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Chronic Immune Thrombocytopenic Purpura

Chronic Idiopathic Thrombocytopenic Purpura

Chronic immune thrombocytopenic purpura (ITP) is a disorder characterized by thrombocytopenia resulting from immune-mediated hyper-destruction of platelets, along with associated impaired thrombocyte synthesis. Chronic ITP occurs in both children and adults. In children, ITP is usually acute in onset and self-limiting, whereas in adults it runs a more chronic course.

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Presentation

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].

Easy Bruising
  • Case Presentation Our patient was a 15 year old female who presented withecchymoses, petechiae, and easy bruising. Her complete blood count(CBC) revealed a platelet count of 3 x 109/L.[austinpublishinggroup.com]
  • The classic ITP patient presents with petechiae and easy bruising with or without mucosal bleeding. The blood count shows only isolated thrombocytopenia with scattered large platelets. Anemia is absent, unless there is bleeding or immune hemolysis.[jhoonline.biomedcentral.com]
  • 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]
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]
  • We describe a child with membranous nephropathy associated with chronic immune thrombocytopenic purpura (ITP) and Coombs'-positive hemolytic anemia. After 3 years of ITP, the patient developed nephrotic syndrome during a flare of ITP.[ncbi.nlm.nih.gov]
  • As such other causes leading to thrombocytopenia, including bone marrow disorders (e.g. aplastic anemia, leukemia) must be ruled out.[symptoma.com]
  • Anemia is absent, unless there is bleeding or immune hemolysis. The bone marrow is normal except for an increase in megakaryocytes.[jhoonline.biomedcentral.com]
  • , fever, chills, headache, blood pressure changes or allergic reactions rarely, severe anemia from breakdown of blood cells can occur; this can possibly result in kidney damage Other treatments for ITP may include: surgery to remove spleen (splenectomy[danafarberbostonchildrens.org]
Fever
  • Rituximab was well tolerated, with two fever episodes following infusion and two reports of skin rash.[ncbi.nlm.nih.gov]
  • The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%).[ncbi.nlm.nih.gov]
  • Side effects of treatment included fever and a flu-like syndrome, which were usually present during the first 14 days of therapy only.[ncbi.nlm.nih.gov]
  • Frequent side effect of interferon alpha is transient fever, less frequently flu-like syndrome may by present. CONCLUSIONS.[stary.lf2.cuni.cz]
  • Similarly, rituximab as an infusion may cause chills, fever or anaphylaxis. Cytotoxic drugs reduce the cell counts and could also predispose to secondary malignancies. Patients on immunosuppressive drugs have an increased risk of infection.[symptoma.com]
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]
  • 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 (2%[novartis.com]
Respiratory Distress
  • Pruritus, urticaria, and throat tightness (but no respiratory distress) occurred with the first infusion in a small number of children. Three patients had serum sickness after the first, second, and third infusions, respectively.[ncbi.nlm.nih.gov]
Rales
  • The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%).[ncbi.nlm.nih.gov]
Tachypnea
  • Because of his lack of dyspnea and tachypnea, and the temporal association of his perioral cyanosis with the initiation of dapsone therapy, a methemoglobin (MetHb) level was obtained and found to be elevated at 9.6%.[ncbi.nlm.nih.gov]
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]
Melena
  • Record any bleeding, including petechiae, ecchymoses, epistaxis, menorrhagia, melena, or hematuria. Determine whether bruising or bleeding is a recurrent problem.[emedicine.medscape.com]
Cyanosis
  • The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%).[ncbi.nlm.nih.gov]
Hypotension
  • Significant drug-related toxicities included third-dose hypotension (n 1) and serum sickness (n 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease.[ncbi.nlm.nih.gov]
Bleeding Gums
  • 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]
  • A decrease in platelets can result in easy bruising, bleeding gums and internal bleeding. "Idiopathic" means the cause is unknown. "Thrombocytopenia" means a decreased number of platelets in the blood.[chop.edu]
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]
Purpura
  • Abstract Hematuria is an uncommon manifestation of chronic immune thrombocytopenic purpura. The occurrence of urolithiasis in children with chronic immune thrombocytopenic purpura has not been described.[ncbi.nlm.nih.gov]
  • , Thrombocytopenic, Idiopathic/blood Purpura, Thrombocytopenic, Idiopathic/complications Purpura, Thrombocytopenic, Idiopathic/genetics Purpura, Thrombocytopenic, Idiopathic/microbiology* Purpura, Thrombocytopenic, Idiopathic/pathology Purpura, Thrombocytopenic[ncbi.nlm.nih.gov]
  • , Thrombocytopenic, Idiopathic/blood Purpura, Thrombocytopenic, Idiopathic/immunology Purpura, Thrombocytopenic, Idiopathic/therapy* Remission Induction Rituximab Self Tolerance Splenectomy Time Factors Substances Antibodies, Monoclonal, Murine-Derived[ncbi.nlm.nih.gov]
  • , 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]
  • Abstract Chronic immune thrombocytopenic purpura has mild bleeding manifestations and severe bleeding requiring hospitalization is rare.[ncbi.nlm.nih.gov]
Petechiae
  • When they do occur, they may include: Easy or excessive bruising Superficial bleeding into the skin that appears as pinpoint-sized reddish-purple spots (petechiae) that look like a rash, usually on the lower legs Bleeding from the gums or nose Blood in[mayoclinic.org]
  • 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]
  • Case Presentation Our patient was a 15 year old female who presented withecchymoses, petechiae, and easy bruising. Her complete blood count(CBC) revealed a platelet count of 3 x 109/L.[austinpublishinggroup.com]
  • Bruising and petechiae in isolation, without mucosal, gastrointestinal or renal tract bleeding. The child is otherwise well.[rch.org.au]
  • The classic ITP patient presents with petechiae and easy bruising with or without mucosal bleeding. The blood count shows only isolated thrombocytopenia with scattered large platelets. Anemia is absent, unless there is bleeding or immune hemolysis.[jhoonline.biomedcentral.com]
Epistaxis
  • 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]
  • 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]
  • 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 (2%[novartis.com]
  • […] children characterized by transient or persistent decrease of the platelet count and depending upon the degree of thrombocytopenia, increased risk of bleeding. [1] The condition is usually asymptomatic, but the patient may have mucocutaneous bleeding like epistaxis[jahjournal.org]
  • Record any bleeding, including petechiae, ecchymoses, epistaxis, menorrhagia, melena, or hematuria. Determine whether bruising or bleeding is a recurrent problem.[emedicine.medscape.com]
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]
  • 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 (2%[novartis.com]
  • Record any bleeding, including petechiae, ecchymoses, epistaxis, menorrhagia, melena, or hematuria. Determine whether bruising or bleeding is a recurrent problem.[emedicine.medscape.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]
  • 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.[symptoma.com]

Workup

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.

Treatment

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.

Prognosis

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].

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No preventive strategies are currently known.

Summary

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.

Patient Information

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.

References

Article

  1. Imbach P, Kühne T, Signer E. Historical aspects and present knowledge of idiopathic thrombocytopenic purpura. Br J Haematol. 2002; 119:894-900.
  2. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002; 346:995-1008.
  3. British Committee for Standards in Haematology General Haematology Task Force. Guidelines in the investigation and management of idiopathic thrombocytopenic purpura in adults, children an in pregnancy. Br J Haematol. 2003; 10:574-96.
  4. McMillan R, Wang L, Tomer A, et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004; 103:1364-1369.
  5. Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: Diagnosis and management. Pediatr Clin North Am. 2008; 55:393-420, ix.
  6. Fogarty PF, Segal JB. The epidemiology of immune thrombocytopenic purpura. Curr Opin Hematol. 2007; 14:515-519.
  7. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, et al. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med. 2000 Jun 12; 160(11):1630-1638.
  8. McMillan R. Therapy for adults with refractory chronic immune thrombocytopenic purpura. Ann Intern Med. 1997, 126(4):307–314.
  9. Wong GC, Lee LH. A study of idiopathic thrombocytopenic purpura (ITP) patients over a ten-year period. Ann Acad Med Singapore. 1998; 27(6):789–793.
  10. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006, 4(8):1664–1672.
  11. George JN. Treatment options for chronic idiopathic (immune) thrombocytopenic purpura. Seminars in hematology 2000; 37(1 Suppl 1):31–34.
  12. George JN, el-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. The New England journal of medicine. 1994; 331(18):1207–1211.
  13. Braendstrup P, Bjerrum OW, Nielsen OJ, et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. American Journal of Hematology. 2005; 78(4):275–280.
  14. Aledort LM, Lyons RM, Okano G, et al. Restrospective Matched Cohort Study of Immune Thrombocytopenic Purpura (ITP): Complications Related to Corticosteroid (CS) Use: Orlando, Florida. ; 2006.
  15. Kojouri K, Vesely SK, Terrell DR, et al. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004; 104(9):2623–2634.

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Last updated: 2018-06-21 17:12