The presentation mostly depends on the platelet count of the patient. The lower the platelet count, the worse the bleeding. Most patients are asymptomatic. The hallmark of presentation is the variation in the degree of bleeding. Patients may present with easy bruisability or mucosal bleeding or with more severe bleeding manifestations, which include menorrhagia, hemorrhage in the gastrointestinal and urinary tracts, and in some cases intracranial hemorrhage [7] [8] [9].

• Anemia

  KEYWORDS: antiplatelet drugs; hemostasis; thrombocytopenia Publication type, MeSH terms, Substances Publication type Clinical Trial MeSH terms Adolescent Anemia, Hemolytic, Autoimmune/blood Anemia, Hemolytic, Autoimmune/drug therapy* Anemia, Hemolytic [ncbi.nlm.nih.gov]

  If there is anemia out of proportion to the amount of bleeding, a reticulocyte count should be performed. A low reticulocyte count would suggest lack of production as seen in leukemia and aplastic anemia. [cancertherapyadvisor.com]

  Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia. Ann Hematol 2010; 89: 1073–1080. [nature.com]

  As such other causes leading to thrombocytopenia, including bone marrow disorders (e.g. aplastic anemia, leukemia) must be ruled out. [symptoma.com]

• Fever

  Rituximab was well tolerated, with two fever episodes following infusion and two reports of skin rash. [ncbi.nlm.nih.gov]

  [6] 49 1–18 33/16 S/CSA/Sp/IGIV anti-D 2–6 34/49 1–17 21/49 1–75 13/34 Three urticaria, two fever, chills This study 12 3–16 4/8 S/IVIG 4 10/12 1–4 6/12 6–20 4/10 None Total 164 76/67 100/164 67/164 36/100 Reference Patients (n) Age (years) Sex (F/M [academic.oup.com]

  Frequent side effect of interferon alpha is transient fever, less frequently flu-like syndrome may by present. CONCLUSIONS. [stary.lf2.cuni.cz]

• Ecchymosis

  The only complication was extensive superficial ecchymosis on the patient's forearm from antiplatelet use, which resolved spontaneously. To the best of our knowledge, this is the first case report of EPC capture stents in a chronic ITP patient. [casereports.bmj.com]

  […] beneath the skin, often leading to organ failure and amputations) and coumarin-induced skin necrosis (a complication of anticoagulant treatment with medicines such as warfarin, causing skin death sl Anakonde so stroji za ubijanje en urticaria, psoriasis, ecchymosis [sl.glosbe.com]

  Events occurring in >=4% of patients in the splenectomized and non-splenectomized groups, respectively, included mouth hemorrhage (4% and 1%), epistaxis (14% and 6%), petechiae (8% and 2%), ecchymosis (2% and 4%), contusion (3% and 4%), and hematuria [novartis.com]

  Bleeding severity Bleeding severity was classified into four categories as follows: 0=no bleeding; 1=petechiae; 2=ecchymosis or dripping with moderate blood loss; 3=bleeding of mucous membranes with copious blood loss without sequellae; 4=bleeding of [omicsonline.org]

  The hallmark presentation of ITP is mucocutaneous bleeding that manifests as purpura (petechiae, ecchymosis), epistaxis, menorrhagia, or oral mucosal, gastrointestinal, or intracranial hemorrhage. [ajhp.org]

• Easy Bruising

  A decrease in platelets can result in easy bruising, bleeding gums, and internal bleeding. ITP may be acute and resolve in less than 6 months, or chronic and last longer than 6 months. [hopkinsmedicine.org]

  ITP symptoms can include any of the following: Abnormally heavy periods in women Bleeding into the skin, often around the shins, causing a skin rash that looks like pinpoint red spots (petechial rash) Easy bruising Nosebleed or bleeding in the mouth In [medlineplus.gov]

  Risk The chances of ITP are higher for: Women—mainly under for 40 years old Children—history of a viral infection or vaccine with a live virus Symptoms ITP may cause: Easy bruising Blood in the urine or stool Bleeding for longer than normal Unexplained [cancercarewny.com]

  The low platelet count causes easy bruising and bleeding, which may be seen as purple areas in the skin, mucous membranes, and outer linings of organs. [icd10data.com]

  When there is a decrease in the platelet cells, then it can result in easy bruising, internal bleeding and bleeding of the gums. The “idiopathic” portion actually means that the cause is not known. [healthlifemedia.com]

• Hemophilia A

  Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. [ncbi.nlm.nih.gov]

  This can cause coagulation problems in patients, including amongst others serious bleeding after childbirth, extensive traumas or operations, sepsis, diffuse intravascular coagulation, hemophilia, von Willebrand disease, idiopathic thrombocytopenic purpura [sanquin.org]

  Also atypical of ITP are extensive hematomas (small area: ecchymosis, large area: sugillations) and joint hemorrhages; those are more common in plasmatic coagulation disorders (e.g., hemophilia A and B). [karger.com]

• Melena

  […] very little interference with daily living May include non-oozing petechiae on oral mucosa or resolved mild epistaxis More severe skin manifestations, with some mucosal lesions and more troublesome epistaxis or menorrhagia Bleeding episodes (epistaxis, melena [cps.ca]

  Record any bleeding, including petechiae, ecchymoses, epistaxis, menorrhagia, melena, or hematuria. Determine whether bruising or bleeding is a recurrent problem. [emedicine.medscape.com]

• Blood in Stool

  People with ITP may sometimes experience one or more of the following symptoms 2 : Unexpected bruises Tiny red or purple dots on the skin (petechiae) Bleeding too easily from gums, nose, and cuts Bleeding that’s hard to stop Blood in stool or urine A [novartisoncology.com]

  For typical ITP, the guideline suggested an approach aimed at achieving a platelet count associated with adequate hemostasis (i.e., with no active bleeding, specifically no epistaxis, menorrhagia or blood in stools), rather than attaining an absolute [cps.ca]

• Oral Bleeding

  In some instances there is oral bleeding, epistaxis, rectal bleeding or haematuria. Morbidity in ITP is usually minimal and parents need to be reassured of this. [rch.org.au]

  Oral bleeding (“wet purpura”) has historically been considered to be a risk factor for more serious bleeding such as intracranial hemorrhage, although there are insufficient data to prove this. [cancertherapyadvisor.com]

  [1] The condition is usually asymptomatic, but the patient may have mucocutaneous bleeding like epistaxis, menorrhagia or oral bleed. [jahjournal.org]

  Other bleeding manifestations may include heavy menstrual bleeding, oral bleeding, and epistaxis. Bleeding is generally but not entirely proportional to the platelet count. [ncbi.nlm.nih.gov]

• Bleeding Gums

  Platelets are cells in the blood that help stop bleeding. A decrease in platelets can cause easy bruising, bleeding gums, and internal bleeding. This disease is caused by an immune reaction against one's own platelets. [hopkinsmedicine.org]

  Platelets are cells in the blood that help stop bleeding. A decrease in platelets can result in easy bruising, bleeding gums and internal bleeding. "Idiopathic" means the cause is unknown. [chop.edu]

  There is evidence of bleeding under the skin, with easy bruising and the development of petechiae. In the acute form there may be bleeding from any of the body orifices, such as hematuria, nosebleed, vaginal bleeding, and bleeding gums. [medical-dictionary.thefreedictionary.com]

• Purpura

  Chronic immune thrombocytopenic purpura (ITP) appeared in monozygotic twin girls during adolescence. An older sister was discovered to have less severe thrombocytopenia without purpura. [jhu.pure.elsevier.com]

  Published Journal Article Romiplostim, a thrombopoietin mimetic, is a novel therapeutic option for patients with chronic immune thrombocytopenic purpura. [scholars.duke.edu]

  Thrombocytopenic, Idiopathic/blood Purpura, Thrombocytopenic, Idiopathic/drug therapy* Purpura, Thrombocytopenic, Idiopathic/immunology Rituximab Thrombocytopenia/blood Thrombocytopenia/drug therapy* Thrombocytopenia/immunology Treatment Outcome Substances [ncbi.nlm.nih.gov]

• Petechiae

  Bleeding into the skin takes the form of purpura or petechiae. Purpura is a purplish or reddish-brown rash or discoloration of the skin; petechiae are small round pinpoint hemorrhages. [medical-dictionary.thefreedictionary.com]

  Bruising and petechiae in isolation, without mucosal, gastrointestinal or renal tract bleeding. The child is otherwise well. [rch.org.au]

  Most children present with mild bruising and petechiae, but approximately 3% present with more serious bleeding from the nose, mucosa or gastrointestinal tract [4]. [cps.ca]

  Petechiae on the lower extremities Oral petechiae/purpura - lower lip 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 Pathogenesis[edit] In approximately 60 percent [en.wikipedia.org]

  These bruises may also appear as pinpoint-sized red or purple dots on the skin called petechiae. Petechiae often look like a rash. ITP can occur in both children and adults. [healthline.com]

• Skin Bleeding

  The initial presentations included: thrombocytopenia revealed by routine blood count or bleeding limited to the skin (bleeding score between 0 to 2) in 27 cases (66%) and severe cutaneous bleeding or visceral bleeding (potentially life-threatening) in [omicsonline.org]

• Epistaxis

  No or very little interference with daily living May include non-oozing petechiae on oral mucosa or resolved mild epistaxis More severe skin manifestations, with some mucosal lesions and more troublesome epistaxis or menorrhagia Bleeding episodes (epistaxis [cps.ca]

  The most common adverse events were headache (37%), nasopharyngitis (32%), contusion (30%), epistaxis (30%), fatigue (30%), arthralgia (25%), and diarrhea (25%). [ncbi.nlm.nih.gov]

  Clinical symptoms were petechiae or bruise(99.1%), epistaxis(34.0%) gastrointestinal bleeding(27.7%), hematuria(8.9%), and gum or oral mucosal bleeding(5.4%). Splenomegaly was observed in 8% of patients. There was no intracranial bleeding. 6. [ir.ymlib.yonsei.ac.kr]

  In some instances there is oral bleeding, epistaxis, rectal bleeding or haematuria. Morbidity in ITP is usually minimal and parents need to be reassured of this. [rch.org.au]

  Eight patients had epistaxis and evidence of other severe mucosal bleeding: postoperative bleeding (from cataract surgery) in Patient 2; hematuria in Patient 3; hematuria, gastrointestinal bleeding, and two episodes of central nervous system bleeding [nejm.org]

• Hematuria

  This child, who had a history of immune thrombocytopenic purpura of 1 year's duration, presented to the emergency department with gross hematuria. The cause of hematuria was initially attributed to his primary disease process. [ncbi.nlm.nih.gov]

  Clinical symptoms were petechiae or bruise(99.1%), epistaxis(34.0%) gastrointestinal bleeding(27.7%), hematuria(8.9%), and gum or oral mucosal bleeding(5.4%). Splenomegaly was observed in 8% of patients. There was no intracranial bleeding. 6. [ir.ymlib.yonsei.ac.kr]

  Eight patients had epistaxis and evidence of other severe mucosal bleeding: postoperative bleeding (from cataract surgery) in Patient 2; hematuria in Patient 3; hematuria, gastrointestinal bleeding, and two episodes of central nervous system bleeding [nejm.org]

  One retrospective, controlled study identified hematuria and history of head trauma, as significant risk factors (in addition to severe thrombocytopenia) for the development of intracranial hemorrhage. [cancertherapyadvisor.com]

• Intracranial Hemorrhage

  Abstract Adult chronic immune thrombocytopenic purpura (ITP) is a disorder manifested by varying degrees of purpura and mucosal bleeding, rarely including intracranial hemorrhage. [ncbi.nlm.nih.gov]

  Major hemorrhages occurred in 8 children (8%), including a non-fatal intracranial hemorrhage in one child (1%). [lup.lub.lu.se]

  Severe headache occurring while the patient is still thrombocytopenic often leads to head CT scan to rule out intracranial hemorrhage. [cancertherapyadvisor.com]

  […] trauma–induced intracranial hemorrhage is the most frequent cause of death in association with ITP. [emedicine.medscape.com]

  The most serious complication of ITP is intracranial hemorrhage, which occurs in approximately 0.17% to 0.6% of cases [1][5][6]. [cps.ca]

Chronic ITP is a diagnosis of exclusion and hence, there is no standard laboratory investigation for the diagnosis of chronic ITP. It is important to rule out other causes of thrombocytopenia and the history, physical examination and investigations are tailored to this aim. The diagnosis should be constantly evaluated in light of an appearance of new clinical or laboratory features.

Amongst the investigations that are recommended are a complete blood count and a blood smear examination to exclude disorders like leukemia, thrombotic thrombocytopenic purpura, and pseudo-thrombocytopenia. A history of autoimmune disorders in the family should be enquired for. Viral screens to rule out HIV, hepatitis C and other viruses must be carried out. Some studies advocate a diagnosis of chronic ITP based on the patient response to intravenous immunoglobulins.

Other optional investigations would include an erythrocyte sedimentation rate (ESR), blood grouping, antibody testing such as ANA and anti-cardiolipin and a direct antiglobulin test. It is to be noted that thrombopoietin and anti-platelet antiphospholipid antibody levels are not routinely measured, despite their central role in the pathogenesis. Bone marrow evaluations and biopsy are usually only done prior to splenectomy in patients aged 60 years or more.

• Decreased Platelet Count

  The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased platelet count. [emedicine.medscape.com]

  Results The literature synthesis and themes from the focus group data suggest that decreased platelet counts, disease symptoms, and treatment side effects influence multiple domains of HRQoL for ITP patients. [hqlo.biomedcentral.com]

The treatment could be medical or surgical. The impact and side effects of all possible treatments should be fully discussed with patients. First-line therapy for individuals with low platelet counts is usually medical. Drugs are also used to manage recurrent cases of chronic ITP as well as patients who do not get better with splenectomy.

The first-line medications in the management of chronic ITP, as per national guidelines, include the use of oral corticosteroids. Second line drugs include intravenous immunoglobulins, rituximab, danazol, cyclosporine, mycophenolate mofetil or cytotoxic agents (e.g cyclophosphamide or azathioprine) [2] [10] [11] [12].

Despite the effectiveness of these drugs, their adverse drug reactions should also be considered [13]. For example, patients receiving corticosteroids have an increased risk of suffering from obesity, gastrointestinal bleeding, myocardial infarction and osteoporosis [14]. Danazol is associated with rashes and liver failure [2]. Similarly, rituximab as an infusion may cause chills, fever or anaphylaxis [10]. Cytotoxic drugs reduce the cell counts and could also predispose to secondary malignancies. Patients on immunosuppressive drugs have an increased risk of infection [2].

Surgery, in the form of splenectomy, is usually reserved for patients who do not respond to medical treatment or relapse after initial medical treatment. Splenectomy is also indicated in patients who require very high intolerable doses of oral drugs to achieve platelet counts that can maintain hemostasis [15]. In about two third of patients who have had a splenectomy, long-term disease management was achieved. However, patients who undergo splenectomy are at an increased risk of developing severe sepsis.

The older the patient (greater than 60 years), the worse the prognosis. Patients with a platelet count of less than 30 x 109 /L are at a risk of severe and fatal bleeding. Such patients under 40 years of age have a 2.2% 5-year mortality rate, while patients older than 60 years have a 47.8% mortality rate within 5 years [7].

Immune thrombocytopenic purpura is a disorder affecting all age groups. In children, it mainly occurs secondary to a viral infection and most often has an acute presentation. In adults, it usually runs a more chronic course. Chronic ITP is usually idiopathic. ITP can also occur in individuals secondary to an underlying disorder such as systemic lupus erythematosus (SLE) and infections like autoimmune hepatitis C and human immunodeficiency virus (HIV) [5]. Some studies indicate a correlation between chronic ITP and Helicobacter pylori infection, although this hasn’t been proven entirely yet.

ITP results from:

Autoantibody production

In chronic ITP, autoantibodies are formed that react against the platelet membrane glycoproteins.

Three-quarters of autoantibodies are formed against platelet GPIIb/IIIa or GPIb/IX GP complexes, while the remaining are formed against other platelet antigens, such as GPV, GPIa/IIa, or GPIV.

Splenic destruction of thrombocytes

In the spleen, there is increased phagocytosis of autoantibody coated platelets because of their sluggish movement through the sinusoids. It is also the site of production of such autoantibodies.

ITP affects 5 in 100,000 children and 2 in 100,000 adults every year [6]. ITP presents in 2 distinct forms, the acute variant found more frequently in children while the chronic type is predominantly a disease of adults. Chronic ITP is more commonly seen in women, with most patients aged 20-50 years.

Chronic ITP is an interplay between the following mechanisms: immune-system led destruction of platelets and reduced production of platelets from the bone marrow, both cumulatively resulting in thrombocytopenia.

T cells stimulate B cells to produce antiplatelet antibodies, which then coat the platelets. These opsonized platelets bind to antigen presenting cells via Fcγ receptors and are hence, phagocytosed and destroyed. Most drugs used in the treatment of chronic ITP are targeted at reducing this platelet destruction.

There is also reduced marrow platelet production as shown by the role of thrombopoietin (TPO), an enzyme which helps in thrombopoiesis. Studies have shown a remarkable increase in the platelet count in individuals who were given TPO mimetics.

Therapy is aimed at reducing the hyper-destruction of platelets by the immune system and hence, immunosuppressant drugs are the treatment of choice for this disease. Ongoing research indicates a future role for TPO in this treatment regimen.

No preventive strategies are currently known.

Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by thrombocytopenia resulting primarily from premature destruction of autoantibody-coated platelets. A disease of both children and adults, it presents mainly with an acute and self-limited course in the former, while a more persistent, recurrent version occurs in adults.

The first mention of this disease was made in 1735 in P.G Werlhof’s "Morbus Maculosus Hemorrhagicus" [1]. Since then, multiple studies (e.g. Harrington's studies) have confirmed the central role played by the immune system in this disease [2]. Platelets, coated with autoantibodies, become a target for destruction by the reticuloendothelial system, especially the spleen. Platelet synthesis and maturation are also affected due to the autoantibodies reacting with the megakaryocytes. Thrombocytopenia in chronic ITP is thus a consequence of both increased platelet destruction (primarily) and a decrease in platelet production.

Chronic ITP is a peculiar disease owing to it being a diagnosis of exclusion. A proper history, physical examination, a complete blood count and peripheral smear are needed to rule out the other causes of thrombocytopenia, including infections, autoimmune diseases, drugs, malignancies etc. [3]. Autoantibodies are usually not measured due to their lack of sensitivity [4]. Bone marrow examination may be needed in some patients such as in the elderly, those with an atypical presentation or in those requiring a splenectomy.

Chronic immune thrombocytopenic purpura (ITP) is a disease in which the immune system of the body attacks its own platelets, thereby reducing the platelet count of the body. Platelets are responsible for prevention of bleeding and hence, these patients with low platelet counts present with various forms of bleeding (e.g. purpura). The body's immune system, for reasons not fully understood, creates autoantibodies against its own platelets. These autoantibodies also cause damage to the platelet-producing cells, the megakaryocytes.

Most patients are asymptomatic and are discovered during routine investigations. Patients may face similar situations upon ingesting certain drugs like quinidine, quinine or sulfa-like drugs. This disorder may be linked to other diseases such as systemic lupus erythematosus, lymphoproliferative disorders (e.g. non-Hodgkin lymphoma) or infections (e.g., HIV disease, cytomegalovirus infection or hepatitis).

Symptoms
Most patients with chronic ITP are asymptomatic. The typical presentation includes pin point bruises on the lower limbs, bleeding from the nose and gums, blood in urine or rarely bleeding from the stomach and bowel. Ingestion of certain drugs (e.g. ibuprofen, aspirin) that interfere with platelet function may worsen the bleeding manifestations. Women may have increased menstrual bleeding while children may show bleeding manifestations in the brain vault.

Diagnosis
Chronic ITP is a diagnosis of exclusion and there is no definitive test to make or exclude its diagnosis. As such other causes leading to thrombocytopenia, including bone marrow disorders (e.g. aplastic anemia, leukemia) must be ruled out. Following investigations ordered for other purposes, a low platelet count may be discovered in otherwise healthy individuals or asymptomatic patients.

It is possible the platelets may appear low due to clumping and this differentiation can be made clearly on examination under a microscope. It is also important to check the size of the platelets and to ascertain that the other blood cells are normal. This also rules out leukemia or anaplastic anemia as possible causes. Furthermore, a bone marrow biopsy may be conducted to gain further clarity on the diagnosis.

To summarize, the diagnosis of chronic ITP is considered in an otherwise healthy patient who has thrombocytopenia and no other abnormality on the complete blood count and also has taken no new medications or has a family history of thrombocytopenia.

Treatment

The first line medications in the management of chronic ITP are oral corticosteroids according to national guidelines. Other agents that may be used include intravenous immunoglobulins and intravenous corticosteroids. Surgery in the form of splenectomy is an option in serious cases. A combination of these treatments may be used if chronic ITP recurs.

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