Non-Immune-Mediated Platelet Destruction
Some of the common types of non-immune-mediated platelet destruction, including disorders that ‘look’ like ITP include:
Disseminated Intravascular Coagulopathy (DIC)
DIC is the abnormal formation of small blood clots within the blood vessels. This process consumes clotting factors and platelets resulting in a reduced platelet count and increased bleeding. DIC can result from a variety of infections, traumas, diseases, and some drugs.
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Thrombotic Thrombocytopenia Purpura (TTP)/Hemolytic Uremic Syndrome
These related diseases are both characterized by low platelet counts, fragmentation and destruction of red blood cells and organ damage, especially the kidneys. TTP can be caused by the inhibition or an inherited defect of the von Willebrand Factor cleaving enzyme, ADAMTS13 and some drugs. HUS is seen more frequently in children after a bacterial infection.
Resources:
- TTP Network
- www.AnsweringTTP.org
- https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura
- https://rarediseases.org/rare-diseases/thrombotic-thrombocytopenic-purpura/
- https://www.ncbi.nlm.nih.gov/books/NBK556038/
- https://rarediseases.org/rare-diseases/atypical-hemolytic-uremic-syndrome/
- https://www.ahuscanada.org/
Liver Disease and Splenomegaly (enlarged spleen)
Liver disease is a common cause for thrombocytopenia. One reason is because thrombopoietin, a protein that stimulates the body to make platelets, is made in the liver. When a person has liver disease, they have a reduced amount of thrombopoietin and consequently, a reduced number of platelets. Another reason why liver disease can lead to a low platelet count includes that portal hypertension (which is increased pressure in the liver’s portal vein), often due to liver cirrhosis, leads to spleen enlargement and the sequestration of platelets in the spleen. The larger the spleen, the lower the platelet count.
Resources:
- https://www.aasld.org/
- https://www.liver.ca/
- https://rarediseases.info.nih.gov/diseases/7684/splenomegaly
Henoch Schönlein Purpura (HSP)
Henoch Schönlein Purpura (HSP) is a type of vasculitis, which means inflammation of the blood vessels. It does not cause platelet destruction, and symptoms are not due to a low platelet count although they may resemble ITP symptoms. The classic symptom of HSP is a red to dark purple rash, called “purpura”, which is often most severe on the legs and buttocks. Other symptoms include painful swelling around the joints and abdominal pain. Many children with HSP recover completely, but up to one-third of patients can develop kidney disease. Treatment depends on the individual child’s symptoms. Monitoring for kidney disease plays an important role in early detection and treatment if this complication happens.
In North America, HSP is the most common form of vasculitis in children. It is most common in ages 3-15 years and is more common in boys than girls. It rarely occurs in adults. HSP can occur at any time of the year, though it is more common in the winter.
Resources:
- https://rarediseases.org/rare-diseases/henoch-schonlein-purpura/
- https://www.hopkinsvasculitis.org/types-vasculitis/henochschnlein-purpura/
- https://rarediseases.info.nih.gov/diseases/8204/henoch-schonlein-purpura
Pseudothrombocytopenia
Pseudothrombocytopenia is a misdiagnosis of thrombocytopenia due to platelet clumping caused by a reaction to chemicals in the laboratory sampling collection process, rather than by a disease affecting platelet production or destruction. The clumping causes the automatic counters to undercount platelets which is why most places will not run the test if there is clotting in the tube. This is a lab error and not a representation of an underlying platelet disorder.
Substance-Induced Thrombocytopenia
While the specific cause behind why ITP develops is usually unknown and can differ from person to person, it is known that numerous medications can cause a short term low platelet count. Although not common, more than 100 drugs as well as some herbal remedies and certain foods have been shown to trigger thrombocytopenia.
Some of the more common types of substance-induced thrombocytopenia include:
Heparin-Induced Thrombocytopenia
Many hospitalized patients receive heparin to prevent clotting. When antibodies form against heparin, they can also bind to a protein on platelets causing them to become very sticky. This process may cause life-threatening clots.
Alcohol-Induced Thrombocytopenia
Drinking alcoholic beverages regularly and in higher than recommended quantity has been shown to cause bone marrow suppression, defective platelet formation, a decrease the lifespan of a platelet leading to premature removal from the body, and impaired platelet function. When repeated over many years, alcohol consumption can damage the liver, the organ responsible for making clotting factors and thrombopoietin, the protein that stimulates platelet production.
Vaccine-Induced Thrombocytopenia
The measles, mumps, and rubella (MMR) vaccination has been shown to cause thrombocytopenia in one of 25,000 to 40,000 vaccinations. There are also reports of low platelets resulting from the pneumonia, H influenzae B, varicella zoster virus (VZV), hepatitis B vaccinations, and even the SARS-CoV-2 vaccines.
Drug-Induced Thrombocytopenia
Almost all chemotherapy drugs used to treat cancer will affect the bone marrow, resulting in impaired platelet production. In other cases, the body can develop a cross-reaction to the medication and develop antibodies to both the drug and platelets.
Toxin-Induced Thrombocytopenia
Many chemicals, both naturally occurring as well as those used in everything from industrial production to lawn care, have been shown to trigger autoimmunity of one type or another.
Food-Induced Thrombocytopenia
Some foods, particularly those that contain quinine (such as tonic water, bitter melon) or aspartame (sweeteners used in diet soda) have been shown to trigger low platelets. Also, food sensitivity or allergies may create a heightened immune response that may lead to a reduced platelet count.
Resources:
- https://www.nhlbi.nih.gov/health/thrombocytopenia
- https://www.ijidonline.com/article/S1201-9712(20)30629-9/pdf
- https://www.itpsupport.org.uk/index.php/en/vaccinations-and-itp
Low Platelets Caused by Infectious Diseases
Most of the time, when thrombocytopenia is caused by bacteria or a virus, the approach is to treat the underlying infection. In all cases, these infections are accompanied by other symptoms not associated with ITP, even though a low platelet count maybe one of the first presenting symptoms.
Human Immunodeficiency Virus (HIV) & Acquired Immunodeficiency Syndrome (AIDS)
HIV and AIDS have been shown to cause a low platelet count. It is a common complication of HIV infection, in addition to the medicines used to treat HIV and AIDS. In fact, often the low platelet count is due to thrombotic thrombocytopenia purpura (TTP). The mechanism causing a low platelet count from HIV/AIDS infection includes immune-mediated platelet destruction, decreased platelet production, and effects of the various drugs use.
Resources:
- The Foundation for AIDS Research
- https://www.aidshealth.org/
- https://academic.oup.com/inthealth/article/13/2/98/5867538
- https://ashpublications.org/hematology/article/2008/1/212/95865/Viral-Associated-Immune-Thrombocytopenic-Purpura
Hepatitis C
The liver makes a protein called thrombopoietin, that prompts the bone marrow to release platelets and clotting factors needed for bleeding to stop. Liver disease such as hepatitis C can cause both thrombocytopenia and increase clotting time. Hepatitis C can be mistaken for ITP.
Resources:
- https://liverfoundation.org/liver-diseases/viral-hepatitis/hepatitis-c/support-for-patients-with-hepatitis-c/
- https://www.liver.ca/professionals/health-professionals/hep-c-resource-centre-healthcare-professionals/
- https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438357/
Malaria
Malaria is an infectious disease transmitted by mosquitos usually found in tropical or sub-tropical climates.
Resources:
- https://www.who.int/teams/global-malaria-programme
- https://www.malariaconsortium.org/
- https://www.scielo.br/j/mioc/a/374jCNsfHzv54BXQ7RkRsFK/?lang=en
Tick-Borne Diseases (Lyme Disease)
Ticks are small, wingless parasites that feed on blood and are found all over the world. Ticks can be infected with bacteria, viruses, or parasites and can easily transmit these infectious organisms to humans and other animals through their bite. It is not uncommon for an individual tick to harbor more than one infectious microorganism and infect the patient with multiple pathogens at the same time, compounding the difficulty in diagnosis and treatment. Low platelets are present in nearly all tick-borne illnesses. Diseases caused by tick-borne pathogens in the United States include Lyme disease, Babesiosis, Ehrlichiosis, Rocky Mountain Spotted Fever, Southern Tick-Associated Rash Illness, Tick-Borne Relapsing Fever, Tularemia, Anaplasmosis, Colorado tick fever, Powassan encephalitis and Q fever.
Resources:
- https://www.lymeactionnetwork.org/co-infections/
- https://academic.oup.com/ofid/article/5/suppl_1/S239/5207518
- https://aldf.com/
Helicobacter Pylori (H. pylori)
Helicobacter pylori (H. pylori) is a bacterium widely associated and studied in conjunction with ITP. There are numerous reports of people diagnosed with ITP, particularly in Italy and Japan, who have recovered after being treated for H. pylori.
Resources:
- Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review
- Helicobacter pylori and ITP: many questions, few answers
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732399/
- https://ashpublications.org/hematology/article/2008/1/206/95856/Helicobacter-pylori-and-Chronic-ITP
Dengue Hemorrhagic Fever
A more severe form of dengue fever, dengue hemorrhagic fever, transmitted by mosquitos, includes thrombocytopenia, petechiae, and bruising among its symptoms. Prior immunity to dengue fever plays a role in developing this more serious variety.
Resources:
- https://apps.who.int/iris/bitstream/handle/10665/164033/dbv29p136.pdf;jsessionid=CE8A5D537BA9788567A2BC20D29EB400?sequence=1
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067496/
Cytomegalovirus (CMV)
Cytomegalovirus (CMV) is a type of herpes virus, and like the other viruses in this family, it can remain dormant in the body for a long period of time.
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Parvovirus B19
Parvovirus B19 is transmitted by humans via respiratory droplets and is associated with low platelets and petechia rash. Parvovirus in animals is not transmitted to humans.
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Hantavirus
Hantavirus is transmitted to humans through rodent bites, urine, saliva or waste.
Resources for Hantavirus, CMV, Parvovirus B19, and other infectious causes of thrombocytopenia:
- https://www.frontiersin.org/articles/10.3389/fimmu.2014.00649/full
- https://pdfs.semanticscholar.org/7f8a/72dea0026eb15298e4c7d745f293f7e76321.pdf
- https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(15)00536-4/fulltext
Immune-Mediated Platelet Destruction
In addition to ITP, there are other diseases where the immune system causes platelet destruction in the bone marrow or in circulation, resulting in thrombocytopenia. Common types of immune-mediated platelet destruction include:
Acquired aplastic anemia
Aplastic anemia is a group of inherited and acquired disorders characterized by pancytopenia, low blood cell counts for all blood cell types. Evidence is accumulating that the disorder is immune mediated.
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Fetal Neonatal Alloimmune Thrombocytopenic Purpura (FNAIT)
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition that results from incompatibility between the expecting mother and her developing baby for platelet-specific antigens. The condition affects 1 out of every 1,000 births in North American. FNAIT is a blood-related condition that leads to the formation of maternal antibodies that result in the developing baby having thrombocytopenia either before or soon after being born. It is a result of an antigen inherited from the father (most commonly HPA-1a) that the babies biological mother lacks. Maternal immunoglobulin G antibodies against this antigen from the biological father form, causing a low platelet count in the baby. The condition in both the fetus and newborn can range from mild thrombocytopenia to severe thrombocytopenia (very low platelet count) with spontaneous bleeding. Typically, the pregnant mother is healthy, and has a normal platelet count, however the fetus or newborn is affected by a low platelet count with variable bleeding symptoms.
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Post-Transfusion Purpura (PTP)
A rare complication of blood transfusions, post-transfusion purpura (PTP) is characterized by severe thrombocytopenia occurring several days to a week after receiving blood or platelets. This condition generally occurs in women who have previously developed antibodies against foreign platelets during pregnancy (called ‘alloantigens’). These individuals do not have problems until they are exposed to foreign platelets by transfusion later in life. The immune response affects not only the transfused platelets, but also the patient’s own platelets.
Resources:
- https://www.blood.ca/en/laboratory-services/post-transfusion-purpura-investigation
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910090/
- https://www.blood.gov.au/system/files/documents/Factsheet-Health-Professionals-Post-transfusion-purpura-PTP-v1.pdf
- https://ashpublications.org/blood/article/122/21/4834/13421/Diagnosis-and-Management-Of-POST-Transfusion
Cyclic (cyclical) Thrombocytopenia
Cyclic thrombocytopenia is a rare platelet disorder characterized by regular fluctuations in platelet count often, but not necessarily, coinciding with a menstrual cycle.
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Common Variable Immune Deficiency (CVID)
Common variable immune deficiency is an immune disorder that may be inherited in some cases. It is characterized by a low level of protective antibodies, recurrent infections and possibly a large spleen. About 25 percent of people with this type of immune deficiency develop ITP.
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Low Platelets Associated with Other Autoimmune Diseases
Autoimmune diseases that sometimes lead to a low platelet count or can occur alongside ITP as a co-existing separate autoimmune condition:
Hashimoto’s Thyroiditis
Hashimoto’s thyroiditis is the most common autoimmune condition and the leading cause of hypothyroidism or an underactive thyroid. ITP may be difficult to treat when associated with thyroid autoimmune disorders, such as Hashimoto’s. In such cases, treating the underlying thyroid disorder may significantly improve platelet count and can either cause remission of disease or improve response to standard ITP therapy.
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Celiac (Coeliac) Disease
Celiac (coeliac) disease, also known as gluten intolerance, is an autoimmune disease of the small bowel caused by a cross-reaction to the gluten in wheat, barley, rye and similar grains.
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Evans Syndrome
Evans syndrome is the combination of autoimmune thrombocytopenia (ITP) and autoimmune destruction of red blood cells (hemolytic anemia).
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Antiphospholpid syndrome (APS)
Antiphospholipid antibodies, those that attack particular cell membranes, can lead to blood clots in the veins and arteries. From 20 to 70 percent of people diagnosed with ITP also have APS, and approximately 25 percent of people with APS develop thrombocytopenia. Due to this, it is important to test for both anticardiolipin and lupus anticoagulant.
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Systemic lupus erythematosus (SLE)
Approximately 25% of patients with SLE, commonly called Lupus, develop thrombocytopenia for a wide variety of reasons related to the pathology of the disease.
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Thyroid (non-Hashimoto’s) disease
Both an over-functioning thyroid gland and an under-functioning thyroid gland have been associated with thrombocytopenia. Thyroid problems are more prevalent in people diagnosed with ITP than the general population. Sometimes restoring normal thyroid level increases the platelet count. It is important to check for thyroid levels and anti-thyroid antibodies.
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Low Platelets Associated with Cancer
Chemotherapy used to treat many types of cancer can damage the bone marrow and result in a low platelet count. However, there are some cancers that have a more direct association with thrombocytopenia due to bone marrow involvement, compromised immune system or an enlarged spleen. Someone with cancer usually has other symptoms in addition to low platelets.
Myelodysplastic Syndromes (MDS)
Blood cells are produced in the bone marrow. In those with myelodysplatic syndrome (MDS) the bone marrow is damaged and blood cell production is impaired, including platelet production. The disease can also transform into acute myeloid leukemia (AML).
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Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is a cancer of B-lymphocytes, which normally make antibodies needed to fight infection. Advanced CLL causes many signs and symptoms resulting from leukemia cells replacing the bone marrow’s normal blood-making cells, including thrombocytopenia or low blood platelets.
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Large Granular Lymphocytic Leukemia (LGL)
This disease is a rare form of chronic leukemia characterized by abnormal CD8+ T cells, a type of white blood cells called “lymphocytes.”
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