Polycythemia vera

from Wikipedia, the free encyclopedia
Classification according to ICD-10
D45 Polycythemia vera
ICD-O 9950/3
ICD-10 online (WHO version 2019)
Most important immediate measure: bloodletting (historical illustration around 1805)

The polycythemia vera (abbr. PV , including polycythemia or polycythemia and primary idiopathic polycythemia rubra vera called; English primary myelopathic polycythemia ; synonym: Crohn Vaquez-Osler and Vaquez-Osler-disease ) is a rare myeloproliferative (the myeloid blood cells in the bone marrow in question) Disease in which there is an abnormal increase in red blood cells ( erythrocytes ) without a physiological stimulus. The main symptoms include increased blood viscosity through to hyperviscosity syndrome and related circulatory disorders. High blood pressure can also occur. Usually the disease is relatively benign and can be treated by bloodletting . PV seldom leads to other diseases (secondary osteomyelofibrosis , acute myeloid leukemia ).

Word meaning

The ancient Greek - Latin components of the name describe the main characteristic of the disease:

  • poly (πολύς) = a lot
  • cyt or zyt (κύτος "vessel") = cell
  • haem (ie) (αἷμα) = blood (disease)
  • vera = true, real

Definitions of terms

Polycythemia vera , d. H. the "real" or "true" polycythemia has been differentiated from other forms of polycythemia, reactive or secondary polycythemia, since 1892 ( Henri Vaquez ) .

Reactive polycythemia generally arises as a reaction to another stimulus, usually an insufficient supply of oxygen ( hypoxemia ), as it is e.g. B. with chronic lung diseases, excessive nicotine consumption , sleep apnea (breathing pauses) or staying at high altitudes (lower oxygen partial pressure). In such situations, the human body reacts with increased production of erythropoietin ("Epo"), which causes increased red blood formation. People who live at high altitudes for a long time (e.g. in the Andean highlands of Bolivia ) therefore have a higher average hemoglobin value and higher erythrocyte values; they have a “physiological” polycythemia that does not count as a disease. Secondary polycythemia can e.g. B. arise in erythropoietin-producing tumors (very rare).

The polycythemia vera , however, is a disease with a genetic cause, caused by a randomly acquired in the course of life genetic disorder in hematopoietic stem cells .

Epidemiology

The prevalence (proportion of the population of the sick) in the USA is 1: 3,300 (≈ 0.03%), the incidence (annual incidence rate) is 1: 36,000 - 1: 100,000, according to another source 1–2: 100,000. It is therefore the most common form of myeloproliferative diseases. Since there are no epidemiological data for Germany, the Swedish statistics were used and an estimate of 2,000 new cases in Germany per year. The self-help forum mpn network speaks of 500 to 600 new cases per year. It can occur in any age group, the age peak is between the 5th and 6th decades of life. The ratio between male and female patients is around 2: 1. A familial accumulation (which suggests inheritance) occurs, but is rare.

course

Often individual latent signs of the disease appear up to a decade before polycythemia vera enters the chronic phase, for example in the form of a moderate enlargement of the blood-degrading organs spleen and liver . The blood-forming bone marrow, however, shows no noticeable changes. However, the JAK2 mutation (see below) is already detectable.

In general, there are two stages of polycythemia vera. A chronic phase with increased erythrocyte production can last for two decades or more, a progressive late phase with various, also acutely life-threatening complications can follow in some of the patients.

Causes and origins

In 2005 one was by several research groups mutation in JAK2 - Gen ( " Janus kinase " 2, a tyrosine kinase ) described. This mutation of the genomic DNA results in an amino acid -exchange ( valine to phenylalanine ) at position 617 of the JAK2 - protein ( "V617F mutation"). The JAK2 protein plays an important role in signal transduction in the cell. The mutation activates it, so that the affected cells have a permanently increased rate of cell division . The V617F mutation can be found in various haematological diseases, but particularly often (in more than 90%) in polycythemia vera. The hematopoietic stem cells concerned are of the stimulation by erythropoietin independently (Epo) and show a hundred-fold increased sensitivity to growth factors such as IGF-1 ( I like nsuline- G rowth F actor 1) and IL-3 ( I nter l eukin-3).

Diagnosis

In most cases, the disease is discovered when a blood count - often as a secondary finding - reveals a massive increase in hematocrit, erythrocytes or hemoglobin concentration. More rarely, unspecific symptoms such as itching, a slight enlargement of the spleen, thrombosis, tinnitus or other clinical symptoms lead to a targeted search for polycythemia vera on the basis of these initial symptoms ( key symptoms ).

WHO diagnostic criteria

The increase in erythrocytes can be demonstrated in the laboratory by measuring the hematocrit value or hemoglobin and erythropoietin . Leukocytes and platelets are also usually increased in the blood count . The blood sedimentation rate (ESR), on the other hand, is slowed; uric acid and LDH in the serum are often increased. The World Health Organization (WHO) has established the diagnostic criteria listed in the table below.

WHO diagnostic criteria
criteria conditions
Major 1 Hemoglobin> 16.5 g / dL or> 16.0 g / dL in men / women or

Hematocrit> 49% or 48% in men / women or

increased amount of erythrocytes (> 25% above the mean normal value)

Major 2 Bone marrow biopsy shows hypercellularity as measured by patient age with an increase in all three rows
Major 3 Detection of the JAK2 V617F mutation or
detection of JAK2 exon 12 mutations
Minor 1 Serum erythropoietin levels below normal

A diagnosis of polycythemia vera can be made
if either:

  • all three major criteria are met,

or:

  • the first two major criteria and the minor criterion are met. Note: In the case of persistent erythrocytosis with hemoglobin values ​​of> 18.5 g / dL in men (hematocrit, 55.5%) or> 16.5 g / dL in women (hematocrit, 49.5%), Major 2 Criterion for diagnosis not required if major 3 criterion and minor 1 criterion are positive.

Specific and non-specific clinical symptoms

Erythromelalgia , a seizure-like skin condition that is rarely associated with a. can occur with PV

The increased number of platelets, granulocytes and erythrocytes makes the blood thicker ( hyperviscosity ). This can lead to circulatory disorders in all areas of the body (especially in the capillary area ), increasing the risk of thrombosis and, as a result, of embolism . At the same time, the risk of bleeding can also increase because the body's own hemostasis as a whole no longer works properly.

Many of the possible symptoms of polycythemia vera are not specific to the disease and provide important information to doctors and patients during the history and the course of the disease. Possible clinical symptoms (not detectable in all patients) include:

As the disease progresses, the number of erythrocytes and also the number of leukocytes and platelets can decrease, the spleen can increase in size, often in connection with myelofibrosis and extramedullary hematopoiesis (blood formation outside the bone marrow).

Some of the individually occurring symptoms, especially if they are related to circulatory disorders, disappear or are weakened as soon as the disease is recognized and treated by lowering the hematocrit value to the normal range of around 45 percent.

Differential diagnosis

If the number of erythrocytes as well as the number of leukocytes and platelets is increased in a patient, the diagnosis of polycythemia vera is very likely. If only the erythrocytes are increased, a comprehensive differential diagnostic examination program must be carried out. In particular, to clarify whether any one as a cause dehydration , a hypoxia , a carbon monoxide intoxication , heart disease (eg. As a right-left shunt ), a Hyperspleniesyndrom , paraneoplastic syndromes , myelodysplastic syndromes , a myelofibrosis , neurological disorders or Drugs (e.g. androgens or erythropoietin ) may be the cause.

therapy

Since a final diagnosis can take several weeks (e.g. with the genetic determination of JAK2), suitable prophylactic measures may have to be taken during the investigation in order to lower a life-threatening high hematocrit value. Basically, therapy runs on several tracks:

  1. Lowering the hematocrit value through regular bloodletting or apheresis ,
  2. Possible inhibition of platelet aggregation to reduce the increased risk of thrombosis through acetylsalicylic acid (e.g. aspirin) or anticoagulants (provided that blood clotting is not impaired due to the disease)
  3. Cell-reducing drugs ( hydroxycarbamide ) ("mild form of chemotherapy") if the other measures are no longer sufficient or if the number of platelets is in a range that dangerously increases the risk of thrombosis
  4. Alpha interferon therapy as an alternative to chemotherapy (not yet officially approved for PV)
  5. Ruxolitinib or INC 424 (trade name Jakavi of the pharmaceutical company Novartis ), as well as Givinostat (still in the study phase in 2017, i.e. not yet approved) a Janus kinase inhibitor, approved since 2015 for resistance or intolerance to hydroxycarbamide or for severe Spleen enlargement and for the treatment of post-polycythemia vera myelofibrosis.

Other complaints accompanying the disease individually can only be treated symptomatically. In many cases, however, ruxolitinib also has a positive effect on the so-called secondary symptoms (e.g. itching, enlarged spleen, tiredness).

Bloodletting and apheresis

When the diagnosis is made, frequent (weekly), later (after normal values) regular (6 to 10 weeks) bloodletting are the most important measures to reduce erythrocytes and, to a lesser extent, other cellular components of the blood.

Device for erythrocyte apheresis

As an alternative measure to multiple bloodletting, therapeutic apheresis (known as blood washing ) is used. This procedure filters out the surplus blood components in about a 20-minute operation. While bloodletting lowers the hematocrit by a maximum of 3 percent, it can be reduced by up to 12 percent with apheresis. In the event of subsequent occasional blood tests, it must be reapplied every three to six months. Currently, apheresis is not part of the standard therapy and must be justified by a doctor. Because of the complex technology and the associated costs, apheresis is carried out nationwide in a few hospitals, hardly in hematological practices.

The proportion of platelets and leukocytes often increases during treatment with bloodletting ( phlebotomy ) or blood washes ( apheresis ), since these measures can only reduce the proportion of red blood cells in the medium term. The other solid blood components (thrombocytes and leukocytes) continue to be produced to an increased extent due to the disease - individually differently. After the hematocrit has been reduced to around 45 percent, the platelet count in particular must be monitored.

Inhibition of platelet aggregation

Due to the increased risk that blood cells, especially platelets ( platelet aggregation ) clump and block blood vessels ( thrombosis ) and that these thromboses dissolve and block the blood flow at another point in the bloodstream ( embolism ), it is important to reduce the increased tendency to thrombosis . The cause of this tendency to thromboembolism is , on the one hand, the increased number of blood cells (especially with greatly increased values ​​of erythrocytes and thrombocytes) and, on the other hand, a not yet fully understood disruption of the entire regulating mechanism of blood coagulation. In the presence of a JAK2-V617F mutation, the tendency to thrombosis is also increased due to an increased tendency for granulocytes to accumulate on the vessel walls.

If there are no contraindications (contraindications), such as If , for example, there is an increased tendency to bleed , the risk of thrombosis can be reduced by long-term use of oral platelet aggregation inhibitors such as acetylsalicylic acid ( ASA ) in relatively low doses (50 or 100 mg per day). It is generally taken before the start of and parallel to the bloodletting therapy. In part of the specialist literature, it is critically pointed out that, because of possible side effects, such drugs should only be taken when thrombosis has already occurred and that at the same time the erythrocyte mass should be strictly controlled.

Cell reductive and interferon therapy

As long as the necessary lowering of the hematocrit can be achieved by bloodletting and no thromboembolic complications occur, chemotherapy is not indicated. If too high a number of leukocytes or platelets leads to increased thrombosis and / or embolism, if a very large enlargement of the spleen can be determined and / or if water-induced itching occurs after bloodletting, it must be investigated whether chemotherapy as a cytoreductive measure (reduction of the high formation of new cells) could be useful. The aim would be to limit the formation of new platelets in particular.

Hydroxyurea (e.g. Litalir), which is approved in Germany, and the drugs alpha interferon, which are not yet approved in Germany, are currently used for treatment, and anagrelide is being tested . As with any chemotherapy, side effects cannot be ruled out. Side effects such as irritation of the mucous membranes, fever, psychological changes, skin tumors, strong fluctuations in platelet values ​​or diarrhea can occur. In rare cases, acute leukemia can also be triggered.

Further measures

Due to the very different symptoms that may be associated with the disease, a number of supplementary measures are carried out that are primarily intended to alleviate the accompanying symptoms. Since there is no causal influence on this, the use ultimately depends on the direct effect on the respective patient.

In addition, the administration of allopurinol may be appropriate (indicated) for the prophylaxis of a gout attack or urate nephropathy due to an increased uric acid attack (especially during cytoreductive therapy) . In general, there is no need to treat asymptomatic hyperuricemia below 10 mg / dL.

Aquagenic itching, which occurs in more than half of the patients and which can significantly impair quality of life, can only be symptomatic in addition to bloodletting with bath additives (e.g. bicarbonate , starch), antihistamines , serotonin reuptake inhibitors , creams that reduce itching (e.g. with Capsaicin ) or phototherapy (not without risk because of a possible carcinogenicity) can be alleviated to a greater or lesser extent.

In some patients with an extremely enlarged spleen that can no longer be treated with medication, an operation may be necessary. Since 2016, the use of ruxolitinib can in many cases cause the spleen to shrink rapidly.

In younger patients (depending on their state of health, up to approx. 65 years of age), a bone marrow or stem cell transplant may also be required in extreme cases and if the disease is very advanced .

Radiophosphorus therapy can also be considered as an alternative in older patients .

forecast

Since the disease is generally indolent (painless) and can last for decades, those affected can live a long life without functional restrictions, provided that the erythrocyte count is permanently controlled by bloodletting. The required bloodletting leads to an iron deficiency , which leads to a reduction in blood production. Side effects of iron deficiency are, for example, tiredness, headaches, reduced performance or dizziness.

Complications can thrombosis, enlargement of the spleen ( splenomegaly ) or liver ( hepatomegaly ), a bone marrow fibrosis (10-20%) and (1-10%) in rare cases - by an additional acute myeloid - particularly after chemotherapy or radiation leukemia arise . Pregnancy is possible in spite of the disease, but must be accompanied intensively on an interdisciplinary basis because of the increased risk of thrombosis, as the risk of miscarriage or damage to the placenta is very high (around 50% live births).

literature

  • Jerry L. Spivak: Polycythemia vera and other myeloproliferative diseases . In: Manfred Dietel (Ed.): Harrison's internal medicine. German edition in cooperation with the Charité . 17th edition. tape 1 , part 6. McGraw-Hill, Berlin 2009, ISBN 978-3-86541-310-9 , chap. 103, p. 838–844 (German version Isrid Sturm and Bernd Dörken).
  • FP Siegel, PE Petrides: Congenital and acquired polycythemia (review article) . In: Deutsches Ärzteblatt . tape 105 , no. 4 , 2008, p. 62–68 ( aerzteblatt.de [PDF]).
  • Polycythemia vera . In: Pschyrembel Clinical Dictionary 2012 . 263rd edition. Walter de Gruyter, Berlin / Boston 2011, ISBN 978-3-11-025166-1 , p. 1666 .
  • A. Rüfer, A. Tobler, A. Tichelli, WA Wuillemin: Myeloproliferative Syndromes: Polycythemia vera, essential thrombocythemia, osteomyelofibrosis . In: Switzerland Medical Forum . No. 43 , October 22, 2003, p. 1026-1033 ( medicalforum.ch [PDF]).
  • S. Gesenhues, R. Zisché: General Practice Practice Guide . 6th edition. Urban & Fischer, Munich 2010, ISBN 978-3-437-22443-0 , 19 Hematology, 19.3.5 Polycythaemia vera and Panmyelopathie, pp. 1066 f .

Web links

Individual evidence

  1. ↑ a b Polycythemia vera . In: Pschyrembel Clinical Dictionary 2012 . 263rd edition. Walter de Gruyter, Berlin / Boston 2011, ISBN 978-3-11-025166-1 , p. 1666 .
  2. ↑ 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. 418 f.
  3. ↑ a b c d e f F. P. Siegel, PE Petrides: Congenital and acquired polycythemia (review article) . In: Deutsches Ärzteblatt . tape 105 , no. 4 , 2008, p. 62–68 ( aerzteblatt.de [PDF; accessed April 15, 2012]).
  4. ↑ Entry on Orphanet, status 2010, accessed May 4, 2016.
  5. ↑ Wolfgang Gerok: The internal medicine: reference work for the specialist . Schattauer Verlag, 2007, ISBN 978-3-7945-2222-4 , p. 68.
  6. ^ FP Siegel, PE Petrides: Congenital and acquired polycythemia. In: Deutsches Ärzteblatt. Volume 105, No. 4, 2008, pp. 62–68, doi: 10.3238 / arztebl.2008.0062
  7. ↑ Polycythemia vera (PV): Frequently Asked Questions. MPN network e. V., August 2015 (accessed May 4, 2016)
  8. ↑ a b various sources, including the medical portal med2click , accessed on March 5, 2012.
  9. ↑ a b c d e f g h i j Jerry L. Spivak: Polycythemia vera and other myeloproliferative diseases . In: Manfred Dietel (Ed.): Harrison's internal medicine. German edition in cooperation with the Charité . 17th edition. tape 1 , part 6. McGraw-Hill Inc., Berlin 2009, ISBN 978-3-86541-310-9 , chap. 103, p. 838–844 (German version Isrid Sturm and Bernd Dörken).
  10. ^ R. Kralovics, F. Passamonti, AS Buser a. a .: A gain-of-function mutation of JAK2 in myeloproliferative disorders. In: N Engl J Med 352, 2005, pp. 1779-1790. Abstrac
  11. ↑ C. James, V. Ugo, JP Le Couedic et al. a .: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera . In: Nature , 2005, 434, pp. 1144-1148
  12. ↑ a b D. A. Arber, A. Orazi, R. Hasserjian, J. Thiele, MJ Borowitz, MM Le Beau, CD Bloomfield, M. Cazzola, JW Vardiman: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia . In: Blood. 127, 2016, pp. 2391-2406, doi : 10.1182 / blood-2016-03-643544 .
  13. ^ A b Classen, Meinhard., Berdel, Wolfgang E .: Internal medicine: with 1246 tables, 216 case reports, 450 summaries and 183 practical questions . Urban & Fischer, 2004, ISBN 3-437-42830-6 .
  14. ↑ Frequently asked questions about polycythemia vera. ( Memento of the original from February 5, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. MPD network; Retrieved April 5, 2012 @1@ 2Template: Webachiv / IABot / www.mpd-netzwerk.de
  15. ↑ Clinical study on the effectiveness in Polycythemia Vera patients as of September 2, 2016.
  16. ↑ Red List. January 2016.
  17. ↑ N. Gupta, B. Edelmann, TM Schnoeder, FC Saalfeld, D. Wolleschak, S. Kliche, B. Schraven, FH Heidel and T. Fischer: JAK2-V617F activates β1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1. In: Leukemia 31, 2017, pp. 1223-1226, doi: 10.1038 / leu.2017.26
  18. ↑ R. Landolfi, R. Marchioli, J. Kutti u. a .: Efficacy and safety of low-dose aspirin in polycythemia vera. In: The New England Journal of Medicine 350, 2004, pp. 114-124, PMID 14711910 .
  19. ↑ Guideline of the German Society for Hematology / Oncology as of June 2014 , accessed on January 25, 2015.
  20. ↑ a b A. Rüfer, A. Tobler, A. Tichelli, WA Wuillemin: Myeloproliferative Syndromes: Polycythemia vera, essential thrombocythemia, osteomyelofibrosis . In: Switzerland Medical Forum . No. 43 , October 22, 2003, p. 1026-1033 ( medicalforum.ch [PDF; 240 kB ]).