Thrombocytopenia

Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes, also known as platelets, in the blood.[2]

Thrombocytopenia
Other namesThrombocytopaenia, thrombopenia
A picture of the blood under a microscope showing thrombocytopenia
A picture of the blood under a microscope showing thrombocytopenia
SpecialtyHematology
CausesBone marrow not making enough, body destroying platelets, spleen holding too many platelets[1]
Diagnostic methodComplete blood count[1]
TreatmentNone, immunosuppressants, platelet transfusion, surgical removal of the spleen[1]

A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood.[3] These limits are determined by the 2.5th lower and upper percentiles, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia requiring emergency treatment is a platelet count below 50,000 per microliter.[4] Thrombocytopenia can be contrasted with thrombocytosis, an abnormally high level of platelets in the blood.[5]

Signs and symptomsEdit

 
Petechia on the lower leg from thrombocytopenia
 
Right upper limb with purpura caused by thrombocytopenia in person with septic shock

Thrombocytopenia usually has no symptoms and is picked up on a routine full blood count (or complete blood count). Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, and/or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin.[6][7]

Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. Ensuring that the other blood cell types, such as red blood cells and white blood cells are not also suppressed, is also important.[6] Painless, round, and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue, or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body.[6]

A person with this disease may also complain of malaise, fatigue, and general weakness (with or without accompanying blood loss). Acquired thrombocytopenia may be associated with the use of certain drugs. Inspection typically reveals evidence of bleeding (petechiae or ecchymoses), along with slow, continuous bleeding from any injuries or wounds. Adults may have large, blood-filled bullae in the mouth.[8] If the person's platelet count is between 30,000 and 50,000/mm3, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm3, spontaneous bruising will be seen (mostly on the arms and legs).[9]

CausesEdit

Thrombocytopenia can be inherited or acquired.[10]

Decreased productionEdit

Abnormally low platelet production may be caused by:[11]

Increased destructionEdit

 
TTP

Abnormally high rates of platelet destruction may be due to immune or nonimmune conditions, including:[13]

Medication-inducedEdit

These medications can induce thrombocytopenia through direct myelosuppression:[14]

Other causesEdit

DiagnosisEdit

Laboratory tests for thrombocytopenia might include full blood count, liver enzymes, kidney function, vitamin B12 levels, folic acid levels, erythrocyte sedimentation rate, and peripheral blood smear. If the cause for the low platelet count remains unclear, a bone marrow biopsy is usually recommended to differentiate cases of decreased platelet production from cases of peripheral platelet destruction.[21]

Thrombocytopenia in hospitalized alcoholics may be caused by spleen enlargement, folate deficiency, and most frequently, the direct toxic effect of alcohol on production, survival time, and function of platelets.[22] Platelet count begins to rise after 2 to 5 days' abstinence from alcohol. The condition is generally benign, and clinically significant hemorrhage is rare.[citation needed]

In severe thrombocytopenia, a bone marrow study can determine the number, size, and maturity of the megakaryocytes. This information may identify ineffective platelet production as the cause of thrombocytopenia and rule out a malignant disease process at the same time.[23]

TreatmentEdit

Treatment is guided by the severity and specific cause of the disease. Treatment focuses on eliminating the underlying problem, whether that means discontinuing drugs suspected to cause it or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist. Corticosteroids may be used to increase platelet production. Lithium carbonate or folate may also be used to stimulate platelet production in the bone marrow.[24]

Platelet transfusionsEdit

Platelet transfusions can be used for people that suffer from thrombocytopenia. Researchers conducted some reviews to evaluate the use of platelet transfusions for people with thrombocytopenia or other hematological diseases while they received other treatments.

A Cochrane review, was conducted, with randomised controlled trials in 2018 to measure the safety and effectiveness of prophylactic platelet transfusions prior to surgery for adult people that suffer from a low platelet count. The participants did not receive a treatment of the low platelet count before and they did not suffer from a bleeding event in the past. Moreover the included people suffered from chronic diseases or haematological malignancies. The exact inclusion and exclusion criteria and information regarding the dose of the intervention can be found in the original Cochrane review. The review conducted three different analyses. The first analysis compared the prophylactic transfusion to no transfusion: The evidence is very uncertain about the effect of prophylactic platelet transfusions on the all-cause mortality up to 30 days after surgery, the number of participants with major bleeding within 7 days of surgery, the number of participants with a minor surgery-related bleeding up to 7 days and the serious adverse events that are surgery-related and occur within 30 days. The second analysis was conducted to compare prophylactic platelet transfusions to alternative treatments: Prophylactic platelet transfusions may have little to no effect on the number of participants that suffer from a major bleeding up to 7 days after surgery, the number of participants with a minor bleeding that is related to the procedure and occurs within 7 days after surgery and the transfusion-related serious adverse events within 24 hours, but the evidence is very uncertain. The last analysis compared different thresholds to determine whether participants received a platelet transfusion: The evidence is very uncertain about the effect of different thresholds for platelet transfusions on the number of participants that suffer from a major bleeding within 7 days of surgery and the number of participants that suffer from a minor procedure-related bleeding that occurs within 7 days.[25]   

Furthermore, another Cochrane review was conducted by comparing retrospective trials in 2018 to determine the effect of platelet transfusions prior to a lumbar puncture or epidural anaesthesia for participants that suffer from thrombocytopenia. There was no age restriction and the participants additionally suffered from leukaemia or other haematological malignancies. People were excluded from study participation if they already got the diagnosis of a coagulopathy or if they already had a bleeding event in the past. A review, conducted one analysis by comparing a platelet transfusion with no platelet transfusion: The evidence is very uncertain about the effect of platelet transfusions prior to lumbar puncture on major surgery-related bleeding within 24 hours and the surgery-related complications up to 7 days after the procedure.[26]

Yet another Cochrane review with randomised controlled trials in 2012 to assess which use of platelet transfusions is the most effective one to prevent bleeding if people suffer from a haematological disorder and undergo a stem cell transplantation or a chemotherapy. A study participation was only possible if the patients did not have an active bleeding within the last 5 days and did not receive a previous platelet transfusion because of the chemotherapy or stem cell transplantation. The exact inclusion and exclusion criteria and details regarding the dose can be found in the original Cochrane review. The review. conducted four analyses to answer their research question. In the first analysis they compared therapeutic/ non-prophylactic platelet transfusions to prophylactic platelet transfusions: The evidence suggests that therapeutic platelet transfusions result in little to no difference in the mortality secondary to bleeding. Furthermore, they may result in a slight reduction in the number of days on which a significant bleeding event occurred. The evidence suggests that therapeutic platelet transfusions result in a large increase in the number of patients with at least one significant bleeding event and they likely result in a large reduction in the number of platelet transfusions. In the second analysis, the review authors conducted a comparison of prophylactic platelet transfusions at threshold of 10.000 to a higher transfusion threshold (20.000 or 30.000): Prophylactic platelet transfusions at threshold of 10.000 may result in little to no difference in the mortality due to bleeding. These transfusions probably reduce the number of platelet transfusions per patient slightly. Prophylactic platelet transfusions at threshold of 10.000 probably increase the number of patients with at least one significant bleeding event and they likely result in a large increase in the number of days on which a significant bleeding event occurred. Prophylactic platelet transfusion with one dose schedules were compared to prophylactic platelet transfusions with another dose schedule in the third analysis: Prophylactic platelet transfusions at one dose schedule may result in little to no difference in the mortality secondary to bleeding if low dosage platelet transfusions are compared to standard dose platelet transfusions. Furthermore, the transfusions at one dose schedule probably result in little to no difference in the mortality secondary to bleeding if high dose platelet transfusions and standard dosage platelet transfusions are compared to each other. Prophylactic platelet transfusions with one dose schedule result in little to no difference in the number of participants with a significant bleeding event if low dosage platelet transfusions or high dosage platelet transfusions are compared to standard dose platelet transfusions. The last analysis was conducted to compare prophylactic platelet transfusions to platelet-poor plasma: The evidence is very uncertain about the effect of prophylactic platelet transfusion on mortality secondary to bleeding, the number of participants with a significant bleeding event and the number of platelet transfusions.[27] Moreover, the review. renewed the second analysis from their Cochrane review from 2012 in 2015 with randomised controlled trials and aimed to evaluate whether different platelet transfusion thresholds for the management of prophylactic platelet transfusions have an influence on the safety and efficacy for patients that suffer from a haematological disorder and receive a stem cell transplantation or myelosuppressive chemotherapy. The review. conducted the following analysis: Prophylactic platelet transfusion at threshold of 10.000 compared to higher transfusion threshold (20.000 or 30.000): The evidence suggests that prophylactic platelet transfusions at threshold of 10.000 result in little to no different in the time to the first bleeding episode, the number of participants with WHO Grade 3 or 4 bleeding and clinically significant bleedings per participant. The evidence suggests that prophylactic platelet transfusions at threshold of 10.000 reduce the number of platelet transfusions per participants slightly. Moreover, the evidence suggests that these transfusions increase the number of participants with at least one significant bleeding event. Prophylactic platelet transfusions at threshold of 10.000 may result in a large increase in the mortality due to all causes. Apart from the time to the first bleeding, all endpoints are related to the first 30 days after the study entry.[28]

Thrombotic thrombocytopenic purpuraEdit

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency, since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis,[29] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.[30]

Idiopathic thrombocytopenic purpuraEdit

 
Oral petechiae/purpura - Idiopathic thrombocytopenic purpura

Many cases of ITP can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.[31][32]

Thrombopoetin analogues have been tested extensively for the treatment of ITP. These agents had previously shown promise, but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.[33]

Heparin-induced thrombocytopeniaEdit

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis.[34] Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.[35] Warfarin is not recommended until platelets have normalized.[35]

Congenital amegakaryocytic thrombocytopeniaEdit

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.[36]

Human induced pluripotent stem cell-derived plateletsEdit

Human induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.[37]

Neonatal thrombocytopeniaEdit

Thrombocytopenia affects a few newborns, and its prevalence in neonatal intensive care units is high. Normally, it is mild and resolves without consequences. Most cases affect preterm birth infants and result from placental insufficiency and/or fetal hypoxia. Other causes, such as alloimmunity, genetics, autoimmunity, and infection, are less frequent.[38]

Thrombocytopenia that starts after the first 72 hours since birth is often the result of underlying sepsis or necrotizing enterocolitis.[38] In the case of infection, PCR tests may be useful for rapid pathogen identification and detection of antibiotic resistance genes. Possible pathogens include viruses (e.g. cytomegalovirus,[38] rubella virus,[38] HIV[38]), bacteria (e.g. Staphylococcus spp.,[39] Enterococcus spp.,[39] Streptococcus agalactiae,[38] Listeria monocytogenes,[38] Escherichia coli,[38][39] Haemophilus influenzae,[38] Klebsiella pneumoniae,[39] Pseudomonas aeruginosa,[39][40] Yersinia enterocolitica[40]), fungi (e.g. Candida spp.[39]), and Toxoplasma gondii.[38] The severity of thrombocytopenia may be correlated with pathogen type; some research indicates that the most severe cases are related to fungal or Gram-negative bacterial infection.[39] The pathogen may be transmitted during[41] or before birth, by breast feeding,[42][43][44] or during transfusion.[45] Interleukin-11 is being investigated as a drug for managing thrombocytopenia, especially in cases of sepsis or necrotizing enterocolitis (NEC).[38]

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