MYELOPROLIFERATIVE DISORDERS

In these disorders there is uncontrolled clonal proliferation of one or more of the cell lines in the bone marrow, namely erythroid, myeloid and megakaryo-cyte lines. Myeloproliferative disorders include polycythaemia vera, essential thrombocythaemia, myelofibrosis (all of which have an mutation of the gene Janus kinase 2, JAK-2) and chronic myeloid leukaemia. These disorders are grouped together as there can be transition from one disease to another; for example, polycythaemia vera can lead to myelofibrosis, and they may also transform into acute leukaemia. They occur principally in middle-aged and elderly people. They differ from the acute leukaemias (also clonal proliferation of a single cell line), where the cells also do not differentiate normally but where there is progressive accumulation of immature cells.

Polycythaemia

Polycythaemia is defined as an increase in Hb, PCV or RCC. These measure-ments are all concentrations and are therefore directly dependent on plasma volume as well as red blood cell mass. The production of red cells by the bone marrow is normally regulated by the hormone erythropoietin, which is produced in the kidney. The stimulus for erythropoietin production is tissue hypoxia.

In absolute polycythaemia there is an increase in the red cell mass. Primary polycythaemia is due to an acquired or inherited mutation leading to an abnormality within red blood progenitors. It includes polycythaemia vera

Fig. 5.4 The causes of polycythaemia.

and rare familial variants. Secondary polycythaemia is caused by an erythropoietin response to chronic hypoxia or by an erythropoietin-secreting tumour (Fig. 5.4).

Relative or apparent polycythaemia (Gaisbock’s syndrome) occurs in middle-aged obese men and is associated with smoking, increased alcohol intake and hypertension. The PCV is normal but plasma volume is decreased.

Polycythaemia vera

Polycythaemia vera arises from a single haematopoietic progenitor cell and leads to excessive proliferation of red cells and a variable increase in platelets and myeloid cells. JAK-2 mutations, present in over 95% of patients, lead to constitutive activation of its tyrosine kinase activity, which plays a pivotal role in cell proliferation and survival.

Clinical features

Symptoms and signs are the result of hypervolaemia and hyperviscosity. Typical symptoms include headache, dizziness, tinnitus, visual disturbance, angina pectoris, intermittent claudication, pruritus and venous thrombosis. Physical signs include a plethoric complexion and hepatosplenomegaly as a result of extramedullary haemopoiesis. Splenomegaly, if present, reliably distinguishes polycythaemia vera from secondary polycythaemia. There is an increased risk of haemorrhage as a result of friable haemostatic plugs, and gout caused by increased cell turnover and uric acid production.

Investigations

Blood count showing raised white cell and platelet counts is suggestive of polycythaemia vera as opposed to other causes of polycythaemia. The diag-nosis is made by demonstrating evidence of increased red cell volume (usually Hb >18.5 g/dL in men and >16.5 g/dL in women) and a gain of function mutation in JAK-2 (e.g. V617F) together with one of:

■ Erythroid hyperplasia, with increased numbers of megakaryocytes and granulocytes on bone marrow examination

■ Serum erythropoietin levels below normal

■ Erythroid colony formation in vitro in the absence of exogenous erythropoietin

Management

There is no cure, and treatment is given to maintain a normal blood count and to prevent the complications of the disease, particularly thrombosis and haemorrhage.

■ Venesection to maintain PCV <0.45 L/L. Regular venesection (e.g. 3-monthly) may be all that is needed in many patients.

■ Chemotherapy. Hydroxycarbamide (hydroxyurea) and busulfan are used to reduce the platelet count.

■ Low-dose aspirin with the above treatments is used for patients with recurrent thrombotic episodes.

■ Radioactive phosphorus (32P) is only given to patients over 70 years of age because of the increased risk of leukaemic conversion with its use.

■ Allopurinol is given to decrease uric acid levels.

Secondary polycythaemia

Secondary polycythaemia presents with similar clinical features to primary polycythaemia, although the white cell and platelet counts are usually normal and the spleen is not enlarged. In patients with tumours the primary disease must be treated to lower the level of erythropoietin. In hypoxic patients, oxygen therapy (p. 520) may reduce the Hb, and a small-volume phlebotomy (400 mL) may help those with severe symptoms. Smokers should be advised to stop smoking.

Essential thrombocythaemia

Patients have normal Hb levels and white cell count but elevated platelet count. Platelet size and function are abnormal, and presentation may be with bleeding or thrombosis. Differential diagnosis is from secondary causes of a

Table 5.12 Differential diagnosis of a raised platelet count

Reactive thrombocytosis

Autoimmune rheumatic disorders

Chronic infections

Inílammatory bowel disease

Malignancy

Haemorrhage

Surgery

Splenectomy and functional hyposplenism

Primary thrombocythaemia

Polycythaemia vera

Myeloíibrosis

Myelodysplasia

raised platelet count and other myeloproliferative disorders (Table 5.12). There is no global gold standard diagnostic test but in general an otherwise well person with a platelet count of >1000 X 109/L will have essential thrombocythaemia. Busulfan, hydroxycarbamide (hydroxyurea), anagrelide or inter^eron alfa are used to reduce platelet production.

Myelofibrosis (myelosclerosis)

Myelofibrosis is characterized by haemopoietic stem cell proliferation associated with marrow fibrosis (abnormal megakaryocyte precursors release fibroblast-stimulating factors, such as platelet-derived growth factor).

Clinical features

There is an insidious onset of weakness, weight loss and lethargy. Bleeding occurs in the thrombocytopenic patient. There is hepatomegaly and massive splenomegaly caused by extramedullary haemopoiesis.

Investigations

■ Blood count shows anaemia. The white cell and platelet counts are high initially, but fall with disease progression as a result of marrow fibrosis.

■ Blood film examination shows a leucoerythroblastic picture (immature red cells caused by marrow infiltration) and ‘teardrop'-shaped red cells.

■ Bone marrow is usually unobtainable by aspiration (‘dry tap'); trephine biopsy shows increased fibrosis.

■ The Philadelphia chromosome is absent; this and the bone marrow appearance helps to distinguish myelofibrosis from chronic myeloid leukaemia, which may present similarly.

Management

■ Transfusions are given for anaemia and allopurinol to decrease serum uric acid levels.

■ Hydroxycarbamide (hydroxyurea) or busulfan are used to reduce the raised white cell and platelet count.

■ Splenic irradiation may be useful to reduce a large painful spleen.

■ Splenectomy is performed if the spleen is very large and painful and the transfusion requirements are high.

Myelodysplasia

Myelodysplasia is a group of acquired bone marrow disorders caused by a defect in stem cells. There is progressive bone marrow failure, which tends to evolve into acute myeloid leukaemia. The myelodysplastic syndromes are predominantly diseases of the elderly, and are increasingly being diagnosed when a routine full blood count shows an unexplained macrocytosis, anaemia, thrombocytopenia or neutropenia. The diagnosis is made on the basis of characteristic blood film and bone marrow appearances. The Paradox of peripheral pancytopenia and a hypercellular bone marrow reflects premature cell loss by apoptosis.

Supportive treatment (red cell and platelet transfusions) is given to elderly patients with symptomatic disease. For younger patients, intensive chemo-therapy (as used for acute myeloblastic leukaemia) or allogeneic BMT are used. Lenalidomide (a thalidomide analogue) is used in the treatment of early-stage disease.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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