Hematopoetic & lymphoid system

anemia -> low RBC mass

polycythemia -> high rbc mass

reduction in o2 transprting capacity

trigger increase of epo production

=> compensatory hyperplasia of erythroid precursors in the bone marrow

rise in BM output

appearance of extrs medullary hematopoiesis

from proerythroblast to reticulocyte (still has RNA) -> released into circulation and mature to RBC

• Pallor

• Tiredness

• Lassitude

• Fatique

• Headaches,dizzines

• Weakness

• Shortnessofbreath

• Somethimes angina pectoris or heartburn

• Blood loss? can also be menstruation

• Decreased production?

• nutrients/BM infiltration/dysplasia

• Increased destruction?

• intra/extravascular

• intra/extracorpuscular

inflammation and bleeding

jaundice

neurological disorders

Normally haemoglobin content in erythrocyte is 0,8-1,05. This index is named color index (CI).

hyperchromic - CI > 1,05 ( B12 and pholate-deficiency)

hypochromic - CI < 0,8 (iron deficiency)

normochromic - CI is normal (inherited haemolytic anaemias)

Normally reticulocytes constitute 0.5 to 1.5% of the RBC.

regenerative - normal reticuloctes count (most of anemias)

hyporegenerative - reticuloctes <0.5 (chronic posthemorrhagic)

non-regenerative anemia - reticulocytes are absent (bone marrow aplasia)

hyperregenerative - reticulocytes >1,5 (inherited hemolytic anemias)

bone marrow respondes and releases reticulocytes

inadequate respond of bone marrow

microcytic anemia (iron)

normocytic anemia (anemia of chronic disease)

macrocytic anemia (B12)

Haemolytic anemia

I. Anemia of blood loss

A. Acute bleeding (hemorrhage)

• •

loss of intravascular volume (cardiovascular colapse, hypovolemic shock – loss exceeds 20%)hemodilution within 2-3 days normocytic, normochromic anemia low E, Hg, Htc high Rtc-> good sign

B. Cronic blood loss

n

sideropenic anemia (storage are gradually

depleted) -> iron related

• Diverse group of disorders that have as a common feature accelerated red cell destruction (hemolysis)

• Hallmark: erythroid hyperplasia

reticulocytosis exstramedullary hematopoiesis

• low erythrocytes

• high EPO

• high RTC

• hyperbiliruninemia -> unconjugated jaundice

• high gallstones

• hemosiderosis

• splenomegalie

1. low haptoglobin

2. Hemoglobinemia

3. Hemoglobinuria

4. Hemosiderinuria

5. Methemalbuminemia

• inherited defects in red cell membrane sceleton that lead to the formation of spherosytes

• Highly vulnerable to sequestration and destruction in the spleen

• Dark red cells

• Lack central pallor

• Reticulocytosis

• Osmotic fragility test

• Hypercelular BM

  
  

AR

mutation in Beta-globin -HgS

hypoxia, hypercapnia, hypertermia

vasooclusive crisis

AR

mutation in globin genens -> decreased synthesis of beta or alpha globin

hypochromic, microcytic anemia

mainly point mutaion

– homozygous - thallasemia major • severe anemia, regular blood transfusions

– heterozygous - thallasemia minor • asymptomatic with mild or absent anemia

• T. major manifests postnatally

– Growth retardation

– Sceletal deformities

– blood transfusion (systemic Fe overload)

– Secundary hemosiderosis and hemochromatosis

• Fatal in 2nd or 3th decade of life

mainly caused by deletion

Severity of the disease is proportional to the number of deleted alpha genes

• 4 genes: fetal hydrops, letal in utero

• 1 gene: silent carrier state

transient episodes of intravascular hemolysis

• oxydative injury:

– oxidants are normally inactivated by reduced glutathione (GSH)

– impaired regeneration of GSH in G6PD-deficient cells

– hydrogen peroxid accumulation – Hg denaturation - Heinz

bodies

X-linked

aquired mut. in PIGA gene

X-linked in erarly hematopoetic progenitor

thrombosis as complication

I Antibody-mediated hemolitic anemia

1. Autoantibodies

• Warm antibody type

• Cold antibody type

  2. Isohemagglutinins

• Transfusion reaction

• Rh disease of the newborn

  II  Infections, toxins

  • malaria • snakebite

• III  Mechanical trauma to red cells

  • Microangiopathic hemolytic anemia (DIC, SLE, TTP, HUS,

  • Defective cardiac valve prostheses

  • Splenomagalia

  • Marathon racing, bongo drumming...

1. IgG: active at 37C

2. Erythrophagocytosis,spherocytes

1. Idiopathic (> 60%)

2. Secundary: CLL, SLE, drugs

3. Moderate splemomegaly

4. Chronic mild anemia

1. Low affinity IgM Below 30C

   2. limphoid neoplasms, mycoplazma infection, IM

   3. Distal parts of the body

   4. E +IgM+ complement– extravascular hemolysis (liver, spleen)

   5. Raynaud phenomenon

• Nutritional deficiency of iron

• Pathogenesis:

– Low intake, poor bioavailability (vegetarian diets)

– Malapsorption

– Chronic blood loss

– Increase demands (pregnancy, infancy)

causes

1. chronic inflammatory disease

   • infection s(TBC)

   • noninfectious (RA;SLE)

2. Malignant disease

Pathogenesis-

• Key regulatory protein - hepcidin which is produced by liver

> High levels of production are encouraged by pro- inflammatory cytokines. especiallyI L -6 .

• Hepcidin binds to ferroportin on the membrane of iron exporting cells, and thereby inhibiting the export of iron from these cells into the blood

Iron remain trapped inside the cells in the form of ferritin, levels of which are therefore normal or high in the tace ot significant anemia

• Stems from metabolic defects that lead to inadequate biosyntesis of thimidine

• Folic acid and B12 : essential factors

• Abnormalities in rapidly dividing cells

• Maturation derangement, apoptosis

• Ineffective hematopoiesis

• Onset - insidious/ gradually progressive sign and symptoms of anemia

• Mildly jaundice- excess breakdown of hb due to increase ineffective erythropoiesis

• Glossitis, angular stomatitis, mild symptoms of malabsorption with loss of weight

• Neuropathy (severe B12 deficiency)

• Neural tube defect in fetus (eg: encephaly, spina bifida)

• Increased melanin pigmentation

Disorder of multipotent myeloid stem cells

BM failure with pancytopenia

• Exposures to toxins and radiation

• Reactions to drugs and viruses

• Inherited defects in telomerase and DNA repair

Anemia is caused extensive infiltration of the BM

1. Metastatic carcinoma (lung, breast, prostate)

2. Granulomatous disease

3. Lipid-storage disease

4. Osteopetrosis

5. MF

high levels of erythrocytes

• relative: Reduced plasma volume (hemoconcentration)

• absolute

  • primary: - abnormal proliferation of myeloid stem cells (PV) - inherited activating mutations in the

    erythropoietin receptor

  • secondary: (increased erythropoietin levels)

    – Adaptive: lung disease, cyanotic heart disease...

    – Paraneoplastic: erythropoietin secretingtumors(RCC,HCC...)

• Complication of a wide variety of disorders

• Caused by the systemic activation of coagulation

• Results in the formation of thrombi throughout the microcirculation

• obstetric complications

• tissue injury

• infections

• neoplasm

• miscellaneous

• Isolated thrombocytopenia: – bleeding tendency – normal coagulation tests

– pts counts 20.000-50.000: increased risk of posttraumatic bleeding

– below 5000: risk of spontaneous bleeding

• Autosomal dominant disorder caused by mutations in vWF

• large protein that promotes the adhesion of platelets to subendothelial collagen

• typically causes a mild to moderate bleeding disorder resembling that associated with thrombocytopenia

• X-linked recessive disorder caused by reduced factor VIII activity

• Mean corpuscular volume (MCV): average volume of a red blood cell

• Mean corpuscular hemoglobin (MCH): average content (mass) of hemoglobin per cell

• Mean corpuscular hemoglobin concentra>on (MCHC): average concentra>on of hemoglobin in a given

  volume of packed erythrocytes

• Red cell distribu>on width (RDW): coeecient of varia>on of red blood cell volume and a measure of

  anisocytosis

 Lymphopenia (immunodeficiency disease, HIV, corticosteroids)

 Neutropenia/agranulocytosis  reduction in the number of granulocytes in blood  risk of fatal bacterial and fungal infection (< 500 cells/μL)

The underlying mechanisms:

1. decreased granulocyte production

    BM hypoplasia, leukemia, BM infiltration

2. increased granulocyte destruction

    immune-mediated injury, infections, splenomegaly

 Depend on the underlying cause

 compensatory hypercellularity

 decreased numbers of granulocytic precursors (e.g. drug exposure)

 reduced all lineages

•  Infections: take the form of ulcerating, necrotizing lesions of the gingiva, floor of the mouth, bucall mucosa

•  Agranulocytic angina

•  Systemic symptoms

•  Sepsis

•  Th: granulocyte colony-stimulating factor (G-CSF)

acute bacterial infections, sterile inflammation

allergic disorders, parasite infestation, drug reaction, MH

Myeloproliferative neoplasm

chronic infections, SLE

viral infections, chronic immunologic stimulation

• EBV

• asymptomatic unfections in children

• symptomatic infections in adults

• fever, sore throat

• generalysed lymphadenitis

•  direct oral contact

•  infection of B cells (3tonsills and adenoids): lytic and latent

  
  

•  host T cell response (CD8 T cells – atypic ly) – controles the proliferation of EBV- infected B cells

• IgM Ab

•  shift to IgG Ab (persist for life)

•  impaired T cell immunity: high risk to EBV-driven B cell proliferation

 lymph node enlargement

 any immune response againts foreign Ag , metastasis, lymphomas

 Infections (acute, chronic)

Isolated to a group of nodes draining a local infection Generalized: systemic infections, inf lammatory conditions

LN: swollen, grey-red, engorged, painful Abscess formation: tender, fluctuant ln Overlying skin: red, draining sinuses

large germinal centers

scarring

microorganisms

immunodeficiency

Autoimmune disease

Foreign bodies

tumors

follicular hyperplasia

paracortical hyperplasia

sinus histiocytosis

• occures with activation of B cells -> germinal center

• RA, toxoplasmosis, early HIV

• DIF. DG.: FOLLICULAR LYMPHOMA

Distension and prominence of the lymphatic sinusoids

Infiltrate of macrophages (histiocytes)

Hypertrophy of lining endothelial cells

lymph nodes draining cancers

•  Immune reaction involving the T cell region

  
  

•  activated parafollicular T cells transform into large

  proliferative immunoblasts

• Viral infection (EBV), drugs, vaccinations (smallpox)

• Self-limited lymphadenitis

• Bartonella hensellae

• Disease of childhood (90%)

• skin lesion

• lymph node enlagemnet (axilla,neck)

• Iregular stellate necrotizing granulomas

 proinf lammatory exposures

trigger activation of macrophages throughout the body

•   inherited defects

•   killer Ly (CD8, NK) – unable to kill theit targets (virus infected cells)

•   excessive release of cytokines that activates macrophages

•   Systemic inf lammatory response sy (SIRS)

• BM: macrophages phagocytosing E, plt, and nucleated cells

   High ferritin level

•  BM transplantation

• fever

• splenomegaly

• Pancytopenia

• leukemias

• lymphomas

• hodgkin

• nonhogkin

•   Accumulation of immature, nonfunctional lymphoblasts:

  pre-B or pre-T cell

•   Childhood leukemias :

  85% B-ALLs (peaks of incidence at age of 3) 90% of childs prognosis very good

•   Adolescents: T -ALLs (as a thymic LL/ALLs)

•   Immunophenotype: TdT+(>95%)

•   Aggressive disease

•   Symptomes related to depression

  of marrow function

•   Mass effects caused by neoplastic infiltration

   Central nervous system manifestation (meningeal spread)

 Aggressive chemotherapy

 95% children obtain a remission

 Factors associated with a worse prognosis:

 age younger then 2 ys (MLL)

 presentation in adolescence or adulthood

 PB count > 100.000

 The most common leukemia of adults in the Western world

 Peripheral blood involvement (dif.dg. CLL vs SLL) PB >5000 cells/μL - CLL

 very very Indolent, slowly growing tumor

 Increased tumor cell survival (bcl2)

 CLL causes immune dysregulation  Accumulation of CLL/SLL cells suppress normal B cell function   At (hypogammaglobulinemia)  15% develops autoAt againts E and Plt

 Immunophenotype: + CD5, CD20

•   Constitutes 40% of the adult NHLs

•   older than 50 ys(males/females)

•   Painless, generalized

  lymphadenopathy

•   BM involved 80%

•   LN: nodular proliferation

•   > 50 ys, males

•   median survival 4-6 ys

•   cells resembling the naive B cells in the mantle zones

•   fatique, lymphadenopathy

•   manifests with advanced disease involving LN (diffuse or nodular pattern), BM and extranodal sites (GIT)

•   t(11,14): fuses cyclin D1 gene to the IgH lokus

•   Indolent B tumor

•   stomach, salivary glands, small and large bowel, lungs, breast, orbit (sustained by chronic inflammation)

•   clonal epithelial infiltration

•   small aggregates: lymphoepithelial

  lesions

•   Th: excision followed by RTh

 the most common type of lymphoma in adults

 any age (median 60 ys), 15% childhood lymphomas

 1/3 bcl-6 rearrangement, 1/3 t(14,18; bcl-2), MYC gene translocation

 de novo/Rihter

 Rapidly enlarging mass at one or several sites

 Extranodal presentation is common O

 Liver, spleen, BM – rare

• EBV-assoiated diffuse large B cell lymphomas -> AIDS iatrogenic immunosuperssion

• Mediastinal large b cell lymphoma -> young women, spred to CNS and abdominal viscera

• Primary effusion lymphoa -> HV8, pleural cavity, pericardium, peritoneum

 Fastest growing human tumor

 Children, young adults

Extranodal sites

 Leukemic presentation

 Endemic (maxillary or mandibullary masses)

 Sporadic (abdominal tumors: bowel, retroperitoneum, ovaries)  Immunodefficiency related (AIDS)

 Neoplastic plasma cells that secrete a monoclonal Ig or Ig fragment

 Monoclonal immunoglobulin – M protein

 Bence-Jones proteinuria – light chains

 Multiple myeloma

 Solitary plasmacytoma

 Smoldering myeloma #

 MGUS

 Primary amyloidosis

 Walderstrom macroglobulinemia

One of the most common lymphoid malignancy

Median age 70 ys, males, median survival 4 to 7 ys

Multifocal destructive skeletal lesions

 > 30% plasma cells in BM

Pathologic fractures

Hypercalcemia, metastatic calcification

Electrophoresis – M protein

Bence Jones proteins – urin

Renal dysfunction (myeloma nephrosis), proteinaceous casts

M osteal lesions C Osteomalc.

Defects in humoral immunity (recurrent bacterial infection)

 Neoplasm that arises from germinal center B cells

• Nonneoplastic inflammatory cell infiltrate

• frequent involvement EBV (70% mix cel.)

• painless lymphadenopathy

• arise in a single lymph node or chain lymph nodes

• Spread in the stepwise fashion to anatomiccaly contiguous nodes

• B simptoms

• bimodal

 Nodular lymphocite predominant Hodgkin lymphoma

 Classical Hodgkin lymphoma

•   Nodular sclerosis

•   Mixed cellularity

•   Limphocyte rich

•   Limphocyte depletion

Nodular lymphocyte

popcorn cells

 Nodular sclerosis

 Mixed cellularity

 Limphocyte rich

 Limphocyte depletion

•   The most common (70%)

•   Males/females

•   Adolescents and young adults

•   Prognosis excellent

•   Collagen bands

•   Lacunar cells

•   Lower cervical, supraclavicular and mediastinal LN

 The most common form in adults > 50 ys, male predominance

 Classic RS cells

 Heterogeneous inf lammatory infiltrates

 More likely to be disseminated

EBV

•   Myeloproliferative neoplasms - MPN

•   Myelodysplastic syndromes - MDS

•   Myelodysplastic/myeloproliferative neoplasms – MDS/MPN

•   Acute myeloid leukaemias - AML

•   Myeloid and lymphoid neoplasms with neutrophilia and abnormalities of PDGFRA, PDGFRB ili FGFR1

neoplastic cells are blocked at an early stage of myeloid development (blasts

accumulation)

 neoplastic clone continues to undergo terminal differentiation with increased

or dysregulated growth

 disordered and ineffective terminal differentiation, dysplastic BM precursor and PB cytopenia