsive to treatment and there is a high clinical suspicion for MDS, bone marrow biopsy should be carried out.

Differential diagnosis

ITP is a diagnosis of exclusion. Thrombocytopenia can be caused by increased destruction of platelets, and/or reduced production of platelets. Important differential diagnoses to consider include:
  • Non-immunological causes of increased destruction of platelets include disseminated intravascular coagulation (DIC) i.e. in the setting of sepsis or malignancy.
  • Pregnancy and its complications such as HELLP syndrome can also cause thrombocytopenia.
  • Chronic liver disease and hypersplenism is associated with thrombocytopenia.
  • Thrombotic thrombocytopenic purpura (TTP) is life-threatening disease which presents with thrombocytopenia but can result in multi-organ failure, cardiac complications, strokes and other thrombotic events. The hallmark for DIC and TTP is the presence of fragments on the blood film.
  • Additionally, drugs such as heparin may result in thrombocytopenia, known as heparin-induced thrombocytopenia or HIT.
  • Immunomodulatory drugs such as gold, alemtuzumab and more recently immunotherapy agents such as nivolumab and pembrolizumab have been associated with ITP.
  • Thrombocytopenia may be the first sign in well patients with underlying viral infections such as HIV or hepatitis.
  • Many haematological malignancies can result in thrombocytopenia such as leukaemia, lymphoma, myelofibrosis, myelodysplasia and myeloma. Therefore it is important to take a careful history, as patients with these diseases often present with constitutional symptoms.
  • Finally, rheumatological diseases such as SLE and rheumatoid arthritis can present with thrombocytopenia.

Management

ITP at first presentation should be referred to and managed by haematologists. The requirement for treatment varies between patient to patient; as such, clinical status is a key determinant for these considerations - i.e. asymptomatic, bleeding or planned surgical/dental procedures. Treatment is only given to those patients that absolutely require it, hence decreasing the risks of adverse effects such as infection as a result of immunosuppression. Below are the recommendations as according to British society of haematology.
  • First line treatment for ITP is oral prednisone at 1mg/kg daily with proton pump inhibitors . This is given over a period of 2 - 4 weeks and weaned off a few weeks after. Most patients respond to this treatment within a week of commencing steroids.
  • Pooled normal human immunoglobulin (IVIG) is also listed as first line treatment. Intravenous immunoglobulin is administered at 1g/kg. The mechanism of action is unknown but it was thought that one way is by blocking the Fc receptor of macrophages.
  • Splenectomy had been used for many years, long before steroids were used. It is now second line for ITP in steroid refractory cases. It works by avoiding platelet destruction by removing the spleen.

Other immunomodulatory drugs such as rituximab, cyclophosphamide and dapsone have also been used to treat ITP. Romiplostim works by activating the thrombopoietin receptor and stimulating JAK2, thus it stimulates platelet production. It has been approved by NICE as an option for ITP. Indications for usage include:
  • ITP is refractory to standard active treatments and rescue therapies or
  • Patients have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies.

Additionally it is important to avoid drugs which make bleeding worse. It is important to avoid antiplatelet drugs such as aspirin and clopidogrel.

In cases of severe bleeding, it is important to treat promptly with transfusion of platelets, IVIG, tranexamic acids and initiate major haemorrhage protocol. Although transfusion of platelets may not improve platelet count, it has been shown to be effective at relieving the symptoms in acutely severe bleeding.

Complications

Complications of treatment are related to side effects of specific drugs used for treatment of ITP. A referral to local haematology department is desirable to weigh up the risks and benefits of choosing a particular modality of treatment against the risks of bleeding. I.e. if platelet counts are stable and above a certain acceptable threshold (depending on hospital guidelines, i.e. >50 and asymptomatic), it may be reasonable to continue monitoring.

Patients who received splenectomy require long term prophylactic penicillin V and pneumococcal/meningococcal vaccines.

Most patients with ITP do not have severe bleeding. In a review of adult ITP cases in Oklahoma over a 10 year period, 83% patients were managed on an outpatient bases. Indications for inpatient management of ITP include:
  • Large bleeding;
  • Haemodynamic compromise;
  • Intracranial haemorrhage;
  • Platelet count of less than < 30.
  • Inadequate response to conventional therapy agents.

Prognosis

In adults, ITP is often a chronic disorder of relapsing and remitting nature. Patients may be in remission for many years before a relapse occurs. A recent study demonstrated that >85% ITP patients with platelet count of >30 had identical long term mortality to the general population. Most patients with ITP have good outcomes and few hospital admissions. Below is a reference from British society of haematology:
  • An estimate of 2/3 of patients respond to steroid therapy, as such it is given as first line therapy.
  • Pooled normal human immunoglobulins are shown to be effective in elevating platelet count in 75% of ITP patients, of which 50% achieve normal platelet count. Nevertheless, the effect of rise in platelet count may be transient and lasts only a few weeks long.

Furthermore, a randomised trial of 122 patients compared the efficacy of high dose methylprednisolone versus IVIG in treating ITP. They measured platelet count at day 5 as an endpoint. 60% of patients who received high dose methylprednisolone responded at day 5 with an increment of >50 platelet count; In the IVIG group, 79% of patients had >50 platelet count at day 5. Moreover, patients in the age group <60 appear to have greater increment in platelet counts following treatment compared with >60 years. The greater increments was observed over a 3-year period.

In steroid refractory ITP and chronic ITP, splenectomy should be considered. 2/3 of patients who receive splenectomy achieve normal platelet count. Those who do not achieve normal count can expect some improvements in platelet count.