Idiopathic thrombocytopenic purpura
Encyclopedia
Idiopathic thrombocytopenic purpura (ITP) is the condition of having an abnormally low platelet
count (thrombocytopenia
) of no known cause (idiopathic
). As most incidents of ITP appear to be related to the production of antibodies
against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to describe this condition. Often ITP is asymptomatic
(devoid of obvious symptoms) and can be discovered incidentally, but a very low platelet count can lead to an increased risk of bleeding
and purpura
(large skin bruises).
ITP is diagnosed with a complete blood count
(a common blood test
). In some situations, additional investigations (such as a bone marrow biopsy
) may be necessary to ensure that the platelet count is not decreased due to other reasons. Treatment may not be necessary in mild cases, but very low counts or significant bleeding might prompt treatment with steroids
, intravenous immunoglobulin
, anti-D immunoglobulin
, or stronger immunosuppresive drugs. Refractory ITP (ITP not responsive to conventional treatment) may require splenectomy
, the surgical removal of the spleen. Platelet transfusions
may be used in severe bleeding together with a very low count.
(purpura) and petechia
e (tiny bruises), especially on the extremities
, bleeding from the nostrils, bleeding at the gums, and menorrhagia
(excessive menstrual bleeding
), any of which may occur if the platelet count is below 20,000 per μl. A very low count (<10,000 per μl) may result in the spontaneous formation of hematoma
s (blood masses) in the mouth or on other mucous membrane
s. Bleeding time from minor lacerations or abrasions is usually prolonged.
Serious and possibly fatal complications
due to an extremely low count (<5,000 per μl) may include subarachnoid
or intracerebral hemorrhage (bleeding inside the skull
or brain
), lower gastrointestinal bleeding
or other internal bleeding. An ITP patient with an extremely low count is vulnerable to internal bleeding caused by blunt abdominal trauma
, as might be experienced in a motor vehicle crash. These complications are not likely in a patient whose platelet count is above 20,000 per μl.
but autoimmune, with antibodies against platelets being detected in approximately 60 percent of patients. Most often these antibodies are against platelet membrane glycoprotein
s IIb-IIIa or Ib-IX, and are of the immunoglobulin G
(IgG) type. The famous Harrington–Hollingsworth experiment
established the immune pathogenesis
of ITP.
The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic
macrophage
s, as well by Kupffer cell
s in the liver
. The IgG autoantibodies are also thought to damage megakaryocyte
s, the precursor cells to platelets, but this is thought 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 drugs referred to as thrombopoietin receptor
agonist
s.
The stimulus for auto-antibody production in ITP is probably abnormal T cell
activity. Preliminary findings suggest that these T cells can be influenced by drugs that target B cell
s, such as rituximab
.
has to determine that there are no blood abnormalities other than low platelet count, and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5–10 percent of suspected ITP cases) should be excluded. Secondary causes could be leukemia
, medications (e.g., quinine
, heparin
), lupus erythematosus
, cirrhosis
, HIV
, hepatitis
C, congenital causes, antiphospholipid syndrome
, von Willebrand factor
deficiency, onyalai
and others. In approximately one percent of cases, autoimmune hemolytic anemia
and ITP coexist, a condition referred to as Evans syndrome
.
Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate 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. A normal bleeding time does not exclude a platelet disorder.
A 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. On examination of the bone 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.
ization may be recommended in cases of very low counts, and is highly advisable if significant internal or mucocutaneous bleeding has developed. A count below 10,000 per μl is potentially a medical emergency
, as the individual may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma. In most cases, treatment will be administered under the direction of a hematologist. Dexamethasone
1mg/Kg for 3 days and 0.5 mg/Kg for 3 days and Prednisone
1-2 mg/Kg per day upto a month.Dosage of Prednisone medication is decreased accordingly.
s, such as methylprednisolone
or prednisone
. A platelet infusion may be administered in an emergency bleeding situation in an attempt to quickly raise the count. After the platelet count has increased to a safe level, an orally administered steroid, such as prednisone (1–2 mg/kg per day), is usually prescribed
. Most cases will respond during the first week of treatment. After several weeks of oral steroid therapy, the dose will be gradually reduced. However, 60 to 90 percent of patients will relapse after the dose has been decreased below 0.25 mg/kg per day and subsequently stopped. Continued use of steroids can result in severe dependence, as well as numerous side-effects.
patients is treatment with Rho(D) immune globulin
(Anti-D), which is intravenously administered. Anti-D is normally administered to Rh-negative women during pregnancy
and after the birth of an Rh-positive infant
to prevent sensitization to the Rh factor in the newborn. Anti-D has been demonstrated effective on some ITP patients, but is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.
and azathioprine
are becoming more popular for their effectiveness. In chronic refractory cases where the immune pathogenesis has been confirmed, the off-label use of vincristine
, a chemotherapy
agent, may be attempted. However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution, especially in children.
Intravenous immunoglobulin
(IVIg) may be infused in some cases. IVIg, while sometimes effective, is costly and produces a short-term improvement that generally lasts less than a month. However, in the case of an ITP patient scheduled for surgery
who has a dangerously low platelet count and has experienced a poor response to other treatments, IVIg can increase the count and reduce bleeding risk.
receptor agonists are pharmaceutical agent
s that treat ITP by stimulating platelet production instead of attempting to curtail platelet destruction. As of 2011, two such products are available:
Medicare
in the USA will cover most of the cost of romiplostim or eltrombopag treatment under Part-A.
(removal of the spleen
) may be considered, as platelets targeted for destruction will usually meet their fate in the spleen. 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 to 65 percent of ITP cases, less so in older subjects. As noted in the introduction, the use of splenectomy to treat ITP has diminished since the development of steroid therapy and other pharmaceutical remedies.
(which normally inhabits the stomach wall and has been associated with peptic ulcer
s), 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. The response rate found in a systematic review of the literature is similar to that of rituximab, but with a lower toxicity and cost. In children, this approach is not supported by evidence, except in high prevalence areas. Urea breath test
ing and stool antigen testing perform better than serology
-based tests; moreover, serology may be false-positive after treatment with IVIG.
The incidence of ITP is estimated at 50–100 new cases per million per year, with children accounting for half of that amount. At least 70 percent of childhood cases will end up in remission within six months, even without treatment. 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).
ITP is usually chronic in adults and the probability of durable remission is 20–40 percent. The male to female ratio in the adult group varies from 1:1.2 to 1.7 in most age ranges (childhood cases are roughly equal for both genders) and the median age of adults at the diagnosis is 56–60. The ratio between male and female adult cases tends to widen with age. In the USA, the adult chronic population is thought to be approximately 60,000—with women outnumbering men approximately 2 to 1, which has resulted in ITP being designated an orphan disease.
The mortality rate
due to chronic ITP varies but tends to be higher relative to the general population for any age range. In a study conducted in Great Britain
, it was noted that ITP causes an approximately 60 percent higher rate of mortality compared to gender- and age-matched subjects without ITP. This increased risk of death with ITP is largely concentrated in the middle-aged
and 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.
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. The name "Werlhof's disease" was used more widely before the current descriptive name became more popular. Platelets were described in the early 19th century, and in the 1880s several investigators linked the purpura with abnormalities in the platelet count. 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
. Splenectomy remained a first-line remedy until the introduction of steroid
therapy in the 1950s.
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count (thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
) of no known cause (idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
). As most incidents of ITP appear to be related to the production of antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to describe this condition. Often ITP is asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
(devoid of obvious symptoms) and can be discovered incidentally, but a very low platelet count can lead to an increased risk of bleeding
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...
and purpura
Purpura
Purpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin...
(large skin bruises).
ITP is diagnosed with a complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(a common blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
). In some situations, additional investigations (such as a bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
) may be necessary to ensure that the platelet count is not decreased due to other reasons. Treatment may not be necessary in mild cases, but very low counts or significant bleeding might prompt treatment with steroids
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
, intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
, anti-D immunoglobulin
Rho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...
, or stronger immunosuppresive drugs. Refractory ITP (ITP not responsive to conventional treatment) may require splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
, the surgical removal of the spleen. Platelet transfusions
Plateletpheresis
Plateletpheresis is the process of collecting thrombocytes, more commonly called platelets, a component of blood involved in blood clotting...
may be used in severe bleeding together with a very low count.
Signs and symptoms
Visible symptoms of ITP include the spontaneous formation of bruisesPurpura
Purpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin...
(purpura) and petechia
Petechia
A petechia is a small red or purple spot on the body, caused by a minor hemorrhage ."Petechiae" refers to one of the three major classes of purpuric skin conditions. Purpuric eruptions are classified by size into three broad categories...
e (tiny bruises), especially on the extremities
Limb (anatomy)
A limb is a jointed, or prehensile , appendage of the human or other animal body....
, bleeding from the nostrils, bleeding at the gums, and menorrhagia
Menorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
(excessive menstrual bleeding
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
), any of which may occur if the platelet count is below 20,000 per μl. A very low count (<10,000 per μl) may result in the spontaneous formation of hematoma
Hematoma
A hematoma, or haematoma, is a localized collection of blood outside the blood vessels, usually in liquid form within the tissue. This distinguishes it from an ecchymosis, which is the spread of blood under the skin in a thin layer, commonly called a bruise...
s (blood masses) in the mouth or on other mucous membrane
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
s. Bleeding time from minor lacerations or abrasions is usually prolonged.
Serious and possibly fatal complications
Complication (medicine)
Complication, in medicine, is an unfavorable evolution of a disease, a health condition or a medical treatment. The disease can become worse in its severity or show a higher number of signs, symptoms or new pathological changes, become widespread throughout the body or affect other organ systems. A...
due to an extremely low count (<5,000 per μl) may include subarachnoid
Subarachnoid hemorrhage
A subarachnoid hemorrhage , or subarachnoid haemorrhage in British English, is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain...
or intracerebral hemorrhage (bleeding inside the skull
Skull
The skull is a bony structure in the head of many animals that supports the structures of the face and forms a cavity for the brain.The skull is composed of two parts: the cranium and the mandible. A skull without a mandible is only a cranium. Animals that have skulls are called craniates...
or brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
), lower gastrointestinal bleeding
Lower gastrointestinal bleeding
Lower gastrointestinal bleeding, commonly abbreviated LGIB, refers to any form of bleeding in the lower gastrointestinal tract. LGIB is a common ailment seen at emergency departments. It presents less commonly than upper gastrointestinal bleeding . It is estimated that UGIB accounts for 100-200 per...
or other internal bleeding. An ITP patient with an extremely low count is vulnerable to internal bleeding caused by blunt abdominal trauma
Abdominal trauma
Abdominal trauma is an injury to the abdomen. It may be blunt or penetrating and may involve damage to the abdominal organs. Signs and symptoms include abdominal pain, tenderness, rigidity, and bruising of the external abdomen. Abdominal trauma presents a risk of severe blood loss and infection...
, as might be experienced in a motor vehicle crash. These complications are not likely in a patient whose platelet count is above 20,000 per μl.
Pathogenesis
In many cases, ITP's cause is not idiopathicIdiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
but autoimmune, with antibodies against platelets being detected in approximately 60 percent of patients. Most often these antibodies are against platelet membrane glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s IIb-IIIa or Ib-IX, and are of the immunoglobulin G
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
(IgG) type. The famous Harrington–Hollingsworth experiment
Harrington–Hollingsworth Experiment
The Harrington–Hollingsworth experiment was an experiment that established the autoimmune nature of the blood disorder immune thrombocytopenic purpura. It was performed in 1950 by the academic staff of Barnes-Jewish Hospital in St. Louis, Missouri.-Experiment:...
established the immune pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of ITP.
The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, as well by Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...
s in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. The IgG autoantibodies are also thought to damage megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s, the precursor cells to platelets, but this is thought to contribute only slightly to the decrease in platelet numbers. Recent research now indicates that impaired production of the glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
thrombopoietin
Thrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
, 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 drugs referred to as thrombopoietin receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s.
The stimulus for auto-antibody production in ITP is probably abnormal T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
activity. Preliminary findings suggest that these T cells can be influenced by drugs that target B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s, such as rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
.
Diagnosis
The diagnosis of ITP is a process of exclusion. First, the clinicianPhysician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
has to determine that there are no blood abnormalities other than low platelet count, and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5–10 percent of suspected ITP cases) should be excluded. Secondary causes could be leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, medications (e.g., quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
), lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
C, congenital causes, antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome , often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots in both arteries and veins as well as pregnancy-related complications such as...
, von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
deficiency, onyalai
Onyalai
Onyalai is a form of thrombocytopenia that affects some of the population in areas of central Africa. Onyalai exhibits similarities to idiopathic thrombocytopenic purpura but differs in pathogenesis. The affected age range is from less than a year to 70 years and seems to not be...
and others. In approximately one percent of cases, autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...
and ITP coexist, a condition referred to as Evans syndrome
Evans syndrome
Evans syndrome is an autoimmune disease in which an individual's antibodies attack their own red blood cells and platelets. Both of these events may occur simultaneously or one follow on from the other....
.
Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate 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. A normal bleeding time does not exclude a platelet disorder.
A bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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. On examination of the bone 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.
Treatment
A platelet count below 20,000 per μl is generally an indication for treatment. Patients with a count between 20,000 and 50,000 per μl are usually evaluated on a case-by-case basis, and, with rare exceptions, there is usually no need to treat patients with a count above 50,000 per μl. HospitalHospital
A hospital is a health care institution providing patient treatment by specialized staff and equipment. Hospitals often, but not always, provide for inpatient care or longer-term patient stays....
ization may be recommended in cases of very low counts, and is highly advisable if significant internal or mucocutaneous bleeding has developed. A count below 10,000 per μl is potentially a medical emergency
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...
, as the individual may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma. In most cases, treatment will be administered under the direction of a hematologist. Dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
1mg/Kg for 3 days and 0.5 mg/Kg for 3 days and Prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
1-2 mg/Kg per day upto a month.Dosage of Prednisone medication is decreased accordingly.
Steroids
Treatment usually is initiated with intravenous corticosteroidCorticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, such as methylprednisolone
Methylprednisolone
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....
or prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
. A platelet infusion may be administered in an emergency bleeding situation in an attempt to quickly raise the count. After the platelet count has increased to a safe level, an orally administered steroid, such as prednisone (1–2 mg/kg per day), is usually prescribed
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
. Most cases will respond during the first week of treatment. After several weeks of oral steroid therapy, the dose will be gradually reduced. However, 60 to 90 percent of patients will relapse after the dose has been decreased below 0.25 mg/kg per day and subsequently stopped. Continued use of steroids can result in severe dependence, as well as numerous side-effects.
Anti-D
Another strategy that is suitable for Rh-positiveRhesus blood group system
The Rh blood group system is one of thirty current human blood group systems. Clinically, it is the most important blood group system after ABO. At Present, the Rh blood group system consists of 50 defined blood-group antigens, among which the 5 antigens D, C, c, E, and e are the most important...
patients is treatment with Rho(D) immune globulin
Rho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...
(Anti-D), which is intravenously administered. Anti-D is normally administered to Rh-negative women during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and after the birth of an Rh-positive infant
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
to prevent sensitization to the Rh factor in the newborn. Anti-D has been demonstrated effective on some ITP patients, but is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.
Steroid-sparing agents
Immunosuppresants such as mycophenolate mofetilMycophenolic acid
Mycophenolic acid INN or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug mycophenolate mofetil to improve oral bioavailability. More...
and azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
are becoming more popular for their effectiveness. In chronic refractory cases where the immune pathogenesis has been confirmed, the off-label use of vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
, a chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agent, may be attempted. However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution, especially in children.
Intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
(IVIg) may be infused in some cases. IVIg, while sometimes effective, is costly and produces a short-term improvement that generally lasts less than a month. However, in the case of an ITP patient scheduled for surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
who has a dangerously low platelet count and has experienced a poor response to other treatments, IVIg can increase the count and reduce bleeding risk.
Thrombopoietin receptor agonists
ThrombopoietinThrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
receptor agonists are pharmaceutical agent
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
s that treat ITP by stimulating platelet production instead of attempting to curtail platelet destruction. As of 2011, two such products are available:
- RomiplostimRomiplostimRomiplostim is a fusion protein analog of thrombopoietin, a hormone that regulates platelet production. The drug was developed by Amgen and is marketed under the trade name Nplate through a restricted usage program called NEXUS...
(trade name Nplate) is a thrombopoiesisThrombopoiesisThrombopoiesis refers to the process of thrombocyte generation.Thromobocytes are ligations of the cytoplasm from megakaryocytes. A single megakaryocyte can give rise to thousands of thrombocytes....
stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injectionSubcutaneous injectionA subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
. Designated an orphan drugOrphan drugAn orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
in 2003 under USA law, clinical trials demonstrated romiplostim to be effective in treating chronic ITP, especially in relapsed post-splenectomy patients. Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.
- EltrombopagEltrombopagEltrombopag is a medication that has been developed for conditions that lead to thrombocytopenia . It is a small molecule agonist of the c-mpl receptor, which is the physiological target of the hormone thrombopoietin...
(trade name Promacta) is an orally-administered agent with an effect similar to that of romiplostim. It too has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. Developed by GlaxoSmithKlineGlaxoSmithKlineGlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.
Medicare
Medicare (United States)
Medicare is a social insurance program administered by the United States government, providing health insurance coverage to people who are aged 65 and over; to those who are under 65 and are permanently physically disabled or who have a congenital physical disability; or to those who meet other...
in the USA will cover most of the cost of romiplostim or eltrombopag treatment under Part-A.
Surgery
SplenectomySplenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
(removal of the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
) may be considered, as platelets targeted for destruction will usually meet their fate in the spleen. 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 to 65 percent of ITP cases, less so in older subjects. As noted in the introduction, the use of splenectomy to treat ITP has diminished since the development of steroid therapy and other pharmaceutical remedies.
Experimental and novel agents
- DapsoneDapsoneDapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
(also called diphenylsulfone, DDS, or avlosulfon) is an anti-infective sulfone drug. In recent years, Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and has had some application as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts in 40–50 percent of patients administered the drug. - The off-label use of rituximabRituximabRituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
, a chimeric monoclonal antibody against the B cellB cellB cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
surface antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
CD20CD20B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
, has been shown in preliminary studies to be an effective alternative to splenectomy in some patients. However, many patients experience significant side-effectsAdverse effect (medicine)In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
, there is a small risk of fatality due to progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
caused by a reactivated JC virusJC virusThe JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
, and randomized controlled trials have yet to be conducted. - Promising results have been reported in a small phase II study of the experimental kinase inhibitor tamatinib fosdium (R788). In a population of 14 patients refractory to other treatments (ten of them having relapsed following splenectomy), nine responded to tamatinib and six achieved platelet counts greater than 100,000.
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.H. pylori eradication
In adults, particularly those living in areas with a high prevalence of Helicobacter pyloriHelicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
(which normally inhabits the stomach wall and has been associated with peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
s), 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. The response rate found in a systematic review of the literature is similar to that of rituximab, but with a lower toxicity and cost. In children, this approach is not supported by evidence, except in high prevalence areas. Urea breath test
Urea breath test
The urea breath test is a rapid diagnostic procedure used to identify infections by Helicobacter pylori, a spiral bacterium implicated in gastritis, gastric ulcer, and peptic ulcer disease. It is based upon the ability of H. pylori to convert urea to ammonia and carbon dioxide...
ing and stool antigen testing perform better than serology
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
-based tests; moreover, serology may be false-positive after treatment with IVIG.
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.The incidence of ITP is estimated at 50–100 new cases per million per year, with children accounting for half of that amount. At least 70 percent of childhood cases will end up in remission within six months, even without treatment. 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).
ITP is usually chronic in adults and the probability of durable remission is 20–40 percent. The male to female ratio in the adult group varies from 1:1.2 to 1.7 in most age ranges (childhood cases are roughly equal for both genders) and the median age of adults at the diagnosis is 56–60. The ratio between male and female adult cases tends to widen with age. In the USA, the adult chronic population is thought to be approximately 60,000—with women outnumbering men approximately 2 to 1, which has resulted in ITP being designated an orphan disease.
The mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
due to chronic ITP varies but tends to be higher relative to the general population for any age range. In a study conducted in Great Britain
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, it was noted that ITP causes an approximately 60 percent higher rate of mortality compared to gender- and age-matched subjects without ITP. This increased risk of death with ITP is largely concentrated in the middle-aged
Middle age
Middle age is the period of age beyond young adulthood but before the onset of old age. Various attempts have been made to define this age, which is around the third quarter of the average life span of human beings....
and 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.
History
After initial reports by the Portugese physician Amato LusitanoAmato Lusitano
João Rodrigues de Castelo Branco, better known as Amato Lusitano and Amatus Lusitanus , was a notable Portuguese Jewish physician of the 16th century. Like Herophilus, Galen, Ibn al-Nafis, Michael Servetus, Realdo Colombo and William Harvey, he is credited as making a discovery in the circulation...
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
Paul Gottlieb Werlhof
Paul Gottlieb Werlhof was a German physician and poet who was a native of Helmstedt. He studied medicine at the University of Helmstedt under Lorenz Heister and Brandanus Meibom , who was the son of Heinrich Meibom . After completing his studies, he practiced medicine in Peine for four...
who in 1735 wrote the most complete initial report of the purpura of ITP. Platelets were unknown at the time. The name "Werlhof's disease" was used more widely before the current descriptive name became more popular. Platelets were described in the early 19th century, and in the 1880s several investigators linked the purpura with abnormalities in the platelet count. The first report of a successful therapy for ITP was in 1916, when a young Polish
Poland
Poland , officially the Republic of Poland , is a country in Central Europe bordered by Germany to the west; the Czech Republic and Slovakia to the south; Ukraine, Belarus and Lithuania to the east; and the Baltic Sea and Kaliningrad Oblast, a Russian exclave, to the north...
medical student, Paul Kaznelson
Paul Kaznelson
Paul Kaznelson was a Polish-born Czech scientist is credited with describing the first case of pure red cell aplasia. He is also known for his contribution to the discovery of the therapeutic role of splenectomy in idiopathic thrombocytopenic purpura.Much of his academic work appeared in the 1920s...
, described a female patient's response to a splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
. Splenectomy remained a first-line remedy until the introduction of steroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
therapy in the 1950s.
Synonyms
ITP is known by a number of synonyms, but idiopathic or immune thrombocytopenic purpura are the most common names. Others include: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura and thrombocytolytic purpura.External links
- The ITP Foundation - A nonprofit organization dedicated to helping children with Immune Thrombocytopenic Purpura
- ITPeducation.com This educational curriculum is designed to provide evidence-based clinical information on the diagnosis and management of patients with ITP to hematologists, oncologists, and other health care professionals
- Platelet Disorder Support Association A non-profit corporation to provide information, support, and encourage research about ITP and other platelet disorders
- ITP Support Association. A UK registered charity which aims to promote and improve the general welfare of patients, and the families of patients, with Idiopathic Thrombocytopenic Purpura.