Hematology DataHematology Data

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Anemia

Understanding anemiaUnderstanding anemiaDisease - to be treated on its own meritsCondition - a secondary manifestation of another

disease

CausesCausesDecreased productionBlood lossHemolysis

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Classification of Anemia

Acute vs. chronicAcute vs. chronicSigns and symptoms

Red cell kineticsRed cell kineticsDetermined by reticulocyte count

Red cell sizeRed cell sizeDetermined by MCV

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Laboratory Evaluation of Anemia

Complete blood countComplete blood count

Reticulocyte countReticulocyte count

Peripheral smearPeripheral smear

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Microcytic Hypochromic Anemia: Diagnosis

Mild (MCV > 70 fl)Mild (MCV > 70 fl)Iron deficiency ThalassemiaLead toxicitySideroblastic anemiaAnemia of chronic disease

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Iron Deficiency Anemia A world-wide problemA world-wide problem3% of toddlers age 1-2 years2-5% of women of child bearing age

Iron metabolismIron metabolism

Iron storesIron stores

Laboratory findings of iron deficiencyLaboratory findings of iron deficiency

Causes of iron deficiencyCauses of iron deficiency

TreatmentTreatment

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Body Iron Distribution and StorageDietary iron

Utilization Utilization

Duodenum(average, 1 - 2 mg

per day)

Muscle(myoglobin)

(300 mg)

Liver(1,000 mg)

Bone marrow(300 mg)Circulating

erythrocytes(hemoglobin)

(1,800 mg)

Reticuloendothelialmacrophages

(600 mg)

Sloughed mucosal cellsDesquamation/Menstruation

Other blood loss(average, 1 - 2 mg per day)

Storageiron

Plasmatransferrin

(3 mg)

Iron loss

MetabolicMetabolicHemoglobin 1800-2500 mgHemoglobin 1800-2500 mgMyoglobin 300-500 mgMyoglobin 300-500 mg

StorageStorageIron storage 0-1000 mgIron storage 0-1000 mg

Transit Serum iron 3 mgTransit Serum iron 3 mgTotalTotal 3000-4000 mg 3000-4000 mg

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Causes of Iron Deficiency Increased UtilizationIncreased Utilization iron requirementsiron requirements Blood lossBlood loss Gastrointestinal tractGastrointestinal tract Genitourinary tractGenitourinary tract Blood donationBlood donation Pregnancy and lactationPregnancy and lactation

Inadequate availabilityInadequate availability iron supplyiron 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 manifestationsBehavioral and neuropsychiatric manifestations

Pica (pagophagia) Pica (pagophagia)

Angular stomatitisAngular stomatitis

GlossitisGlossitis

Esophageal webs and stricturesEsophageal webs and strictures

Koilonychia (spooning)Koilonychia (spooning)

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Treatment with Oral Iron: General Principles

Ferrous salts are absorbed better than ferricFerrous salts are absorbed better than ferric All ferrous salts are absorbed to the same extentAll ferrous salts are absorbed to the same extent Ascorbic acid increases absorption and toxicityAscorbic acid increases absorption and toxicity Iron is absorbed best on an empty stomachIron is absorbed best on an empty stomach Iron should not be given with antacidsIron should not be given with antacids Iron polysaccharide complex (Niferex) Iron polysaccharide complex (Niferex)

seems to be better tolerated than other iron saltsseems to be better tolerated than other iron salts

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Anemia of Chronic Disease Associated conditionsAssociated conditions

Chronic infection (TB, HIV, osteomyelitis)Chronic inflammatory disorder (rheumatoid arthritis)Neoplasm

EtiologyEtiologyImpaired erythropoietin productionImpaired iron utilization from RE systemDirect inhibition of erythropoiesisConsequence of inflammatory cytokines

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Anemia of Chronic Disease

CharacteristicsCharacteristicsAnemia of variable severity (mild-severe)Low erythropoietin levelLow reticulocyte countWBC and platelet counts are normal

TreatmentTreatmentUnderlying conditionErythropoietin

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Anemia of Chronic Renal Disease CharacteristicsCharacteristics

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 LVHRisk factor for mortality

EtiologyEtiologyInsufficient production of erythropoietin

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Anemia in Other Clinical Conditions

Condition treated Condition treated with RBC or Erythropoietinwith RBC or Erythropoietin Outcome measuredOutcome measured

Critical care patientsCritical care patients Trend to improved survivalTrend to improved survival

Elderly patients with Elderly patients with Improved 30 day survivalImproved 30 day survivalmyocardial infarctionmyocardial infarction

Congestive heart failureCongestive heart failure Decreased hospital daysDecreased hospital days

Cancer and cancer therapyCancer and cancer therapy Improved quality of lifeImproved quality of lifeImproved local control with Improved local control with radiationradiation

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Macrocytic Anemia with Low Reticulocyte Count

Megaloblastic anemiaMegaloblastic anemiaVitamin B12 deficiencyFolate deficiency

Non-megaloblastic macrocytic anemiaNon-megaloblastic macrocytic anemiaLiver diseaseHypothyroidismDrug-induced (DNA synthesis block)Myelodysplastic syndrome

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Diet

Vitamin B12Vitamin B12(Cobalamin) (Cobalamin) FolateFolate

SourceSource Animal productsAnimal products WidespreadWidespreadBody storesBody stores 5 mg5 mg 5 mg5 mgDaily requirementDaily requirement 2-5 µg2-5 µg 50-200 µg50-200 µgDaily intakeDaily intake 10-20 µg10-20 µg 400-800 µg400-800 µgDietary deficiencyDietary deficiency RareRare CommonCommon

Folate and Cobalamin Daily Requirements

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Vitamin B12 Deficiency: Common Mechanisms

Intragastric eventsIntragastric events Total or partial gastrectomyTotal or partial gastrectomy Absent intrinsic factor secretionAbsent intrinsic factor secretion Bacterial overgrowthBacterial overgrowth Diphylobothrium latum (fish tapeworm)Diphylobothrium latum (fish tapeworm) Disease of the terminal ileumDisease of the terminal ileum

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Pernicious Anemia

Most common cause of vitamin BMost common cause of vitamin B1212 deficiencydeficiencyAssociated with-autoimmune diseasesAssociated with-autoimmune diseasesScreen for thyroid disease every 1-2 yearsScreen for thyroid disease every 1-2 yearsPernicious anemia is a systemic diseasePernicious anemia is a systemic diseaseGastrointestinal tract involvementGastrointestinal tract involvementNeurologic involvementNeurologic involvement

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Pernicious Anemia: Laboratory Diagnosis

Anti-intrinsic factor antibodiesAnti-intrinsic factor antibodies Anti-parietal cell antibodiesAnti-parietal cell antibodies Schilling testSchilling test ProcedureProcedure Absorption of radiolabeled cobalamin ± Intrinsic factorAbsorption of radiolabeled cobalamin ± Intrinsic factor Measure urinary excretion of radioactivityMeasure urinary excretion of radioactivity

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Treatment of Vitamin B12 Deficiency

Parenteral cobalaminParenteral cobalamin1 mg/day x 7 days1 mg/week x 4 weeks1 mg/month for life

Oral cobalaminOral cobalamin1 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 µgMinimum daily folate requirement is 50 µg Usual dietary folate 50-500 µgUsual dietary folate 50-500 µg Absorption in upper small intestineAbsorption in upper small intestine Causes of folate deficiency- Causes of folate deficiency- Dietary (90%)Dietary (90%) Alcohol abuseAlcohol abuse PregnancyPregnancy MalabsorptionMalabsorption Drug-inducedDrug-induced Treatment - oral folic acid supplementationTreatment - oral folic acid supplementation

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Glucose-6-Phosphate Dehydrogenase Deficiency

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

Acute Leukemia

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Overview

Concepts, biologyConcepts, biology EpidemiologyEpidemiology Clinical and laboratory manifestationsClinical and laboratory manifestations DiagnosisDiagnosis Management and prognosisManagement and prognosis

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Classification of leukemias

AcuteAcute ChronicChronic

Myeloid Myeloid originorigin

Lymphoid Lymphoid originorigin

Acute Myeloid Acute Myeloid Leukemia (AML)Leukemia (AML)

Acute Acute Lymphoblastic Lymphoblastic Leukemia (ALL)Leukemia (ALL)

Chronic Myeloid Leukemia Chronic Myeloid Leukemia (CML)(CML)

Chronic Lymphocytic Chronic Lymphocytic Leukemia (CLL)Leukemia (CLL)

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HematopoieticHematopoieticstem cellstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytesB-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALLALL

AMLAML

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Acute Leukemia accumulation of blasts in the marrowaccumulation of blasts in the marrow

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Significance of adult acute leukemia a hematologic urgencya hematologic urgency usually fatal within weeks to months without usually fatal within weeks to months without

chemotherapychemotherapy with treatment, high mortality due to disease or with treatment, high mortality due to disease or

treatment-related complications (unlike childhood acute treatment-related complications (unlike childhood acute leukemia)leukemia)

notify Hematologist promptly if acute leukemia is notify Hematologist promptly if acute leukemia is suspectedsuspected

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Classification of acute leukemias

ALLALL mainly childrenmainly children M > FM > F curable in 70% of childrencurable in 70% of children curable in minority of adultscurable in minority of adults

AMLAML mainly adultsmainly adults M > FM > F

curable in minority of adultscurable in minority of adults

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Causes of acute leukemias

idiopathic (most)idiopathic (most) underlying hematologic disordersunderlying hematologic disorders chemicals, drugschemicals, drugs ionizing radiationionizing radiation viruses (HTLV I)viruses (HTLV I) hereditary/genetic conditionshereditary/genetic conditions

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Clincal manifestations

symptoms due to:symptoms due to:marrow failuretissue infiltrationleukostasisconstitutional symptomsother (DIC)

usually short duration of symptomsusually short duration of symptoms

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Marrow failure

neutropenia: neutropenia: infections, sepsisinfections, sepsis anemia: anemia: fatigue, pallorfatigue, pallor thrombocytopenia: thrombocytopenia: bleedingbleeding

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Infiltration of tissues/organs

enlargement of liver, spleen, lymph nodesenlargement of liver, spleen, lymph nodes gum hypertrophygum hypertrophy bone painbone pain other organs: CNS, skin, testis, any organother organs: CNS, skin, testis, any organ

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Gum hypertrophy

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Leukostasis

accumulation of blasts in microcirculation with impaired accumulation of blasts in microcirculation with impaired perfusion perfusion

lungs: lungs: hypoxemia, pulmonary infiltrateshypoxemia, pulmonary infiltrates CNS: CNS: strokestroke only seen with WBC >> 50 x 10only seen with WBC >> 50 x 1099/L/L

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Constitutional symptoms

fever and sweats commonfever and sweats common weight loss less commonweight loss less common

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Laboratory features

WBC usually elevated, but can be normal or lowWBC usually elevated, but can be normal or low blasts in peripheral bloodblasts in peripheral blood normocytic anemianormocytic anemia thrombocytopeniathrombocytopenia neutropenianeutropenia DICDIC

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Bone marrow in acute leukemia

necessary for diagnosisnecessary for diagnosis useful for determining typeuseful for determining type useful for prognosisuseful for prognosis Acute leukemias are defined by the presence of > 20% Acute leukemias are defined by the presence of > 20%

blasts in bone marrow (% of nucleated marrow cells)blasts in bone marrow (% of nucleated marrow cells)

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Treatment of acute leukemias

Choice of Rx is influenced by:Choice of Rx is influenced by: type (AML vs ALL)type (AML vs ALL) ageage curative vs palliative intentcurative vs palliative intent

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Principles of treatment

combination chemotherapycombination chemotherapyfirst goal is complete remissionfurther Rx to prevent relapse

supportive medical caresupportive medical caretransfusions, antibiotics, nutrition

psychosocial supportpsychosocial supportpatient and family

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Hematopoietic stem cell transplantation

permits “rescue” from otherwise excessively toxic permits “rescue” from otherwise excessively toxic treatmenttreatment

additional advantage of graft-vs-leukemia effect in additional advantage of graft-vs-leukemia effect in allogeneic transplantsallogeneic transplants

trade-off for allogeneic transplantation: greater anti-trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxicleukemic effect but more toxic

LYMPHOID DISORDERS

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Topics to be Covered

Non-Hodgkin’s LymphomaNon-Hodgkin’s Lymphoma Hodgkin’s DiseaseHodgkin’s Disease Multiple MyelomaMultiple Myeloma

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Lymphoma and Multiple Myeloma2004 U.S. Predicted Values

MalignancyMalignancyNew CasesNew Cases DeathsDeaths

All CancerAll Cancerss 1,368,030 1,368,030 563,700 563,700Non-Hodgkin’s Non-Hodgkin’s LymphomaLymphoma 54,370 54,370 19,41019,410

Hodgkin’s DiseaseHodgkin’s Disease 7,8807,880 1,320 1,320

Multiple Myeloma 15,270Multiple Myeloma 15,270 11,070 11,070

CA Cancer J Clin 2004; 54:8-29

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Non-Hodgkin’s Lymphoma

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Non-Hodgkin’s Lymphoma (NHL)

6th most common cause of cancer death in United 6th most common cause of cancer death in United States.States.

Increasing in incidence and mortality.Increasing in incidence and mortality. Since 1970, the incidence of lymphoma has almost Since 1970, the incidence of lymphoma has almost

doubled.doubled.

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Types of Lymphoma

Indolent (low grade)Indolent (low grade) Life expectancy in years, untreatedLife expectancy in years, untreated

85-90% present in Stage III or IVIncurable

IntermediateIntermediate Aggressive (high grade)Aggressive (high grade)

Life expectancy in weeks, untreatedPotentially curable

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Etiology of NHL

Immune suppressionImmune suppressioncongenital (Wiskott-Aldrich)organ transplant(cyclosporine)AIDSincreasing age

DNA repair defectsDNA repair defectsataxia telangiectasiaxeroderma pigmentosum

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Etiology of NHL

Chronic inflammation and antigenic stimulationChronic inflammation and antigenic stimulationHelicobacter pylori inflammation, stomachChlamydia psittaci inflammation, ocular tissuesSjögren’s syndrome

Viral causes-Viral causes-EBV and Burkitt’s lymphomaHTLV-I and T cell leukemia-lymphomaHTLV-V and cutaneous T cell lymphomaHepatitis C

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Clinical Features

LymphadenopathyLymphadenopathy CytopeniasCytopenias Systemic symptomsSystemic symptoms HepatosplenomegalyHepatosplenomegaly FeverFever Night sweatsNight sweats

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Clinical Features

Lymphadenopathy may fluctuate or spontaneously Lymphadenopathy may fluctuate or spontaneously remit, especially in low-grade lymphomas.remit, especially in low-grade lymphomas.

Body symptoms more common in high-grade Body symptoms more common in high-grade lymphomas.lymphomas.

Hematogenous spread of disease, with no Hematogenous spread of disease, with no predictable pattern.predictable pattern.

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Clinical Features Classic lymphoma: arises in Classic lymphoma: arises in

lymph node or bone marrow.lymph node or bone marrow. Extranodal primary more common in high-Extranodal primary more common in high-

grade lymphoma.grade lymphoma. Waldeyer’s ring involvement Waldeyer’s ring involvement

frequent in GI lymphomas.frequent in GI lymphomas.

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Diagnosis of NHL Chromosome changesChromosome changes

14;18 translocation in follicular lymphomabcl-2 oncogene

t(8;14), t(2;8), t(8;22) in Burkitt’s lymphoma c-myc oncogene

t(11;14) in mantle cell lymphomacyclin D1 gene

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Staging Workup

CBC, chemistries, urinalysisCBC, chemistries, urinalysis CT scans of chest, abdomen and pelvisCT scans of chest, abdomen and pelvis Bone marrow biopsy and aspirateBone marrow biopsy and aspirate (Lumbar puncture)(Lumbar puncture)

AIDS lymphomaT cell lymphoblastic lymphomaHigh grade lymphoma with positive marrow

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Treatment Options:Indolent lymphomas

10-15% in Stage I or II10-15% in Stage I or IIpotentially curablelocal radiotherapy

85-90% Stage III or IV85-90% Stage III or IVincurabletreatment does not prolong survival

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CHOP Chemotherapy

CCyclophosphamide (Cytoxan)yclophosphamide (Cytoxan) HHydroxydaunorubicin (Adriamycin)ydroxydaunorubicin (Adriamycin) OOncovin (vincristine)ncovin (vincristine) PPrednisonerednisone

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Burkitt’s Lymphoma

African variety: jaw tumor, strongly linked to Epstein-African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection.Barr Virus infection.

In U.S., about 50% EBV infection.In U.S., about 50% EBV infection. May present as abdominal mass.May present as abdominal mass. Most rapidly growing human tumor.Most rapidly growing human tumor. Typical chromosome abnormality: Typical chromosome abnormality: c-mycc-myc oncogene oncogene

linked to one of the immunoglobulin genes.linked to one of the immunoglobulin genes.

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Burkitt’s Lymphoma

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

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AIDS Lymphoma

Aggressive lymphomas of B cell origin.Aggressive lymphomas of B cell origin. Burkitt’s, Burkitt’s-like, and large cell Burkitt’s, Burkitt’s-like, and large cell

immunoblastic.immunoblastic. Treatment often limited by immune Treatment often limited by immune

compromise of the patient.compromise of the patient. Prognosis improved with HAART therapy.Prognosis improved with HAART therapy.

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MALT Lymphoma

MMucosa-ucosa-AAssociated ssociated LLymphoid ymphoid TTissueissue Chronic infection of the stomach by Chronic infection of the stomach by Helicobacter pylori.Helicobacter pylori. Localized to the stomach, indolent course.Localized to the stomach, indolent course. Can be cured in many cases by antibiotics against Can be cured in many cases by antibiotics against H. H.

pylori.pylori.

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Thomas HodgkinThomas Hodgkin

English pathologist, English pathologist, described the disease that bears his name in 1832.described the disease that bears his name in 1832.

Hodgkin’s DiseaseHodgkin’s Disease

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Hodgkin’s Disease

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

diagnosis.diagnosis.

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Reed-Sternberg Cell

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Epidemiology

In developed countries, bimodal distribution of In developed countries, bimodal distribution of patients.patients.young adulthoodafter age 50

More common in affluent families with few More common in affluent families with few siblings.siblings.

In developing countries, more common in young In developing countries, more common in young children.children.

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Signs and Symptoms

Lymph node enlargement, usually cervical or Lymph node enlargement, usually cervical or mediastinal.mediastinal.

Systemic “B” symptoms common.Systemic “B” symptoms common. Pel-Ebstein fever.Pel-Ebstein fever.

Relapsing, high-grade fever that can reach 105-106°F, periodicity of 7-10 days. Fever spikes abrupt in onset and resolution

Pain on drinking alcohol.Pain on drinking alcohol.

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Pel-Ebstein Fever

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Clinical Features

T cell mediated immune deficiency, even in early stage T cell mediated immune deficiency, even in early stage disease. Prone to infections:disease. Prone to infections:Herpes zoster (“shingles”) in one fourth of patientsFungal or mycobacterial infections

Immune defect may persist even after lymphoma is Immune defect may persist even after lymphoma is cured.cured.

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Clinical Features

Predictable contiguous spread of disease:Predictable contiguous spread of disease:cervical nodes to mediastinum or axillamediastinum to periaortic nodes or spleen,

etc. Basis for staging and treatment decisions.Basis for staging and treatment decisions.

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Diagnosis

Excisional biopsy of a lymph node.Excisional biopsy of a lymph node.

Fine needle aspirate is Fine needle aspirate is notnot sufficient to make the sufficient to make the diagnosis of Hodgkin’s disease.diagnosis of Hodgkin’s disease.

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Staging of Hodgkin’s Disease

Same as for non-Hodgkin’s:Same as for non-Hodgkin’s:

H + P, labs, CT scans, bone marrow biopsyH + P, labs, CT scans, bone marrow biopsy

PLUS:PLUS:

Gallium scanGallium scan Lymphangiogram or staging laparotomy ONLY if Lymphangiogram or staging laparotomy ONLY if

results would affect treatment decisionsresults would affect treatment decisions

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Treatment by Stage

Stage Therapy % Cure

IA XRT 95

IIA XRT 85

IB, IIB XRT (Total Nodal) 70

IIIA XRT 70

IIIB, IV Combination Chemo 50

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Chemotherapy Regimens

MOPPMOPP

Mechlorethamine, Oncovin, Procarbazine, Prednisone

ABVDABVD

Adriamycin, Bleomycin, Vinblastine, Dacarbazine

BEACOPPBEACOPP

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Treatment Options

Often, patients who relapse after radiotherapy can be Often, patients who relapse after radiotherapy can be cured by salvage chemotherapy.cured by salvage chemotherapy.

Combined chemotherapy and radiotherapy is given for Combined chemotherapy and radiotherapy is given for bulky mediastinal masses.bulky mediastinal masses.

Chemotherapy now being tested for earlier stages of the Chemotherapy now being tested for earlier stages of the disease.disease.

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Late Complications ofHodgkin’s Disease

High incidence of second malignanciesHigh incidence of second malignanciesleukemia first 10 years, solid tumors over time.

Leukemia in patients receiving alkylating agents or Leukemia in patients receiving alkylating agents or combined chemo/XRT.combined chemo/XRT.

Lung cancer and breast cancer in patients receiving XRT Lung cancer and breast cancer in patients receiving XRT to chest. Lung cancer especially high in smokers.to chest. Lung cancer especially high in smokers.

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Late Complications ofHodgkin’s Disease

Hypothyroidism after irradiation of the neck.Hypothyroidism after irradiation of the neck. Constrictive pericarditis after radiotherapy to the Constrictive pericarditis after radiotherapy to the

mediastinum.mediastinum. Infertility after use of alkylating agents.Infertility after use of alkylating agents. Heart failure after Adriamycin treatment.Heart failure after Adriamycin treatment.

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Multiple Myeloma

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Overview of Multiple Myeloma

Less common than non-Hodgkin’s lymphoma, more Less common than non-Hodgkin’s lymphoma, more deadly. deadly.

Average life expectancy 30 -36 months. Average life expectancy 30 -36 months. Some patients develop a very indolent form and live Some patients develop a very indolent form and live

for 10 years or more.for 10 years or more. Potentially curable with high dose chemotherapy (bone Potentially curable with high dose chemotherapy (bone

marrow or stem cell transplantation).marrow or stem cell transplantation).

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Overview of Multiple Myeloma

Disease of malignant B-lymphocytes.Disease of malignant B-lymphocytes. Little similarity to lymphoma in presentation, age at Little similarity to lymphoma in presentation, age at

diagnosis, treatment, or prognosis.diagnosis, treatment, or prognosis. Signs and symptoms of multiple myeloma are quite Signs and symptoms of multiple myeloma are quite

variable. variable. Approximately 20% of patients have no symptoms.Approximately 20% of patients have no symptoms.

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Etiology of Multiple Myeloma

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

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Multiple Myeloma

More than 15% plasma cells in the bone marrow.More than 15% plasma cells in the bone marrow. Monoclonal immunoglobulin peak on SPEP Monoclonal immunoglobulin peak on SPEP

more than 3 gm/dL. Presence of Bence Jones protein in urine.Presence of Bence Jones protein in urine. Decreased levels of normal immunoglobulins.Decreased levels of normal immunoglobulins.

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Clinical Features Bone marrow failureBone marrow failure

- Anemia, thrombocytopenia, neutropenia- Anemia, thrombocytopenia, neutropenia Renal failure Renal failure Bone disease with skeletal destructionBone disease with skeletal destruction

lytic lesionsgeneralized decrease in bone density

HypercalcemiaHypercalcemia

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Clinical Features Hyperviscosity syndromeHyperviscosity syndrome Recurrent infectionsRecurrent infections AmyloidosisAmyloidosis

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Diagnosis and Staging Workup

Bone marrow biopsy and aspirateBone marrow biopsy and aspirate Serum protein electrophoresis and immunofixationSerum protein electrophoresis and immunofixation Skeletal surveySkeletal survey

Plain x-rays are better than bone scan.Lytic lesions do not show up well on bone scan.

Quantitative immunoglobulinsQuantitative immunoglobulins

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Serum Protein Electrophoresis

Total protein 7.2 aTotal protein 7.2 a22 globulin 0.5 globulin 0.5 albumin 4.5albumin 4.5 b globulins 0.7 b globulins 0.7 aa11 globulin 0.15 g globulin 1.4 globulin 0.15 g globulin 1.4

Total protein 7.9 aTotal protein 7.9 a22 globulin 0.6 globulin 0.6albumin 3.9albumin 3.9 b globulins 0.7 b globulins 0.7aa11 globulin 0.19 globulin 0.19 g globulin 2.4 g globulin 2.4

Normal Monoclonal Spike

Alb. 1 2 Alb. Alb. 11 22

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http://140.251.5.102/Pathology_Images/http://wheeless.orthoweb.be/o6/129.htm

Lytic Bone Lesions in Multiple Myeloma

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Treatment of Multiple Myeloma

Standard ChemotherapyStandard Chemotherapy Melphalan and prednisoneMelphalan and prednisone VAD (vincristine, adriamycin, dexamethasone)VAD (vincristine, adriamycin, dexamethasone)

High Dose ChemotherapyHigh Dose Chemotherapy Bone marrow transplantBone marrow transplant Peripheral stem cell transplantPeripheral 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:Poor prognosis:

Age > 65Age > 65 High tumor massHigh tumor mass High High 2 microglobulin2 microglobulin Renal failure, hypercalcemiaRenal failure, hypercalcemia

Bleeding And Clotting Disorders B

BruisingClotting

Bleeding Bleeding DisordersDisorders HemophiliaHemophiliaVon Willebrand Disease (vWD)Von Willebrand Disease (vWD)

94

Vasoconstriction – Vasoconstriction – Platelet activationPlatelet activationHaemostatic plugHaemostatic plugCoagulationCoagulationStable clot formationStable clot formationClot dissolutionClot dissolution

Haemostasis:

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Stage 1: Release of platelet factors Stage 1: Release of platelet factors to initiate clottingto initiate clottingStage 2: Generation of Stage 2: Generation of Thromboplastin by other factorsThromboplastin by other factorsStage 3: Conversion of Stage 3: Conversion of prothrombin to thrombinprothrombin to thrombinStage 4: Formation of Stage 4: Formation of fibrin from fibrinogenfibrin from fibrinogen

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PT/INR Screens for abnormalities in the extrinsic and common Screens for abnormalities in the extrinsic and common pathways of coagulation pathways of coagulation

A typical normal range for the PT is between 10 and 13 A typical normal range for the PT is between 10 and 13 sec. sec.

An INR > 1.5 or a PT ≥ 3 sec longer than a laboratory's An INR > 1.5 or a PT ≥ 3 sec longer than a laboratory's normal control value is usually abnormal and requires normal control value is usually abnormal and requires further evaluation. further evaluation.

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PTT

Partial thromboplastin time (PTT) screens plasma for Partial thromboplastin time (PTT) screens plasma for abnormalities in factors of the intrinsic and common abnormalities in factors of the intrinsic and common pathways pathways

A normal range of 28 to 34 sec is typical. A normal range of 28 to 34 sec is typical. A normal result indicates that at least 30% of all coagulation A normal result indicates that at least 30% of all coagulation

factors in the pathway are present in the plasma factors in the pathway are present in the plasma Heparin prolongs the PTT, and the PTT is often used to Heparin prolongs the PTT, and the PTT is often used to

monitor heparinmonitor heparin

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Hemophilia Hemophilia :Affects 18,000 in USHemophilia :Affects 18,000 in US caused by deficiencies of either clotting factor caused by deficiencies of either clotting factor VIII or IXVIII or IX Hemophilia Hemophilia AA (factor (factor VIII VIII deficiency), which affects about 80% of deficiency), which affects about 80% of

hemophilic patients, and hemophilia hemophilic patients, and hemophilia BB (factor (factor IX IX deficiency) > 30% deficiency) > 30% normal valuenormal value

elevated elevated PTTPTT and and

normalnormal PT PT and and Normal platelet count; Normal platelet count; it is confirmed by specific factor assays 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 Most common bleeding disorder affects 1-2% (more common in women)women)

causes platelet dysfunction causes platelet dysfunction Screening coagulation tests reveal :Screening coagulation tests reveal : normal platelet count; normal platelet count; normal INRnormal INR; ;

Prolonged bleeding timeProlonged bleeding time; and, ; and, normal PTTnormal PTT Diagnosis is based on low levels of VWF antigen and abnormal Diagnosis is based on low levels of VWF antigen and abnormal

ristocetin cofactor activity.ristocetin cofactor activity.

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TYPES OF TREATMENT

Local TherapyLocal Therapy

PressurePressure

Cautery

Suturing

Topical Thrombin

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TYPES OF TREATMENTSystemic Pharmacological TherapySystemic Pharmacological Therapy

Antifibrinolytic agents

Tranexamic Acid: Cyklokapron

Epsilon amino caproic acid: Amicar

DDAVP: desmopressin

Hormone preparations: estrogens

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BLOOD COMPONENT THERAPYCryoprecipitate Cryoprecipitate

Factor VIII

VWF

Fibrinogen

Coagulation factor concentratesCoagulation factor concentrates

Factor VIII

Factor IX

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CONSIDERATIONS IN THE TX OF HEMOSTATIC PROBLEMS

Transmissible DiseasesTransmissible DiseasesHIV, Hepatitis A, B and C, Parvovirus, ??CJD

Coagulation Factor Concentrates

Donor screening

Viral inactivation

Donor pools

Plasma and cryoprecipitate

Bleeding And Clotting Disorders Bleeding

BClotting

Bruising Bruising DisordersDisorders HENCOH-SCHONLEIN PURPURA (HSP)HENCOH-SCHONLEIN PURPURA (HSP)Idiopathic Thrombocytopenic Purpura - ITPIdiopathic Thrombocytopenic Purpura - ITP

PURPURAS

HENCOH-SCHONLEIN PURPURA HENCOH-SCHONLEIN PURPURA (HSP)(HSP)

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Henoch Schonlein Purpura

Purpura on extensor surfaces of arms, legs, buttocksGI disturbancesGI disturbances

Renal involvement

Fever

Previous URIPrevious URI

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Epidemiology Incidence is 13.5-18/100000Incidence is 13.5-18/100000 Male to female 1.5:1Male to female 1.5:1 Can occur from 6 months- adulthoodCan occur from 6 months- adulthood

50% of cases are under 5 years of age Wide geographical distributionWide geographical distribution More common in winter and springMore common in winter and spring Upper Respiratory infections may precedeUpper Respiratory infections may precede Genetics play a small role Genetics play a small role

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Clinical Presentation

Classic Triad of symptoms is the most common Classic Triad of symptoms is the most common presentationpresentationPurpuraColicky abdominal painarthritis

50% of children may present with symptoms other than 50% of children may present with symptoms other than purpurapurpura

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Dermatologic

Younger children- Younger children-

urticariaurticaria

edema of- the feet, dorsum of the edema of- the feet, dorsum of the hands, face and hands, face and scalp.scalp.

New crops can present for up to three New crops can present for up to three months or months or longerlonger

Erythema nodosum Erythema nodosum Blistering lesionsBlistering lesions

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Natural History for HSP without Nephritis

Self limited illness.Self limited illness. No treatment is required for the purpuraNo treatment is required for the purpura NSAIDs are used to treat arthralgiasNSAIDs are used to treat arthralgias

Steroids are not beneficial

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Bleeding conditions: Clinical Features

1.1. Local - Vs - General, spontaneous . .Local - Vs - General, spontaneous . .2.2. Hematoma & Joint bleed - Hematoma & Joint bleed - CoagulationCoagulation3.3. Skin/Mucosal Petechiae & Purpura – Skin/Mucosal Petechiae & Purpura – PLTPLT4.4. wound / surgical bleeding – wound / surgical bleeding – Immediate - (PLT)Immediate - (PLT) Delayed - (Coagulation)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)Young female – 20-35y (15-50)Easy bruising, Petechiae, menorrhagiaEasy bruising, Petechiae, menorrhagiaAnti PLT Antibody (IgG) – destruction of pltAnti PLT Antibody (IgG) – destruction of pltLow Platelet number.Low Platelet number.

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Disorders of platelets Decreased Number:ThrombocytopeniaDecreased Number:Thrombocytopenia

Decreased ProductionDecreased Survival – Immune (ITP)Increased utilization - DIC

Defective Platelet function:Defective Platelet function:Acquired – Drugs – Aspirin, MPS, MDSCongenital – Eg. Thrombasthenia.

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 HaemorrhageLow PLT

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Dengue – Hemorrhagic fever PLATELETS