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Pathophysiology of the diseases of the blood:Pathophysiology of the diseases of the blood:

Anemias and haemorhagic Anemias and haemorhagic ggdiathesesdiatheses

Blagoi Marinov MD PhDBlagoi Marinov MD PhDBlagoi Marinov, MD, PhDBlagoi Marinov, MD, PhD

Pathophysiology DepartmentPathophysiology Department

Medical University of PlovdivMedical University of Plovdiv

Haemopietic system

Blood production

Blood wasting

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Haemopoiesis Haemopoiesis

Blood Blood -- structure structure

4-5 L

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Characteristics of normal Characteristics of normal ErEr

Highly elastic bi concave discsHighly elastic bi concave discs ((55..10101212))..

Without nucleus and mitochondriaWithout nucleus and mitochondria(anaerobic metabolism).(anaerobic metabolism).

Contain large quantities of enzyme carbonic Contain large quantities of enzyme carbonic h dh danhydraseanhydrase

Lifecycle ~ 120 days.Lifecycle ~ 120 days.

Structure and function of Structure and function of HbHb

90% of the protein content of Ers is haemoglobin.90% of the protein content of Ers is haemoglobin.

•• transportstransports OO22 and part of the COand part of the CO22..•• represents mighty buffer systemrepresents mighty buffer system

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DefinitionDefinition

AnemiasAnemias are diseases of the blood having less are diseases of the blood having less than the normal number of red blood cells or less than the normal number of red blood cells or less than the normal quantity of hemoglobin in the than the normal quantity of hemoglobin in the blood. The oxygenblood. The oxygen--carrying capacity of the blood carrying capacity of the blood is, therefore, substantially decreased.is, therefore, substantially decreased.

ClassificationsClassifications

ClinicalClinical ClinicalClinical AcuteAcute SubacuteSubacute ChronicChronic

Erythrocytes morphologyErythrocytes morphology MicrocyticMicrocytic MacrocyticMacrocytic ((megaloblasticmegaloblastic)) SpherocyticSpherocytic

HaemoglobinHaemoglobin contentcontent HypochromicHypochromic HyperchromicHyperchromic

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PathogeneticPathogenetic classification classification of of anemiasanemias

HaemorrhagicHaemorrhagic anemiasanemiasHaemorrhagicHaemorrhagic anemiasanemias

Impaired Impaired erythroproductionerythroproduction((depressed erythropoiesisdepressed erythropoiesis))

IncreasedIncreased erythrodestructionerythrodestruction((pathologic pathologic haemolysishaemolysis))

Lab tests to consider in Lab tests to consider in anemic statesanemic states

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Hemorrhagic anemiasHemorrhagic anemias

HAEMORRHAGE SpeedQuantity HAEMORRHAGE pQ y

Hemodilution S

ANEMIA Time

Hb , Ers , Hct

Hyperkinetic circulation

Activated erythropoiesisC

OM

PEN

SATI

ON

S

Anemias due to impaired Anemias due to impaired erythroproductionerythroproduction

Impaired synthesis of haemoglobinImpaired synthesis of haemoglobin Impaired synthesis of haemoglobinImpaired synthesis of haemoglobinFeFe deficitdeficit

Altered DNA synthesisAltered DNA synthesisBB1212 defectdefectFolate deficitFolate deficit

HH dd l ti il ti i HypoHypo-- andand aplastic anemiasaplastic anemiasIdiopaticIdiopatic (ЕРО(ЕРО** insensitiveinsensitive))Erythropoietin deficitErythropoietin deficit

**ЕРОЕРО -- ErythropoietinErythropoietin

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Iron metabolismIron metabolism

FeFe--deficient anemias deficient anemias --etiologyetiology

Chronic haemorrhagesChronic haemorrhages Chronic haemorrhagesChronic haemorrhages Increased physiologic requirementsIncreased physiologic requirements Decreased FeDecreased Fe--uptakeuptake Altered FeAltered Fe--transformationtransformation

Decreased FeDecreased Fe absorptionabsorption Decreased FeDecreased Fe--absorptionabsorption Improper FeImproper Fe--transport to hemopoietic transport to hemopoietic

organsorgans

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FeFe--deficient anemias deficient anemias --etiologyetiology

Stages

of Fe deficiency

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FeFe--deficient anemias deficient anemias --pathogenesispathogenesis

Decrease of the Fe stores in the organismDecrease of the Fe stores in the organismDecrease of the Fe stores in the organismDecrease of the Fe stores in the organism Prelatent FePrelatent Fe--deficitdeficit

FeritinFeritin Intestinal absorptionIntestinal absorption

Latent FeLatent Fe--deficitdeficit SerumSerum Fe Fe FeritinFeritin total iron binding capability (TIBC) total iron binding capability (TIBC)

Manifest FeManifest Fe--deficient anemiadeficient anemia Ers Ers ; Hb ; Hb ; MCV ; MCV ; ;

FeFe--deficient anemia :deficient anemia :Ers morphologyErs morphology

Fe-deficient anemia is microcytic and hypochromic !!!

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FeFe--deficient anemias deficient anemias --signs and symptomssigns and symptoms

Megaloblastic anemia Megaloblastic anemia --etiologyetiology

Autosomal recessive inheritance

Genetic predispositionGenetic predisposition –– HLAHLA--A3, A3, HLAHLA--B7B7

Autosomal-recessive inheritance (Addison-Biermer anemia)

Auto AB againstAuto AB against:: Parietal cells in the gastric mucosaParietal cells in the gastric mucosa

GastromucoproteinGastromucoprotein

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Vit BVit B1212 metabolismmetabolism

Megaloblastic anemia Megaloblastic anemia -- pathogenesispathogenesis

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Erythrocyte profile in Erythrocyte profile in megaloblastic anemiamegaloblastic anemia

Anisocytosis poikilocytosis Macrocytes Ovalocytes Howell-Jolly bodies

Megaloblastic anemia Megaloblastic anemia ––signs and syptomssigns and syptoms

GI symptoms – Hunter glossitis

Subacute combined degeneration of spinal cord, due to demyelination secondary to deficiency of vitamin B12.

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SecondarySecondary mmegaloblastic egaloblastic anemiaanemiass

Primary liver diseasePrimary liver disease

Surgical interventions on the stomach Surgical interventions on the stomach and intestinesand intestines

Neoplastic processesNeoplastic processes

Parasitic diseasesParasitic diseases

MedicationsMedications ((cytostatics, cytostatics, immunosuppressors, antiepilepticsimmunosuppressors, antiepileptics))

Hypo- and aplastic anemias

Pluripotentstem cell

Radiation

Cytostatics

A ibi i

Replicationdefects

StimulatoryIL 1Antibiotics

Antithyroid drugs

Benzol derivatives

Viral infections

Metastases

Genetic defects

Stimulatorydefficit

Inhibitory effect

T-suppressormechanism

Apoptosismechanism

IL - 1

IL - 6

IL - 3

STEMCELLS

Leukopoesis Erythropoesis

Thrombopoesis

Bone marrow insufficiency (PANCYTOPENIA)

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Anemias due to iAnemias due to increased ncreased erythrodestructionerythrodestruction

InbornInborn ((inheritedinherited))InbornInborn ((inheritedinherited))Disorders in the structure of Er membraneDisorders in the structure of Er membraneDisorders in Ers enzymatic contentDisorders in Ers enzymatic contentDisorders in the synthesis of the globin moleculeDisorders in the synthesis of the globin molecule

HaemoglobinosesHaemoglobinoses ThalassemiasThalassemias

AcquiredAcquiredImmunologic mechanismsImmunologic mechanisms

IsoimmuneIsoimmune Drug inducedDrug induced ((haptenshaptens)) AutoimmuneAutoimmune

SymptomaticSymptomatic ((secondarysecondary) )

Anemias due to disorders in Anemias due to disorders in the structure of Er membranethe structure of Er membrane

Microspherocytosis (M Minkowski Chauffard)

Quantitative and qualitative changes of Quantitative and qualitative changes of membrane protein membrane protein spectrin spectrin ((autosomal dominant trait)

Disturbance in ATP metabolismDisturbance in ATP metabolism

Decreased activity of the enzyme Decreased activity of the enzyme proteinkinaseproteinkinase

Microspherocytosis (M. Minkowski-Chauffard)

Spectrin deficit

Increased permeability

Shortened life cycle

Haemolytic anemia

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Anemias due to dAnemias due to disorders in isorders in Ers enzymatic contentErs enzymatic content

GlucoseGlucose--66--phosphate dehydrogenase phosphate dehydrogenase deficient anemiadeficient anemiaSex-linked recessive inheritance.The most common enzymopathyThe most common enzymopathy

Pyruvatekinase deficient anemiaPyruvatekinase deficient anemiaAutosomalAutosomal--recessive inheritancerecessive inheritance

Anomalies in Ers enzymesAnomalies in Ers enzymes

Anomalies of erythrocytic enzymes

Defect in PK

Glutation Reductase

Defect in G6PDH

??

NADP H2

Defect in PK

Glycolysis

NAD H2

ATP

Glutation Oxydase

Erythrocytic Reductases

Broad Beans Medicaments

Glutation SH

Hb-Fe 2+

Glutation S-S

Hb-Fe 3+

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G6PD

Genetic defectsGenetic defects Deficit of Deficit of G6PD Impaired glutathione synthesisImpaired glutathione synthesis Oxygen stressOxygen stressygyg Denaturation of hemoglobinDenaturation of hemoglobin Hemolysis of Ers with enzyme defectsHemolysis of Ers with enzyme defects

ThalassemiasThalassemias

Beta thalassemiasBeta thalassemias Beta thalassemiasBeta thalassemiasHomozygotic formHomozygotic form ((--thalassemia mayor, thalassemia mayor,

Morbus Cooley)Morbus Cooley)Heterozygotic forms (Heterozygotic forms (--thalassemia minor)thalassemia minor)

Alpha thalassemiasAlpha thalassemiasHomozygotic formHomozygotic formHeterozygotic formsHeterozygotic forms

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Thalassemia mayor Thalassemia mayor (M. Cooley)(M. Cooley)

Abnormally high quantity of Hb FAbnormally high quantity of Hb F and and Hb AHb A2 2 is synthesisedis synthesised

Due to deficit or inappropriate Due to deficit or inappropriate synthesis of synthesis of --chains in Ers there is an chains in Ers there is an excess of uncoupledexcess of uncoupled --chainschainsexcess of uncoupled excess of uncoupled chainschains

The uncoupled The uncoupled --chains precipitatechains precipitate The permeability of Ers is increasedThe permeability of Ers is increased HemolysisHemolysis

Sickle cell anemiaSickle cell anemia

I i d h i th i ith f ti fImpaired -chain synthesis, with formation ofpathologic haemoglobin S

Hardly soluble in liquids

homozygote

OXY-state DEOXY- state

Haemoglobin crystals in hypoxic environment

heterozygote

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Sickle cell anemia Sickle cell anemia --distributiondistribution

Hemolytic disease of the Hemolytic disease of the newbornnewborn

Isoimmune conflict between the mother and the foetus due to antigen incompatibility in Rh or АВО systems

Rh - mother Rh+ foetus

Incompleteanti-Rh АB

HEMOLYSIS

FORMSFORMS Hemolytic disease of the newbornHemolytic disease of the newborn Icterus gravisIcterus gravis Foetoplacentar anasarcaFoetoplacentar anasarca Nuclear icterus (Kernicterus)Nuclear icterus (Kernicterus)

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Acquired autoimmune Acquired autoimmune anemiasanemias

Types of antibodiesTypes of antibodies

I l t h t l ti iI l t h t l ti i

Autoimmune conflict between specific AB and body’s own unchanged erythrocyte antigens

Incomplete heat agglutininsIncomplete heat agglutinins

Heat hemolysisnsHeat hemolysisns

Complete cold agglutininsComplete cold agglutinins

BiBi--phase hemolysinsphase hemolysins

Bone marow transplantationBone marow transplantation

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Hemorrhagic diatheses

IntrinsicPathway

ExtrinsicPathway

CommonPathway

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Hemorrhagic diatheses

Coagulation abnormalities Coagulation abnormalities

Quantitative and qualitative platlet abnormalities (thrombocitopenias & thrombocitopathias)thrombocitopathias)

Damage to the vascular wall(vasopathies)

Hemophilia

Disorder of hemostasis a coagulopathy Disorder of hemostasis, a coagulopathy Hemophilia A - Factor VIII deficiency Hemophilia B – Factor IX deficiency

Hemophilia C – Factor XI, XII

Prevalence: 13.4 cases per 100,000 males Incidence: 1 in 5032 live male births

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Queen Victoria

How do you get it? Hemophilia is a genetic disease and is passed on by the X

chromosome (the chromosome that carries the clotting factor)chromosome (the chromosome that carries the clotting factor). If a boy gets the X chromosome that carries the hemophilia

gene he will become a hemophiliac. If a girl get the gene, she will become the carrier of the gene,

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Severity of Factor Deficiencies

Severe: <1% Severe: <1%– Hemarthrosis with minimal trauma or ADLs

Moderate: 1 to 5%– Intermediate symptoms with fewer

hemarthroses

Mild: >5% Mild: >5%– Joint bleeds rarely develop except with

significant trauma

Hemophilic Arthropathy

As blood is catabolized it is absorbed by As blood is catabolized, it is absorbed by synovium

Iron is toxic to cells – synovial cells disintegrate releasing lysosomes which destroy cartilage and inflame synovium

Chondrocytes also affected

FIBROSIS

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1/3 of all Hospital Hematology Consults are1/3 of all Hospital Hematology Consults are

Thrombocitopenia

1/3 of all Hospital Hematology Consults are 1/3 of all Hospital Hematology Consults are for thrombocytopeniafor thrombocytopenia

5 to 10% of all hospitalized patients are 5 to 10% of all hospitalized patients are thrombocytopenic in the ICU the number thrombocytopenic in the ICU the number increases to 35%increases to 35%increases to 35%increases to 35%

Thrombocytopenic patients in the hospital Thrombocytopenic patients in the hospital suffer a twofold greater mortality rate than suffer a twofold greater mortality rate than those who are notthose who are not

Echymoses

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Platelet count Symptoms

Thrombocytopenia

Platelet count Symptoms

50-100,000 Prolonged bleeding following trauma

< 50,000 Easy bruisingPurpura following minor traumap g

< 20,000 Spontaneous bleedingPetechiaeMay suffer spontaneous internal and intracranial bleeding

Mechanisms of Thrombocytopenia

Decreased platelet production Decreased platelet production Increased platelet destruction Dilutional Thrombocytopenia Splenomegaly or splenic sequestration

Pseudothrombocytopenia Pseudothrombocytopenia

The primary reason for evaluating thrombocytopenia is to assess the The primary reason for evaluating thrombocytopenia is to assess the risk of bleeding and assess the presence of underlying disordersrisk of bleeding and assess the presence of underlying disorders

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Decreased Platelet Production

Factors causing bone marrow suppression Factors causing bone marrow suppression or damage

Viral illness HIV (direct damage to Megakaryocytes) Chemo- or radiation therapy Congenital or acquired bone marrow aplasia

or hypoplasia Vit. B12 or Folate deficiency

Increased Platelet Destruction

Idiopathic (Immune) Thrombocytopenic Purpura

Alloimmune destruction—Posttransfusion, Post-transplantation

Disseminated Intravascular Coagulation Disseminated Intravascular Coagulation Thrombotic Thrombocytopenic Purpura Antiphospholipid Antibody Syndrome Certain drugs—Heparin, quinidine, valproate

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Splenic Sequestration

Normally ~1/3 of platelets are sequestered Normally, 1/3 of platelets are sequestered in the spleen in any given time

In extreme splenomegaly, up to 90% of platelets can be trapped in the spleen

Cirrhosis, Portal HTN, splenomegaly can all present with apparent thrombocytopenia, although these pts are not usually at risk for clinical bleeding

Qualitative platelet disorders -thrombocytopathy

Hereditary Aquired

Glanzmann Drugs (aspirin)Thrombasthenia

Bernard Soulier disease

Plt granules deficiency

Inhibitors (Ab)

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Vasopathias

Schönlein-Henoch Purpura Schönlein-Henoch Purpura

Sympthomatic hemorrhagic vasculites Krimean hemorrhagic fever Measels

Hereditary vasopathias Rendu-Osler-Weber

Schönlein-Henoch Purpura anaphylactoid purpura

Schönlein-Henoch Purpura is a common vasculitis with cutaneous and systemic complications.

The usual location of the acute small vessel damage is primarily in the skin GI tract anddamage is primarily in the skin, GI tract, and kidneys

It is the most common cause of nonthrombocytopenic purpura in children.

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History

First described in 1801 by William Heberden, y ,a physician in London, who wrote about a case of a 5 year old boy with hematuria, abdominal pain, joint pains and a skin rash.

In 1837, Johann Schönlein and later in 1874, Edouard Henoch described multiple case reports of similar cases. They also showed an association of an upper respiratory infection preceding development of symptoms.

Pathogenesis

Likely mechanism thought to be an immune- Likely mechanism thought to be an immunecomplex mediated disease with deposits in the glomerular capillaries, dermal capillaries and GI tract.

Mesangial deposits of IgA are the same as Mesangial deposits of IgA are the same as those seen in IgA nephropathy

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Epidemiology

More frequent in children than adults, with More frequent in children than adults, with most cases occurring between 2 and 8 yr of age,

Most frequently in the winter months. The overall incidence is estimated to be

9/100 000 population9/100,000 population. Males are affected twice as frequently as

females.

Rash (95-100%) especially involving the

Clinical manifestations

Rash (95 100%), especially involving the legs, may not be present on initial presentation

Subcutaneous edema (20-50%) Abdominal pain and vomiting (85%)

Joint pain (60 80%) especiall in ol ing the Joint pain (60-80%), especially involving the knees and ankles

Scrotal edema (2-35%) Bloody stools

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Clinical Presentation

Petechiae Petechiae Purpura Ecchymoses

Arthritis

Present in more than ⅔ of children with HSP,

Is usually localized to the knees and ankles and appears to be concomitant with edema.

The effusions are serous, not hemorrhagic,

Resolve after a few days without residual deformity or Resolve after a few days without residual deformity or articular damage.

They may recur during a subsequent reactive phase of the disease.

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Gastrointestinal tract

Intermittent abdominal pain that is often colicky in tnature.

There may be peritoneal exudate, enlarged mesenteric lymph nodes, segmental edema, and hemorrhage into the bowel.

More than half of patients have occult heme-positive stools,

Diarrhea (with or without visible blood) or hematemesis Diarrhea (with or without visible blood), or hematemesis. Complete bowel obstruction or infarction with bowel

perforation.

Renal involvement

occurs in 25-50% of children

may manifest with: hematuria, proteinuria, or both; nephritis or nephrosis; acute renal failure acute renal failure.

Renal involvement at presentation may lead to chronic hypertension or end-stage renal disease in the future

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The ENDThe END

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