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Approach to the Patient with Increased Blood Counts Hasan Atilla Özkan, MD 1 A. Approach to the patient with erythrocytosis B. Approach to the patient with leukocytosis C. Approach to the patient with thrombocytosis 2 A. Erythrocytosis 1. General Information • Most commonly suspected in a patient with an abnormally high result an one or more of the following blood tests - Htc: >48% woman, >52% man - Hgb: > 16.5 woman, > 18.5 man - RBC count 3 2. Terminology • Relative polycythemia: due to reduced plasma volume • Absolute polycythemia: increased red cell mass - primary polycythemia; caused by aquired or inherited mutation leading to an abnormality within RBC progenitors - secondary polycythemia; caused by a circulating factors stimulating erythropoiesis, usually erythropoietin (hypoxia, Eposecreting tumors) 4 • Combined polycythemia; increased RCM + reduced plasma volume (smokers polycythemia) • Inapparent polycythemia; both RCM + plasma volume increased. Need for blood volume studies 5 3. Physiology of erythropoiesis • RBC are derived from the pluripotent hematopoietic stem cell • Under normal conditions, the earliest, erythroidcommited progenitor cells depend on the Epo to further differentiate and produce RBC 6 7 • 90% of the circulating Epo is synthesized by the kidneys in response to hypoxic signal - anemia - reduced Hgb-O2 saturation (hypoxemia) - decreased O2 released from Hgb (high-O2affinity hemoglobinopathies) - reduced O2 delivery to kidney (vascular occulusion) • A negative feedback inhibition mechanism down regulates Epo production with increasing O2 delivery 8 9 10 4. Evaluation Do not forget: Most common cause of polycythemia is hypoxia secondary to pulmonary disease a) History: • Symtoms pertaining to altered lung function • Living at high attitude • İntracardiac or intrapulmonary shunts • Renal tx • Hemorragic or thrombotic events 11 • Post-bath pruritus • Family history • Medications • Smoking history • Chronic exposure to carbon monoxide • Pulmonary arteriovenous malformations 12 b) Physical examination • Cyanosis in the lips, earlobes and fingers • Clubbing in the nailbeds • Shortness of the breath • Plethoric face, painful erythema • Cardiac murmurs • Hepato-splenomegaly • purple striae, hirsutism, buffalo hump, central obesity (Chushing syndrome) 13 c) Laboratory testing • Hgb, Htc and RBC count • A high RBC count with reduced Hgb and MCV – thalassemia minor • Elevated WBC and/or plt count and/or reduced MCV – PV • Testing for Jak-2 mutation • Hematuria with a high Epo – renal cell Ca • Abnormal liver function – hepatoma 14 • Blood volume measurements - RBC mass: 24 to 30 ml/kg - plasma volume: 39-49 ml/kg • Pulse oximetry, arterial oxygen tension • Serum erythropoietin - low Epo with erythrocytosis – PV - normal-high Epo – secondary eythrocytosis 15 • Tumors may lead to eythrocytosis - hepatocellular Ca - renal cell Ca - hemangioblastoma - pheochromocytoma - uterine myoma 16 d) Management of secondary erythrocytosis • Control of the underlying disease • Limited phlebotomy - < 45% - man - < 42% - woman 17 18 19 B. Leukocytosis • Normal total WBC count; 4000-11000 cells/µL • Leukocytosis WBC > 11000 • Leukomoid rxn -WBC >50000 (other than leukemia) • Aproximattely 60% mature neutrophils • Leukocytosis is most commonly due to an increase in the absolute number of mature neutrophils (neutrophilia) • But, also reflect increase in lymphocytes, eosinophils, monocytes, basophils or blast cells, 20 • Normal leukocyte count, differential count: WBC 4400-11000 Segmented N 1800-7000 Band 0-700 Eosinophils 0-450 Basophils 0-200 Lymphocytes 1000-4800 Monocytes 0-800 21 • ANC= WBC X percent (PMNs + bands) / 100 • Neutrophilic leukocytosis: - WBC > 11000 + ANC > 7000 • Neutrophilia: - WBC < 11000 + ANC > 7000 22 • Evaluation of a patient with leukocytosis should include a CBC, Plt count, WBC differential and examination of the peripheral blood smear; - presence of a ‘left shift’ - evaluation for infection/inflammation - presence of anemia or polycythemia, thrombocytemia or thrombocytosis, and/or abnormal cells - presence of predominance of lymphocytes 23 Neutrophilia • Mechanism; - increased production in bone marrow - increased released from stores - shift from marginal poll to circulation 24 25 1) Evaluation of neutrophilia a) • • • • • • • • • History; İnflammation or infection Smoking Pregnancy Emotional stress Prior hematologic disease Heavy exercise Trauma, surgery, thermal burn, electric shock Splenectomy medications 26 b) Physical examination; to determine presence or absence of infection, inflammation or malignancy • Fever • Hypotention, shock, tacycardia, hypothermia • Evidence of infection • Abdominal rebound, tenderness • Joint swelling, erythema • Hepatosplenomegaly • Lymphadenopathy • Diarrhea 27 c) Laboratory testing • WBC differantial and peripheral blood smear - left shift, toxic granulation, döhle body – infection - howell-joly bodies – splenectomy or asplenia - blasts – leukemia - peripheral blood smear mimicing bone marrow – CML - leukocytosis + thrombocytosis ± erythrocytosis – MPD - leukoerytroblastic picture – infiltrative marrow disease - platelet clumping, cryoglobulinemia 28 • Bone marrow examination: When ? - in the presence of leukomoid rxn, leukoerythroblastic picture or immature cells on the peripheral smear • CRP, ESR • Cultures, imaging, etc 29 30 31 32 33 34 Monocytosis • > 10% of total WBC or > 800/µL • Causes; - infections (brucellosis, varicella-zoster, bacterial endocarditis, tbc, malaria, thyhoid fever, syphilis) - inflammatory (eg. Sarcoidosis, inflammatory bowel disease) - treatment with steroids, GM-CSF - pregnancy - malignancy ; - chronic myelomonocytic leukemia - acute monoblastic/myelomonocytic leukemia - hodgkin lymphoma 35 Lymphocytosis • Subset of WBC that form an integral part of the immune system • Facilitate humoral and cellular immunity againts foreign proteins and pathogens • Absolue lymphocyte count (ALC) = WBC X percent lymphocytes/100 • Lymphocytosis: ALC > 4000/µL 36 • Lymphocyte subpopulation - T cells (eg. CD3+) – 60-80% * T helper (CD4+) – 60-70 % * T suppressor (CD8+) – 30-40 % - B cells (eg. CD20+) – 10-20% - NK cells (eg. CD56+) – 5-10 % 37 • Lymphocytosis; - Reactive lymphocytosis - polyclonal nonmalignant - Clonal lymphocytosis – almost always lymphoproliferative disorder • Blood lymphocyte morphology is very important for diagnosis 38 • Causes of malignant and premalignant lymphocytosis: - thymoma - hereditary polyclonal B cell lymphocytosis - monoclonal B cell lymphocytosis - chronic lymphocytic leukemia - lymphoproliferative disease of large granular lymphocytes 39 40 41 42 43 44 45 46 Eosinophilia • > 500/µL - 500-1000 : mild - 1000-5000: modarate - > 5000 : severe • Catagories of eosinophilia; - primary: usually due to hematologic malignancy - secondary: allergic disorders, parasitic infections, medications, etc.. - idiopathic 47 48 49 50 Basophilia • > 200/µL • Most common causes; - myeloproliferative disorders (CML, PV, PMF, ET) - hematologic malignancy (basophilic leukemia, mastocytosis, hypereosinophilic syndrome, atypical acute or chronic leukemias, MDS) - allergic or inflammatory reactions (hypersensitivity rxn, ulserative colitis, RA) - endocrinopathy (hypothroidism, administration of estrogens) - infections (viral, Tbc, helminth infections) 51 52 C. Thrombocytosis • > 450.000/µL • Two questions should be addressed in any patient with newly diagnosed thrombocytosis: - a reactive phenomenon or a clonal hematologic disorder - what is the risk to the patient and how should it be managed ? 53 a) Definitions • Reactive thrombocytosis (eg. Surgery, trauma, infection) • Autonomous (primary) thrombocytosis (eg. PV, CML, PMF, 5q-syndrome) 54 1) Reactive Thrombocytosis • RT is more common than AT • Coomon causes of extreme RT (>106) are; - infection – 31% - postsplenectomy – 19% - malignancy – 14% - trauma – 14% - inflammation – 9% - blood loss – 6% - rebound thrombocytosis – 3% - unknown – 4% 55 56 • Thrombopoietic growth factors (thrombopoietin, IL-6) have been implicated as the cause of RT in various infections, inflammatory, malignant, necrotic, and traumatic processes • Symptoms; - vasomotor (headache, visiual symptoms, chest pain, acral dysesthesia, erythromelalgia) - thrombosis - bleeding • Degree of thrombocytosis does not predict the likelihood of AT. But, thrombohemorrahagic manifestations suggest the diagnosis of AT 57 Erythromelalgia Plethoric face 59 2) Spurious (False) Thrombocytosis • mixed cryoglobulinemia • Cytoplasmic fragments (severe hemolysis, burn, etc) 3) Autonomous (primary) Thrombocytosis • Essential thrombocythemia • CML • PV • MDS (5q-syndrome) • Acute myeloid leukemia (t(3;3) and inv(3) in AML) 60 61 62 63 64 b) Management 1) Bleeding: - discontinue the use of any antiaggregant agent - laboratory evaluation for DIC and coagulation factor deficiency - platelet and/or FFP transfusion 65 2) Thrombosis • Occlusion of the hepatic and/or inferior vena cava, portal or splenic vein suggests AT (especially in female < 45 y) • Platelet apheresis, if Plt > 800.000 • Platelet lowering agent to Plt < 400.000 (hydroxyurea, anegralide) • Testing for other thrombotic causes 66 3) Vasomotor symptoms • Low dose aspirin • Calcium – chanel blockers • penthoxyphilline 67