2023 ITP Conference

Information About Other Platelet Disorders

Information About Other Platelet Disorders

A low platelet count is often assumed to be ITP (immune thrombocytopenia).  However, there are many other possible causes of thrombocytopenia, with clinical severity ranging from trivial to life threatening.  ITP is a diagnosis of exclusion. It can only be diagnosed after all other causes of low platelets are ruled out. An incorrect diagnosis may lead to wasteful or harmful treatments. This makes it important to know, or at least be aware of, other diseases that may be mistaken for or misdiagnosed as ITP. 

Distinguishing ITP from other conditions is usually done by a physical examination, illness and medication history, assessment of a blood smear, additional blood tests, and perhaps a bone marrow biopsy. When thrombocytopenia is severe (a platelet count less than 20-30,000/microliter), and other obvious causes are ruled out, many doctors administer the first-line treatments for ITP: prednisone, anti-D, or IVIG. A rapid response to these therapies supports the diagnosis of ITP. Failure to respond should lead to further investigation of alternate causes of a low platelet count.  PDSA has a list of questions to aid in your discussion with your hematologist and help you get the correct diagnosis.

There are more than 200 diseases that include low platelets among their symptoms. Some of the most common low-platelet diseases are listed below. There are diseases on the list that are caused by a combination of factors and therefore could be in several categories.

Other than the inherited disorders, low platelets associated with additional diseases are sometimes referred to as 'secondary ITP.'  A good source of information on this subject is "Pathobiology of secondary immune thrombocytopenia."

This page contains a brief description and some representative links divided into the following categories:


Inherited Thrombocytopenia

Inherited thrombocytopenia may be caused by an inherited defect in platelet production or a process that influences platelet destruction. There are many forms of inherited thrombocytopenia, all of them rare. This means that physicians, even hematologists, will frequently mistake them for something else. Some of the more common examples are listed below. See "ITP and Families" for more information. 

MYH9 Related Diseases
(includes May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome or Epstein syndrome)

These diseases are grouped because they are all caused by mutations of the MYH9 gene. May-Hegglin anomaly, the most familiar, is an autosomal dominant condition in which either affected parent can pass the trait to their children, with a 50% likelihood of each child having low platelets. It is characterized by abnormally large platelets (that are frequently undercounted by automated machines), mild to moderate bruising, and potential for hearing and kidney problems.

Wiskott-Aldrich Syndrome (WAS)

Wiskott-Aldrich Syndrome is an X-linked disorder occurring almost exclusively in males, although it is also reported in females. In WAS sufferers, platelets are very small and are often accompanied by immunodeficiency and eczema.

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

CAMT is a recessive condition in which both parents are carriers but neither has low platelets. One fourth of their children (on average) will be affected with severe thrombocytopenia and absence of megakaryocytes in the bone marrow. Because of the severity of this disease, it is usually recognized shortly after birth. This disease is caused by mutations that affect the major platelet growth factor receptor and usually worsens over time until no cells are made in the bone marrow (aplastic anemia).

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS is both inherited and immune-mediated and can be noticed in children as well as adults. People with ALPS have large numbers of white blood cells (lymphocytes) and low numbers of red blood cells and platelets.

Gray Platelet Syndrome (GPS)

Patients with GPS bleed longer than other people because their platelets lack some of the protein-carrying sacs needed for a normal blood-clotting process. Platelets without sacs look pale gray under the microscope rather than pink, hence the name. Except in rare cases, the bleeding tendency in GPS is usually mild to moderate. Patients often experience easy bruising, nosebleeds, and, in women, excessive menstrual bleeding.

Bernard-Soulier Syndrome

Bernard-Soulier Syndrome is an autosomal recessive inherited disease (both parents must carry the genetic trait) caused by a defect in platelet glycoprotein complex 1b-IX-V. In addition to thrombocytopenia, people with Bernard-Soulier Syndrome have very large platelets and platelet function defects that prompt much more bleeding at a particular platelet count than people with ITP.

Von Willebrand Disease Type 2B

Von Willebrand factor is a protein in the blood needed for normal clotting. Von Willebrand Disease is caused by a defect in that protein, leading to abnormal bleeding. In the Type 2b variety of this disease, platelets stick to the abnormal von Willebrand factor rather than to each other. This action forms platelet clumps and causes thrombocytopenia. Type 2b can be inherited from either parent and affects males and females equally.

ANKRD26-related thrombocytopenia

Thrombocytopenia cases caused by a mutation in the ANKR26 gene are more prevalent than previously thought, researchers reported in 2011. This mutation, transmitted by one parent, results in fewer platelets being released from the bone marrow.

Common Variable Immune Deficiency

This genetic disorder is characterized by a low level of protective antibodies, recurrent infections, and possibly a large spleen. About 25% of people with this type of immune deficiency develop ITP. Primary immunodeficiencies (PID) can also present with low platelets.

Mutations in Filamin-A

People with mutations in the X-linked (male) FLNa gene have large platelets and possibly hemorrhage, abnormal clotting, as well as low platelets. This can be associated with periventricular nodular heterotopia (FLNA-PVNH), a disease characterized by the migration of grey matter to places outside of the cortex in the brain.

Mutations in GATA-1

The GATA1 gene on the X-chromosome regulates red cell and platelet development, so people with a mutation in GATA1 have both low red cells and low platelets. Because GATA1 is on the X-chromosome, boys- who only have a single X-chromosome- are affected more often than girls, a pattern referred to as X-linked inheritance. Platelets in boys who have inherited a mutant GATA1 are typically large and have few of the granules found in normal platelets.

For more information about inherited thrombocytopenia see "Inherited thrombocytopenia: when a low platelet count does not mean ITP." by Dr. Jonathan Drachman.


Substance-Induced Thrombocytopenia

Heparin-Induced Thrombocytopenia

Many hospitalized patients receive heparin to prevent clotting. When antibodies form against the heparin they can also bind to a protein on platelets, causing the platelets to become very sticky. This process may cause life-threatening clots.

Alcohol-Induced Thrombocytopenia

Drinking alcoholic beverages regularly and in quantity will cause bone marrow suppression, defective platelet formation, a decrease in platelet lifespan, 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 causes thrombocytopenia  in 1 of  25,000 to 40,000 vaccinations. There are also reports of low platelets resulting from pneumonia , H influenzae B, varicella zoster virus (VZV), and hepatitis B vaccinations.

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. There is a long list of drugs and other substances that can cause thrombocytopenia.  See the Warnings page for more information.

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. Some can trigger thrombocytopenia. See the Warnings page for more information.

Food-Induced Thrombocytopenia

Some foods, particularly those that contain quinine (ex. tonic water, bitter melon) or aspartame (ex. in diet soda) can trigger low platelets. Also food sensitivity or allergies may create a heightened immune response that may lead to a reduced platelet count. See the Warnings  page for more information.


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. 

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.

Neonatal Alloimmune Thrombocytopenic Purpura (NAITP, NAIT)
(alloimmune thrombocytopenia in newborns)

Rarely, a fetus may inherit a platelet antigen or “type” from the father that looks different to the mother’s immune system than her own platelets. In this case, the mother’s immune system develops antibodies to the platelets of the growing fetus, resulting in the baby being born with an extremely low platelet count.

Fetal Alloimmune Thrombocytopenic Purpura (FAITP, FAIT)

Fetal alloimmune thrombocytopenia (FAIT) is similar to NAITP described above in that both disorders involve the mother's antibody attacking the fetus' (and later the newborn's) platelets. In Fetal Alloimmune Thrombocytopenia the condition is discovered and possibly treated before the baby is born.

Other Causes of Newborn Thrombocytopenia

Other conditions associated with low platelets in newborns include congenital abnormalities such as Kasabach-Merritt syndrome, thrombocytopenia-absent radius (TAR) syndrome, Paris-Trousseau, metabolic diseases such as methylmalonicacidemia, ketotic glycemia or isovalericacidemia, other genetic diseases such as Fanconi's anemia, and infections such as bacterial sepsis. (NEJM, August 14, 2003)

Post-Transfusion Purpura (PTP)

A rare complication of blood transfusions, 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 (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.

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. 


Non-Immune-Mediated Platelet Destruction

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.

Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS)

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.

Enlarged Spleen (splenomegaly)

The spleen usually stores about 1/3 of the body’s platelets. If it becomes enlarged due to various diseases, it will store additional platelets leading to thrombocytopenia. In ITP, the spleen is expected to be a normal size, not significantly enlarged.

Henoch-Schönlein Purpura (HSP)

HSP is a type of vasculitis, inflammation of the blood vessels. In HSP immune complexes attach to the blood vessels causing purpura along with the possibility of joint and stomach pain and kidney involvement. This condition can present with or without thrombocytopenia.

Pseudothrombocytopenia

Pseudothrombocytopenia is an erroneous diagnosis of thrombocytopenia due to platelet clumping caused by a reaction to chemicals in the blood collecting tubes. The most common chemical that causes this problem is EDTA. The clumping causes the automatic counters to undercount platelets and leads to the erroneous diagnosis of thrombocytopenia. This clumping is not known to be associated with any pathology. Reading the blood smear is the most common way to confirm the clumping and correct the platelet count.


Low Platelets Caused by Infectious Diseases

In most cases of thrombocytopenia caused by bacteria or virus, the treatment approach is to treat the underlying infection. In all cases, these diseases are accompanied by other symptoms that are not associated with ITP, although the person may present only with low platelets. The usual treatments for ITP can be harmful as well as ineffective in some of these diseases.

Human immunodeficiency virus (HIV)+

The association between HIV and low platelets has known since the 1980s. Thrombocytopenia, in these cases, can be caused by a combination of impaired bone marrow, compromised immune system, and a reaction to some medications.

Hepatitis C+

The liver makes thrombopoietin, the protein that prompts the bone marrow to release platelets, as well as clotting factors needed for blood to clot. Liver disease can cause both thrombocytopenia and increased clotting time. Of the liver diseases, hepatitis C is most often associated with low platelets and mistaken for ITP.

Malaria

Malaria is a mosquito-borne infectious disease usually found in tropical or sub-tropical climates.

Ehrlichiosis

Ehrlichiosis is tick-borne bacterial infection that can be transmitted by other infected animals such as dogs.  There are several strains of this bacteria.

H. Pylori+

Helicobacter pylori is a bacteria 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.

Hantavirus

Hantavirus is transmitted to humans through rodent bites, urine, saliva, or waste.

Cytomegalovirus (CMV)+

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. 

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. 

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.


Low Platelets Associated with Other Autoimmune Diseases

Hashimoto’s Thyroiditis

ITP may be difficult to treat when associated with thyroid autoimmune disorders. 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.

Celiac (Coeliac) Disease

Celiac disease is an autoimmune disease of the small bowel caused by a cross-reaction to the gluten in wheat, barley, rye, and similar grains.

Evans syndrome

Evans Syndrome is the combination of autoimmune thrombocytopenia (ITP) and autoimmune destruction of red blood cells (hemolytic anemia).

Antiphospholpid syndrome (APS)+

Andiphospholip antibodies, those that attack particular cell membranes, can lead to blood clots in the veins and arteries.  From 20% to 70% of people diagnosed with ITP also have APS and about 25% of people with APS develop thrombocytopenia.  It is important to test for both anticardiolipin and lupus anticoagulant.

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 that disease.

Thyroid 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 antithyroid antibodies.


Low Platelets Associated with Cancer

Chemotherapy for 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 Syndrome (MDS)

Blood cells are produced in the bone marrow.  In MDS the bone marrow is damaged and blood cell production is impaired, including platelets.  The disease can transform into acute myelogenous leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

In CLL there is a gradual increase in the B-cells, a type of white blood cell, and eventually bone marrow failure.  You can get ITP in addition to CLL

CD8 T-lymphocyte large granular lymphocytic leukemia (LGL)

This diseases is a rare form of leukemia characterized by abnormal CD8+ T cells, a type of white blood cell.

 


+ Specifically testing for these conditions is considered very or potentially helpful in the recommendations of the "International consensus report on the investigation and management of primary immune thrombocytopenia."


PDSA thanks Dr. Amy Geddis for her review and comments.

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