Essential thrombocythemia

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Classification according to ICD-10
D47.3 Essential (hemorrhagic) thrombocythemia
ICD-O 9962/3
ICD-10 online (WHO version 2019)
Blood smear for essential thrombocythemia with a clear increase in platelets (blue)

The essential thrombocythemia (also essential thrombocythemia , abbreviated ET ) belongs to the group of myeloproliferative neoplasms (MPN), i.e. a group of malignant diseases of the blood-forming system . Persistent thrombocytosis is characteristic of ET . H. excessive increase in thrombocytes (platelets) in the blood .

Epidemiology

According to recent studies in the USA and Sweden, the incidence is around 2.5 people per 100,000 inhabitants per year. Due to the relatively normal life expectancy, the prevalence is significantly higher. Bipolar age distribution, between 20 and 40 or 60 and 70 years. 10–25% of patients are under 40 years of age. The disease is more common in women, the female / male ratio is around 2: 1.

Pathogenesis

Like all myeloproliferative neoplasms and all tumors in general, ET is a genetic disease. Why the disease occurs in an individual patient can usually not be clearly justified. It is assumed that there are spontaneous gene mutations in haematopoietic stem cells , which mean that these stem cells can no longer perform their normal function (controlled formation of various blood cells). The genetic background of ET is not yet fully understood. However, important advances in knowledge have been made in recent years. In 2005, a mutation in the tyrosine kinase JAK2 ( JAK2 mutation -V617F) was described independently by various scientific working groups in ET patients . This mutation can be detected in around half of all clinically diagnosed cases of ET (for the diagnostic criteria see below). In contrast, this mutation can never be detected in healthy people. The mutation leads to the tyrosine kinase JAK2 being activated permanently and in an uncontrolled manner, with the result that the clinical picture of a blood disease arises. The JAK2-V617F mutation is not only detectable in about half of the cases of ET, but also in other MPN, especially in polycythemia vera (in almost 100% of cases) and osteomyelofibrosis (in about 50% or less of the Cases). The detection of the JAK2 V617F mutation is also of therapeutic interest, since an approved JAK2 inhibitor ( ruxolitinib ) is now available as a drug.

A small percentage (less than 5%) of the ET patients shows instead of the JAK2 mutation is a mutation in the gene for thrombopoietin - receptor MPL . This mutation leads to permanent growth stimulation of the affected blood stem cell.

In 2013, a new gene mutation was also found by several scientific working groups , which affects the CALR gene , which codes for the calreticulin protein. Notably, CALR , MPL , and JAK2 mutations were virtually exclusive; H. never together. Around 70% of all MPN patients who did not have a JAK2 mutation showed a CALR mutation.

Symptoms

Microcirculation disorders or functional complaints are the most common symptoms. Thromboembolic complications are the leading cause of morbidity and mortality from the disease. There is an increased risk of stroke and heart attack . While bleeding events were previously considered to be common symptoms of essential thrombocythemia (also known as idiopathic haemorrhagic thrombocythemia ), more recent studies show that larger or life-threatening bleeding occurs rarely in ET and is usually only observed with very high platelet counts . This tendency to bleed is explained by a dysfunction of the platelets (so-called functional Von Willebrand syndrome ).

Other symptoms can be caused by insufficient blood flow in parts of the body: pain when walking (insufficient blood flow in the legs), difficulty concentrating and impaired vision can occur. In the advanced stage, pain in the upper abdomen occurs due to the enlargement of the liver and spleen .

About a third of all ET patients are symptom-free at the time of diagnosis and often remain symptom-free for many years.

Clinic and course

Today the diagnosis or the suspected diagnosis is usually made in the asymptomatic stage as part of a routine blood count . The typical complications of the disease such as venous and arterial thromboses , possibly with subsequent embolisms or bleeding, lead to the diagnosis less often. The venous thromboses can be localized at typical locations (deep vein thrombosis), but also occur at atypical locations (liver vein thrombosis, so-called Budd-Chiari syndrome , portal vein thrombosis). Bleeding typically occurs with extremely high platelet counts (> 2,000,000 / µl) and is due to a dysfunction of the platelets. Other possible complications are microcirculatory disorders, which can lead to a number of unspecific complaints such as headaches, paresthesia in the hands and feet, visual disturbances, burning pain with reddening in the hands and feet ( erythromelalgia ).

Diagnosis

Mutated genes are more common in ET
gene approximate
frequency
JAK2 ~ 50%
Calreticulin ( CALR ) ~ 30%
MPL ~ 5%
Others (most common:
ASXL1 , EZH2 , TET2 , IDH1 / IDH2 ,
SRSF2 , SF3B1 , U2AF1 )
and unknown		 together
> 15-20%

The suspected diagnosis arises from repeated detection of platelet counts> 450,000 / µl without any indication of the causes of reactive thrombocytosis . Reactive thrombocytoses occur e.g. B. on iron deficiency , infections, or other tumor diseases. Occasionally, ET is also found to have mild leukocytosis, and anemia is common. By means of the detection of a JAK2 mutation or, more recently, the CALR mutation and, rarely, an MPL mutation, a molecular biological confirmation of the diagnosis and differentiation from reactive thrombocytosis is possible in many cases. If a mutation is detected in one of the three genes mentioned, then a myeloproliferative neoplasia (MPN) is present. It then still has to be decided what type of MPN it is exactly (ET, polycythemia vera, osteomyelofibrosis or others). In order not to overlook a possible chronic myeloid leukemia (CML), a blood test for the oncogene BCR-ABL typical for CML should always be carried out, which must be negative. CML is also often associated with thrombocytosis in the initial phase.

An examination of the bone marrow using a bone marrow puncture is required. The bone marrow examination can answer various questions, such as: B. the question of the presence of a bone marrow fibrosis (connective tissue proliferation in the bone marrow), abnormalities in the megakaryocytes (the cells that form platelets), dysplasias (disorders of the maturation of blood cells). A cytogenetic examination should also be made from the bone marrow in order to identify any chromosomal abnormalities that may be present .

A differential diagnosis that can be clarified by the bone marrow examination is the so-called RARS-T (refractory anemia with ring sideroblasts and thrombocytosis). The detection of ring sideroblasts in the bone marrow is diagnostically groundbreaking . RARS-T has the JAK2 V617F mutation in the majority of cases.

WHO diagnostic criteria, modified according to DGHO
criteria conditions
1 Platelet count persistently> 450,000 / µl
2 Exclusion of another cause of the thrombocytosis (iron deficiency?, Chronic infection?)
3 ET-typical bone marrow histology with enlarged, mature megakaryocytes
4th Detection of a mutation in the genes JAK2 , CALR or MPL , or other, more rarely mutated genes
5 Exclusion of polycythemia vera ( PV ), chronic myeloid leukemia ( CML ), primary myelofibrosis ( OMF ), reactive thrombocytosis , myelodysplastic syndrome ( MDS )

The diagnosis ET is confirmed when all criteria are met. Sometimes no mutation can be diagnosed in one of the genes mentioned. In these cases, all differential diagnoses must be ruled out particularly thoroughly and then the diagnosis ET can still be made.

therapy

Risk classification

There are no confirmed randomized studies on the optimal time to start therapy. In order to find an optimal treatment strategy for each patient, a risk classification is first carried out according to the guidelines of the DGHO. This differentiates between high, intermediate and low-risk patients. The risk is assessed using a scoring system . There are three factors to consider:

  1. History of known thromboembolic events or major bleeding events
  2. Age over 60 years
  3. Platelet counts> 1.5 million / µl

For each of the three criteria mentioned, one point is awarded if it is met. The following then applies:

  • 0 points = low risk
  • 1 or more points = high risk

Patients who do not have any of the above risk factors but have vascular risk factors, i. H. have or are at high risk of blood vessel disease (e.g. generalized arteriosclerosis , diabetes mellitus , hypercholesterolemia , smoking , coronary artery disease, or a previous heart attack ) are considered an intermediate risk .

Drug treatment is always recommended for high risk patients . This can consist of:

In the case of intermediate risk patients, it must be weighed individually whether treatment appears necessary. This can e.g. B. be done with low-dose acetylsalicylic acid .

Low-risk patients do not require treatment.

General measures to minimize the risk of thromboembolism are recommended for all ET patients:

  • Weight normalization,
  • regular exercise,
  • Avoidance of dehydration ( desiccosis ) and prolonged sitting,
  • Pay attention to early symptoms of a thrombosis , in this case contact a doctor immediately

literature

  1. ↑ Martin Griesshammer et al .: Essential Thrombocythemia: Clinical Significance, Diagnosis and Therapy . In: Deutsches Ärzteblatt . No. 104 , 2007, p. 2341 ( article ).
  2. ↑ The designation V617F means that at position 617 of the JAK2 protein the amino acid valine (V) has been exchanged for the amino acid phenylalanine (F)
  3. ↑ AD Pardanani, RL Levine, T. Lasho, Y. Pikman, RA Mesa, M. Wadleigh, DP Steensma, MA Elliott, AP Wolanskyj, WJ Hogan, RF McClure, MR Litzow, Gilliland DG, A. Tefferi: MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients . In: Blood . 2006; 108 (10), pp. 3472-3476. PMID 16868251
  4. ↑ J. Nangalia, CE Massie, EJ Baxter, Nice FL, G. Gundem, DC Wedge, E. Avezov, J. Li, K. Kollmann, DG Kent, A. Aziz, AL Godfrey, J. Hinton, I. Martincorena , P. Van-Loo, AV Jones, P. Guglielmelli, P. Tarpey, HP Harding, JD Fitzpatrick, CT Goudie, CA Ortmann, SJ Loughran, K. Raine, DR Jones, AP Butler, JW Teague, S. O ' Meara, S. McLaren, M. Bianchi, Y. Silber, D. Dimitropoulou, D. Bloxham, L. Mudie, M. Maddison, B. Robinson, C. Keohane, C. Maclean, K. Hill, K. Orchard, S. Tauro, MQ Du, M. Greaves, D. Bowen, BJ Huntly, CN Harrison, NC Cross, D. Ron, AM Vannucchi, E. Papaemmanuil, PJ Campbell, AR Green: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2 . In: New England Journal of Medicine . 2013; 369 (25), pp. 2391-2405. doi: 10.1056 / NEJMoa1312542 . PMID 24325359
  5. ↑ T. Klampfl, H. Gisslinger, AS Harutyunyan, H. Nivarthi, E. Rumi, JD Milosevic, NC Them, T. Berg, B. Gisslinger, D. Pietra, D. Chen, GI Vladimer, K. Bagienski, C Milanesi, IC Casetti, E. Sant'Antonio, V. Ferretti, C. Elena, F. Schischlik, C. Cleary, M. Six, M. Schalling, A. Schönegger, C. Bock, L. Malcovati, C. Pascutto, G. Superti-Furga, M. Cazzola, R. Kralovics: Somatic mutations of calreticulin in myeloproliferative neoplasms. In: New England Journal of Medicine. 2013 Dec 19; 369 (25), pp. 2379-2390. doi: 10.1056 / NEJMoa1311347 . PMID 24325356
  6. ↑ See for example Ludwig Heilmeyer , Herbert Begemann: Blood and Blood Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, pp. 376-449, here: pp. 443 f. ( The hemorrhagic thrombocythemia ).
  7. ↑ a b Petro E. Petrides, Gabriela M. Baerlocher, Heinz Gisslinger, Martin Grießhammer, Eva Lengfelder: Essential (or primary) thrombocythemia (ET). September 2014, accessed on October 6, 2016 (guideline of the DGHO).

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