Clonal Disorders of hematopoietic stem cells Antonio Rivas PA-C
Objectives  <ul><li>Become familiar with pathogenesis, epidemiology, diagnosis and treatment of : </li></ul><ul><ul><li>Th...
Arterial-thrombosis <ul><li>Commonly related to coronary artery disease (ruptured atherosclerotic plaque) </li></ul><ul><l...
Thrombosis  <ul><li>Virchow’s triad-defines mechanism underlying thrombosis </li></ul><ul><ul><li>Diminished blood flow </...
Thrombosis  <ul><li>Data shows unique regulation of hemostasis in different vascular beds: </li></ul><ul><li>Cong.deficien...
Atherothrombosis- Endothelial Damage   <ul><li>Associated with increased levels of Homocysteine(HCY) in congenitals syndro...
Atherothrombosis - Platelets <ul><li>Platelet activation and adherence critical to the development of the thrombus </li></...
Thrombosis-DVT <ul><li>Inherited: recurrent thrombosis at early age, unusual sites, or family history </li></ul><ul><li>Ad...
Risk Factors for Venous Thrombosis <ul><li>Inherited </li></ul><ul><ul><li>Factor V Leiden  </li></ul></ul><ul><ul><li>Pro...
Inherited risk factors for DVT <ul><li>Factor V Leiden mutation -most common inherited disorder causing DVT </li></ul><ul>...
<ul><li>Heterozygous in 5% of the population with five fold increased risk for DVT-PE </li></ul><ul><li>Homozygous less fr...
Prothrombin G20210A Mutation <ul><li>Mutation leads to increased prothrombin levels </li></ul><ul><li>Two-fold increased r...
Inherited deficiency of natural anticoagulant proteins <ul><li>ATIII, protein C, protein S </li></ul><ul><li>Less common t...
Acquired risk factors for DVT Surgery-Trauma <ul><li>Surgery-orthopaedic-trauma: associated  with immobilization and stasi...
Other Acquired risk factors for DVT <ul><li>Pregnancy increases risk of DVT 5 fold(venous stasis and altered coagulation f...
Antiphospholipid Antibody Syndrome <ul><li>APA Syndrome acquired prothrombic disorder </li></ul><ul><li>Primary or Seconda...
DVT general considerations <ul><li>More frequent - Deep veins of the lower extremities and pelvis  </li></ul><ul><li>80% a...
DVT-Symptoms / Signs <ul><li>Dull ache - tight feeling - frank pain in the calf or whole leg, worse with walking (leg clau...
DVT-Diagnosis <ul><li>Doppler Ultrasonography-test of choice </li></ul><ul><li>Respiratory/cardiac symptoms -V/Q scan, spi...
DVT-Laboratory Test <ul><li>Evaluate for hereditary and acquired hyper-coagulable state specially young patients W/O predi...
DVT-Diff.Dx. <ul><li>Calf muscle strain or contusion, difficult </li></ul><ul><li>Cellulitis where you might find a wound ...
DVT-Prophylactic <ul><li>Elevation of the legs 15-20 degrees intra and post-operatively with knees slightly flexed </li></...
DVT-Treatment <ul><li>Mandatory anticoagulant therapy in most cases to decrease the risk of PE </li></ul><ul><ul><li>UHT- ...
Thrombolytic Therapy <ul><li>Streptokinase, Urokinase and TPA  </li></ul><ul><li>Risk of therapy :local and generalized bl...
Myelodysplastic Syndrome <ul><li>heterogeneous </li></ul><ul><li>ineffective and disordered hematopoiesis  </li></ul><ul><...
Myelodysplastic Syndrome <ul><li>1 in 500 patients between the ages of 60 and 75 years </li></ul><ul><li>Most idiopathic ,...
Myelodysplastic Syndrome <ul><li>Pat. referred for evaluation of incidental cytopenias </li></ul><ul><li>If Symptomatic ,b...
Myelodysplastic Syndrome-Lab.Studies <ul><li>Erythroid cells macrocytic, often with basophilic stippling.  </li></ul><ul><...
World Health Organization Classification of Myelodysplastic Syndromes <ul><li>Refractory Anemia (RA) </li></ul><ul><li>Ra ...
Myelodysplastic Syndrome <ul><li>Median survival is usually less than 2 years </li></ul><ul><li>15 - 20% of patients die o...
Myelodysplastic Syndrome treatment <ul><li>Chronic RBC / Plt transfusion- iron overload-secondary hemochromatosis </li></u...
Chronic Myeloproliferative Disorders <ul><li>Clonal stem cell disorders  </li></ul><ul><li>Leukocytosis, thrombocytosis, e...
Chronic Myeloproliferative Disorders Polycythemia Vera (PV) <ul><li>Absolute erythrocytosis </li></ul><ul><li>Half of the ...
Polycythemia Vera (PV). Clinical features <ul><li>Median age of onset 65 yo </li></ul><ul><li>Most common cause of death i...
Polycythemia Vera (PV).Labs <ul><li>P.exam : retinal - vein occlusion , cyanosis, splenomegaly </li></ul><ul><li>Microcyti...
Polycythemia Vera (PV).Treatment  <ul><li>W/O treatment 50% mortality at 18 months of Dx </li></ul><ul><li>With therapy-ch...
Polycythemia Vera (PV).treatment <ul><li>Intermittent phlebotomy </li></ul><ul><li>Cytoreductive therapy/allopurinol if hy...
Essential Thrombocythemia <ul><li>Increased Plts and WBCs </li></ul><ul><li>Plt count >600,000  with normal RBC mass </li>...
Essential Thrombocythemia. Clinical Features <ul><li>60-65yo, 10-25% younger than 40yo </li></ul><ul><li>Headaches , dizzi...
Essential Thrombocythemia <ul><li>Low risk of leukemic transformation </li></ul><ul><li>High morbidity from hemorrhagic an...
Myelofibrosis <ul><li>Excessive marrow fibrosis leading to marrow failure </li></ul><ul><li>Dysplastic megakaryocytes prod...
Myelofibrosis  <ul><li>Early- asymptomatic, occasional low blood counts </li></ul><ul><li>Rare, chronic disease of the eld...
Myelofibrosis  <ul><li>Leukoerythroblastic changes in smear: </li></ul><ul><ul><li>Tear-drop cells  </li></ul></ul><ul><ul...
Myelofibrosis <ul><li>Progressive fatigue and dypsnea </li></ul><ul><li>Early satiety and LUQ pain </li></ul><ul><li>Massi...
Myelofibrosis <ul><li>Treatment, not shown to prolong survival: </li></ul><ul><ul><ul><li>Palliative transfusions </li></u...
Chronic Myeloid Leukemia CML <ul><li>Overproduction myeloid cells </li></ul><ul><li>Normal differentiation during early ph...
Chronic Myeloid Leukemia CML <ul><li>Median age at presentation 55 yo  </li></ul><ul><li>Hypermetabolic state signs </li><...
Chronic Myeloid Leukemia CML <ul><li>On P.Exam  </li></ul><ul><ul><li>Enlarged spleen </li></ul></ul><ul><ul><li>Sternal t...
Chronic Myeloid Leukemia CML <ul><li>Laboratory findings: </li></ul><ul><ul><li>Elevated WBC counts - Hallmark (150,000/mc...
Chronic Myeloid Leukemia <ul><li>Bone Marrow changes: </li></ul><ul><ul><li>Initial - hypercellular / left shifted </li></...
Chronic Myeloid Leukemia  CML <ul><li>Differential Diagnosis </li></ul><ul><ul><li>From Reactive leukocytosis </li></ul></...
CML-Treatment <ul><li>Chronic phase </li></ul><ul><ul><li>Imatinib mesylate :inhibits the activity of the oncogene </li></...
CML-Treatment <ul><li>Quantitative asesment Philadelphia Chromosome by Polymerase Chain Reaction (PCR) </li></ul><ul><li>O...
CML-prognosis <ul><li>Past - 3 to 4years median survival </li></ul><ul><li>Now - Imatinib - more than 80% of patients aliv...
 
 
Chronic Lymphocytic Leukemias CLL <ul><li>Malignant disorder of B-lymphocytes </li></ul><ul><li>Most common leukemia in US...
Chronic Lymphocytic Leukemia CLL <ul><li>30-50% patients show cytogenetics abnormalities (trisomy 12) poor prognostic  </l...
Chronic Lymphocytic Leukemias CLL <ul><li>Clinical symptoms </li></ul><ul><ul><li>Lymphadenopathy </li></ul></ul><ul><ul><...
Chronic Lymphocytic Leukemias CLL <ul><li>Laboratory findings </li></ul><ul><ul><li>Hallmark - isolated lymphocytosis >20k...
Chronic Lymphocytic Leukemias CLL <ul><li>Classification - Rai system </li></ul><ul><ul><li>Stage 0 - lymphocytosis only <...
Chronic Lymphocytic Leukemias CLL <ul><li>Indications for therapy include: </li></ul><ul><li>Fatigue, lymphadenopathy, ane...
 
Acute Leukemias <ul><li>Classification by: </li></ul><ul><ul><li>Cell lineage </li></ul></ul><ul><ul><li>Morphology </li><...
Acute Leukemias <ul><li>Classification by cell lineage: </li></ul><ul><ul><li>Acute Myeloblastic Leukemia (AML)  </li></ul...
Acute Leukemias <ul><li>Unregulated proliferation of  immature cells  that are incapable of further differentiation ( blas...
Acute Leukemias <ul><li>Results in marrow replacement </li></ul><ul><li>Hematopoietic failure </li></ul><ul><li>Organ infi...
Acute Lymphoblastic Leukemia (ALL) <ul><li>Affects  immature lymphoblasts </li></ul><ul><li>FAB class. L1, L2, L3(cell mor...
Acute Leukemias  <ul><li>Cure rates 80% in children, 20-40% in adults </li></ul><ul><li>Patient not feeling well for days ...
Acute Leukemias <ul><li>Risk of infection increases with neutrophils counts below 500/mcl </li></ul><ul><li>Common pathoge...
Acute Leukemia PE <ul><li>Pallor, purpura or petechiae  </li></ul><ul><li>Stomatitis , gum hyperthrophy </li></ul><ul><li>...
Laboratory Findings  <ul><li>Hallmark-pancytopenias with circulating blasts </li></ul><ul><li>BM- hypercellular with more ...
Laboratory Findings <ul><li>Patients with ALL may  have a mediastinal mass present on chest Xray </li></ul><ul><li>Auer ro...
ALL
 
 
 
Laboratory Findings <ul><li>ALL. considered if no morphological or histochemical stains demonstrate Myeloid precursors </l...
<ul><li>Monoclonal antibodies to Lymphocytes antigens: </li></ul><ul><ul><li>Primitive B lymphocytes-CD19/CD10 </li></ul><...
Acute Leukemias Treatment <ul><li>ALL </li></ul><ul><ul><li>Lengthy /multiple chemotherapy given over a period of 2-3 year...
Acute Leukemias Treatment <ul><li>Consolidation therapy : continuing chemotherapy same agents to induce elimination of fur...
Acute Leukemias Treatment <ul><li>Remission : presence of less  than 5 % blasts in the BM with restoration of normal perip...
Acute Myeloid Leukemia <ul><li>See Classification for AML in the Book </li></ul><ul><li>Leukostasis / hyperleukocytosis sy...
Acute Myeloid Leukemia  AML <ul><li>Blast cells may also injure vasculature causing  CNS bleeding </li></ul><ul><li>Hyperk...
Acute Myeloid Leukemia  AML <ul><li>Stem cell transplant only hope for cure in some patients with AML and poor prognosis, ...
 
 
Lymphocytes Disorders  <ul><li>Neoplasia of Lymphoid origin </li></ul><ul><ul><li>Non Hodgkin’s Lymphoma </li></ul></ul><u...
Lymphadenopathy  <ul><li>Painless enlargement of the lymph nodes is the most common presentation of lymphoid malignancy in...
Lymphadenopathy <ul><li>Unilateral axillary, inguinal, or femoral adenopathy </li></ul><ul><ul><li>may be caused by local ...
Lymphadenopathy <ul><li>Excisional lymph node biopsy is done if no apparent cause </li></ul><ul><li>Histological examinati...
Non Hodgkin’s Lymphoma <ul><li>Heterogeneous group of cancers of the lymphocytes </li></ul><ul><li>From indolent course to...
Non Hodgkin’s Lymphoma
Non Hodgkin’s Lymphoma <ul><li>Different classifications through the years  </li></ul><ul><li>Most updated one REAL/WHO </...
Non Hodgkin’s Lymphoma <ul><li>Most common types in the US: </li></ul><ul><ul><li>Follicular lymphomas </li></ul></ul><ul>...
Non Hodgkin’s Lymphoma <ul><li>Associated with oncogenic viruses: </li></ul><ul><li>EBV-AIDS related lymphomas </li></ul><...
Non Hodgkin’s Lymphoma <ul><li>Extra nodal site involvement in the GI , BM, liver, and Waldeyer’s ring or any part of the ...
Non Hodgkin’s Lymphoma <ul><li>After diagnosis of Lymphoma  </li></ul><ul><li>Staging: determines the extent of involvemen...
<ul><li>Stage l: single lymph node region or structure, or extra lymphatic site </li></ul><ul><li>Stage ll: two or more ly...
Staging evaluation <ul><li>History-constitutional symptoms (fever, nights sweats, and weight loss-B symptoms) </li></ul><u...
Non Hodgkin’s Lymphoma <ul><li>Low grade/indolent includes : </li></ul><ul><ul><li>Follicular lymphomas </li></ul></ul><ul...
Non Hodgkin’s Lymphoma <ul><li>Patients with diffuse aggressive lymphoma are treated immediately because these are potenti...
Non Hodgkin’s Lymphoma <ul><li>Burkitt’s Lymphoma: </li></ul><ul><li>High grade B cell Lymphoma, rare in adults ,endemic i...
Non Hodgkin’s Lymphoma <ul><li>Lymphoblastic lymphoma (ALL) T-cell lymphoma </li></ul><ul><li>+ tdt (terminal deoxynucleot...
<ul><li>Both require intensive treatment with multiple therapy  </li></ul><ul><li>intrathecal therapy to prevent relapse  ...
Prognosis  <ul><li>Adverse prognosis factors: </li></ul><ul><li>Age over 60 yo </li></ul><ul><li>Elevated serum LDH  </li>...
Hodgkin’s disease <ul><li>Painless lymphadenopathy </li></ul><ul><li>Constitutional symptoms may or may not be present </l...
Hodgkin’s disease <ul><li>Reed-Sternberg cell: bi-nucleated cell with nucleoli - owl’s eyes, B cell in nature, present in ...
Hodgkin’s disease <ul><li>Bimodal age distribution 20yo and >50yo </li></ul><ul><li>Presents as painless mass(neck) and sp...
Hodgkin’s disease <ul><li>Four Pathological Variants: </li></ul><ul><ul><li>Nodular Sclerosing(80%) </li></ul></ul><ul><ul...
HL Mixed Cellularity
Hodgkin’s disease <ul><li>Advanced disease: BM failure and malaise , cachexia , infections </li></ul><ul><li>Staging the s...
Staging Workup <ul><li>Similar to NHL </li></ul><ul><li>Thorough H & P </li></ul><ul><li>Blood work including ESR </li></u...
HL Treatment <ul><li>Radiation therapy- initial for low risk IA and IIA disease </li></ul><ul><li>Trial limited chemothera...
HL prognosis <ul><li>IA, IIA- excellent >80% surv.rate after 10 years </li></ul><ul><li>IIIB, IV- 50-60% at 5 years </li><...
 
Plasma cells Disorders <ul><li>B cells neoplasm with production and secretion of monoclonal(M) immunoglobulin or part of a...
Plasma cells Disorders <ul><li>Clinically characterized by: </li></ul><ul><li>Systemic effect of the M protein  </li></ul>...
Plasma cells Disorders <ul><li>M proteins found also in benign and malignant conditions  </li></ul><ul><li>Autoreactive an...
Plasma cells Disorders <ul><li>Multiple Myeloma (MM) </li></ul><ul><ul><li>Neoplastic infiltration of bone  and BM </li></...
Plasma cells Disorders <ul><li>20% of patients lack the M protein in serum but show light chains protein in urine </li></u...
Plasma cells Disorders <ul><li>Clinical Manifestations MM </li></ul><ul><li>Results from  </li></ul><ul><ul><li>Bone or BM...
Plasma cells Disorders MM <ul><li>Bone Pain- Bone Xray-osteolytic -punched out lesions- low back and ribs </li></ul><ul><l...
Plasma cells Disorders <ul><li>Hyperviscocity ,cryoglobulinemia- vertigo, nausea, visual disturbances, alter mental status...
Plasma cells Disorders <ul><li>Lab Findings </li></ul><ul><li>RBC morphology WNL - Rouleau formation </li></ul><ul><li>Hal...
Plasma cells Disorders MM <ul><li>Diff Diagnosis </li></ul><ul><li>MGUS </li></ul><ul><li>Waldestrom’s macroglobulinemia  ...
Plasma cells Disorders MM <ul><li>Treatment  </li></ul><ul><li>Thalidomide + dexamethasone </li></ul><ul><li>Stem cell tra...
Waldestrom’s Macroglobulinemia <ul><li>Hybrid cell between B  lymphocyte and plasma cell </li></ul><ul><li>Secrete IgM par...
Waldestrom’s Macroglobulinemia <ul><li>PE </li></ul><ul><ul><li>Retinal vein engorgement  </li></ul></ul><ul><ul><li>Lymph...
Waldestrom’s Macroglobulinemia <ul><li>Laboratory Findings </li></ul><ul><li>Anemia- expansion of plasma (protein) </li></...
Waldestrom’s Macroglobulinemia <ul><li>Treatment  </li></ul><ul><ul><li>Emergency plasmapheresis - hyperviscocity </li></u...
WBC disorders <ul><li>Leukocytosis  : non specific term, denotes increased in either neutrophils or lymphocytes </li></ul>...
WBC disorders <ul><li>Leukemoid reaction: </li></ul><ul><ul><li>Associated with inflammatory reactions and infections </li...
WBC disorders <ul><li>Neutropenia   </li></ul><ul><ul><li>Decreased production (congenital/acquired) </li></ul></ul><ul><u...
WBC disorders <ul><li>Cyclic neutropenia : asymptomatic patients, evaluate with serial CBCs </li></ul><ul><ul><li>Neutroph...
WBC disorders <ul><li>Congenital Agranulocytosis (Kostmann’s syndrome) </li></ul><ul><ul><li>Profound neutropenia </li></u...
WBC disorders <ul><li>Post viral neutropenia </li></ul><ul><ul><li>Common in children </li></ul></ul><ul><ul><li>Increased...
WBC disorders <ul><li>Drug induced Neutropenia </li></ul><ul><ul><li>Dose dependent or idiosyncratic reaction </li></ul></...
WBC disorders <ul><li>Autoimmune neutropenia </li></ul><ul><ul><li>Associated to Systemic autoimmune disorders </li></ul><...
Neutropenia. Laboratory Eval. <ul><li>Serologic studies to rule out CVD </li></ul><ul><li>BM examination indicated early –...
Neutropenia management <ul><li>1000-1500/mcl  no significant  impairment, no treatment needed, find the cause and treat co...
 
<ul><li>the end </li></ul>
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Hematology Rivas2008 Lecture4&5

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  • Hematology Rivas2008 Lecture4&5

    1. 1. Clonal Disorders of hematopoietic stem cells Antonio Rivas PA-C
    2. 2. Objectives <ul><li>Become familiar with pathogenesis, epidemiology, diagnosis and treatment of : </li></ul><ul><ul><li>Thrombosis-DVT </li></ul></ul><ul><ul><li>Myelodisplastic Syndromes </li></ul></ul><ul><ul><li>Myeloproliferative disorders </li></ul></ul><ul><ul><li>Chronic Myeloid Leukemia </li></ul></ul><ul><ul><li>Acute Leukemias : AML , ALL </li></ul></ul><ul><ul><li>Neutropenia </li></ul></ul>
    3. 3. Arterial-thrombosis <ul><li>Commonly related to coronary artery disease (ruptured atherosclerotic plaque) </li></ul><ul><li>Atherombolic disorder (ischemic stroke) </li></ul>
    4. 4. Thrombosis <ul><li>Virchow’s triad-defines mechanism underlying thrombosis </li></ul><ul><ul><li>Diminished blood flow </li></ul></ul><ul><ul><li>Damage to the vascular wall </li></ul></ul><ul><ul><li>Imbalance favoring procoagulants over anticoagulants </li></ul></ul>
    5. 5. Thrombosis <ul><li>Data shows unique regulation of hemostasis in different vascular beds: </li></ul><ul><li>Cong.deficiency of ATIII, protein C or protein S lead to: </li></ul><ul><ul><ul><li>DVT of lower extremities, but not upper </li></ul></ul></ul><ul><li>Inherited hypercoagulable disorders associated with factor V Leiden and the prothrombin G20210A mutation </li></ul><ul><ul><ul><li>produce DVT of the lower extremities and venous thrombosis of the brain </li></ul></ul></ul>
    6. 6. Atherothrombosis- Endothelial Damage <ul><li>Associated with increased levels of Homocysteine(HCY) in congenitals syndromes, with damage to the vascular endothelium and downregulation of the Ecs anticoagulant functions </li></ul><ul><li>Increased HCY levels in people with deficiency in the cofactors for HCY metabolism: B6,B12,and Folates </li></ul>
    7. 7. Atherothrombosis - Platelets <ul><li>Platelet activation and adherence critical to the development of the thrombus </li></ul><ul><li>Anti-platelet therapy : </li></ul><ul><ul><li>Aspirin-inhibits COX - blocks TXA2 release </li></ul></ul><ul><ul><li>Clopidogrel(Plavix) - block ADP receptors in Plts, used with ASA to prevent ischemic stroke </li></ul></ul><ul><ul><li>Abciximab/Integrilin/Aggrastat - block plts receptors from binding with Fibrinogen and vWF </li></ul></ul>
    8. 8. Thrombosis-DVT <ul><li>Inherited: recurrent thrombosis at early age, unusual sites, or family history </li></ul><ul><li>Adquired : systemic disorders ( auto- immune hemolytic anemia), collagen vascular disease(vasculitis), malignant disease </li></ul>
    9. 9. Risk Factors for Venous Thrombosis <ul><li>Inherited </li></ul><ul><ul><li>Factor V Leiden </li></ul></ul><ul><ul><li>Prothrombin G20210A </li></ul></ul><ul><ul><li>Deficiency of natural anticoagulant proteins </li></ul></ul>
    10. 10. Inherited risk factors for DVT <ul><li>Factor V Leiden mutation -most common inherited disorder causing DVT </li></ul><ul><li>Activated protein C unable to inactivate factor V mutation with increased formation of thrombin </li></ul>
    11. 11. <ul><li>Heterozygous in 5% of the population with five fold increased risk for DVT-PE </li></ul><ul><li>Homozygous less frequent, with 90% increased risk for DVT </li></ul><ul><li>Weak hypercoagulable risk </li></ul><ul><li>DVT-PE usually Associated to concomitant acquired factors: pregnancy, immobilization and oral contraceptives </li></ul>
    12. 12. Prothrombin G20210A Mutation <ul><li>Mutation leads to increased prothrombin levels </li></ul><ul><li>Two-fold increased risk for DVT </li></ul><ul><li>3% European-derived population </li></ul><ul><li>Diagnosis examining DNA for mutation </li></ul>
    13. 13. Inherited deficiency of natural anticoagulant proteins <ul><li>ATIII, protein C, protein S </li></ul><ul><li>Less common than previous ones </li></ul><ul><li>More likely to produce symptomatic venous thrombosis at early age </li></ul><ul><li>Accounts for fewer than 5-10% of all patients with DVT/PE </li></ul><ul><li>Functional and Antigenic Assays (quant/qualt-deficiencies) </li></ul>
    14. 14. Acquired risk factors for DVT Surgery-Trauma <ul><li>Surgery-orthopaedic-trauma: associated with immobilization and stasis of lower extremities blood flow </li></ul><ul><li>Also associated with fat embolism and tissue damage(massive TF release) </li></ul><ul><li>More than 50% incidence of DVT </li></ul><ul><li>Prophylactic-temporary IVC filters used </li></ul><ul><li>to protect from PE in these cases </li></ul>
    15. 15. Other Acquired risk factors for DVT <ul><li>Pregnancy increases risk of DVT 5 fold(venous stasis and altered coagulation factors) </li></ul><ul><li>Oral Contraceptives /hormonal changes, increased risk for smokers </li></ul><ul><li>Prothrombotic states </li></ul><ul><ul><li>Nephrotic syndromes-loss of ATIII through the kidneys </li></ul></ul><ul><ul><li>Blood cell destruction-exposure of procoagulant membrane phospholipids (artificial heart valves, hemolytic anemias, sickle cell disease) </li></ul></ul><ul><ul><li>HIT, TTP-increased Plt activation and clearance </li></ul></ul><ul><ul><li>Myeloproliferative disorders-increased aggregability of the Plts </li></ul></ul>
    16. 16. Antiphospholipid Antibody Syndrome <ul><li>APA Syndrome acquired prothrombic disorder </li></ul><ul><li>Primary or Secondary to autoimmune Dis.SLE </li></ul><ul><li>Recurrent venous or arterial thrombosis, thrombocytopenia, fetal loss </li></ul><ul><li>Anticardiolipin Abs / Lupus anticoagulant present in serum </li></ul><ul><li>Antibodies directed against phospholipid - binding proteins such as: </li></ul><ul><ul><ul><ul><ul><li>Beta 2 glycoprotein I </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Prothrombin </li></ul></ul></ul></ul></ul>
    17. 17. DVT general considerations <ul><li>More frequent - Deep veins of the lower extremities and pelvis </li></ul><ul><li>80% arise in the deep calf veins </li></ul><ul><li>Development up to 2 weeks post - operatively </li></ul><ul><li>Higher incidence in Total Hip replacement surgery </li></ul><ul><li>Half patients has no symptoms in early stage </li></ul>
    18. 18. DVT-Symptoms / Signs <ul><li>Dull ache - tight feeling - frank pain in the calf or whole leg, worse with walking (leg claudication) </li></ul><ul><li>Slight swelling calf muscle </li></ul><ul><li>Distention superficial veins </li></ul><ul><li>Slight fever and tachycardia </li></ul><ul><li>Occlusion of femoral and iliac veins more symptomatic </li></ul><ul><li>Severe obstruction: cyanosis skin, and marked swelling </li></ul>
    19. 19. DVT-Diagnosis <ul><li>Doppler Ultrasonography-test of choice </li></ul><ul><li>Respiratory/cardiac symptoms -V/Q scan, spiral CT scan chest - to exclude PE </li></ul><ul><li>On Physical Exam patients may have pain in the affected calf muscle with Dorsi-flexion of the foot (Homan’s sign) </li></ul>
    20. 20. DVT-Laboratory Test <ul><li>Evaluate for hereditary and acquired hyper-coagulable state specially young patients W/O predisposing event </li></ul><ul><li>Coagulation Profile, protein S, protein C, DNA-testing for factor V Leiden and prothrombin mutations </li></ul><ul><li>Anti-phospholipids Abs, Lupus Anticoagulant, ANA </li></ul>
    21. 21. DVT-Diff.Dx. <ul><li>Calf muscle strain or contusion, difficult </li></ul><ul><li>Cellulitis where you might find a wound and inflammation is more striking </li></ul><ul><li>Lymphatic obstruction by tumor is usually painless and chronic </li></ul><ul><li>Acute arterial obstruction is more painful, absent peripheral pulses, no swelling present </li></ul><ul><li>Heart, Kidney, or liver disease edema is bilateral </li></ul><ul><li>Ruptured Baker’s cyst, history of arthritis in the same side knee </li></ul>
    22. 22. DVT-Prophylactic <ul><li>Elevation of the legs 15-20 degrees intra and post-operatively with knees slightly flexed </li></ul><ul><li>Intermittent pneumatic compression of the legs(sequential compressions devices) </li></ul><ul><li>Elastic anti-phlebitic stockings </li></ul><ul><li>Walking briefly but regularly after surgery, or during long airplane and automobile trips </li></ul><ul><li>Anticoagulants-low dose Heparin 5000 units every 8-12 hrs subcutaneously </li></ul>
    23. 23. DVT-Treatment <ul><li>Mandatory anticoagulant therapy in most cases to decrease the risk of PE </li></ul><ul><ul><li>UHT- bolus titrated to achieve a PTT 1.5-2.0 times baseline-requires hospitalization, 4 days or more </li></ul></ul><ul><ul><li>LMWH-subcutaneous </li></ul></ul><ul><ul><li>Warfarin started within 24hrs to achieve INR 2.0-2.5 for at least 2 consecutive days before stopping heparin </li></ul></ul><ul><ul><li>1rst episode - treat for 6 months </li></ul></ul><ul><ul><li>2nd episode - variable </li></ul></ul><ul><ul><li>3rd episode - lifelong, also if the trigger factor for the thrombosis is chronic (CHF,inherited disorder) </li></ul></ul>
    24. 24. Thrombolytic Therapy <ul><li>Streptokinase, Urokinase and TPA </li></ul><ul><li>Risk of therapy :local and generalized bleeding, intracraneal hemorrhage </li></ul><ul><li>Patients without complications return to their routine in 3-6 weeks after appropriate treatment </li></ul>
    25. 25. Myelodysplastic Syndrome <ul><li>heterogeneous </li></ul><ul><li>ineffective and disordered hematopoiesis </li></ul><ul><li>affects myeloid cell lines </li></ul><ul><li>one or more cytopenias </li></ul><ul><li>Disordered maturation and increased intramedullary apoptosis (programmed cell death) </li></ul><ul><li>decreased mature cells into the periphery </li></ul><ul><li>normal or increased hematopoietic cells in the bone marrow </li></ul>
    26. 26. Myelodysplastic Syndrome <ul><li>1 in 500 patients between the ages of 60 and 75 years </li></ul><ul><li>Most idiopathic , 25 % overall risk of transformation to acute myelogenous or myeloid leukemia </li></ul><ul><li>Exposure to radiation, chemotherapy, and organic chemicals (benzene) increase risk of MDS. </li></ul><ul><li>Secondary MDS, after treatment for other cancers, may occur at any age ,comprises 10% to 15% of all MDS cases. </li></ul>
    27. 27. Myelodysplastic Syndrome <ul><li>Pat. referred for evaluation of incidental cytopenias </li></ul><ul><li>If Symptomatic ,bleeding and bruising, infection, or fatigue and dyspnea related to anemia </li></ul><ul><li>PExam occasional splenomegaly, development of skin lesions with fever (acute febrile neutrophilic dermatosis, or Sweet's syndrome) may herald transformation of MDS into acute leukemia. </li></ul>
    28. 28. Myelodysplastic Syndrome-Lab.Studies <ul><li>Erythroid cells macrocytic, often with basophilic stippling. </li></ul><ul><li>Neutrophils hypogranular and hypolobulated, bilobed nucleus, pseudo-Pelger-Hu et abnormality. </li></ul><ul><li>Bone marrow : normo-hypercellular, dysplastic changes in all three cell lines </li></ul><ul><ul><li>Shift to the left </li></ul></ul><ul><ul><li>Micro-megakariocytes / hypogranular </li></ul></ul><ul><ul><li>blasts </li></ul></ul>
    29. 29. World Health Organization Classification of Myelodysplastic Syndromes <ul><li>Refractory Anemia (RA) </li></ul><ul><li>Ra with Ringed Sideroblasts (RARS) </li></ul><ul><li>Ref.Cytopenia with Multilineage Dysplasia (RCMD) </li></ul><ul><li>RC with MD and RS (RCMD-RS) </li></ul><ul><li>RA with excess Blasts 1 (RAEB-1) </li></ul><ul><li>RA with excess Blasts 2 (RAEB-2) </li></ul><ul><li>Myelodysplastic Syndrome Unclassified (MDS-U) </li></ul><ul><li>MDS associated with isolated del(5q) </li></ul>
    30. 30. Myelodysplastic Syndrome <ul><li>Median survival is usually less than 2 years </li></ul><ul><li>15 - 20% of patients die of AML </li></ul><ul><li>Treatment is limited and dictated by age, performance status, quality of life, severity of disease, and prognostic category </li></ul><ul><li>Most managed supportively </li></ul>
    31. 31. Myelodysplastic Syndrome treatment <ul><li>Chronic RBC / Plt transfusion- iron overload-secondary hemochromatosis </li></ul><ul><li>EPO, G-CSF reduce transfusion needs </li></ul><ul><li>In patients with high risk transformation to AML- Chemotherapy </li></ul><ul><li>Only curative therapy- allogeneic stem cell transplant(<40 years of age) </li></ul><ul><li>Immune-suppresive therapy has been used (cyclosporin,thalidomide) </li></ul>
    32. 32. Chronic Myeloproliferative Disorders <ul><li>Clonal stem cell disorders </li></ul><ul><li>Leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercellularity </li></ul><ul><li>Failure to respond to normal feedback mechanisms regulating cell mass </li></ul><ul><li>Stem cells demonstrate clonal colony growth in vitro in the presence of serum without the addition of exogenous cytokines </li></ul>
    33. 33. Chronic Myeloproliferative Disorders Polycythemia Vera (PV) <ul><li>Absolute erythrocytosis </li></ul><ul><li>Half of the patients have leukocytosis and/or thrombocytosis </li></ul><ul><li>Clonal genetic abnormalities in marrow cells </li></ul><ul><li>No causes of secondary erythrocytosis </li></ul><ul><li>Low serum EPO levels </li></ul><ul><li>Palpable splenomegaly </li></ul>
    34. 34. Polycythemia Vera (PV). Clinical features <ul><li>Median age of onset 65 yo </li></ul><ul><li>Most common cause of death is thrombosis cerebral, coronary or mesenteric </li></ul><ul><li>Headaches, visual problems, mental clouding, pruritus after bathing </li></ul><ul><li>Stroke, TIAs , Myocardial ischemia, paresthesias, digital pain, and gangrene </li></ul><ul><li>Pulmonary, hepatic and portal venous thrombosis </li></ul><ul><li>Hemorrhagic events, GI bleeding </li></ul>
    35. 35. Polycythemia Vera (PV).Labs <ul><li>P.exam : retinal - vein occlusion , cyanosis, splenomegaly </li></ul><ul><li>Microcytic cells </li></ul><ul><li>Hypercellular marrow </li></ul>
    36. 36. Polycythemia Vera (PV).Treatment <ul><li>W/O treatment 50% mortality at 18 months of Dx </li></ul><ul><li>With therapy-chronic progressive disease </li></ul><ul><li>5-20% risk of Myelofibrosis/Myeloid leukemia over 20 years </li></ul><ul><li>Excellent long term survival/effective therapy </li></ul><ul><li>Goal of therapy: </li></ul><ul><ul><li>Hematocrit <45% in men </li></ul></ul><ul><ul><li>Hematocrit <42% in women </li></ul></ul>
    37. 37. Polycythemia Vera (PV).treatment <ul><li>Intermittent phlebotomy </li></ul><ul><li>Cytoreductive therapy/allopurinol if hyperuricemia </li></ul><ul><li>Hydroxyurea -low cytotoxic agent </li></ul><ul><li>Interferon alpha </li></ul><ul><li>Anagrelide megakaryotoxic agent </li></ul><ul><li>ASA or NSAIDS </li></ul>
    38. 38. Essential Thrombocythemia <ul><li>Increased Plts and WBCs </li></ul><ul><li>Plt count >600,000 with normal RBC mass </li></ul><ul><li>Iron studies are normal </li></ul><ul><li>Predominant proliferation in mature Megakariocytes </li></ul><ul><li>No “factor independent”colony growth </li></ul>
    39. 39. Essential Thrombocythemia. Clinical Features <ul><li>60-65yo, 10-25% younger than 40yo </li></ul><ul><li>Headaches , dizziness, visual changes, and erythromelalgia(burning pain and erythema in the hands and feet) </li></ul><ul><li>TIAs, strokes, seizure, angina, MI may occur </li></ul><ul><li>Great long term survival rate </li></ul>
    40. 40. Essential Thrombocythemia <ul><li>Low risk of leukemic transformation </li></ul><ul><li>High morbidity from hemorrhagic and thrombotic events </li></ul><ul><li>Aggressive management Cardio- vascular risk factors recommended </li></ul><ul><li>Therapy: ASA, 1rts line-Hydroxyurea, 2nd line-Anagrelide, interferon alpha </li></ul>
    41. 41. Myelofibrosis <ul><li>Excessive marrow fibrosis leading to marrow failure </li></ul><ul><li>Dysplastic megakaryocytes producing increased levels of fibroblast growth factors </li></ul><ul><li>Abnormal proliferation and collagen deposition which displaces precursors cells to the periphery: extramedullary hematopoiesis </li></ul>
    42. 42. Myelofibrosis <ul><li>Early- asymptomatic, occasional low blood counts </li></ul><ul><li>Rare, chronic disease of the elderly </li></ul><ul><li>Median survival poor, 2-5 years </li></ul><ul><li>Diagnosis : </li></ul><ul><ul><li>Fibrosis in BM </li></ul></ul><ul><ul><li>Normal RBC mass </li></ul></ul><ul><ul><li>Lack of Philadelphia chromosome </li></ul></ul>
    43. 43. Myelofibrosis <ul><li>Leukoerythroblastic changes in smear: </li></ul><ul><ul><li>Tear-drop cells </li></ul></ul><ul><ul><li>Giant platelets </li></ul></ul><ul><ul><li>Immature RBCS and WBCs </li></ul></ul>
    44. 44. Myelofibrosis <ul><li>Progressive fatigue and dypsnea </li></ul><ul><li>Early satiety and LUQ pain </li></ul><ul><li>Massive hepatosplenomegaly </li></ul><ul><li>With progressive BM failure, DIC may be present </li></ul><ul><li>Constitutional symptoms: </li></ul><ul><ul><li>Fevers, weight loss, night sweats </li></ul></ul>
    45. 45. Myelofibrosis <ul><li>Treatment, not shown to prolong survival: </li></ul><ul><ul><ul><li>Palliative transfusions </li></ul></ul></ul><ul><ul><ul><li>EPO </li></ul></ul></ul><ul><ul><ul><li>Hydroxyurea (to manage leukocytosis/thrombocytosis) </li></ul></ul></ul><ul><ul><ul><li>Splenectomy(extra medullary hematopoiesis) </li></ul></ul></ul><ul><ul><ul><li>Palliative splenic irradiation </li></ul></ul></ul><ul><ul><ul><li>Allogeneic stem cell transplantation </li></ul></ul></ul>
    46. 46. Chronic Myeloid Leukemia CML <ul><li>Overproduction myeloid cells </li></ul><ul><li>Normal differentiation during early phases </li></ul><ul><li>Transform into more malignant disease: accelerated acute blast phase </li></ul><ul><li>Philadelphia chromosome : reciprocal translocation between the long arms of chromosomes 9 and 22 - producing the oncogene-fusion gene bcr/abl </li></ul>
    47. 47. Chronic Myeloid Leukemia CML <ul><li>Median age at presentation 55 yo </li></ul><ul><li>Hypermetabolic state signs </li></ul><ul><ul><li>Chronic fatigue </li></ul></ul><ul><ul><li>Night sweats </li></ul></ul><ul><ul><li>Low grade fever </li></ul></ul><ul><li>Abdominal fullness - splenomegaly </li></ul><ul><li>Leukostasis(WBCs >500,000/mcl) - blurred vision, repiratory distress, or priapism </li></ul>
    48. 48. Chronic Myeloid Leukemia CML <ul><li>On P.Exam </li></ul><ul><ul><li>Enlarged spleen </li></ul></ul><ul><ul><li>Sternal tenderness (marrow overexpansion) </li></ul></ul><ul><ul><li>Acceleration of disease associated to: </li></ul></ul><ul><ul><ul><li>High fever in the absence of infection </li></ul></ul></ul><ul><ul><ul><li>Bone pain </li></ul></ul></ul><ul><ul><ul><li>splenomegaly </li></ul></ul></ul>
    49. 49. Chronic Myeloid Leukemia CML <ul><li>Laboratory findings: </li></ul><ul><ul><li>Elevated WBC counts - Hallmark (150,000/mcl) </li></ul></ul><ul><ul><li>Peripheral blood-left shifted </li></ul></ul><ul><ul><li>Mature cells predominate </li></ul></ul><ul><ul><li>Basophilia and Eosinophilia </li></ul></ul><ul><ul><li>Blasts <5% </li></ul></ul><ul><ul><li>Philadelphia chromosome present </li></ul></ul>
    50. 50. Chronic Myeloid Leukemia <ul><li>Bone Marrow changes: </li></ul><ul><ul><li>Initial - hypercellular / left shifted </li></ul></ul><ul><ul><ul><li>Myeloblasts comprise 5% marrow cells </li></ul></ul></ul><ul><ul><li>Blast phase </li></ul></ul><ul><ul><ul><li>Blasts constitute >20% of the BM cells </li></ul></ul></ul>
    51. 51. Chronic Myeloid Leukemia CML <ul><li>Differential Diagnosis </li></ul><ul><ul><li>From Reactive leukocytosis </li></ul></ul><ul><ul><ul><li>WBC <50,000/mcl </li></ul></ul></ul><ul><ul><ul><li>Splenomegaly absent </li></ul></ul></ul><ul><ul><ul><li>Philadelphia chromosome not present </li></ul></ul></ul><ul><ul><li>From other myeloproliferative disorders. On CML you find: </li></ul></ul><ul><ul><ul><li>Hct is normal </li></ul></ul></ul><ul><ul><ul><li>RBC morphology normal </li></ul></ul></ul><ul><ul><ul><li>Nucleated RBCs rare or absent </li></ul></ul></ul>
    52. 52. CML-Treatment <ul><li>Chronic phase </li></ul><ul><ul><li>Imatinib mesylate :inhibits the activity of the oncogene </li></ul></ul><ul><ul><li>400mg daily , oral </li></ul></ul><ul><li>98% control of chronic phase </li></ul><ul><ul><li>Complete hematologic remission(3months) </li></ul></ul><ul><ul><ul><li>Normal blood counts and resolution of splenomegaly </li></ul></ul></ul><ul><ul><li>Cytogenetic response (6-12months) </li></ul></ul><ul><ul><ul><li>Major cytogenetic response <35%cont. Phil. Chromosome </li></ul></ul></ul><ul><ul><ul><li>Complete cytogenetic response - absence of Phil.Chromosome </li></ul></ul></ul>
    53. 53. CML-Treatment <ul><li>Quantitative asesment Philadelphia Chromosome by Polymerase Chain Reaction (PCR) </li></ul><ul><li>Only curative therapy is allogeneic stem cell transplantation </li></ul><ul><li>Original therapy with Imatimib, if not optimum response-BM transplant is done </li></ul>
    54. 54. CML-prognosis <ul><li>Past - 3 to 4years median survival </li></ul><ul><li>Now - Imatinib - more than 80% of patients alive and in remission at 4years </li></ul>
    55. 57. Chronic Lymphocytic Leukemias CLL <ul><li>Malignant disorder of B-lymphocytes </li></ul><ul><li>Most common leukemia in US </li></ul><ul><li>More common in men </li></ul><ul><li>Incidence increases with age </li></ul><ul><li>90% cases adults >50 yo </li></ul><ul><li>Cause unknown </li></ul><ul><li>Clonal proliferation of mature B cells </li></ul>
    56. 58. Chronic Lymphocytic Leukemia CLL <ul><li>30-50% patients show cytogenetics abnormalities (trisomy 12) poor prognostic </li></ul><ul><li>Indolent course </li></ul><ul><li>Cells are immuno-incompetent </li></ul><ul><li>Immunosuppression, BM failure , and organ infiltration </li></ul><ul><li>Inadequate antibody production </li></ul><ul><li>Tissue damage by direct organ infiltration </li></ul>
    57. 59. Chronic Lymphocytic Leukemias CLL <ul><li>Clinical symptoms </li></ul><ul><ul><li>Lymphadenopathy </li></ul></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Enlarged liver or spleen </li></ul></ul><ul><ul><li>May complicate with autoimmune hemolytic anemia, or thrombocytopenia </li></ul></ul><ul><ul><li>Isolated lymph node transforms into large cell lymphoma(Richter’s syndrome) </li></ul></ul>
    58. 60. Chronic Lymphocytic Leukemias CLL <ul><li>Laboratory findings </li></ul><ul><ul><li>Hallmark - isolated lymphocytosis >20k or several hundred thousand </li></ul></ul><ul><ul><li>Main cell - small mature looking lymphocytes </li></ul></ul><ul><ul><li>Hct and Plt count normal at presentation </li></ul></ul><ul><ul><li>BM infiltration by small mature looking lymphocytes </li></ul></ul><ul><ul><li>hypogammaglobulinemia </li></ul></ul>
    59. 61. Chronic Lymphocytic Leukemias CLL <ul><li>Classification - Rai system </li></ul><ul><ul><li>Stage 0 - lymphocytosis only </li></ul></ul><ul><ul><li>Stage I - lymphocytosis + lymph-adenopathy </li></ul></ul><ul><ul><li>Stage II- organomegaly </li></ul></ul><ul><ul><li>Stage III-anemia </li></ul></ul><ul><ul><li>Stage IV- thrombocytopenia </li></ul></ul>
    60. 62. Chronic Lymphocytic Leukemias CLL <ul><li>Indications for therapy include: </li></ul><ul><li>Fatigue, lymphadenopathy, anemia or thrombocytopenia </li></ul><ul><li>Combination therapy with fludarabine + rituxan given for 6 months </li></ul><ul><li>Chlorambucil for the elderly </li></ul><ul><li>Alemtuzumab- monoc.ab for refractory cases </li></ul>
    61. 64. Acute Leukemias <ul><li>Classification by: </li></ul><ul><ul><li>Cell lineage </li></ul></ul><ul><ul><li>Morphology </li></ul></ul><ul><ul><li>Cytogenetics </li></ul></ul><ul><ul><li>Cell surface and Cytoplasmic markers </li></ul></ul><ul><ul><li>Molecular studies </li></ul></ul>
    62. 65. Acute Leukemias <ul><li>Classification by cell lineage: </li></ul><ul><ul><li>Acute Myeloblastic Leukemia (AML) </li></ul></ul><ul><ul><li>90% adult Leukemias </li></ul></ul><ul><ul><li>Acute Lymphoblastic Leukemia (ALL) </li></ul></ul><ul><ul><li>90% of childhood Leukemias </li></ul></ul>
    63. 66. Acute Leukemias <ul><li>Unregulated proliferation of immature cells that are incapable of further differentiation ( blasts )>20% in BM </li></ul><ul><li>Not clear cause </li></ul><ul><li>Risk factors: radiations, toxins, chemotherapeutic agents </li></ul>
    64. 67. Acute Leukemias <ul><li>Results in marrow replacement </li></ul><ul><li>Hematopoietic failure </li></ul><ul><li>Organ infiltration(GI, Skin, Meninges) </li></ul><ul><li>AML - affects adults – 60 yo </li></ul><ul><li>ALL – affects children 3-7 yo </li></ul>
    65. 68. Acute Lymphoblastic Leukemia (ALL) <ul><li>Affects immature lymphoblasts </li></ul><ul><li>FAB class. L1, L2, L3(cell morphology) </li></ul><ul><li>More recent, WHO classification. </li></ul><ul><li>Precursor B ALL </li></ul><ul><li>Precursor T ALL </li></ul><ul><li>Based on cell surface Ags present on these cells during maturation </li></ul>
    66. 69. Acute Leukemias <ul><li>Cure rates 80% in children, 20-40% in adults </li></ul><ul><li>Patient not feeling well for days or weeks </li></ul><ul><li>Anemia, infection, and bleeding from peripheral cytopenias </li></ul><ul><li>Bone pain f.marrow infiltration </li></ul>
    67. 70. Acute Leukemias <ul><li>Risk of infection increases with neutrophils counts below 500/mcl </li></ul><ul><li>Common pathogens: gram neg.bact. and Fungi </li></ul><ul><li>Cellulitis, pneumonia, and perirectal infections </li></ul><ul><li>Gum hyperthrophy and bone and joint pain is possible </li></ul>
    68. 71. Acute Leukemia PE <ul><li>Pallor, purpura or petechiae </li></ul><ul><li>Stomatitis , gum hyperthrophy </li></ul><ul><li>Lymphadenopathy, hepato-splenomegaly </li></ul><ul><li>Bone tenderness sternum ,tibia, and femur </li></ul>
    69. 72. Laboratory Findings <ul><li>Hallmark-pancytopenias with circulating blasts </li></ul><ul><li>BM- hypercellular with more than 20% blasts (required for Dx) </li></ul><ul><li>Hyperuricemia may be present </li></ul><ul><li>If DIC present-decreased fibrinogen level, Pt is prolonged and FDP present </li></ul>
    70. 73. Laboratory Findings <ul><li>Patients with ALL may have a mediastinal mass present on chest Xray </li></ul><ul><li>Auer rods-eosinophilic needle like in the Cytoplasm-pathognomonic for AML </li></ul><ul><li>Histochemical stains- </li></ul><ul><ul><li>Myeloid lineage - Myeloperoxidase </li></ul></ul><ul><ul><li>Monocytic lineage – butyrate esterase </li></ul></ul>
    71. 74. ALL
    72. 78. Laboratory Findings <ul><li>ALL. considered if no morphological or histochemical stains demonstrate Myeloid precursors </li></ul><ul><li>Surface markers for lymphoid precursors are demonstrate by flow cytometry –TdT terminal present in 95% of ALL </li></ul>
    73. 79. <ul><li>Monoclonal antibodies to Lymphocytes antigens: </li></ul><ul><ul><li>Primitive B lymphocytes-CD19/CD10 </li></ul></ul><ul><ul><li>Primitive T cell-CD2/CD5/CD7 </li></ul></ul><ul><li>Cytogenetics studies are used to determine prognosis </li></ul>Laboratory Findings
    74. 80. Acute Leukemias Treatment <ul><li>ALL </li></ul><ul><ul><li>Lengthy /multiple chemotherapy given over a period of 2-3 years </li></ul></ul><ul><li>Induction chemotherapy : reduce blasts to undetectable levels, and restores normal hematopoiesis </li></ul><ul><ul><li>Vincristine </li></ul></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><li>L-asparaginase </li></ul></ul><ul><ul><li>Cytabarine </li></ul></ul>
    75. 81. Acute Leukemias Treatment <ul><li>Consolidation therapy : continuing chemotherapy same agents to induce elimination of further leukemic cells </li></ul><ul><li>Intensification therapy : to treat cells resistant to the induction regimen </li></ul><ul><li>Maintenance therapy : low-dose intermittent chemotherapy to prevent relapse </li></ul>
    76. 82. Acute Leukemias Treatment <ul><li>Remission : presence of less than 5 % blasts in the BM with restoration of normal peripheral blood counts </li></ul><ul><li>Intratechal chemotherapy and brain irradiation to destroy cells in the CNS and testes ( leukemia Sanctuaries ) </li></ul><ul><li>The worse the prognosis the early the transplant of BM should be offered </li></ul>
    77. 83. Acute Myeloid Leukemia <ul><li>See Classification for AML in the Book </li></ul><ul><li>Leukostasis / hyperleukocytosis syndrome </li></ul><ul><ul><li>High levels of circulating blasts </li></ul></ul><ul><ul><li>Diffuse pulmonary infiltrates </li></ul></ul><ul><ul><li>Acute respiratory distress </li></ul></ul>
    78. 84. Acute Myeloid Leukemia AML <ul><li>Blast cells may also injure vasculature causing CNS bleeding </li></ul><ul><li>Hyperkalemia , acidosis and hyperuricemia caused by increased cell breakdown can precipitate renal failure </li></ul><ul><li>Leukophoresis , Hydroxyurea, and hydration to avoid more damage </li></ul>
    79. 85. Acute Myeloid Leukemia AML <ul><li>Stem cell transplant only hope for cure in some patients with AML and poor prognosis, or after relapse </li></ul>
    80. 88. Lymphocytes Disorders <ul><li>Neoplasia of Lymphoid origin </li></ul><ul><ul><li>Non Hodgkin’s Lymphoma </li></ul></ul><ul><ul><li>Hodgkin’s Lymphoma </li></ul></ul><ul><ul><li>Lymphoid Leukemia </li></ul></ul><ul><ul><li>Plasma cells Dyscrasias </li></ul></ul>
    81. 89. Lymphadenopathy <ul><li>Painless enlargement of the lymph nodes is the most common presentation of lymphoid malignancy in adults </li></ul><ul><li>Cervical lymphadenopathy: </li></ul><ul><ul><li>URI </li></ul></ul><ul><ul><li>IM </li></ul></ul><ul><ul><li>Bacterial pharyngitis </li></ul></ul><ul><ul><li>Other viral syndromes </li></ul></ul>
    82. 90. Lymphadenopathy <ul><li>Unilateral axillary, inguinal, or femoral adenopathy </li></ul><ul><ul><li>may be caused by local skin infections involving the affected area </li></ul></ul><ul><li>Generalized lymphadenopathy caused by </li></ul><ul><ul><li>systemic infections such as HIV, drug reactions, autoimmune Ds, lymphoma, or others </li></ul></ul>
    83. 91. Lymphadenopathy <ul><li>Excisional lymph node biopsy is done if no apparent cause </li></ul><ul><li>Histological examination and immunophenotyping for classification </li></ul>
    84. 92. Non Hodgkin’s Lymphoma <ul><li>Heterogeneous group of cancers of the lymphocytes </li></ul><ul><li>From indolent course to rapidly progressing </li></ul><ul><li>Cause not known </li></ul><ul><li>Frequently associated with chromosomal translocations </li></ul>
    85. 93. Non Hodgkin’s Lymphoma
    86. 94. Non Hodgkin’s Lymphoma <ul><li>Different classifications through the years </li></ul><ul><li>Most updated one REAL/WHO </li></ul><ul><li>REAL: Revised European-American Lymphoma Classification updated by WHO: World Health Organization in 2001 </li></ul>
    87. 95. Non Hodgkin’s Lymphoma <ul><li>Most common types in the US: </li></ul><ul><ul><li>Follicular lymphomas </li></ul></ul><ul><ul><li>Chronic Lymphocytic Leukemia(CLL) or small lymphocytic lymphoma </li></ul></ul><ul><ul><li>Mantel cell lymphomas </li></ul></ul><ul><ul><li>Diffuse large B-cell Lymphomas </li></ul></ul>
    88. 96. Non Hodgkin’s Lymphoma <ul><li>Associated with oncogenic viruses: </li></ul><ul><li>EBV-AIDS related lymphomas </li></ul><ul><li>EBV-related to the Burkitt’s lymphoma that is endemic in Africa </li></ul><ul><li>HTLV-1 causally linked to T-cell leukemia endemic in Japan and the Caribbean </li></ul>
    89. 97. Non Hodgkin’s Lymphoma <ul><li>Extra nodal site involvement in the GI , BM, liver, and Waldeyer’s ring or any part of the body </li></ul><ul><li>More aggressive types have more extra nodal or diffuse involvement including CNS (Burkitt’s and Lymphoblastics) </li></ul>
    90. 98. Non Hodgkin’s Lymphoma <ul><li>After diagnosis of Lymphoma </li></ul><ul><li>Staging: determines the extent of involvement , prognosis, and may influence the choice of therapy </li></ul><ul><li>Modified Ann Arbor staging classification is used for both non H. and Hodgkin’s Lymphoma </li></ul>
    91. 99. <ul><li>Stage l: single lymph node region or structure, or extra lymphatic site </li></ul><ul><li>Stage ll: two or more lymph node regions on the same side of the Diaphragm or contiguous extra lymphatic site and lymph node region </li></ul><ul><li>Stage lll: involvement of lymph nodes regions on both sides of the Diaphragm , accompanied by extra lymphatic site or spleen or both </li></ul><ul><li>Stage lV diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement </li></ul><ul><li>Page 520 </li></ul>
    92. 100. Staging evaluation <ul><li>History-constitutional symptoms (fever, nights sweats, and weight loss-B symptoms) </li></ul><ul><li>Complete PE – Lymph Nodes size and distribution </li></ul><ul><li>Blood work </li></ul><ul><li>CT scan ABD.CHEST.PELVIS </li></ul><ul><li>BM aspirate and Biopsy </li></ul><ul><li>PET scan </li></ul><ul><li>Lumbar puncture </li></ul>
    93. 101. Non Hodgkin’s Lymphoma <ul><li>Low grade/indolent includes : </li></ul><ul><ul><li>Follicular lymphomas </li></ul></ul><ul><ul><li>Small lymphocytic lymphomas(CLL) </li></ul></ul><ul><li>Are mature clonal B cell neoplasm </li></ul><ul><li>Advanced stage or disseminated at presentation (80-90%) </li></ul><ul><li>Non curable, and long natural Hx, watch and wait strategy </li></ul><ul><li>Advanced stage – systemic chemotherapy </li></ul>
    94. 102. Non Hodgkin’s Lymphoma <ul><li>Patients with diffuse aggressive lymphoma are treated immediately because these are potentially curable </li></ul><ul><li>Multidrug chemotherapy including anthracycline </li></ul><ul><li>CHOP: most common regimen, includes cyclophosphamide, doxorubicin, vincristine, and prednisone </li></ul><ul><li>30-40% cure rate </li></ul>
    95. 103. Non Hodgkin’s Lymphoma <ul><li>Burkitt’s Lymphoma: </li></ul><ul><li>High grade B cell Lymphoma, rare in adults ,endemic in children in Africa (EBV), curable </li></ul><ul><li>Involve BM , and CNS </li></ul><ul><li>Urgent inpatient treatment, highly aggressive/rapid growth </li></ul><ul><li>Frequent abdominal pain and fullness /abdomen predilection </li></ul><ul><li>Tumor Lysis Syndrome common </li></ul>
    96. 104. Non Hodgkin’s Lymphoma <ul><li>Lymphoblastic lymphoma (ALL) T-cell lymphoma </li></ul><ul><li>+ tdt (terminal deoxynucleotide tranferase) </li></ul><ul><li>Young male adults </li></ul><ul><li>Involves mediastinum and BM </li></ul>
    97. 105. <ul><li>Both require intensive treatment with multiple therapy </li></ul><ul><li>intrathecal therapy to prevent relapse </li></ul><ul><li>Prophylaxis for “tumor lysis syndrome” with hydration, alkalinization of the urine and allopurinol </li></ul><ul><li>BM autologous transplant used </li></ul><ul><li>MALT(mucosal associated lymp.tumors) of the stomach treated with antibiotics-H.pilory </li></ul>Non Hodgkin’s Lymphoma
    98. 106. Prognosis <ul><li>Adverse prognosis factors: </li></ul><ul><li>Age over 60 yo </li></ul><ul><li>Elevated serum LDH </li></ul><ul><li>Stage lll or IV </li></ul><ul><li>Poor performance state </li></ul><ul><li>Durable complete response 80%-no risk patients </li></ul><ul><li>Early treatment with high dose therapy and autologous stem cell transplant improves the outcome </li></ul>
    99. 107. Hodgkin’s disease <ul><li>Painless lymphadenopathy </li></ul><ul><li>Constitutional symptoms may or may not be present </li></ul><ul><li>Diagnosis by lymph node biopsy </li></ul><ul><li>Reed-sternberg(RS) cells present in lymphoid tissue involved </li></ul>
    100. 108. Hodgkin’s disease <ul><li>Reed-Sternberg cell: bi-nucleated cell with nucleoli - owl’s eyes, B cell in nature, present in only half the HD patients </li></ul>
    101. 109. Hodgkin’s disease <ul><li>Bimodal age distribution 20yo and >50yo </li></ul><ul><li>Presents as painless mass(neck) and spreads to contiguous lymph nodes </li></ul><ul><li>Some have constitutional symptoms only, and generalized pruritus </li></ul><ul><li>Pain in in lymph node after alcohol ingestion </li></ul><ul><li>Late in course - Vascular invasion and hematogenous spread </li></ul>
    102. 110. Hodgkin’s disease <ul><li>Four Pathological Variants: </li></ul><ul><ul><li>Nodular Sclerosing(80%) </li></ul></ul><ul><ul><ul><li>Young adults/mediastinum/above Diaph </li></ul></ul></ul><ul><ul><li>Mixed cellularity (15%) </li></ul></ul><ul><ul><ul><li>Any age group/subdiaphragmatic common </li></ul></ul></ul><ul><ul><li>Lymphocyte depleted (1%) </li></ul></ul><ul><ul><ul><li>Older adults/HIV patients </li></ul></ul></ul><ul><ul><li>Lymphocyte predominant (5%) </li></ul></ul><ul><ul><ul><li>Peripheral nodes involvement </li></ul></ul></ul><ul><ul><ul><li>Polylobated nuclei RS cells(popcorn cells) </li></ul></ul></ul>
    103. 111. HL Mixed Cellularity
    104. 112. Hodgkin’s disease <ul><li>Advanced disease: BM failure and malaise , cachexia , infections </li></ul><ul><li>Staging the same as for NHL with the addition of A or B for the absence or presence of B symptoms respectively </li></ul>
    105. 113. Staging Workup <ul><li>Similar to NHL </li></ul><ul><li>Thorough H & P </li></ul><ul><li>Blood work including ESR </li></ul><ul><li>Chest Xray </li></ul><ul><li>CT chest, abdomen, pelvis </li></ul><ul><li>BM aspirate /Biopsy </li></ul><ul><li>PETscan/gallium scan </li></ul><ul><li>Bone scan, spinal magnetic resonance if needed </li></ul>
    106. 114. HL Treatment <ul><li>Radiation therapy- initial for low risk IA and IIA disease </li></ul><ul><li>Trial limited chemotherapy for some patients- </li></ul><ul><li>IIIB, IV - combination chemotherapy </li></ul><ul><ul><li>Adriamycin(doxorubicin) </li></ul></ul><ul><ul><li>Bleomycin </li></ul></ul><ul><ul><li>Vincristine </li></ul></ul><ul><ul><li>dacarbazine </li></ul></ul>
    107. 115. HL prognosis <ul><li>IA, IIA- excellent >80% surv.rate after 10 years </li></ul><ul><li>IIIB, IV- 50-60% at 5 years </li></ul><ul><li>Better prognosis - the Lymphocyte Predominant subtype </li></ul><ul><li>Treatment after relapse is high dose chemotherapy and autologous stem cell transplant </li></ul>
    108. 117. Plasma cells Disorders <ul><li>B cells neoplasm with production and secretion of monoclonal(M) immunoglobulin or part of an immunoglobulin molecule </li></ul><ul><li>Mature plasma cells which produce large amount of immunoglobulins </li></ul><ul><li>Protein can be detected in serum or urine by Protein Electrophoresis test </li></ul>
    109. 118. Plasma cells Disorders <ul><li>Clinically characterized by: </li></ul><ul><li>Systemic effect of the M protein </li></ul><ul><li>direct effect of bone and BM infiltration by the M protein </li></ul><ul><li>Classification by the immunoglobulin produced(G,A,D,M,E,) or component produced(heavy or light chain) </li></ul>
    110. 119. Plasma cells Disorders <ul><li>M proteins found also in benign and malignant conditions </li></ul><ul><li>Autoreactive and infectious disorders </li></ul><ul><li>MGUS </li></ul><ul><ul><li>Low level M protein on serum </li></ul></ul><ul><ul><li>No associated abnormalities </li></ul></ul><ul><ul><li>More common than Multiple Myeloma </li></ul></ul><ul><ul><li>Considered pre-malignant </li></ul></ul><ul><ul><li>Monitor patient annual PE </li></ul></ul>
    111. 120. Plasma cells Disorders <ul><li>Multiple Myeloma (MM) </li></ul><ul><ul><li>Neoplastic infiltration of bone and BM </li></ul></ul><ul><ul><li>M Immunoglobulin or light chains in the serum or urine </li></ul></ul><ul><li>Dx >30% plasma cells in BM </li></ul><ul><ul><li>Serum M protein other than IgM </li></ul></ul><ul><ul><ul><li>IgG >3g/dl </li></ul></ul></ul><ul><ul><ul><li>IgA >2g/dl </li></ul></ul></ul><ul><ul><li>Urine M protein </li></ul></ul><ul><ul><ul><li>1g/24 hrs </li></ul></ul></ul>
    112. 121. Plasma cells Disorders <ul><li>20% of patients lack the M protein in serum but show light chains protein in urine </li></ul><ul><li>Diagnosis made in this cases by presence of hypogammaglobulinemia, lytic bone lesions, or plasmacytoma </li></ul>
    113. 122. Plasma cells Disorders <ul><li>Clinical Manifestations MM </li></ul><ul><li>Results from </li></ul><ul><ul><li>Bone or BM infiltration of Plasma Cells </li></ul></ul><ul><ul><li>Systemic effects of the M protein </li></ul></ul><ul><ul><li>And humoral immune deficiency </li></ul></ul>
    114. 123. Plasma cells Disorders MM <ul><li>Bone Pain- Bone Xray-osteolytic -punched out lesions- low back and ribs </li></ul><ul><li>Osteopenia-pathologic fractures-spinal cord compression </li></ul><ul><li>Hypercalcemia - bony involvement </li></ul><ul><li>Anemia - BM infiltration </li></ul><ul><li>Decreased WBC and Plts less common </li></ul><ul><li>Increased infections </li></ul><ul><li>Renal insufficiency - hypercalcemia/uricemia </li></ul>
    115. 124. Plasma cells Disorders <ul><li>Hyperviscocity ,cryoglobulinemia- vertigo, nausea, visual disturbances, alter mental status </li></ul><ul><li>Clotting abnormalities </li></ul><ul><li>Enlarged tongue - amyloidosis </li></ul>
    116. 125. Plasma cells Disorders <ul><li>Lab Findings </li></ul><ul><li>RBC morphology WNL - Rouleau formation </li></ul><ul><li>Hallmark - paraprotein in SPEP </li></ul><ul><li>Immunofixation to determine if monoclonal </li></ul><ul><li>BM plasma cells 20-100% abnormal </li></ul>
    117. 126. Plasma cells Disorders MM <ul><li>Diff Diagnosis </li></ul><ul><li>MGUS </li></ul><ul><li>Waldestrom’s macroglobulinemia </li></ul><ul><li>Reactive polyclonal hypergammaglobulinemia </li></ul><ul><li>Lymphomas </li></ul><ul><li>Primary amyloidosis </li></ul>
    118. 127. Plasma cells Disorders MM <ul><li>Treatment </li></ul><ul><li>Thalidomide + dexamethasone </li></ul><ul><li>Stem cell transplant </li></ul><ul><li>Treat hypercalcemia </li></ul><ul><li>Biphosphonates </li></ul>
    119. 128. Waldestrom’s Macroglobulinemia <ul><li>Hybrid cell between B lymphocyte and plasma cell </li></ul><ul><li>Secrete IgM paraprotein </li></ul><ul><li>Symptoms related to the macroglobulin </li></ul><ul><li>Insidious course in the elderly </li></ul><ul><li>Hyperviscocity in serum- GI bleeding </li></ul><ul><li>Lethargy , stupor , or comma </li></ul><ul><li>Peripheral neuropathy </li></ul>
    120. 129. Waldestrom’s Macroglobulinemia <ul><li>PE </li></ul><ul><ul><li>Retinal vein engorgement </li></ul></ul><ul><ul><li>Lymphadenopathy </li></ul></ul><ul><ul><li>Hepatosplenomegaly </li></ul></ul><ul><ul><li>Purpura </li></ul></ul>
    121. 130. Waldestrom’s Macroglobulinemia <ul><li>Laboratory Findings </li></ul><ul><li>Anemia- expansion of plasma (protein) </li></ul><ul><li>Rouleau formation </li></ul><ul><li>Other blood counts normal </li></ul><ul><li>BM infiltrated by plasmacytic lymphocytes </li></ul><ul><li>Hallmark- IgM spike on SPEP </li></ul><ul><li>No renal failure </li></ul><ul><li>No bone lesions </li></ul>
    122. 131. Waldestrom’s Macroglobulinemia <ul><li>Treatment </li></ul><ul><ul><li>Emergency plasmapheresis - hyperviscocity </li></ul></ul><ul><ul><li>Fludarabine and Rituxan </li></ul></ul><ul><ul><li>Autologous cell transplant </li></ul></ul>
    123. 132. WBC disorders <ul><li>Leukocytosis : non specific term, denotes increased in either neutrophils or lymphocytes </li></ul><ul><li>Neutrophilia : increase in netrophils </li></ul><ul><li>Leukemoid reaction : </li></ul><ul><ul><li>Extreme elevation of WBCs >50,000/mcl and early myeloid precursors </li></ul></ul>
    124. 133. WBC disorders <ul><li>Leukemoid reaction: </li></ul><ul><ul><li>Associated with inflammatory reactions and infections </li></ul></ul><ul><li>Leukopenia : decrease in lymphocytes or neutrophils </li></ul><ul><li>Neutropenia : neutrophil count <1500/mcl </li></ul>
    125. 134. WBC disorders <ul><li>Neutropenia </li></ul><ul><ul><li>Decreased production (congenital/acquired) </li></ul></ul><ul><ul><li>Increased sequestration (splenomegaly) </li></ul></ul><ul><ul><li>Peripheral destruction (overwhelming infections, drug related, Collagen vascular disease </li></ul></ul>
    126. 135. WBC disorders <ul><li>Cyclic neutropenia : asymptomatic patients, evaluate with serial CBCs </li></ul><ul><ul><li>Neutrophil count varies by ethnic group, lower in African-Americans </li></ul></ul><ul><ul><li>Relative benign condition </li></ul></ul><ul><ul><li>If neutrophil count is very low can develop infections </li></ul></ul>
    127. 136. WBC disorders <ul><li>Congenital Agranulocytosis (Kostmann’s syndrome) </li></ul><ul><ul><li>Profound neutropenia </li></ul></ul><ul><ul><li>Infections perinatal period </li></ul></ul><ul><ul><li>Associate with development of acute leukemias </li></ul></ul><ul><ul><li>Better prognosis with cytokines therapy </li></ul></ul>
    128. 137. WBC disorders <ul><li>Post viral neutropenia </li></ul><ul><ul><li>Common in children </li></ul></ul><ul><ul><li>Increased neutrophil consumption and viral suppression of BM </li></ul></ul><ul><ul><li>When associated to overwhelming sepsis-poor prognosis </li></ul></ul>
    129. 138. WBC disorders <ul><li>Drug induced Neutropenia </li></ul><ul><ul><li>Dose dependent or idiosyncratic reaction </li></ul></ul><ul><ul><li>Chemotherapy, Bactrin, Chloramphenicol </li></ul></ul><ul><ul><li>Most respond to discontinuation of the drug and G-CSF therapy </li></ul></ul>
    130. 139. WBC disorders <ul><li>Autoimmune neutropenia </li></ul><ul><ul><li>Associated to Systemic autoimmune disorders </li></ul></ul><ul><ul><li>SLE, RA </li></ul></ul><ul><ul><li>Not usually severe, indicator of disease activity </li></ul></ul>
    131. 140. Neutropenia. Laboratory Eval. <ul><li>Serologic studies to rule out CVD </li></ul><ul><li>BM examination indicated early – frequently diagnostic </li></ul><ul><li>Most often reflects hematological conditions </li></ul>
    132. 141. Neutropenia management <ul><li>1000-1500/mcl no significant impairment, no treatment needed, find the cause and treat condition as needed </li></ul><ul><li>500-1000/mcl alert patient to increase risk of infection </li></ul><ul><li><500/mcl significant risk of infection , should notify MD at any signs of infections-fever, aggressive antibiotic management </li></ul><ul><li>Patients with immune mediated neutropenia are managed with steroids and IVIG </li></ul>
    133. 143. <ul><li>the end </li></ul>

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