Low Platelet Disorders

(Adapted by the PDSA Staff from A Low Platelet Count Must Be ITP, Right?, by Jonathan G. Drachman M.D, Puget Sound Blood Center. The article appeared in The Platelet News, vol.4, no 4, winter 2002/2003. See our newsletter page.

A low platelet count is frequently assumed to represent ITP (immune thrombocytopenic purpura). However there are many other possible causes of thrombocytopenia, with clinical severity ranging from trivial to life threatening. ITP is a diagnosis of exclusion. This means that only after all other possible causes of low platelets have been ruled out, can a diagnosis of ITP be settled.

This makes it important to know or at least be aware of the other common causes of low platelets that may be mistaken for or misdiagnosed as ITP. These other causes are either platelet production problems centered in the bone marrow or platelet destruction problems centered in the liver or spleen. Some low platelet conditions are characterized by both a low rate of production and a high rate of platelet destruction. The most common conditions or defects responsible for low platelets are listed in the following categories. Click on the links below for details.

I. Platelet Production Problems
A. Inherited
B. Non-inherited

II. Platelet Destruction Problems
A. Immune Mediated
B. Non-immune Mediated

Some of the diseases and conditions listed could be included in several of these categories. Autoimmune Lymphoproliferative Syndrome (ALPS) is an example; it is both inherited and immune-mediated. This brief review covers the most frequent causes of thrombocytopenia but is not meant to be comprehensive. Distinguishing ITP from other conditions is usually done clinically, paying careful attention to the onset of symptoms, family history, medication use, and recent illnesses. When thrombocytopenia is severe (i.e. platelet count less than 20-30,000/microliter), a trial of immunosuppression is generally administered (prednisone, anti-D, IVIG). A rapid response (within a week) to these therapies helps confirm the diagnosis as ITP. Failure to respond should lead to further investigation of alternate causes.

General disease sites that may be useful.

I. Platelet Production Problems

Platelet production problems or defects can be inherited, that is they run in families; or non-inherited, caused or triggered by medications, drugs, or toxins, for example.

I. A. Inherited Platelet Production Problems

Have the symptoms been present for a long time? Were platelet counts ever found to be low in the past? Are there any other family members who might have similar symptoms or thrombocytopenia?

If the answer to these questions is yes, the cause of thrombocytopenia may be an inherited defect in platelet production, rather than autoimmune disease. Inherited thrombocytopenias are due to mutations in specific genes that play an important role during the development of platelets or the cells that make them, megakaryocytes. There are many forms of inherited thrombocytopenia, and all of them are rare. This means that physicians, even hematologists, will frequently mistake them for something else. Inherited thrombocytopenias are categorized by the pattern of inheritance, the size of the platelets, and whether or not there are other signs or symptoms that are part of a syndrome. None of these disorders respond to standard ITP treatments. Several of the more common examples of these include:

May-Hegglin Anomaly (MHA)

This is an autosomal dominant condition in which either affected parent can pass the trait to their children with a 50% likelihood of each child being thrombocytopenic. MHA is characterized by abnormally large platelets (that are frequently undercounted by automated machines), mild-moderate bruising that usually does not cause serious problems, and potential for problems affecting hearing and kidneys. Because it is so mild, adults will sometimes not be aware they have the disorder.

Wiskott-Aldrich Syndrome (WAS)

Wiskott-Aldrich Syndrome is an X-linked disorder, affecting only males (females can be carriers but are unaffected). Platelets are very small, and there is frequently associated 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). Currently, this can only be cured by transplantation of stem cells from someone else.

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS is both inherited and immune-mediated. The inherited component is complex, not thoroughly understood but well documented. It affects both children and adults who are characterized with large numbers of white blod cells (lymphocytes), and low numbers of red blood cells and platelets. Steroids are the first line of treatment. Blood transfusions and vaccines are also important treatments.

Pearson's Syndrome

Patients with Pearson’s Syndrome may have poor food absorption (malabsorption) and low white blood cell counts (neutropenia). Low red cell counts (anemia) can be a major problem, and low platelet counts (thrombocytopenia) can also occur. Symptoms are often present in infancy. Liver and kidney disease usually develop. Examination of the bone marrow under the microscope reveals characteristic holes ("vacuoles") in many cells. The disease is caused by a loss, or deletion, of large pieces of DNA from tiny structures in the substance of cells, which are called mitochondria. Mitochondria are responsible for producing much of the energy that cells need in order to function normally.

http://marrowfailure.cancer.gov/PEARSON.html

Gray Platelet Syndrome

"When a blood vessel is injured (like a cut on a finger), platelets release the proteins stored in their sacs to help form a blood clot. Patients with GPS bleed longer than other people because their platelets lack some of these protein-carrying sacs. Platelets without sacs look pale gray under the microscope rather than pink, giving the syndrome its name. Except for rare patients with severe hemorrhage, the bleeding tendency in GPS is usually mild to moderate, with patients experiencing easy bruising, nosebleeds, and, in women, excessive menstrual bleeding."

http://www.clinicaltrials.gov/ct/show/NCT00069680?order=1

22q11 Deletion Syndrome/VeloCardioFacial Syndrome

"Thrombocytopenia in 22q11.2 deletion syndrome patients is associated with decreased expression of glycoprotein Ib-beta because of the hemizygosity. 22q11.2 deletion syndrome patients with thrombocytopenia require total management, especially for schizophrenia"

I. B. Non-inherited defects in bone marrow function

Drug Induced Thrombocytopenia

Heparin-Induced Thrombocytopenia with Thrombosis (HITT): Many hospitalized patients receive heparin to prevent clotting. Sometimes, it is given in small doses to prevent an IV from clotting, and the patient is not aware that they even received it. When antibodies form against the heparin, they can also bind to a protein on platelets, causing the platelets to become very sticky. Life-threatening clots will sometimes form, even when the platelets are “low”. It is essential to stop the heparin and treat the patient with a different kind of anticoagulant.

Other Drug-induced Thrombocytopenia

If the bone marrow is damaged or becomes a poor environment for blood cells to grow, there will be thrombocytopenia due to inadequate platelet production. Medications will frequently cause thrombocytopenia, and this can be difficult to figure out, particularly if a patient is very sick and is on many medications. Almost all chemotherapy drugs used to treat cancer can affect production of platelets as well as other bone marrow cells. Other medications that are associated with depressed platelet production include quinine, quinidine, diuretics, anti-seizure medications, and antibiotics. However, many other drugs can cause thrombocytopenia on occasion. With a new diagnosis of thrombocytopenia, it is important to think about whether any new medications have been started.

Alcohol Induced Thrombocytopenia

Drinking alcoholic beverages regularly and in quantity (alcohol poisoning) will cause bone marrow suppression. When repeated over many years, this is often associated with liver damage, which can cause thrombocytopenia by a different mechanism (see Liver Failure/Enlarged Spleen below).

Bone Marrow Failures and Low Platelets

Disorders of the “hematopoietic stem cells” that give rise to all mature blood cells will also cause inadequate platelet production. This may take the form of aplastic anemia, myelodysplastic syndrome (also known as “preleukemia”), and leukemia. Occasionally, the bone marrow space will become scarred or filled with cells that shouldn’t be there, leaving inadequate room for blood development. This often occurs in myelofibrosis, advanced lymphoma, or advanced solid tumors (i.e. breast cancer). When the marrow space gets damaged, the body may try to make blood cells in other tissues, especially the spleen, causing severe enlargement of this organ (in the upper left portion of the abdomen).

II. Platelet Destruction

Platelet destruction can be immune-mediated in which case the immune system tags or identifies platelets for destruction and elimination in the spleen and/or liver. Other syndromes or conditions cause low platelets without immune system involvement.

II. A. Immune-Mediated Platelet Destruction

In the disorders described below, the immune system destroys platelets in the blood but usually does not damage the megakaryocytes in the bone marrow that produce platelets. In fact, megakaryocytes may be increased in the bone marrow in an attempt to compensate for the platelet destruction.

Immune thrombocytopenic purpura (ITP): Several types of immune-mediated platelet destruction can occur, the most common of which is ITP. In these disorders, the immune system incorrectly identified something on platelets as “foreign” and produces antibodies that recognize platelets and mark them for destruction, which occurs in the spleen. It is still not clear why the immune system makes this mistake. However, ITP is more common in individuals and families with other autoimmune disorders (i.e. hypothyroidism, inflammatory bowel diseases, lupus). There may also be environmental triggers, such as viruses or bacteria that “look” to the immune system a little bit like platelet proteins. After a normal response to an infection, the immune system might continue attacking the platelets. Although it is still controversial, Helicobacter pylori may be such an organism in some people with ITP.

There is evidence that in some ITP patients production of platelets by the bone marrow may be defective as well. It’s unclear whether this is due to platelet destruction in the bone marrow (when it is released from the megakaryocyte), an inadequate response of the megakaryocyte to thrombocytopenia, or both.

http://www.itppeople.com/aboutitp.htm

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. Immunosuppressive medications are the first course of treatment. For some patients immediate stem cell transplantation is recommended.

Evans’ syndrome

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

Neonatal Alloimmune Thrombocytopenic Purpura (NAITP)

(Alloimmune thrombocytopenia in new borns)

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. This means that her immune system can attack the platelets of the growing fetus, and the baby will be extremely thrombocytopenic immediately after birth. Optimal treatment is to transfuse the baby with the mother’s platelets for several months, until the antibodies are gone.

Other conditions associated with low platelets in newborns include congenital abnormalities such as Kasabach-Merritt syndrome, 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 transfusion, 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 (for unknown reasons).

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 are thought to trigger thrombocytopenia. The links below offer significant opportunities to learn of some of the associations between various toxins and autoimmunity.

Cyclical Thrombocytopenia

Cyclical thrombocytopenia is a rare platelet disorder characterized by regular fluctuations in platelet count often, but not necessarily, coinciding with a menstrual cycle.

II. B. Non-immune Mediated Platelet Destruction

Disseminated Intravascular Coagulopathy (DIC): Severe illnesses, such as overwhelming bacterial infection, crush injuries, and pregnancy disasters can trigger activation of all the body’s clotting mechanisms. This will frequently lead to the peripheral destruction/consumption of platelets and clotting factors so that the patient oozes blood from many sites. This will not get better until the underlying illness is corrected.

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

These related diseases are characterized by low platelet counts, fragmentation of red blood cells, and kidney dysfunction. TTP/HUS can be triggered by bacteria often found in contaminated and undercooked food (E. coli 0157) or an antibody against the von Willebrand Factor cleaving enzyme. When this is suspected, treatment should include plasmapheresis, a process that removes blood plasma along with the potential antibodies that may be present and replacement with normal plasma containing a protein that may be deficient in patients with TTP.

TTP Links

http://moon.ouhsc.edu/jgeorge/DITP.html

HUS Links

Liver Failure/Enlarged Spleen

Repeated damage to the liver results in scarring or cirrhosis. The blood from the lower half of the body and the spleen, which normally drains through the liver, then encounters resistance. The spleen, which is the largest organ in the immune system, normally acts as a passive reservoir for platelets. When flow is reduced and/or the spleen enlarges, a greater proportion of the platelets end up sequestered in the spleen rather than circulating in blood. This is different from the role of the spleen in ITP, in which platelets that are coated with antibody are recognized and destroyed.

Liver Failure

Enlarged Spleen

Schönlein-Henoch Purpura

Schonlein-Henoch Purpura is a condition characterized by purpura, lesions, edema, itching, and bleeding. This condition can present with or without thrombocytopenia. It has been associated with Helicobacter pylori by some investigators. Treatment includes bed rest, corticosteroids, and avoiding aspirin.

Pseudothrombocytopenia

Pseudothrombocytopenia is an erroneous diagnosis of thrombocytopenia that is the result of platelet clumping caused by chemicals used to prevent coagulation in the collecting tubes. The most common chemical is EDTA but several others can have the same result. The clumping cause the automatic counters to undercount platelets and leads to the erroneous diagnosis. 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..

Other Possibilities

Ciliac Disease