Done by: Charlie Amjad Qusar Mohammad Monther Salahat Basil Faiq Haddaden Baraa Ayman Fahmawi

Definition: Myeloproliferative disorders is the name for a group of conditions that cause blood cells ( platelets, white blood cells, and red blood cells) to grow abnormally in the bone marrow. Though myeloproliferative disorders are serious, and may cause certain health risks, people with these conditions often live for many years after diagnosis. The prognosis largely depends on the type of disorder.

Myeloproliferative disorders include: Polycythemia vera -- occurs when the bone marrow produces too many blood cells, especially red blood cells. More than 95% of people with polycythemia vera carry the blood mutation JAK2 V617F. Essential thrombocytosis -- occurs when the body produces too many platelet cells, which help blood to clot. Clots can block blood vessels leading to heart attack or stroke. Primary or idiopathic myelofibrosis, also known as myelosclerosis -- occurs when the bone marrow produces too much collagen or fibrous tissue in the bone marrow. This reduces bone marrow's ability to produce blood cells. Chronic myelogenous leukemia (CML) -- cancer of the bone marrow that produces abnormal granulocytes, a type of white blood cell, in the bone marrow.

Causes: All myeloproliferative disorders are caused by overproduction of one or more types of cells. No one knows what triggers the overproduction of cells, but theories include: Genetics -- Some people with CML have an abnormally shortened chromosome known as the Philadelphia chromosome 22. Environment -- Some studies suggest that myeloproliferative disorders may result from an overexposure to radiation, electrical wiring, or chemicals.

Polycythemia vera Malignant clonal proliferation of hematopoietic stem cells leading to excessive erythrocyte production. The increase in RBC mass occurs independent of erythropoietin. Men are 2 times more likely than women to develop the condition. People older than 60 years are most likely to develop the condition. Exposure to intense radiation may increase the risk for developing polycythemia vera.

Clinical features Symptoms of hyperviscosity: Headache, dizziness, weakness, pruritus ( patient complains of intense itching after a hot bath or shower), visual impairment, dyspnea, loss of concentration. Thrombotic phenomena: DVT, CVA, MI, portal vein thrombosis. Bleeding: GI or GU bleeding, epistaxis, ecchymoses. Spleenomegaly and hepatomegaly. Hypertension.

Diagnosis 1. Rule out causes of secondary polycythemia (e.g: hypoxemia, carbon monoxide exposure, heavy smoking, chronic pulmonary diseases, renal disease). 2. CBC: i. Elevated RBC count, hemoglobin, hematocrit (usually >50) ii. Thrombocytosis, leukocytosis may be present.

3. Serum erythropoietin levels are reduced. 4. elevated vitamin B12 level 5. Hyperuricemia 6. Bone marrow biopsy confirms the diagnosis.

Treatment Is objective to reduce the viscosity (thickness) of blood. 1. Phlebotomy: Lower RBC count by removing blood. 2. hydroxyurea: reduces number of blood cells 3. Antihistamines: decreases itching. 4. Allopurinol: reduces symptoms of hyperuricemia.

Essential thrombocythaemia also known as essential thrombocytosis, primary thrombocytosis. increased proliferation of megakaryocytes results in a raised level of circulating platelets that are often dysfunctional. Platelet count >600,000mm

Epidemiology Gender : women are 1.5 times more likely than man. Age : older than 60 more likely to develop the disease

causes Mostly idiopathic About half the people with the disorder have a mutation of the Janus kinase 2 (JAK2) gene, This mutation is diagnostic. This mutation appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin, because the receptors for these growth factors require JAK2 for signal transduction.

If one has essential thrombocythemia, his bone marrow makes too many platelet-forming cells (megakaryocytes) Due to increased sensitivity to growth factors, which release too many platelets into the blood. The excess platelets may not function normally, leading to abnormal clotting or bleeding.

Sign and symptoms Most people with ET are asymptomatic at the time of diagnosis, as the condition is usually discovered upon routine blood work. The most common symptoms are : Bleeding.( defective platelet function ) Blood clots (thrombosis). Psudohyperkalemia. Nausea, Vomiting, Abdominal pain. Headache, Visual disturbances, Enlarged spleen. Numbness in the extremities Erythromelagia “burning pain” and erythema of extremities due to microvascular occlusion.

Diagnosis The diagnosis of ET is not straightforward as there is no global gold standard test BUT : 1- JAK2 gene mutation test,are useful in that the gene is mutated in about half of all cases of ET, confirming a myeloproliferative disorder 2- Sustained platelet count of at least 450 × 10 9 /L. 3-Not meeting criteria for polycythemia vera (p. vera), primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm. 4- Erythrocyte sedimentation rate test (to roll out inflammation) 5- Iron test ( to roll out iron deficiency). Bone marrow biopsy : increase the number of megakaryocytes Peripheral smear : abnormal shaped platelets “hypogranular

Treatment Low-dose aspirin : may treat headache and burning pain in skin Hydroxyurea or anagrelide (agrylin): reduce number of blood cell Aminocaproic acid: reduce bleeding, given before surgery to prevent bleeding

Myelofibrosis Myelofibrosis (connicteve tissue or fibroblast being produced in the bone marrow) In myelofibrosis, the marrow is initially hypercellular, with an excess of abnormal megakaryocytes which release growth factors, e.g. platelet-derived growth factor platelet-derived growth factor  resulting in a reactive proliferation of fibroblasts ( produce connective tissue ) As the disease progresses, the marrow becomes fibrosed

extramedullary haematopoiesis (blood cell formation outside the bone marrow),  splenomegaly, Hepatomegaly

Presentation Most patients present over the age of 50 years weight loss, fever and night sweats, The spleen can be massively enlarged As spleen enlarges, pts may have abdominal pain, early satiety. >50% pts present with anemia and thrombocytopenia Physical finding “ hepatosplenomegaly ”

Lab finding Early on, pts may have  Plts and normal Hb and WBC. as disease progresses Anemia, and  Plts and  WBC seen Blood film shows leukoerythroblastic picture, with teardrops, NRBC and early granulocytes “Dry tap” or inability to aspirate liquid marrow frequently seen Increased collagen and reticulin fibrosis on BM biopsy 50 % may have JAK2 mutation

Teardrop RBC

Leukoerythroblastic anemia

Management and prognosis Median survival is 4 years from diagnosis, but ranges from 1 year to over 20 years. Treatment is directed at control of symptoms, e.g. red cell transfusions for anaemia. Folic acid should be given to prevent deficiency. Splenectomy may be required for a grossly enlarged spleen or symptomatic pancytopenia. HSCT (Hematopoietic stem cell Transplantation)may be considered for younger patients

Chronic myeloid leukemia CML is a clonal malignant myeloproliferative disorder characterized by abnormal production of cells of the myeloid lineage, specially WBC (predominantly neutrophiles), and because its chronic; cells tend to be mature, as opposed to the immature cells of AML

Incidence This leukemia is very rare in children peak incidence is at age years, with a slight male predominance.

Pathogenesis Almost all leukemia cells in patients with CML contain a specific cytogenetic marker, the Philadelphia or Ph chromosome (more than 95%, although BCR-ABL fusion gene is present in 100% of pts), which is the cause of the disease. It emerges after a translocation between chromosomes 22 and 9, resulting in fusion of the BCR gene (ch22) with the ABL gene (ch9) this PH chromosome produces an abnormal protein > receptor tyrosine kinase> continuous division of stem cells that differentiate to cells of myeloid lineage > specially WBC’s.

Clinical course can be divided into a chronic or “stable” phase and an advanced phase, the latter term covering both accelerated and blastic phases. Chronic phase : 95% asymptomatic;, in which the disease is responsive to treatment and is easily controlled, which used to last 3–5 years. With the introduction of imatinib therapy, this phase has been prolonged to longer than 8 years in many patients. *Fever (WBC’s + BMR) *Hepatosplenomegaly ( cell lysis + BMR) Accelerated phase: (not always seen), more rapid production defected or immature cells *anemia (RBC defect) *bleeding and easy bruising > petechiae and ecchymoses (platelet defect) *fever > infections (WBC defect)

Blastic phase: (more rapid pdtn of immature myeloblasts) in which the disease transforms into an acute leukemia, either myeloid (70%) or lymphoblastic (30%), which is relatively refractory to treatment. BMB shows >20% blasts. This is the cause of death in the majority of patients (imatinib decreases the transformation to this phase) *bone pain > accumulation of cells in BM *fever (causes mentioned)

Presentation Constitutional symptoms: Fatigue Weight loss Sweating Malaise Night sweats Low grade fever symptoms of Anemia symptoms of thrombocytopenia : Hemorrhage —i.e. easy bruising, discrete ecchymoses Splenomegaly with or without hepatomegaly In severe disease Splenic infarction Leucostasis (WBC over 300K usually) which leads to Retinal hemorrhages, blurred or loss of vision Priapism decreased cognition respiratory distress *treated by leukapheresis

Diagnosis Increased WBC count > 50k-200k usually CBC> normocytic anemia Basophilia is common in all types of leukemia PBS shows leukocytosis FISH (fluorescent in situ Hybridization) ; lights up to show the PH chromosome (or the BCR-ABL fusion gene) BM aspiration shows myeloblasts BM biopsy must show the PH chromosome and it’s the most accurate test

LAB score Increased WBC’s count may be caused by a normal response to chronic or autoimmune diseases, and that’s a normal response called leukemoid reaction. We differentiate this normal response from that of CML by measuring Leukocyte alkaline phosphatase, which is produced by normal leukocytes Decreased LAP score relative to the number of leukocytes point to CML

Treatment Hydroxyurea and interferon a work by reducing mass production of WBC’s by different mechanisms. The most important drug is imatinib which blocks tyrosine kinase receptor protein(the product of BCR-ABL gene) > the best initial therapy Death without it in 5y With use 5 year survival is 90% The most definitive treatment remains BM transplantation which is indicated in patients who don’t respond to imatinib