Thrombocytosis
What every physician needs to know:
Thrombocytosis is defined as a platelet count greater than two standard deviations above normal, or above 400,000 per microliter in most clinical laboratories. In approaching a patient with an elevated platelet count, the clinician must first verify that the count is elevated consistently. Several transient reactive responses (for example, inflammation and certain infections) are known to increase platelet levels temporarily. Those responses are of little or no long-term consequence, except as determined by the underlying inciting event. If two measurements 3 months apart are clearly elevated, the clinician should determine the cause of the thrombocytosis.
There are many causes of bone fide thrombocytosis, and one cause of “distributive” thrombocytosis (in which the asplenic patient redistributes [usually temporarily] the one third to one half of total body mass of platelets that normally pool in the spleen, into the peripheral blood stream). This “distributive” thrombocytosis is rarely of any consequence to the patient. In contrast, bone fide, consistent thrombocytosis is usually due either to a primary marrow disease of excess myeloproliferation, usually polycythemia vera (PV) or essential thrombocythemia (ET), or is far more commonly reactive, usually due to iron deficiency or chronic inflammation.
In most individuals with thrombocytosis, treatment can await, if treatment is indicated at all, a specific causative diagnosis. It is very unusual that treatment for thrombocytosis is emergent; the only indication for the acute lowering of an elevated platelet count is ongoing arterial thrombosis (coronary, cerebral, peripheral), in which case platelet apheresis plus/minus platelet function inhibition is the treatment of choice. In nearly every case in which platelet apheresis is performed for thrombocytosis, the cause is a myeloproliferative neoplasm.
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In the chronic setting, treatment is usually indicated only for thrombocytosis due to a myeloproliferative neoplasm (see “What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?”). This is likely due to one of many functional abnormalities present in the blood cells of patients with ET or PV, in contrast to the functionally normal platelets and other blood cells produced in patients with reactive thrombocytosis. The diagnosis of a myeloproliferative neoplasm is usually made by a careful history (fevers, sweats, weight loss, early satiety, ruddy complexion), physical examination (splenomegaly, skin color), laboratory examination (complete blood count, including leukocyte differential), radiological evaluation (abdominal ultrasound), and, more recently, molecular testing for the acquired mutations (e.g. Jak2V617F, calreticulin or the thrombopoietin receptor [c-Mpl] missense mutations) that are commonly found in such patients. In addition to a definitive diagnosis, identification of one vs. two alleles of Jak2V617F may have some prognostic benefit in patients with PV, and identification of a mutation in calreticulin may reveal a more benign outcome for such patients than those with a mutation in Jak2.
What features of the presentation will guide me toward possible causes and next treatment steps:
World-wide, iron deficiency is the most common cause for reactive thrombocytosis. The symptoms of anemia are reduced energy, lethargy, exertional dyspnea, cardiac palpitations, and, when extreme, coronary insufficiency or other end organ ischemia. Iron deficiency presents like most other causes of anemia, although the peculiar symptoms of pica (craving for ice, clay, or other unusual “foods”), perioral cheilitis, and glossitis can occur when iron deficiency is severe or very long standing.
The second major cause of reactive thrombocytosis is inflammation; usually, the symptoms and signs of rheumatoid arthritis, inflammatory bowel disease, and cancer, the leading causes of inflammation induced reactive thrombocytosis, are obvious. In such cases, treatment of the underlying disorder is called for, and if successful, almost always eliminates the thrombocytosis.
In contrast, the presentation of a myeloproliferative neoplasm is usually subtle, or found upon routine blood testing. Occasionally, an acute thrombosis of the coronary arteries, cerebral arteries, or deep venous or hepatic vein thrombosis is the presenting feature of a myeloproliferative neoplasm such as PV or ET. It is in this setting, or thrombosis in a patient known to have ET, that emergent treatment with apheresis may be required.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
The first diagnostic test is nearly always a complete blood count (CBC) with a differential leukocyte count. By definition, the platelet count is elevated in everyone with thrombocytosis, but the presence of abnormalities in other blood cell types will often lead one to the correct diagnosis. For example, an elevated leukocyte count could indicate inflammation, especially if neutrophilia is noted, or if basophilia and/or eosinophilia are noted, the likelihood of a primary myeloproliferative neoplasm rises substantially.
An elevated red cell count could indicate PV, as inflammation and iron deficiency both cause anemia, and an examination of the red cell mean corpuscular volume (MCV) is important, as a patient with PV who is also iron deficient (such patients have an increased incidence of gastrointestinal bleeding) may present with normal or low red cell counts, and only with thrombocytosis.
Once the CBC is evaluated, other laboratory tests that confirm specific diagnoses are appropriate. If inflammation is suspected, a C-reactive protein might confirm that suspicion, and more specific tests (evaluations for rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease) will usually confirm the diagnosis. If iron deficiency is suspected because of an appropriate patient history and low MCV, serum iron, iron binding capacity, and ferritin levels will nearly always establish the diagnosis.
If a primary marrow disorder is suspected, the Jak2V617F test will establish a myeloproliferative neoplasm as causative, and while positive in nearly every person with PV, it is positive in only about 50% of patients with ET. A mutation in c-Mpl is found in an additional 5-10% of patients with ET, and mutation of the calreticulin gene is found in most of the remaining patients. A bone marrow exam can also strongly suggest a diagnosis of ET, marked by megakaryocytic hyperplasia, but occasionally, ET is a diagnosis of exclusion.
What conditions can underlie thrombocytosis:
The most common causes of thrombocytosis are iron deficiency, inflammation due to other conditions, and acute infections (for example, pneumonia, especially in children).
Myeloproliferative neoplasms, ET and PV are not uncommon, each present in about 1 in 100,000 individuals in the population. Other rare causes are congenital, inheritance of a mutant form of the thrombopoietin or thrombopoietin receptor genes, or paraneoplastic production of a megakaryocyte active cytokine, such as interleukin 6 or thrombopoietin.
When do you need to get more aggressive tests?
If iron deficiency or inflammation is present, no further tests are warranted. If a primary myeloproliferative disease is suspected, a test for mutant Jak2 is warranted, as it establishes the diagnosis, and while still not absolutely certain, there is much evidence supporting the idea that gene dosage (one or two copies of the mutant gene) is prognostic for thrombotic complications A similar consideration exists for screening for mutations in c-Mpl receptor or calreticulin, especially since the various mutations predict prognosis in primary myelofibrosis (calreticulin=good, Mpl and Jak2=intermediate, and no mutations=poor).
What imaging studies (if any) will be helpful?
Occasionally, abdominal ultrasound can reveal a modest splenomegaly or hepatic or portal vein thrombosis, not obvious on physical examination, and point to either chronic inflammation (which is usually obvious), or a primary myeloproliferative neoplasm.
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
The only indication for emergent therapy of thrombocytosis per se (as opposed to emergent therapy for one of the inflammatory causes of thrombocytosis) is impending or ongoing thrombosis, either arterial or venous. Such circumstances are almost always found in the setting of a myeloproliferative neoplasm, PV, or ET. The platelet count should be reduced immediately by daily apheresis, and if/once a myeloproliferative neoplasm is confirmed, therapy with a cytoreductive agent (almost always hydroxyurea), and unless contraindicated (because of bleeding), an anti-platelet function agent should begin immediately.
What other therapies are helpful for reducing complications?
As for all acute thrombotic events, interventions aimed at restoring blood flow are paramount, and their effectiveness time limited. Thrombolytic therapy, percutaneous coronary intervention with stenting, cerebral vascular interventions, and bypass surgery are all appropriate for certain settings. Once out of the acute setting, anti-platelet agents to reduce thrombotic complications are usually indicated.
More recently, Jak2 inhibitors have become available for the treatment of Jak2 mutation-positive primary myelofibrosis. This treatment is usually reserved for patients who have failed other modalities, but does reduce complications related to splenomegaly, and very recent studies suggest it can improve survival of patients with primary myelofibrosis (the third major myeloproliferative neoplasm). Whether Jak2 inhibitors will prove useful in patients with ET will require clinical trials, currently underway.
What should you tell the patient and the family about prognosis?
For most patients with thrombocytosis, the elevated platelet count is inconsequential, and the patient’s prognosis dependent entirely on the underlying cause of marrow reactivity (iron deficiency, inflammation). In patients with myeloproliferative neoplasms (PV, ET most common), prognosis is usually good, with minimal impact on long-term survival in most patients, especially since these disorders are more common in older individuals.
In the past, several therapies that greatly increased the risk of transformation of PV and ET to acute leukemia were used (for example, radioactive phosphorus or alkylating agents), and this dictated prognosis. Today, with hydroxyurea as the primary therapy, and several anti-platelet agents to help reduce the risk of thrombosis, the prognosis has improved as only an occasional patient develops these complications.
“What if” scenarios.
Occasionally, a patient with bone fide myeloproliferative neoplasm induced thrombocytosis, who is at high risk for thrombosis, does not tolerate hydroxyurea. Alternate therapies include anagrelide, and interferon. Each have their drawbacks, but are occasionally useful to reduce platelet counts toward normal when indicated.
Pathophysiology
The pathophysiology of reactive thrombocytosis is becoming increasingly understood, at least for those patients in which inflammation is the causative mechanism. Interleukin (IL)-6 is a well known inflammatory mediator, released from leukocytes stimulated with bacterial or tissue breakdown products, which then acts on hepatocytes to stimulate the production and release of thrombopoietin, the primary regulator of platelet production. Some cases of cancer associated thrombocytosis are also due to either the inflammation evoked by the cancer, or by direct tumor production of IL-6.
Far less understood is the cause of iron deficiency induced thrombocytosis. Initially, reports focused on erythropoietin as the thrombocytosis-inducing hormone, based on the hypothesis that the structural similarity of thrombopoietin and erythropoietin allows the latter, elevated in patients with iron deficiency anemia, to cross react with the thrombopoietin receptor, enhancing platelet production. However, this hypothesis does not account for the unique linkage between iron deficiency and thrombocytosis (erythropoietin is elevated in most patients with anemia but platelets are elevated only in iron deficiency anemia), or the fact that erythropoietin does not cross react with the thrombopoietin receptor.
The pathophysiology of the myeloproliferative neoplasms is becoming increasingly well understood. Mutation of the pseudokinase domain of the signalling kinase Jak2 causes its activation, with subsequent activation of a number of downstream signalling pathways, for the most part identical to the binding of an activating growth factor. Mutation of the thrombopoietin receptor, c-Mpl, activates the receptor akin to binding thrombopoietin, again driving cell growth. Most recently, truncation mutations of the calreticulin gene, an endoplasmic reticulum (ER) chaperone and calcium buffering protein, has been shown to eliminate the ER tether, allowing the remainder of the protein to bind to c-Mpl and activate it.
What other clinical manifestations may help me to diagnose thrombocytosis?
Most patients with PV or ET are asymptomatic, but a ruddy complexion (in PV), early satiety (due to splenomegaly, in PV or ET), erythromelalgia (pain in the distal extremities, in PV), or pruritis (due to basophils, in PV or ET) can indicate a myeloproliferative disease.
What other additional laboratory studies may be ordered?
N/A
What’s the Evidence?
Kaushansky, K.. “The molecular mechanisms that control thrombopoiesis”. J Clin Invest.. vol. 115. 2005. pp. 3339(This article discussed the mechanisms that regulate platelet production, both in normal and neoplastic hematopoiesis.)
Harrison, CN, Bareford, D, Butt, N. “Guideline for investigation and management of adults and children presenting with a thrombocytosis”. Br J Haematol.. vol. 149. 2010. pp. 352-375. (This guideline gives a general approach to both children and adults with an elevated platelet count.)
Skoda, RC.. “Thrombocytosis”. Hematology Am Soc Hematol Educ Program. 2009. pp. 159-67. (An outstanding review of myeloproliferative diseases that lead to thrombocytosis from a leader in the field.)
Beer, PA, Green, AR.. “Pathogenesis and management of essential thrombocythemia”. Hematology Am Soc Hematol Educ Program. 2009. pp. 621-8. (A review paper from the investigators that conducted the largest therapeutic study of essential thrombocythemia. That work proved that hydroxyurea is superior to anagrelide in the treatment of patients with essential thrombocythemia at high risk for thrombosis.)
Ruggeri, M, Tosetto, A, Frezzato, M, Rodeghiero, F.. “The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis”. Ann Intern Med.. vol. 139. 2003. pp. 470(A discussion of the leukemic risks for patients with myeloproliferative thrombocytosis.)
Harrison, CN, Campbell, PJ, Buck, G. “Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia”. N Engl J Med.. vol. 353. 2005. pp. 33-45. (Hydroxyurea/aspirin was superior to anagrelide/aspirin.)
Dahabreh, IJ, Zoi, K, Giannouli, S. “Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia”. Leuk Res.. vol. 33. 2008. pp. 67(An analysis of several studies examining whether the presence of the JAK2 mutation has an impact on patients with essential thrombocythemia; it does, and it correlates with an elevation of the leukocyte count.)
Vannucchi, AM, Antonioli, E, Guglielmelli, P. “Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia”. Blood. vol. 110. 2007. pp. 840(Discusses the role of two copies of a mutant JAK2 gene on the outcome of patients with myeloproliferative diseases.)
Barosi, G, Besses, C, Birgegard, G. “A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group”. Leukemia. vol. 21. 2007. pp. 277(While hydroxyurea is the current best therapy for patients with essential thrombocythemia and a risk for thrombosis, not all patients can tolerate the drug and not all patients “respond”; this paper attempts to provide some useful guidelines for design of future studies of therapeutic trials.)
Verstovsek, S, Kantarjian, HM, Estrov, Z. “Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls”. Blood. vol. 120. 2012. pp. 1202(This work is the first to identify a survival advantage for use of a JAK2 inhibitor in a myeloproliferative neoplasm.)
Klampfl, T, Gisslinger, H, Harutyunyan, AS. “Somatic mutations of calreticulin in myeloproliferative neoplasms”. N Engl J Med.. vol. 369. 2013. pp. 2379
Nangalia, J, Massie, CE, Baxter, EJ. “Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2”. N Engl J Med.. vol. 369. 2013. pp. 2391(These two papers described the acquired mutation found in the majority of patients with ET who do not display a mutant Jak2 allele.)
Rotunno, G, Mannarelli, C, Guglielmelli, P. “Impact of calreticulin on clinical and hematological phenotype and outcome in essential thrombocythemia”. Blood. vol. 123. 2014. pp. 1552(This work was the first to show that patients with ET associated with CALR mutations display a lower risk of transformation to acute leukemia and of developing acute thrombosis than patients with a Jak2 mutation.)
Rumi, E, Pietra, D, Pascutto, C. “Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis”. Blood. vol. 124. 2014. pp. 1062(This paper reports the differential outcomes of patients with primary myelofibrosis with mutations in Jak2, c-Mpl, or calreticulin.)
Saeidi, K.. “Myeloproliferative neoplasms: Current molecular biology and genetics”. Crit Rev Oncol Hematol.. vol. 98. 2016. pp. 375(A review of the genetics and pathogenesis of myeloproliferative neoplasms.)
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