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Myeloproliferative Disorder

Myeloproliferative Disorder. Dr Farzane Ashrafi Hematologist/ Medical Oncologist. PATIENT PRESENTATION. A 50-year-old man presents with a two-month history of fatigue and early satiety. His complete blood count shows the following:. HISTORY.

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Myeloproliferative Disorder

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  1. Myeloproliferative Disorder Dr FarzaneAshrafi Hematologist/ Medical Oncologist

  2. PATIENT PRESENTATION • A 50-year-old man presents with a two-month history of fatigue and early satiety. His complete blood count shows the following:

  3. HISTORY • What are the hematologic abnormalities present here? • Granulocytosis • Anemia • Thrombocytosis • Normal Differential • Basophilia

  4. HISTORY • Granulocytosis • Correct! • COMMENT: This patient has leukocytosis (an increase in the total white blood cell count) due to an increased number of neutrophils

  5. HISTORY • Anemia   • Incorrect.No. The hemoglobin and hematocrit are within the normal range

  6. HISTORY • Thrombocytosis • Correct! • COMMENT: The elevated platelet count indicates thrombocytosis

  7. HISTORY • Normal Differential   • Incorrect.No. There is a “left shift” in the differential of the white blood cell count.  “Left shift” refers to the presence of immature granulocytes in the peripheral blood, including bands, metamyelocytes and myelocytes.

  8. HISTORY • Basophilia • Correct! • COMMENT: Basophils are granulocytes with large purple cytoplasmic granules. They mediate allergic and inflammatory reactions and are increased in these situations as well as in certain chronic infections such as tuberculosis. They are also increased in certain hematologic diseases, including the myeloproliferative disorders. Basophilia is the term for the presence of increased numbers of basophils in the peripheral blood.

  9. HISTORY • Summary of hematologic abnormalities in this patient: • Leukocytosis (increased WBC count) due to granulocytosis with a left shift • Thrombocytosis (elevated platelet count) • Basophilia (elevated basophils

  10. HISTORY • Which of the following questions would be helpful in distinguishing a primary from a reactive cause of neutrophilia or thrombocytosis?

  11. HISTORY • Have you lost weight recently without dieting? • Do you drink alcohol? • Have you had any fevers? • Do you have an ongoing infection? • Do you have any itching? • Have you had any episodes of pain in your fingers or toes? • Do you have any joint pains? • Do you have bleeding from any site (for example, heavy menstrual bleeding, bright red blood per rectum, or black tarry stools)? • Have you ever had a heart attack, stroke, or blood clot (myocardial infarction, cerebrovascular accident, deep vein thrombosis)? • Are you taking any medications?

  12. HISTORY • Have you lost weight recently without dieting?   • Good choice.PATIENT’S RESPONSE: No. • COMMENT:  Constitutional symptoms such as fever, anorexia, weight loss and night sweats may be seen in infections (particularly chronic infections such as tuberculosis), malignancies, chronic inflammatory diseases, and hypermetabolic states (thyrotoxicosis, hematologic malignancies associated with rapid cell turnover), all of which may be associated with granulocytosis and thrombocytosis.

  13. HISTORY • Do you drink alcohol?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Liver disease resulting in portal hypertension is associated with splenomegaly. Alcohol can suppress bone marrow production of platelets. "Rebound thrombocytosis" can occur with cessation of drinking.

  14. HISTORY • Have you had any fevers?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Constitutional symptoms such as fever, anorexia, weight loss and night sweats may be seen in infections (particularly chronic infections such as tuberculosis), malignancies, chronic inflammatory diseases, and hypermetabolic states (thyrotoxicosis, hematologic malignancies associated with rapid cell turnover), all of which may be associated with granulocytosis and thrombocytosis.

  15. HISTORY • Do you have an ongoing infection?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Acute and chronic infections may be associated with reactive thrombocytosis and granulocytosis.

  16. HISTORY • Do you have any itching?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Pruritus (itching) is a common finding in polycythemiavera, which is associated with granulocytosis and thrombocytosis. Pruritus may also occur in patients with hematologic malignancies such as Hodgkin's Disease and non-Hodgkin's lymphoma

  17. HISTORY • Have you had any episodes of pain in your fingers or toes?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Erythromelalgia is a symptom of ischemia secondary to small vessel digital thrombosis seen in the myeloproliferative disorders polycythemiavera and essential thrombocythemia

  18. HISTORY • Do you have any joint pains?   • Good choice.PATIENT’S RESPONSE: No.COMMENT:  Collagen vascular diseases such as systemic lupus erythematosus and rheumatoid arthritis may be associated with reactive granulocytosis, thrombocytosis and splenomegaly

  19. HISTORY • Do you have bleeding from any site (for example, heavy menstrual bleeding, bright red blood per rectum, or black tarry stools)?   • Good choice.PATIENT’S RESPONSE: No.COMMENT:  Bleeding and iron deficiency may be associated with reactive thrombocytosis. Qualitative platelet defects and bleeding may be seen in the myeloproliferative disorders

  20. HISTORY • Have you ever had a heart attack, stroke, or blood clot (myocardial infarction, cerebrovascular accident, deep vein thrombosis)?   • Good choice.PATIENT’S RESPONSE: No.COMMENT:  Thrombotic complications are increased in patients with myeloproliferative disorders. Malignancies may be associated with increased thrombotic risk

  21. HISTORY • Are you taking any medications?   • Good choice.PATIENT’S RESPONSE: No.COMMENT: Steroids, lithium and hematopoietic growth factors (granulocyte-colony stimulating factor and granulocyte-macrophage colony) can cause granulocytosis. Vincristine (a chemotherapeutic agent) and epinephrine can cause thrombocytosis.

  22. HISTORY • Summary of History • The most important elements from the history are the apparent absence of evidence of acute or chronic infections or inflammatory conditions that might lead to reactive granulocytosis and thrombocytosis

  23. PHYSICAL EXAM • Physical examination reveals a well-developed man in no acute distress. • [Note: cachexia (profound wasting) would suggest chronic illness (inflammatory or infectious) or malignancy.] • Afebrile • Head, ears, eyes, nose, throat: anicteric (absence of jaundice) • No lymphadenopathy

  24. PHYSICAL EXAM • Lungs are clear (no pulmonary signs of infection or malignancy) • Heart: no murmurs • Abdomen: no signs of ascites; liver edge is not palpable; spleen edge is palpable 4 cm below the left costal margin • Skin:  no petechiae.  No ecchymoses. No spider angiomata.   • Neurologic exam: normal

  25. PHYSICAL EXAM • Which of the following negative findings can help you rule out reactive causes of neutrophilia and thrombocytosis? • Afebrile • Absence of jaundice • No Lymphadenopathy • No cardiac murmurs • Normal neurologic exam

  26. PHYSICAL EXAM • Afebrile • Correct!COMMENT: This is a pertinent negative because infection is the main differential for neutrophilia. Note, however, that fever can occasionally be present in myeloproliferative disorders

  27. PHYSICAL EXAM • Absence of jaundice   • Correct!COMMENT: Jaundice may be seen in patients with liver disease (impaired hepatic metabolism of bilirubin or biliary tract obstruction) or hemolytic anemias (increased release of bilirubin from the hemoglobin of destroyed red cells). Patients with liver disease have splenomegaly secondary to portal hypertension. Patients with chronic hemolytic anemias have splenomegaly secondary to "work hypertrophy."

  28. PHYSICAL EXAM • No Lymphadenopathy • Correct!COMMENT: Lymphadenopathy may be secondary to infection, inflammation or malignancy, either metastatic solid tumors or hematologic malignancies such as non-Hodgkin's lymphoma and Hodgkin's Disease

  29. PHYSICAL EXAM • No cardiac murmurs   • Correct!COMMENT: Cardiac murmurs may indicate the presence of endocarditis, which may be associated with neutrophilia, thrombocytosis and splenomegaly.

  30. PHYSICAL EXAM • Normal neurologic exam   • No. This is not relevant for ruling out reactive causes of neutrophilias and thrombocytosis

  31. PHYSICAL EXAM • How does the finding of a palpable spleen on physical examination narrow the differential diagnosis in this patient? • It might not narrow the differential diagnosis, since a spleen may normally be palpable. • The presence of splenomegaly makes infection unlikely. • Myeloproliferative disorders are often associated with splenomegaly

  32. PHYSICAL EXAM • It might not narrow the differential diagnosis, since a spleen may normally be palpable.   • Incorrect.COMMENT: A normal spleen is not palpable, except perhaps in a very thin individual. A palpable spleen generally indicates splenomegaly.

  33. PHYSICAL EXAM • The presence of splenomegaly makes infection unlikely.   • Incorrect.COMMENT: Infections such as bacterial endocarditis, infectious mononucleosis, tuberculosis, malaria and parasitic infections may all cause splenomegaly.

  34. PHYSICAL EXAM • Myeloproliferative disorders are often associated with splenomegaly.   • Correct!COMMENT: All of the myeloproliferative disorders may be associated with splenomegaly, which is secondary to extramedullaryhematopoiesis.

  35. Mechanisms of splenomegaly

  36. LABORATORY DATA • Which laboratory and diagnostic studies would be helpful in making a diagnosis? • Creatinine • Calcium • CXR • Liver enzymes • Uric acid • Serial stool testing for occult blood (guaiac tests) • Iron studies • Evaluation of peripheral smear

  37. LABORATORY DATA • Creatinine • Not relevant in this case

  38. LABORATORY DATA • Calcium   • Not relevant in this case.

  39. LABORATORY DATA • CXR   • Good choice!PATIENT RESULT: NormalCOMMENT: Chronic infections such as tuberculosis may lead to reactive granulocytosis and thrombocytosis

  40. LABORATORY DATA • Liver enzymes   • Good choice!PATIENT RESULT: NormalCOMMENT: Splenomegaly may occur in patients with liver disease secondary to portal hypertension. However, this is usually associated with cytopenias secondary to hypersplenism, and not elevated blood counts.

  41. LABORATORY DATA • Uric acid   • Good choice!PATIENT RESULT: 9 mg/dLCOMMENT: An elevated uric acid level can result from gout, renal failure or increased purine catabolism that occurs with highly proliferative malignancies, including acute myelogenous leukemia and the myeloproliferative disorders. It may also be seen during treatment of these malignancies with chemotherapy, when the rapid destruction of cells releases large amounts of uric acid into the blood, so called "tumor lysis

  42. LABORATORY DATA • Serial stool testing for occult blood (guaiac tests)   • Good choice!PATIENT RESULT: Negative for occult bloodCOMMENT: Gastrointestinal bleeding may be associated with reactive thrombocytosis. Peptic ulcer disease has a 4-5 fold increased incidence in patients with polycythemiavera

  43. LABORATORY DATA • Iron studies   • Good choice!PATIENT RESULT: NormalCOMMENT: Iron deficiency and bleeding may be associated with reactive thrombocytosis. Polycythemiavera is often associated with iron deficiency secondary to gastrointestinal blood loss and increased iron utilization from the marked increase in erythropoiesis.

  44. LABORATORY DATA • Evaluation of peripheral smear   • Good choice!PATIENT RESULT:

  45. LABORATORY DATA

  46. LABORATORY DATA • The peripheral smear shows a marked increase in granulocytic cells with a left shift (the presence of immature granulocytes in the peripheral blood including bands, metamyelocytes and myelocytes). There is an increase in platelets.

  47. DIFFERENTIAL DIAGNOSIS • Given this patient’s clinical and laboratory findings, what is the most likely diagnosis? • Acute Myelogenous Leukemia • Polycythemia Vera • Essential Thrombocythemia • Chronic Myelogenous Leukemia • Reactive thrombocytosis and granulocytosis secondary to infection • Reactive thrombocytosis and granulocytosis secondary to malignancy

  48. DIFFERENTIAL DIAGNOSIS • Acute Myelogenous Leukemia   • Incorrect.COMMENT: Although acute myelogenous leukemia frequently presents with an elevated total WBC count, the white blood cells are last forms.  Mature white blood cells such as bands and neutrophils (granulocytes) are decreased.  Patients usually have thrombocytopenia (a decreased platelet count).  Patients are typically acutely ill with fever and signs of bleeding.

  49. DIFFERENTIAL DIAGNOSIS • Polycythemia Vera   • Unlikely.COMMENT:  Polycythemiavera may be associated with the constitutional symptoms described as well as with splenomegaly, granulocytosis, basophilia and thrombocytosis. However, one of its defining features, an elevated hematocrit, is not present in this patient. Sometimes, with profound iron deficiency, the hematocrit may not be elevated. Iron studies would indicate iron deficiency (low serum iron, elevated total iron binding capacity) and the MCV would be decreased. This patient has normal iron studies and a normal MCV. Mutations in JAK2, a tyrosine kinase involved in the physiology of the bone marrow response to erythropoietin and in cell proliferation, have recently been identified in more than 95% of patients with polycythemiavera(but not in patients with secondary erythrocytosis). 

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