Maintained By: Joyce Niblack JNiblack@Aol.com
This FAQ was last updated January 13,2001
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Statements contained herein are of a general nature and should not be construed as personal advice in lieu of recommendations by your physician or other relevant professional consultant |
Essential thrombocythemia is one of the myeloproliferative diseases (MPD). It is the MPD variant which is characterized by platelet counts greater than 400,000. The MPDs also include polycythemia vera (PV), Agnogenic Myeloid Metaplasia (AMM), secondary myelofibrosis (MF) and chronic myelogenous leukemia (CML). Each of these variants have predominant features which permit classifications which are named for the cell type showing the most marked involvement. There is a great deal of overlap in the features of these various syndromes and transition from one to another is common. This is discussed in greater detail below. Note-this is not to be confused with Thrombocytopenia (low platelets).
"Myelo" is
the Greek word for marrow "Proliferative" means growing or reproducing "Disease"
is the improper function of a body organ.
MPD is literally "Marrow
Proliferative Disease" or improper function of the bone marrow organ.
Bone marrow is the body's blood-forming (hematopoeitic) organ. It contains blood-forming
cells called "hematopoeitic precursor or stem cells" that have two
important functions:
1. self-renewal to maintain a pool of stem cells for future proliferation or
growth.
2. ability to mature into adult blood cells that will leave the marrow and enter
the circulation.. These precursor cells produce several types of blood cells; red blood
cells (RBC), some varieties of white blood cells (WBC) and plalelets. Because of this
versatility, they are called "pluripotential hematopoeitic precursor cells
("PHPC"). Each PHPC is a stem cell that can reproduce itself (clone) as well
as produce a number of daugher cells (blasts). Normal bone marrow is composed of a family
of hematopoeitic clones all reproducing themselves and forming daughter cells that will,
in turn, develop into red blood cells, white blood cells and platelets. The dedicated
daughter cells divide over and over again and it is their growth that fills the marrow
with the diverse types of immature and developing blood cells that are seen in a normal
bone marrow specimen. The normal marrow also balances production of different cell types
so they appear in the blood in their proper proportions.
In
MPD, one abnormal PHPC clone has a growth advantage that allows it to overgrow at the
expense of the normal PHPC clones. While this PHPC clone is "abnormal",
it is still able to self-renew and to produce several types of blood cells. The cells
produced by the abnormal clone may be difficult to distinguish from those produced by
normal cells. But what we do have in the myeloproliferative disorders is abnormal over or
under production of a particular cell type. Thus MPD involves the improper balance between
production of different blood cell types just as much as it involves abnormality of any
given blood cell type.
Thrombocythemia (or thrombocytosis) is defined as the occurence of a platelet count in excess of 400,000 per microliter in the setting of a myeloproliferative disease. When this is the predominant abnormality, the sydrome is classified as essential thrombocythemia. Abnormal megakarocyte proliferation (platelet precursors) is seen in all variants of MPD and elevated platelet counts is common in PV, CML and the proliferative states of AMM. On the other hand, ET patients can also have elevated white cell count (WBC), hematocrit (HCT) and hemoglobin (HG) counts so a careful differential diagnosis is essential.
No one knows why it develops. In all of the myeloproliferative disorders, the stem cell that is capable of producing red cells, certain white cells and platelets somehow goes haywire and no longer keeps the blood elements produced by the marrow in balance. In essential thrombocythemia, the marrow produces too many platelets.
The diagnosis of essential thrombocythemia is primarily one of exclusion. If platelet counts are elevated with:
1. no identifiable cause of secondary thrombocytosis i.e. from infection, cancer or
other disease state);
2. the red cell volume is normal (excludes polycythemia vera);
3. iron is present in the bone marrow or reduced iron stores have been repleted by
oral iron administration for one month withot inducing an increase in hemoglobin;
4. collagen fibrosis is absent from the bone marrow biopsy(excludes myelofibrosis);
and
5. the Philadelphia chromosome is absent from the bone marrow aspirate (excludes
chronic myelogenous leukemia).
However, in several 1997 publications and meeting lectures, there is work towards an European Consensus on the Diagnostic Criteria of Essential Thrombocythemia (ET).
The proposed diagnostic criteria are
A1 Platelet count in excess of 400,000 and no known cause of reactive thrombocytosis
A2 Increase and clusters of mature giant megakarocytes with hyperploid nuclei in bone marrow biopsies
A3 No preceding or allied other subtype of myeloproliferative disorders or myelodysplastic syndrome
Confirmative
B1 Normal or elevated leukocyte alkaline phosphatase(LAP) score, normal ESR, and no fever
B2 Normal or slighly increased cellularity and no or minimal reticulin fibrosis in bone marrow biopsies
B3 Splenomegaly on palpation or >11 cm on ultrasound scan or on computer tomogram (CT)
B4 Spontaneous endogenous erythroid colony (EEC) and/or spontaneous mekarocyte colony formation
See JJ Michiels et al, Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Sem Thromb Hemostas 1997; 23:339-347; JJ Michiels et al Diagnosis, Pathogenesis and Treatment of Myeloproliferative Disorders Essential Thrombocythemia, Polycythemia Vera and Idiopathic Myelofibrosis*, Goodheart Institute MPD Center Europe, Rotterdam Institute of Pathology, Cologne, Department of Clinical Hematology, Academic Medical Center, Amsterdam and The European Working Group on Myeloproliferative Disorders (EWGMPD) *Proceedings of the Rotterdam MPD-Workshop March 13-14, 1998. In press Netherlands Journal of Medicine.
By
the criteria discussed above. If other disease states such as cancer, infection, etc. have
been ruled out and the bone marrow findings are present, then the diagnosis is primary
thrombocythemia.
Essential thrombocytosis, thrombocytosis, primary thrombocytosis, ET.
This is a chronic condition. The only potential cure at the moment is a matched donor bone marrow transplant. Most ET patients are not eligible for this procedure. Because of its associated risk and expense, bone marrow transplants are generally reserved for life-threatening diseases. ET patients generally do not fall in this category. But a lot can be done to reduce symptoms and risks of complications.
ET patients have an excellent chance of living out a normal life span if properly monitored and treated as necessary. We had an ET patient in our mpd-net online discussion group who lived to 92 and died of diseases of old age. Forget the old statistics in the medical literature which scared some of us half to death when we were diagnosed in the 80's. Many physicians did not routinely check platelet counts and this condition would be diagnosed after someone had a heart attack or stroke and was already in trouble. It also once was thought to be a disease of the elderly. The youngest in our mpd-net support group was diagnosed at age 6 years old.
Do
keep in mind that this is a chronic hematologic malignancy and it is prudent to be
monitored regularly by a hematologist, it is important to report any symptoms such as
visual distrubances, unexplained pain, numbness, tingling, bruising to your physician, and
for those who have had symptoms from their ET, treatment will be required. But it can be
controlled, and you can live with it for a long time.
The published annual incidence for ET ranges from 0.1-2.4/100,000. It is rare and is classified as an orphan disease. Mesa RA, Tefferi A et al, The incidence and epidemology of essential thrombocythemia and agnogenic myeloid metaplasia: an Olmstead Country study. Blood 1997; 90 (supp 1): abstract 1547; Chaiter Y et al, High incidences of myeloproliferative disorders is Ashkezi Jews in Northern Israel, Leuk Lymph 1992; 7:251-255; Dougan LE et al, The effect of diagnostic review on the estimated incidence of lymphatic and hematopoitic neoplasms in Western Australia. Cancer 1981; 48:866-872.
In essential thrombocythemia, in addition to elevated platelet counts, platelets generally can be abnormal in size, shape, density and function. Spontaneous aggregation (clumping) can occur putting ET patients at higher risk for clotting events. There can also be an increased risk of bleeding. According to Dr. Gilbert, clinical manifestations are dominated by hemorrhage (bruising, nosebleeds , unexplained gastrointestinal bleeding, and postoperative hemorrhage) and microvascular occlusions erythema(redness) and burning as well as a host of neurological complaints such as headache, parathesis-numbness and tingling and transient ischemic attacks).
It
also is not uncommon for all MPD patients to have other elevated blood counts. For
example, in addition to high platelet counts, white cell counts may also be increase.
The answer is a definite maybe. Platelet counts alone are not predictors of complications. Elevated platelets can present a risk of thombosis or bleeding (see below for symptoms and complications. Elevated platelets can also cause excessive bleeding during surgery and your physician is likely to want to reduce platelet counts before surgery. But this is not a monolithic, everyone acts in a predictable fashion kind of disease. Go on the principal that risks are increased if platelet counts are elevated and then work with your doctor based on your own disease course and whether or not you are symptomatic or have independent risk factors that can complicate the course of your disease.
Dr. Michiels presented a talk at the October, 1998 San Diego MPD Conference sponsored by the MPD Research Center and chaired by Dr. Harriet S. Gilbert which summarized thrombotic complications in ET patients and there was also a report on this at the March 1998 MPD Rotterdam workshop. In patients ranging from age 28-86 with essential thrombocythemia at platelet counts between 300,000 and 1 million, followed for a median of 45 months, "minor manifestations" of ET included headache, dizziness, tinnitus, visual disturbances, erythromelalgia, parathesias, leg pain, digital cyanosis. Major complications were defined as transient ischemic attacks (TIAs), cerabrovascular accident (CVA or stroke), digital gangrene, heart attack, deep vein thrombosis, pulmonary emoblism. Bleeding symptoms included ecchymosis, epistaxis and gingival bleeding. 82% of patients had clinical symptoms related to their ET. Of the symptomatic patients, 67% had neurological symptoms, 37% had peripheral vascular thrombotic complications and 7% had hemorrhagic complications.
See Stark P et al. Thrombotic Complications in essential thrombocythemia with relatively low platelet counts. Am J Hematol 1997; 56:168-172; Griesshammer M et al, Aspirin in essential thrombocythemia: status quo and quo vadis. Sem Thromb Hemostas 1997; 23:371-356; Ravandi-Kashani F et al, Microvascular disturbances, thrombosis and bleeding in thrombcythemia, current concepts and perspectives Sem Thromb Hemostas 1997; 23:479-488; Cortelazzo S. et al. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990; 8:556-562; Van Genderen PJJ et al, Erythromelalgia: a pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera. Sem Thromb Hemostas 1997; 23:36555-370; Michiels JJ et al, Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. An Int Med 1995; 102:466-471; Michiels JJ et al, Transient neurologic ischemic attacks and ocular manifestations in primary thrombocythemia. Neurology 1993; 43:1107-1110.
A number of ET patients in our mpd-net support group report that their doctors brush off their symptoms as having nothing to do with their ET or claim their platelet count isn't high enough to run into problems. Not so. Dr. Michiels presented a distribution chart on this point. Clinical symptoms attributable to ET were recorded at platelet counts lower than 600,000 in 56% of patients studied, in 40% of patients with platelet counts lower than 500,000, in 18% of those with platelet counts lower than 400,000 and in 11% of patients with platelet counts of 300,000-350,000.
This depends upon the patient and whether there have been symptoms or complications. The current treatment options include nothing, baby aspirin, interferon, anagrelide or hydroxyurea alone or in combination.
Our
92 year old ET patient, Ben, was never been bothered by his disease other than a
recent prolonged bleeding episode after a shopper in a hurry ran into him with her grocery
cart and removed a serious chunk of skin and flesh. He also periodically complained of
skin sensations-tingling, feeling like something is crawing on his skin. He was only been
treated with very brief cycles of Hydrea to rapidly reduce platelet counts when he has
needed surgery. He was put on baby aspirin for a while but developed nose bleeds. His
daughter, Joyce, on the other hand had a stroke and thrombophlebitis which led to
her diagnosis and at times when platelets were not well controlled, experienced
visual disturbances including transient vision loss and other symptoms associated with her
ET. While Ben tolerated platelet counts in excess of 1 million, Joyce is symptomatic
at platelet counts above 500,000 and is most comfortable at counts of between
200,000-300,000.
Since this is a chronic condition, it requires treatment for life in patients who have had complications.
For simple, uncomplicated ET where the patient does not have an enlarged spleen and
elevated plaletet counts are the only concern, anagrelide may be the drug of choice. It is
the first agent useful in this disorder other than aspirin which is neither a
chemotherapeutic agent nor an immunomodulator. This drug was approved in the US in
the spring of 1997 and subsequently approved in Canada and Israel. Additional
approvals are expected. Platelet counts will rebound once this drug is stopped and
headache and cardiovascular side effects are of some concern.
Tefferi A, Silverstein MN, Petitt RM et al, Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of action, efficacy, toxicty, current indications. Sem Thromb Hemostas 1997; 23:379-383. Petrides PE et al, Anagrelide, a novel platelet lowering option in essential thrombocythemia treatment experience in 48 patients in Germany. Eur J Haematol 1998; 61:71-76. A. Tefferi, M.S. Elliot, L.A. Solberg, M.N. Silverstein, New Drugs in essential thrombocythemia and polycythemia vera, Blood Reviews 1997; 11. 1-7.
Hydrea (hydroxyurea) has been used for decades. It is a chemotherapeutic agent that
depresses marrow function. Some physicians do not like to use it in younger patients
because of reported risks of increasing the incidences of secondary acute leukemias after
around 8 years of continual treatment. Converting to acute leukemia occurs in a very small
percentagage of untreated ET patients. Figures vary in the literature but seem to indicate
a 5- 10% rate in patients treated with Hydrea. Some doctors feel this risk is minimal and
acceptable. Others do not. Some people have no choice as they cannot tolerate other
treatment options. This is an issue that each patient has to work out with their own
hem-onc. Platelet and other counts will rebound when this drug is stopped. Hydrea may
cause leg ulcers in a small percentage of patients. These can be debilating and
life-threatening and should be taken seriously. We have one ET patient in mpd-net
who suffered with this problem for 8 years before coming onto the internet and learning
that her treatment was the cause. She switched to interferon and the ulcers cleared
up within a month or two.
See for example Sterkers et al, Acute myeloid leukemia and myelodysplastic syndrome following essential thrombocythemia treated with hydroxyurea; high proportion of cases with 17p deletion. Blood 1998; 91:616-622.
Interferon is also one of the treatment options. There is a split in the medical community
about treating/not treating with interferon. Some doctors will not use interferon for a
variety of reasons-they do not want their patients to have to deal with shots when they
can swallow a pill. They argue that the long term side effects aren't known (interferon
has been used since the mid-80's for this condition). They don't see any particular
advantage over cheaper more convenient therapies. However, the literature and patient
experience in our mpd-net group indicate the drug is indeed beneficial.
See for example, Harriet S. Gilbert, M.D., Long Term Treatment of Myeloproliferative Disease with Interferon-alpha-2b Feasibility and Efficacy Cancer September 15,1998, Vol 83, No. 6, 1205-1213. A. Tefferi et al, New Drugs in essential thrombocythemia and polycythemia vera, Blood Review 1997, 11, 1-7. Gilbert HS. The Role of alfa interferon in treating myeloproliferative disease MPD):indications and results of long term management (abstract) Proc Am Soc Clin Oncol 1995; 14 429A. Gilbert HS, Persistence of remission of myeloid metaplasia after treatment with recombinant interferon alpha-2b (abstract) Blood 1988; 72:200a. Silver RT, A new treatment for ppolycythemia vera: recombinant interferon (rIFN) alfa-2b (abstract) Blood 1988; 72:227a. (This is by no means a comprehensive list of literature citations)
There
is a split among doctors who do treat with interferon Some believe in cycling as needed.
Some believe in keeping their patients on low maintenance dose once their conditions are
controlled. Dr. Gilbert has found that the benefit of interferon therapy, while not a
cure, is more lasting than other therapies. One of her patients was able to go three years
without needing further treatment. You don't "lose it" immediately when
you go off interferon as with Hydrea and Anagrelide. Doctors are also not in
agreement as to how much, how long and how frequently. If you feel this may be a
good treatment option for you and your doctor has little experience with its use in our
disorders, you may want to consider a consultation with one who does use it in his
or her practice in our disorders and let him/her guide your local hematologist in treating
you.
Yes. Patient experience varies. Basically, you lie down on your stomach and a special needle is used to drill into the hip bone and extract a core of bone and an aspirate of the marrow contents. Before the procedure, a local anesthetic is injected to numb the bone. But there is no way to numb the interior marrow so there will be momentary sharp pain. This procedure can be made much more comfortable by insisting that the doctor wait until the local has had a chance to take effect. Do not let them inject and start drilling immediately. Taking a mild tranquilizer about an hour before the procedure can reduce anxiety and make the procedure more comfortable. Finally, some doctors will use a combination of intravenous drugs (demerol and versed, demerol and ativan, morphine and valium) which allows the patient to sleep through the procedure. Either way, this is an outpatient procedure usually performed in your hematologists' office.
There are any number of symptoms that can go along with this condition. Visual disturbances when platelets are too high are experienced by many. These generally are described as "light shows" or "silent migraines". One patient in our group noted an increase in the frequency shortly before having a mild stroke. Minor symptoms can include bruising, bleeding such as bleeding gums, nose bleeds, heavy menstrual periods, pain, tingling, burning or numbness in fingers and toes, skin sensations-tingling, feeling of something crawling on your arm, headache and fatigue. More serious symptoms can include stroke, heart attack, pulmonary embolism, thrombophlebitis (pain and swelling will be usually be present in the affected leg), hemorrage. If myeloid metaplasia is present, the patient may have a sense of fullness in the area of the liver or spleen. There may be pain in those areas.
Many doctors seem to be under the impression that young ET patients do not require treatment and any symptoms reported have nothing to do with their ET. From the postings on MPD-NET and responses to the MPD Survey, we know this is not true.
On March 13-14, 1998, a number of experts in the field attended the Rotterdam MPD-Workshop. Four of the attendees were also speakers at the October 1998 MPD Conference in San Diego: J.J. Michiels, M.D., T.C. Pearson, M.D., S.M. Fruchtman, M.D. and R.T. Silver, M.D.) At the Rotterdam MPD Conference, Dr. Stark reported on thrombotic complications in 57 ET patients ranging in ages from 28-86 at platelet counts of between 300,000 to 1,000,000. These patients were followed for a median of 45 months (range 3-172 months). Minor manifestations of ET included headache, dizziness, tinnitus, visual disturbances, erythromelalgia, paresthesis, leg pain, digital cyanosis. Major complications included transient ischemic attack (TIA), cerebrovascular accident (CVA or stroke), digital gangrene and deep vein thrombosis. (Heart attack, pulmonary emoblism and portal vein clot have also been reported in our mpd-net group). Bleeding symptoms included those large bruises under the skin, bleeding from the gums and GI bleeding. 82% of patients were symptomatic. Of these, 67% had neurological symptoms and 37% had peripheral vascular thrombotic complications. 7% had hemorrhagic complications.
Some doctors claim that treatment is not necessary until platelets reach 1 million. Those of us who have had serious complications at much lower counts know this is not true for us. What is interesting is figures given at the Rotterdam and San Diego MPD conferences acknowledged that patients may be symptomatic with counts as low as 300,000. Looking at patients with platelet counts lower than 600,000: 56% had symptoms with counts lower than 600,000; 40% were symptomatic with platelet counts lower than 500,000; 18% were symptomatic with platelet counts lower than 400,000; and 11% were symptomatic with platelet counts between 300,000-350,000.
There are also a whole gaggle of metabolic abnormalities that go along in patients with
myeloproliferative disorders. These include:
1. -Elevated uric acid counts are seen in about half of MPD patients during the
course of their disease. If untreated, this leads to uric acid stones, uric acid
neuropathy, acute gout, and chronic gouty arthritis. Patients may experience joint pain as
a result.
2. -Low cholesterol levels (hypocholestoremia), particularly in those with enlarged
spleens.
3. -Elevated histamine levels. Symptoms of increased histamine release include
puritis (itching characteristically produced by bathing or showering), heartburn, acid
eructation (gas) , peptic ulcer, small bowel hypermotility, flushing and angioneurotic
edema (swelling of skin, mucous membranes or viscera). This occurs in 2/3rds of MPD
patients and correlates with presence of elevated basophil count and hyperhistaminemia.
4. -Hypermetabolism which commonly manifests as weakness and fatigue in the absence
of anemia.
This must be discussed with your own doctor. We have three patients in our mpd-net group
who ran into trouble after starting hormone replacement therapy. One had a
thrombophlebitis in one leg and a mild stroke about 6 weeks after starting on oral ERT.
She was been told to avoid HRT other than use of the vaginal cream and has had no further
problems. But more recently, in a consultation with an endocrinologist, she
was also told to avoid the cream since it is systemically absorbed. The other
had a clot of the vein leading to her liver and nearly died while usin the patch. She too
has been told only to use the vaginal cream. But we have one woman who had a transient
loss of the use of both legs after starting use of the vaginal cream. And we have an
ETer who has been using the patch for years without difficulty. This is something each
woman has to discuss with her hematologist (not gynecologist) because clotting factors
differ from patient to patient and your hematologist is in the best position to evaluate
your individual situation.
This may vary from physician to physician. Generally, if the patient is not experiencing any problems from their ET, baby aspirin (unless the patient tends to bleed) may be the only treatment suggested along with close monitoring. If a patient presents with a stroke, heart attack, thrombophlebitis, clearly reduction of platelet counts will be deemed necessary to get them out of danger and reduce the risk of further complications and treatment will be started immediately. If a patient shows up with enlarged spleen or liver which means that you have blood production taking place outside the bone marrow, treatment is a very good idea. When symptoms are "mONT COLOR="#008080">message: get MPD-NET.CML-FAQ - Frequently Asked Questions about chronic myelogenous leukemia
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