Hematology%20Data

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• Hematology Data

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Anemia

• Understanding anemia
• Disease - to be treated on its own merits
• Condition - a secondary manifestation of another
  disease
• Causes
• Decreased production
• Blood loss
• Hemolysis

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Classification of Anemia

• Acute vs. chronic
• Signs and symptoms
• Red cell kinetics
• Determined by reticulocyte count
• Red cell size
• Determined by MCV

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Laboratory Evaluation of Anemia

• Complete blood count
• Reticulocyte count
• Peripheral smear

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Microcytic Hypochromic Anemia Diagnosis

• Mild (MCV gt 70 fl)
• Iron deficiency
• Thalassemia
• Lead toxicity
• Sideroblastic anemia
• Anemia of chronic disease

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Iron Deficiency Anemia

• A world-wide problem
• 3 of toddlers age 1-2 years
• 2-5 of women of child bearing age
• Iron metabolism
• Iron stores
• Laboratory findings of iron deficiency
• Causes of iron deficiency
• Treatment

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Body Iron Distribution and Storage
Duodenum
Storage Iron storage 0-1000 mg Transit
Serum iron 3 mg Total 3000-4000 mg
Dietary iron
(average, 1 - 2 mg
Utilization
Utilization
per day)
Metabolic Hemoglobin 1800-2500 mg Myoglobin
300-500 mg
Plasma
transferrin
(3 mg)
Bone
Muscle
marrow
(myoglobin)
(300 mg)
Circulating
(300 mg)
erythrocytes
Storage
(hemoglobin)
iron
(1,800 mg)
Sloughed mucosal cells
Desquamation/Menstruation
Other blood loss
(average, 1 - 2 mg per day)
Reticuloendothelial
Liver
macrophages
(1,000 mg)
Iron loss
(600 mg)
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Causes of Iron Deficiency

• Increased Utilization
• iron requirements
• Blood loss
• Gastrointestinal tract
• Genitourinary tract
• Blood donation
• Pregnancy and lactation

• Inadequate availability
• iron supply
• Insufficient dietary iron
• Impaired iron absorption
• Gastric surgery
• Intestinal malabsorption
• Celiac disease

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Systemic Manifestations of Iron Deficiency

• Behavioral and neuropsychiatric manifestations
• Pica (pagophagia)
• Angular stomatitis
• Glossitis
• Esophageal webs and strictures
• Koilonychia (spooning)

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Treatment with Oral Iron General Principles

• Ferrous salts are absorbed better than ferric
• All ferrous salts are absorbed to the same extent
• Ascorbic acid increases absorption and toxicity
• Iron is absorbed best on an empty stomach
• Iron should not be given with antacids
• Iron polysaccharide complex (Niferex)
• seems to be better tolerated than other iron
  salts

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Anemia of Chronic Disease

• Associated conditions
• Chronic infection (TB, HIV, osteomyelitis)
• Chronic inflammatory disorder (rheumatoid
  arthritis)
• Neoplasm
• Etiology
• Impaired erythropoietin production
• Impaired iron utilization from RE system
• Direct inhibition of erythropoiesis
• Consequence of inflammatory cytokines

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Anemia of Chronic Disease

• Characteristics
• Anemia of variable severity (mild-severe)
• Low erythropoietin level
• Low reticulocyte count
• WBC and platelet counts are normal
• Treatment
• Underlying condition
• Erythropoietin

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Anemia of Chronic Renal Disease

• Characteristics
• Widespread - 8 of US population has increased
  creatinine
• 23 of patients with chronic renal disease have
  HCT 30
• Long-term anemia is a risk for LVH
• Risk factor for mortality
• Etiology
• Insufficient production of erythropoietin

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Anemia in Other Clinical Conditions
Condition treated with RBC or
Erythropoietin Outcome measured Critical care
patients Trend to improved survival Elderly
patients with Improved 30 day
survival myocardial infarction Congestive heart
failure Decreased hospital days Cancer and
cancer therapy Improved quality of life Improved
local control with radiation
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Macrocytic Anemia with Low Reticulocyte Count

• Megaloblastic anemia
• Vitamin B12 deficiency
• Folate deficiency
• Non-megaloblastic macrocytic anemia
• Liver disease
• Hypothyroidism
• Drug-induced (DNA synthesis block)
• Myelodysplastic syndrome

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Folate and Cobalamin Daily Requirements
Diet Vitamin B12 (Cobalamin)
Folate Source Animal products Widespread Body
stores 5 mg 5 mg Daily requirement 2-5
µg 50-200 µg Daily intake 10-20 µg 400-800
µg Dietary deficiency Rare Common
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Vitamin B12 Deficiency Common Mechanisms

• Intragastric events
• Total or partial gastrectomy
• Absent intrinsic factor secretion
• Bacterial overgrowth
• Diphylobothrium latum (fish tapeworm)
• Disease of the terminal ileum

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Pernicious Anemia

• Most common cause of vitamin B12 deficiency
• Associated with-autoimmune diseases
• Screen for thyroid disease every 1-2 years
• Pernicious anemia is a systemic disease
• Gastrointestinal tract involvement
• Neurologic involvement

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Pernicious Anemia Laboratory Diagnosis

• Anti-intrinsic factor antibodies
• Anti-parietal cell antibodies
• Schilling test
• Procedure
• Absorption of radiolabeled cobalamin Intrinsic
  factor
• Measure urinary excretion of radioactivity

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Treatment of Vitamin B12 Deficiency

• Parenteral cobalamin
• 1 mg/day x 7 days
• 1 mg/week x 4 weeks
• 1 mg/month for life
• Oral cobalamin
• 1 mg/day for life

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Tongue in B12 Deficiency
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Folate (Vitamin B9) Deficiency

• Minimum daily folate requirement is 50 µg
• Usual dietary folate 50-500 µg
• Absorption in upper small intestine
• Causes of folate deficiency-
• Dietary (90)
• Alcohol abuse
• Pregnancy
• Malabsorption
• Drug-induced
• Treatment - oral folic acid supplementation

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Glucose-6-Phosphate Dehydrogenase Deficiency

• G-6-PD reduces NADP/oxidizes glucose-6-phosphate
• Detoxifies free radicals and peroxides
• Sex-linked disorder
• Effects gt 200 million people
• Hemolytic anemia occurs in the presence of stress
  (infection or drugs)
• African form - mild hemolysis
• Mediterranean form - more severe
• Unique sensitivity to fava beans

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Acute Leukemia
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Overview

• Concepts, biology
• Epidemiology
• Clinical and laboratory manifestations
• Diagnosis
• Management and prognosis

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Classification of leukemias
Acute
Chronic
Myeloid origin
Acute Myeloid Leukemia (AML)
Chronic Myeloid Leukemia (CML)
Lymphoid origin
Acute Lymphoblastic Leukemia (ALL)
Chronic Lymphocytic Leukemia (CLL)
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Acute Leukemia

• accumulation of blasts in the marrow

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Significance of adult acute leukemia

• a hematologic urgency
• usually fatal within weeks to months without
  chemotherapy
• with treatment, high mortality due to disease or
  treatment-related complications (unlike childhood
  acute leukemia)
• notify Hematologist promptly if acute leukemia is
  suspected

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Classification of acute leukemias

• ALL
• mainly children
• M gt F
• curable in 70 of children
• curable in minority of adults

• AML
• mainly adults
• M gt F
• curable in minority of adults

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Causes of acute leukemias

• idiopathic (most)
• underlying hematologic disorders
• chemicals, drugs
• ionizing radiation
• viruses (HTLV I)
• hereditary/genetic conditions

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Clincal manifestations

• symptoms due to
• marrow failure
• tissue infiltration
• leukostasis
• constitutional symptoms
• other (DIC)
• usually short duration of symptoms

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Marrow failure

• neutropenia infections, sepsis
• anemia fatigue, pallor
• thrombocytopenia bleeding

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Infiltration of tissues/organs

• enlargement of liver, spleen, lymph nodes
• gum hypertrophy
• bone pain
• other organs CNS, skin, testis, any organ

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Gum hypertrophy
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Leukostasis

• accumulation of blasts in microcirculation with
  impaired perfusion
• lungs hypoxemia, pulmonary infiltrates
• CNS stroke
• only seen with WBC gtgt 50 x 109/L

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Constitutional symptoms

• fever and sweats common
• weight loss less common

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Laboratory features

• WBC usually elevated, but can be normal or low
• blasts in peripheral blood
• normocytic anemia
• thrombocytopenia
• neutropenia
• DIC

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Bone marrow in acute leukemia

• necessary for diagnosis
• useful for determining type
• useful for prognosis
• Acute leukemias are defined by the presence of gt
  20 blasts in bone marrow ( of nucleated marrow
  cells)

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Treatment of acute leukemias

• Choice of Rx is influenced by
• type (AML vs ALL)
• age
• curative vs palliative intent

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Principles of treatment

• combination chemotherapy
• first goal is complete remission
• further Rx to prevent relapse
• supportive medical care
• transfusions, antibiotics, nutrition
• psychosocial support
• patient and family

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Hematopoietic stem cell transplantation

• permits rescue from otherwise excessively toxic
  treatment
• additional advantage of graft-vs-leukemia effect
  in allogeneic transplants
• trade-off for allogeneic transplantation greater
  anti-leukemic effect but more toxic

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LYMPHOID DISORDERS
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Topics to be Covered

• Non-Hodgkins Lymphoma
• Hodgkins Disease
• Multiple Myeloma

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Lymphoma and Multiple Myeloma2004 U.S. Predicted
Values

• Malignancy New Cases Deaths
• All Cancer s 1,368,030 563,700
• Non-Hodgkins
• Lymphoma 54,370 19,410
• Hodgkins Disease 7,880 1,320
• Multiple Myeloma 15,270 11,070

CA Cancer J Clin 2004 548-29
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Non-Hodgkins Lymphoma
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Non-Hodgkins Lymphoma (NHL)

• 6th most common cause of cancer death in United
  States.
• Increasing in incidence and mortality.
• Since 1970, the incidence of lymphoma has almost
  doubled.

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Types of Lymphoma

• Indolent (low grade)
• Life expectancy in years, untreated
• 85-90 present in Stage III or IV
• Incurable
• Intermediate
• Aggressive (high grade)
• Life expectancy in weeks, untreated
• Potentially curable

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Etiology of NHL

• Immune suppression
• congenital (Wiskott-Aldrich)
• organ transplant(cyclosporine)
• AIDS
• increasing age
• DNA repair defects
• ataxia telangiectasia
• xeroderma pigmentosum

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Etiology of NHL

• Chronic inflammation and antigenic stimulation
• Helicobacter pylori inflammation, stomach
• Chlamydia psittaci inflammation, ocular tissues
• Sjögrens syndrome
• Viral causes-
• EBV and Burkitts lymphoma
• HTLV-I and T cell leukemia-lymphoma
• HTLV-V and cutaneous T cell lymphoma
• Hepatitis C

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Clinical Features

• Lymphadenopathy
• Cytopenias
• Systemic symptoms
• Hepatosplenomegaly
• Fever
• Night sweats

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Clinical Features

• Lymphadenopathy may fluctuate or spontaneously
  remit, especially in low-grade lymphomas.
• Body symptoms more common in high-grade
  lymphomas.
• Hematogenous spread of disease, with no
  predictable pattern.

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Clinical Features

• Classic lymphoma arises in
• lymph node or bone marrow.
• Extranodal primary more common in high-grade
  lymphoma.
• Waldeyers ring involvement
• frequent in GI lymphomas.

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Diagnosis of NHL

• Chromosome changes
• 1418 translocation in follicular lymphoma
• bcl-2 oncogene
• t(814), t(28), t(822) in Burkitts lymphoma
• c-myc oncogene
• t(1114) in mantle cell lymphoma
• cyclin D1 gene

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Staging Workup

• CBC, chemistries, urinalysis
• CT scans of chest, abdomen and pelvis
• Bone marrow biopsy and aspirate
• (Lumbar puncture)
• AIDS lymphoma
• T cell lymphoblastic lymphoma
• High grade lymphoma with positive marrow

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Treatment OptionsIndolent lymphomas

• 10-15 in Stage I or II
• potentially curable
• local radiotherapy
• 85-90 Stage III or IV
• incurable
• treatment does not prolong survival

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CHOP Chemotherapy

• Cyclophosphamide (Cytoxan)
• Hydroxydaunorubicin (Adriamycin)
• Oncovin (vincristine)
• Prednisone

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Burkitts Lymphoma

• African variety jaw tumor, strongly linked to
  Epstein-Barr Virus infection.
• In U.S., about 50 EBV infection.
• May present as abdominal mass.
• Most rapidly growing human tumor.
• Typical chromosome abnormality c-myc oncogene
  linked to one of the immunoglobulin genes.

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Burkitts Lymphoma

• Treated with multidrug regimen similar to
  pediatric leukemia/lymphoma regimens.

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AIDS Lymphoma

• Aggressive lymphomas of B cell origin.
• Burkitts, Burkitts-like, and large cell
  immunoblastic.
• Treatment often limited by immune compromise of
  the patient.
• Prognosis improved with HAART therapy.

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MALT Lymphoma

• Mucosa-Associated Lymphoid Tissue
• Chronic infection of the stomach by Helicobacter
  pylori.
• Localized to the stomach, indolent course.
• Can be cured in many cases by antibiotics against
  H. pylori.

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Thomas Hodgkin
Hodgkins Disease
English pathologist, described the disease that
bears his name in 1832.
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Hodgkins Disease

• One-seventh as common as non-Hodgkins lymphoma.
• Highly treatable and curable, even when
  disseminated.
• Presence of Reed-Sternberg cell is necessary to
  make diagnosis.

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Reed-Sternberg Cell
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Epidemiology

• In developed countries, bimodal distribution of
  patients.
• young adulthood
• after age 50
• More common in affluent families with few
  siblings.
• In developing countries, more common in young
  children.

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Signs and Symptoms

• Lymph node enlargement, usually cervical or
  mediastinal.
• Systemic B symptoms common.
• Pel-Ebstein fever.
• Relapsing, high-grade fever that can reach
  105-106F, periodicity of 7-10 days. Fever spikes
  abrupt in onset and resolution
• Pain on drinking alcohol.

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Clinical Features

• T cell mediated immune deficiency, even in early
  stage disease. Prone to infections
• Herpes zoster (shingles) in one fourth of
  patients
• Fungal or mycobacterial infections
• Immune defect may persist even after lymphoma is
  cured.

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Clinical Features

• Predictable contiguous spread of disease
• cervical nodes to mediastinum or axilla
• mediastinum to periaortic nodes or spleen, etc.
• Basis for staging and treatment decisions.

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Diagnosis

• Excisional biopsy of a lymph node.
• Fine needle aspirate is not sufficient to make
  the diagnosis of Hodgkins disease.

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Staging of Hodgkins Disease

• Same as for non-Hodgkins
• H P, labs, CT scans, bone marrow biopsy
• PLUS
• Gallium scan
• Lymphangiogram or staging laparotomy ONLY if
  results would affect treatment decisions

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Treatment by Stage
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Chemotherapy Regimens

• MOPP
• Mechlorethamine, Oncovin, Procarbazine,
  Prednisone
• ABVD
• Adriamycin, Bleomycin, Vinblastine, Dacarbazine
• BEACOPP

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Treatment Options

• Often, patients who relapse after radiotherapy
  can be cured by salvage chemotherapy.
• Combined chemotherapy and radiotherapy is given
  for bulky mediastinal masses.
• Chemotherapy now being tested for earlier stages
  of the disease.

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Late Complications ofHodgkins Disease

• High incidence of second malignancies
• leukemia first 10 years, solid tumors over time.
• Leukemia in patients receiving alkylating agents
  or combined chemo/XRT.
• Lung cancer and breast cancer in patients
  receiving XRT to chest. Lung cancer especially
  high in smokers.

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Late Complications ofHodgkins Disease

• Hypothyroidism after irradiation of the neck.
• Constrictive pericarditis after radiotherapy to
  the mediastinum.
• Infertility after use of alkylating agents.
• Heart failure after Adriamycin treatment.

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Multiple Myeloma
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Overview of Multiple Myeloma

• Less common than non-Hodgkins lymphoma, more
  deadly.
• Average life expectancy 30 -36 months.
• Some patients develop a very indolent form and
  live for 10 years or more.
• Potentially curable with high dose chemotherapy
  (bone marrow or stem cell transplantation).

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Overview of Multiple Myeloma

• Disease of malignant B-lymphocytes.
• Little similarity to lymphoma in presentation,
  age at diagnosis, treatment, or prognosis.
• Signs and symptoms of multiple myeloma are quite
  variable.
• Approximately 20 of patients have no symptoms.

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Etiology of Multiple Myeloma

• Unknown. Suggested predisposing factors include
• Viral infection with Human Herpesvirus 8 (HHV-8).
• MGUS (monoclonal gammopathy of undetermined
  significance).

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Epidemiology

• Average age at presentation is about 65.
• Males are affected more often than females.
• Incidence in blacks is twice that of whites.
• Five-year survival is approximately 25-30.
• Median survival 30-36 months.

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Multiple Myeloma

• More than 15 plasma cells in the bone marrow.
• Monoclonal immunoglobulin peak on SPEP
• more than 3 gm/dL.
• Presence of Bence Jones protein in urine.
• Decreased levels of normal immunoglobulins.

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Clinical Features

• Bone marrow failure- Anemia, thrombocytopenia,
  neutropenia
• Renal failure
• Bone disease with skeletal destruction
• lytic lesions
• generalized decrease in bone density
• Hypercalcemia

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Clinical Features

• Hyperviscosity syndrome
• Recurrent infections
• Amyloidosis

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Diagnosis and Staging Workup

• Bone marrow biopsy and aspirate
• Serum protein electrophoresis and immunofixation
• Skeletal survey
• Plain x-rays are better than bone scan.
• Lytic lesions do not show up well on bone scan.
• Quantitative immunoglobulins

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Serum Protein Electrophoresis
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Lytic Bone Lesions in Multiple Myeloma
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Treatment of Multiple Myeloma

• Standard Chemotherapy
• Melphalan and prednisone
• VAD (vincristine, adriamycin, dexamethasone)
• High Dose Chemotherapy
• Bone marrow transplant
• Peripheral stem cell transplant

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Treatment of Multiple Myeloma

• Other Modalities
• Pulse dexamethasone
• Interferon
• Local radiotherapy to bony lesions
• Pamidronate and other bisphosphonates
• Thalidomide
• Velcade (Bortezomib, PS-341)
• Bendamustine

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Prognostic Factors

• Poor prognosis
• Age gt 65
• High tumor mass
• High b2 microglobulin
• Renal failure, hypercalcemia

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Bleeding And Clotting Disorders
B Bruising Clotting
BLEEDING

• Bleeding Disorders
• Hemophilia
• Von Willebrand Disease (vWD)

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Haemostasis

• Vasoconstriction
• Platelet activation
• Haemostatic plug
• Coagulation
• Stable clot formation
• Clot dissolution

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Stage 1 Release of platelet factors to initiate
clotting Stage 2 Generation of Thromboplastin
by other factors Stage 3 Conversion of
prothrombin to thrombin Stage 4 Formation of
fibrin from fibrinogen
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PT/INR

• Screens for abnormalities in the extrinsic and
  common pathways of coagulation
• A typical normal range for the PT is between 10
  and 13 sec.
• An INR gt 1.5 or a PT 3 sec longer than a
  laboratory's normal control value is usually
  abnormal and requires further evaluation.

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PTT

• Partial thromboplastin time (PTT) screens plasma
  for abnormalities in factors of the intrinsic and
  common pathways
• A normal range of 28 to 34 sec is typical.
• A normal result indicates that at least 30 of
  all coagulation factors in the pathway are
  present in the plasma
• Heparin prolongs the PTT, and the PTT is often
  used to monitor heparin

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Hemophilia

• Hemophilia Affects 18,000 in US
• caused by deficiencies of either clotting factor
  VIII or IX
• Hemophilia A (factor VIII deficiency), which
  affects about 80 of hemophilic patients, and
  hemophilia B (factor IX deficiency) gt 30 normal
  value
• elevated PTT and
• normal PT and
• Normal platelet count
• it is confirmed by specific factor assays

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Von Willbrand Disease (vWD)

• Most common bleeding disorder affects 1-2 (more
  common in women)
• causes platelet dysfunction
• Screening coagulation tests reveal
• normal platelet count
• normal INR
• Prolonged bleeding time and,
• normal PTT
• Diagnosis is based on low levels of VWF antigen
  and abnormal ristocetin cofactor activity.

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TYPES OF TREATMENT

• Local Therapy
• Pressure
• Cautery
• Suturing
• Topical Thrombin

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TYPES OF TREATMENT

• Systemic Pharmacological Therapy
• Antifibrinolytic agents
• Tranexamic Acid Cyklokapron
• Epsilon amino caproic acid Amicar
• DDAVP desmopressin
• Hormone preparations estrogens

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BLOOD COMPONENT THERAPY

• Cryoprecipitate
• Factor VIII
• VWF
• Fibrinogen
• Coagulation factor concentrates
• Factor VIII
• Factor IX

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CONSIDERATIONS IN THE TX OF HEMOSTATIC PROBLEMS

• Transmissible Diseases
• HIV, Hepatitis A, B and C, Parvovirus, ??CJD
• Coagulation Factor Concentrates
• Donor screening
• Viral inactivation
• Donor pools
• Plasma and cryoprecipitate

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Bleeding And Clotting Disorders
Bleeding B Clotting
Bruising

• Bruising Disorders
• HENCOH-SCHONLEIN PURPURA (HSP)
• Idiopathic Thrombocytopenic Purpura - ITP

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PURPURAS

• HENCOH-SCHONLEIN PURPURA (HSP)

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Henoch Schonlein Purpura
Fever
Previous URI
Purpura on extensor surfaces of arms, legs,
buttocks
GI disturbances
Renal involvement
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Epidemiology

• Incidence is 13.5-18/100000
• Male to female 1.51
• Can occur from 6 months- adulthood
• 50 of cases are under 5 years of age
• Wide geographical distribution
• More common in winter and spring
• Upper Respiratory infections may precede
• Genetics play a small role

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Clinical Presentation

• Classic Triad of symptoms is the most common
  presentation
• Purpura
• Colicky abdominal pain
• arthritis
• 50 of children may present with symptoms other
  than purpura

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Dermatologic

• Younger children-
• urticaria
• edema of- the feet, dorsum of the hands, face
  and scalp.
• New crops can present for up to three months or
  longer
• Erythema nodosum
• Blistering lesions

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Natural History for HSP without Nephritis

• Self limited illness.
• No treatment is required for the purpura
• NSAIDs are used to treat arthralgias
• Steroids are not beneficial

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Bleeding conditions Clinical Features

• Local - Vs - General, spontaneous . .
• Hematoma Joint bleed - Coagulation
• Skin/Mucosal Petechiae Purpura PLT
• wound / surgical bleeding
• Immediate - (PLT)
• Delayed - (Coagulation)

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Platelet Coagulation
Petechiae, Purpura Hematoma, Joint bl.
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Idiopathic T. Purpura - ITP

• Young female 20-35y (15-50)
• Easy bruising, Petechiae, menorrhagia
• Anti PLT Antibody (IgG) destruction of plt
• Low Platelet number.

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Disorders of platelets

• Decreased NumberThrombocytopenia
• Decreased Production
• Decreased Survival Immune (ITP)
• Increased utilization - DIC
• Defective Platelet function
• Acquired Drugs Aspirin, MPS, MDS
• Congenital Eg. Thrombasthenia.

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Clinical Cases
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Nail bed - Hematoma

• Red
• Blue/Gr
• Brown

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Contusion - Hematoma
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Petechiae Echymoses -?Plt
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Petechiae Ecchymoses -?Plt
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Bleeding-Coagulation disorder

• Deep bleeding
• Haematoma
• Joint bleeds
• Haemophilia

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Sub Conjuctival Haemorrhage
Low PLT
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Dengue Hemorrhagic fever ?PLATELETS