Red blood cell and its bleeding disorders

The study of red blood cell and its pathologies

1. RBC and BLEEDING DISORDERS

2. RBC and Bleeding Disorders
•NORMAL
–Anatomy, histology
–Development
–Physiology
•ANEMIAS
–Blood loss: acute, chronic
–Hemolytic
–Diminished erythropoesis
•POLYCYTHEMIA
•BLEEDING DISORDERS

6. TABLE 13-2 --Adult Reference Ranges for Red Blood Cells
*
Measurement (units) Men Women
Hemoglobin (gm/dL) 13.6–17.212.0–15.0
Hematocrit (%) 39–49 33–43
Red cell count (10
6/µL) 4.3–5.9 3.5–5.0
Reticulocyte count (%) 0.5–1.5
Mean cell volume (µm
3) 82–96
Mean corpuscular hemoglobin (pg) 27–33
Mean corpuscular hemoglobin
concentration (gm/dL)
33–37
RBC distribution width 11.5–14.5

8. WHERE is MARROW?
•Yolk Sac: very early embryo
•Liver, Spleen: NEWBORN
•BONE
–CHILDHOOD: AXIAL SKELETON & APPENDICULAR
SKELETON BOTH HAVE RED (active) MARROW
–ADULT: AXIAL SKELETON RED MARROW,
APPENDICULAR SKELETON YELLOW MARROW

9. MARROW FEATURES
•CELLULARITY
•MEGAKARYOCYTES
•M:E RATIO
•MYELOID MATURATION
•ERYTHROID MATURATION
•LYMPHS, PLASMA CELLS
•STORAGE IRON, i.e., HEMOSIDERIN
•“FOREIGN CELLS”

10. MARROW
“DIFFERENTIATION”

12. ANEMIAS*
•BLOOD LOSS
–ACUTE
–CHRONIC
•IN-creased destruction (HEMOLYTIC)
•DE-creased production
*A good definition would be a decrease in OXYGEN CARRYING
CAPACITY, rather than just a decrease in red blood cells, because
you need to have enough blood cells THAT FUNCTION, and not just
enough blood cells.

13. Featuresof ALL anemias
•Pallor
•Tiredness
•Weakness
•Dyspnea
•Palpitations
•Heart Failure (high output)

14. Blood Loss
Acute: trauma
Chronic: lesions of gastrointestinal tract,
gynecologic disturbances. The features of
chronic blood loss anemia are the same as iron
deficiency anemia, and is defined as a situation
in which the production cannot keep up with
the loss

15. HEMOLYTIC
•HEREDITARY
–MEMBRANE disorders: e.g., spherocytosis
–ENZYME disorders: e.g., G6PD deficciency
–HGB disorders (hemoglobinopathies)
•ACQUIRED
–MEMBRANE disorders (PNH)
–ANTIBODY MEDIATED, transfusion or autoantibodies
–MECHANICAL TRAUMA
–INFECTIONS
–DRUGS, TOXINS, HYPERSPLENISM

16. IMPAIRED PRODUCTION
•Disturbance of proliferation and differentiation of
stem cells: aplastic anemias, pure RBC aplasia,
renal failure
•Disturbance of proliferation and maturation of
erythroblasts
•Defective DNA synthesis: (Megaloblastic)
•Defective heme synthesis: (Fe)
•Deficient globin synthesis: (Thalassemias)

17. Glucose-6-Phosphate
Dehydrogenase (G6PD) Deficiency
•A
-
and Mediterranean are most significant types

18. MODIFIERS
•MCV, microcytosis, macrocytosis
•MCH
•MCHC, hypochromic
•RDW, anisocytosis

19. HEMOLYTIC ANEMIAS
•Life span LESS than 120 days
•Marrow hyperplasia (M:E), EPO+
•Increased catabolic products, e.g.,
bilirubin, serum HGB, hemosiderin
•Decreased haptoglobin

20. HEMOLYSIS
•INTRA-vascular (vessels)
•EXTRA-vascular (spleen)

21. M:E Ratio normally 3:1

22. HEREDITARY SPHEROCYTOSIS
Genetic defects affecting
ankyrin, spectrin, usually
autosomal dominant
Children, adults
Anemia, hemolysis,
jaundice, splenomegaly,
gallstones (what kind?)

23. FEATURES of G6PD Defic.
•Genetic: Recessive, X-linked
•Can be triggered by foods (fava beans),
oxidant substances drugs (primaquine,
chloroquine), or infections
•HGB can precipitate as HEINZbodies
•Acute intravascular hemolysis can occur:
–Hemoglobinuria
–Hemoglobinemia
–Anemia

24. Sickle Cell Disease
•Classic hemoglobinopathy
•Normal HGB is α2β2: β-chain defects (Val->Glu)
•Reduced hemoglobin “sickles” in homozygous
•8% of American blacks are heterozygous

25. Clinical features of HGB-S disease
•Severe anemia
•Jaundice
•PAIN (pain CRISIS)
•Vaso-occlusive disease: EVERYWHERE, but
clinically significant bone, spleen
(autosplenectomy)
•Infections: Pneumococcus, Hem. Influ.,
Salmonella osteomyelitis

27. THALASSEMIAS
•A WIDE VARIETY of diseases involving GLOBIN synthesis,
COMPLEX genetics
•Alphaor betachains deficient synthesis involved
•Often termed MAJOR or MINOR, depending on severity,
silent carriers and “traits” are seen
•HEMOLYSIS is uniformly a feature, a microcytic anemia
•A “crew cut” skull x-ray appearance may beseen

29. Hemoglobin H Disease
•Deletion of THREE alpha chain genes
•HGB-H is primarilly Asian
•HGB-H has a HIGH affinity for
oxygen
•HGB-H is unstable and therefore has
classical hemolytic behavior

30. HYDROPS FETALIS
•FOUR alpha chain genes are deleted, so this is
the MOST SEVERE form of thalassemia
•Many/most never make it to term
•Children born will have a SEVERE hemolytic
anemia as in the erythroblastosis fetalis of Rh
disease:
–Pallor (as in all anemias)
–Edema (hence the name “hydrops”)
–Massive hepatosplenomegaly (hemolysis)

31. Paroxysmal Nocturnal
Hemoglobinuria (PNH)
•ACQUIRED, NOT INHERITED like all the previous
hemolytic anemias were
•ACQUIRED mutations in phosphatidylinositol
glycan A (PIGA)
•It is “P” and “N” only 25% of the time
GlycosylphosPhatidylInositol

32. Immunohemolytic Anemia
•All of these have the presence of antibodies
and/or compliment present on RBC surfaces
•NOT all are AUTOimmune, some are caused
by drugs
•Antibodies can be
–WARM(IgG)
–COLDAGGLUTININ(IgM)
–COLD HEMOLYSIN(paroxysmal) (IgG)

33. IMMUNOHEMOLYTIC ANEMIAS
•WARM (IgG), will NOT hemolyze at room temp
–Primary Idiopathic (most common)
–Secondary (Tumors, especially leuk/lymph, drugs)
•COLD AGGLUTININS: (IgM), WILL hemolyze at
room temp
–Mycoplasma pneumoniae, HIV, mononucleosis
•COLD HEMOLYSINS: (IgG) Cold Paroxysmal
Hemoglobinuria, hemo-LYSIS in body, ALSO often
follows mycoplasma pneumoniae

34. COOMBSTEST
•DIRECT: Patient’s CELLSare
tested for surface Ab’s
•INDIRECT: Patient’s SERUMis
tested for Ab’s.

35. HEMOLYSIS/HEMOLYTIC ANEMIAS
DUE TO RBC TRAUMA
•Mechanical heart valves
breaking RBC’s
•MICROANGIOPATHIES:
–TTP
–Hemolytic Uremic Syndrome

36. NON-Hemolytic Anemias:
i.e., DE-creased Production
•“Megaloblastic” Anemias
•B12 Deficiency (Pernicious Anemia)
•Folate Deficiency
•Iron Deficiency
•Anemia of Chronic Disease
•Aplastic Anemia
•“Pure” Red Cell Aplasia
•OTHER forms of Marrow Failure

37. MEGALOBLASTIC ANEMIAS
•Differentiating megaloblasts
(marrow) from macrocytes
(peripheral smear, MCV>94)
•Impaired DNA synthesis
•For all practical purposes,
also called the anemias of
B12 and FOLATE deficiency

38. Vit-B12 Physiology
•Oral ingestion
•Combines with INTRINSIC FACTOR in the
gastric mucosa
•Absorbed in the terminal ileum
•DEFECTS at ANY of these sites can
produce a MEGALOBLASTIC anemia

39. Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency
Pernicious anemia
Gastrectomy
Malabsorption states
Diffuse intestinal disease, e.g.,lymphoma, systemic sclerosis
Ileal resection, ileitis
Competitive parasitic uptake
Fish tapeworm infestation
Bacterial overgrowth in blind loops anddiverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism,disseminated cancer

40. Please remember that ALL
megaloblastic anemias are also
MACROCYTIC (MCV>94 or
MCV~100), and that not only are
the RBC’s BIG, but so are the
neutrophils, and neutrophilic
precursors in the bone marrow
too, and even more so,
HYPERSEGMENTED!!!

41. PERNICIOUS ANEMIA
•MEGALOBLASTIC anemia
•LEUKOPENIA and HYPERSEGS
•JAUNDICE
•NEUROLOGIC posterolateral spinal tracts
•ACHLORHYDRIA
•Can’t absorb B12
•LOW serum B12
•Flunk Schilling test, i.e., can’t absorb B12,
using a radioactive tracer

42. FOLATE DEFICIENCY
MEGALOBLASTIC AMEMIAS
•Decreased Intake: diet, etoh-ism, infancy
•Impaired Absorption: intestinal disease
•DRUGS: anticonvulsants, BCPs, CHEMO
•Increased Loss: Hemodialysis
•Increased Requirement: Pregnancy, infancy
•Impaired Usage

43. Fe Deficiency Anemia
•Due to increased loss or decreased
ingestion, almost always, in USA,
nowadays, increased loss is the reason
•Microcytic (low MCV), Hypochromic
(low MCHC)
•THE ONLY WAY WE CAN LOSE IRON IS BY
LOSING BLOOD

44. Fe
Transferrin
Ferritin (GREAT test)
Hemosiderin

45. Clinical Fe-Defic-Anemia
•Adult men: GI Blood Loss
•PRE menopausal women:
menorrhagia
•POST menopausal women: GI Blood
Loss

47. 2 BEST lab tests:
•Serum Ferritin
•Prussian blue hemosiderin
stain of marrow (also
called an “iron” stain)

49. Anemia of Chronic Disease*
•CHRONIC INFECTIONS
•CHRONIC IMMUNE
DISORDERS
•NEOPLASMS
•LIVER, KIDNEY failure
* Please remember these patients may very very much
look like iron deficiency anemia, BUT, they have
ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

50. APLASTIC ANEMIAS
•ALMOST ALWAYS involve platelet and
WBC suppression as well
•Some are idiopathic, but MOST are
related to drugs, radiation
•FANCONI’s ANEMIA is the only one that
is inherited, and NOT acquired
•Act at STEM CELL level, except for “pure”
red cell aplasia

51. APLASTIC ANEMIAS

52. APLASTIC ANEMIAS
•CHLORAMPHENICOL
•OTHER ANTIBIOTICS
•CHEMO
•INSECTICIDES
•VIRUSES
–EBV
–HEPATITIS
–VZ

53. MYELOPHTHISIC ANEMIAS
•Are anemias caused by metastatic
tumor cells replacing the bone
marrow extensively

54. POLYCYTHEMIA
•Relative (e.g., hemoconcentration)
•Absolute
–POLYCYTHEMIA VERA(Primary) (LOWEPO)
–POLYCYTHEMIA (Secondary) (HIGH EPO)
•HIGH ALTITUDE
•EPO TUMORS
•EPO “Doping”
•CVAC, the trendy California bubble pods

55. P. VERA
•A “myeloproliferative”
disease
•ALL cell lines are increased,
not just RBCs

56. BLEEDING DISORDERS
(aka, Hemorrhagic “DIATHESES”)
•Blood vessel wall abnormalities
•Reduced platelets
•Decreased platelet function
•Abnormal clotting factors
•DIC (Disseminated INTRA-vascular
Coagulation)

57. VESSEL WALL ABNORMALITIES
(NON-thrombotic cytopenic purpuras)
•Infections, especially, meningococcemia, and rickettsia
•Drug reactions causing a leukocytoclastic vasculitis
•Scurvy, Ehlers-Danlos, Cushing syndrome
•Henoch-Schönlein purpura (mesangial deposits too)
•Hereditary hemorrhagic telangiectasia
•Amyloid

58. THROMBOCYTOPENIAS
•Like RBCs:
–DE-creased production
–IN-creased destruction
–Sequestration (Hypersplenism)
–Dilutional
•Normal value 150K-300K

59. DE-CREASED PRODUCTION
•APLASTIC ANEMIA
•ACUTE LEUKEMIAS
•ALCOHOL, THIAZIDES, CHEMO
•MEASLES, HIV
•MEGALOBLASTIC ANEMIAS
•MYELODYSPLASTIC SYNDROMES

60. IN-CREASED DESTRUCTION
•AUTOIMMUNE (ITP)
•POST-TRANSFUSION (NEONATAL)
•QUINIDINE, HEPARIN, SULFA
•MONO, HIV
•DIC
•TTP
•“MICROANGIOPATHIC”

61. THROMBOCYTOPENIAS
•ITP (Idiopathic Thrombocytopenic
Purpura)
•Acute Immune
•DRUG-induced
•HIV associated
•TTP, Hemolytic Uremic Syndrome

62. I.T.P.
•ADULTS AND ELDERLY
•ACUTE OR CHRONIC
•AUTO-IMMUNE
•ANTI-PLATELET ANTIBODIES PRESENT
•INCREASEDMARROW
MEGAKARYOCYTES
•Rx: STEROIDS

63. ACUTE ITP
•CHILDREN
•Follows a VIRAL illness (~ 2 weeks)
•ALSO have anti-platelet antibodies
•Platelets usually return to normal in a
few months

64. DRUGS
•Quinine
•Quinidine
•Sulfonamide antibiotics
•HEPARIN

65. HIV
•BOTH DE-creased production
AND IN-creased destruction
factors are present

66. Thrombotic Microangiopathies
•BOTH are very SERIOUS CONDITIONS with a
HIGH mortality:
–TTP (THROMBOTIC THROMBOCYTOPENIC PURPURA)
–H.U.S. (HEMOLYTIC UREMIC SYNDROME)
•These can also be called “consumptive”
coagulopathies

67. “QUALITATIVE” platelet disorders
•Mostly congenital (genetic):
–Bernard-Soulier syndrome (Glycoprotein-1-
b deficiency)
–Glanzmann’s thrombasthenia (Glyc.-IIB/IIIA
deficiency)
–Storage pool disorders, i.e., platelets mis-
function AFTER they degranulate
•ACQUIRED: ASPIRIN, ASPIRIN, ASPIRIN

68. BLEEDING DISORDERS due to
CLOTTING FACTOR DEFICIENCIES
•NOT spontaneous, but following surgery or trauma
•ALL factor deficiencies are possible
•Factor VIII and IX both are the classic X-linked
recessive hemophilias, A and B, respectively
•ACQUIRED disorders often due to Vitamin-K
deficiencies
•von Willebrand disease the most common, 1%

69. vonWillebrand Disease
•1% prevalence, most common bleeding disorder
•Spontaneous and wound bleeding
•Usually autosomal dominant
•Gazillions of variants, genetics even more complex
•Prolonged BLEEDING TIME, NL platelet count
•vWF is von Willebrand Factor, which complexes with
Factor VIII, it is the von Willebrand Factor which is
defective in von Willebrand disease
•Usually BOTH platelet and FactorVIII-vWF
disorders are present

70. HEMOPHILIA A
•The “classic” HEMOPHILIA
•Factor VIII decreased
•Co-factor of Factor IX to activate Factor X
•Sex-linked recessive
•Hemorrhage usually NOT spontaneous
•Wide variety of severities
•Prolonged PTT (intrinsic) only
•Rx: Recombinant Factor VIII

71. HEMOPHILIA B
•The “Christmas” HEMOPHILIA
•Factor IX decreased
•Sex-linked recessive
•Hemorrhage usually NOT spontaneous
•Wide variety of severities
•Prolonged PTT (intrinsic) only
•Rx: Recombinant Factor IX

72. DIC, Disseminated INTRA-vascular,
Coagulation
•ENTOTHELIAL INJURY
•WIDESPREAD FIBRIN DEPOSITION
•HIGH MORTALITY
•ALL MAJOR ORGANS COMMONLY INVOLVED

73. DIC, Disseminated INTRA-vascular,
Coagulation
•Extremely SERIOUS condition
•NOT a disease in itself but secondary to many
conditions
–Obstetric: MAJOR OB complications, toxemia, sepsis,
abruption
–Infections: Gm-, meningococcemia, RMSF, fungi,
Malaria
–Many neoplasms, acute promyelocytic leukemia
–Massive tissue injury: trauma, burns, surgery
•“Consumptive” coagulopathy

74. Common Coagulation TESTS
•PTT (intrinsic)
•PTINR (extrinsic)
•Platelet count, aggregation
•Bleeding Time
•Fibrinogen
•Factor Assays