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)
Hemoglobin (gm/dL)
Men
13.6–17.2
39–49
Hematocrit (%)
Red cell count (10 /µL)
6
Women
12.0–15.0
33–43
4.3–5.9
3.5–5.0
Reticulocyte count (%)
0.5–1.5
Mean cell volume (µm ) MCV
82–96
Mean corpuscular hemoglobin (pg) MCH
27–33
Mean corpuscular hemoglobin
concentration (gm/dL) MCHC
33–37
3
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 50%
MEGAKARYOCYTES at least 1-2/hpf
M:E RATIO  3:1
MYELOID MATURATION  1/3 bands or more
ERYTHROID MATURATION  nucleus/cytoplasm
LYMPHS, PLASMA CELLS  small percentage
STORAGE IRON, i.e., HEMOSIDERIN present
“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. Features of ALL anemias
• Pallor, where?
• Tiredness
• Weakness
• Dyspnea, why?
• Palpitations
• Heart Failure (high output), why?

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 (vascular or mechanic)
– 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. MODIFIERS
• MCV, microcytosis, macrocytosis
• MCH
• MCHC, hypochromic
• RDW, anisocytosis

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

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

20. M:E Ratio normally 3:1

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

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

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

24. Sickle Cell Disease
• Classic hemoglobinopathy
• Normal HGB is α2 β2:
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
• Alpha or beta chains deficient synthesis involved
• Often termed MAJOR or MINOR, depending on severity,
silent carriers and “traits” are seen
• HEMOLYSIS is uniformly a feature, and microcytic anemia,
i.e, LOW MCV (just like iron deficiency anemia has a low
MCV)
• A “crew cut” skull x-ray appearance may be seen in severe
erythroid hyperplasia.

29. Hemoglobin H Disease
• Deletion of THREE alpha chain genes
• HGB-H is primarilly Asian
H
HIGH
• HGB- has a
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), jaundice, kernicterus
– Edema (hence the name “hydrops”)
– Massive hepatosplenomegaly (hemolysis)

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

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 AGGLUTININ (IgG)
– COLD AGGLUTININ (IgM)
– COLD HEMOLYSIN (paroxysmal) (IgG)

33. IMMUNOHEMOLYTIC ANEMIAS
• WARM AGGLUTININS (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. COOMBS TEST
• DIRECT: Patient’s CELLS are
tested for surface Ab’s
• INDIRECT: Patient’s SERUM is
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
• Often VERY
hyperplastic/hypercellular
marrow* (* exception to the
rule)

38. 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 and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer

39. 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

40. Please remember that ALL
megaloblastic anemias are also
MACROCYTIC (MCV>94 or
MCV~100), and that not only are
the RBC’s BIG and
hyperplastic/hypercellular, 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, because FE is
recycled!

44. Fe
Transferrin
Ferritin/apo- (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)

48. ?

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, benzene, toluene, TNT
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) (LOW EPO), mutation in
tyrosine kinase, making RBCs hyper responsive to EPO
– 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), also has ↓ plats.

57. VESSEL WALL ABNORMALITIES
(angiopathic thrombocytopenias)
(NON-thrombotic 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
• INCREASED
MARROW
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, just like a DIC

67. “QUALITATIVE” platelet disorders
• Mostly congenital (genetic):
– Bernard-Soulier syndrome (Glycoprotein1-b deficiency)
– Glanzmann’s thrombasthenia (Glyc.IIB/IIIA deficiency)
– Storage pool disorders, i.e., platelets misfunction because of defective granulation
• ACQUIRED: ASPIRIN, ASPIRIN, ASPIRIN

68. PTT
PT/INR

69. 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 (II, VII, IX, X)
• von Willebrand disease the most common, 1%

70. •
•
•
•
•
•
von Willebrand 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, to join platelets with the exposed ECM in
endothelial disruption. it is the von Willebrand Factor
which is defective in von Willebrand disease
• Usually BOTH platelet and FactorVIII-vWF disorders are
present

71. PTT
PT/INR

72. •
•
•
•
•
•
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

73. •
•
•
•
•
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

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

75. 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

76. Common Coagulation TESTS
• PTT (intrinsic)
• PT INR (extrinsic)
• Platelet count, aggregation
• Bleeding Time, so EASY to do
• Fibrinogen
• Factor Assays

77. RBC LAB
http://www.chronolab.com/hematology/2_1.htm