RBCs and Bleeding
Disorders
Anemias
Anemias of blood loss
– Acute blood loss
– Chronic blood loss
 Hemolytic anemias
– Hereditary spherocytosis (HS)
– Hemolytic disease due to red cell enzyme defects: Glucose-6-phosphate
dehydrogenase deficiency
– Sickle cell disease
– Thalassemia syndromes
– Paroxysmal nocturnal hemoglobinuria
– Immunohemolytic anemia
– Hemolytic anemia resulting from trauma to red cells – cardiac valve
prostheses, microangiopathic disorders
 Anemias of diminished erythropoiesis

Anemias
Anemia = A reduction of the total circulating red
cell mass below normal limits, reduces the
oxygen-carrying capacity of the blood, leading to
tissues hypoxia
 In practice, usually diagnosed based on a
reduction in H/H, correlate with RBC mass,
except when changes in plasma volume caused
by fluid retention or dehydration
 RBC indices, Table 14-2, adult reference ranges
 Clinical – pale, weakness, malaise, fatigue, DOE

Anemia of Blood Loss
Acute blood loss – mainly effects due to
loss of intravascular volume
 Significant bleeding – predictable changes
in the blood involving WBCs and
platelets as well as RBCs
 Chronic blood loss – anemia only if rate of
loss exceeds the regenerative capacity
of the marrow or iron stores are
depleted

Hemolytic Anemias
Premature destruction of red cells and a
shortened red cell life span below the
normal 120 days
 Elevated erythropoietin levels and a
compensatory increase in
erythropoiesis
 Accumulation of hemoglobin degradation
products released by red cell breakdown
derived from hemoglobin

Hemolytic Anemias

Extravascular hemolysis
– Premature destruction also occurs in
phagocytes
– Hyperplasia of phagocytes leading to
splenomegaly
– Generally caused by alterations in RBCs that
make them less deformable
– Principal clinical features – anemia,
splenomegaly, jaundice, often benefit from
splenectomy, decreased haptoglobin
Hemolytic Anemias

Intravascular hemolysis
– Caused by mechanical injury, complement
fixation, intracellular parasites, or exogenous
toxic factors
– Clinical – anemia, hemoglobinemia,
hemoglobinuria, hemosiderinuria, jaundice, no
splenomegaly
Hereditary Spherocytosis
Intrinsic defects in the red cell membrane
skeleton that render red cells, spheroid, less
deformable, and vulnerable to splenic
sequestration and destruction
 Diverse mutations lead to an insufficiency of
membrane skeletal components
 Compound heterozygosity
 Deficiency of membrane skeleton reduces the
stability of the lipid bilayer, leading to the loss of
membrane fragments as red cells age in
circulation

Hereditary Spherocytosis
Spleen has a cardinal role in the premature
demise of spherocytes, trapped in splenic cords
and phagocytized, erthyrostasis leading to
decreased glucose and pH
 Increased MCHC due to dehydration because of
loss of K+ and H2O
 Anemia, Splenomegaly, jaundice, gall stones,
aplastic crises, hemolytic crises, splenectomy is
beneficial

Glucose-6-phosphate
Dehydrogenase Deficiency



Abnormalities in the hexose monophosphate shunt or
glutathione metabolism resulting from deficient or
impaired enzyme function reduce the ability of red cells
to protect themselves from oxidative injuries and leads
to hemolysis
G6PD deficiency is a recessive X-linked trait, G6PD- and
G6PD Mediterranean cause most of clinically significant
anemias
Episodic hemolysis is characteristic caused by exposures
that generate oxidant stress, infections, drugs, foods
(e.g. fava beans, antimalarials)
G6PD Deficiency
Heinz bodies removed by spleen , bite
cells in peripheral smear
 Both intravascular and extravascular
hemolysis
 Anemia, hemoglobinemia, hemoglobinuria
 Self-limited usually

Sickle Cell disease
Common hereditary hemoglobinopathy
that occurs primarily in individuals of
African descent, 8-10% of African
Americans have HbS trait (heterozygotes)
 Point mutation in the 6th codon of Betaglobin that leads to replacement of
glutamate with valine leading to the HbS
molecule undergoing polymerization when
deoxygenated, sickle shape

Sickle Cell Disease
Chronic hemolysis, microvascular
occlusions, tissue damage
 Variables affecting the rate and degree of
sickling

– Interaction of HbS with other types of
hemoglobin in the cell
– MCHC
– Intracellular pH
– Transit time of red cells through the
microvascular beds
Sickle Cell Disease

Peripheral blood – variable numbers of
irreversibly sickled cells, reticulocytosis,
target cell, Howell-Jolly bodies, pigment
gallstones, hyperbilirubinemia,
autosplenectomy, infarctions in many
tissues
Sickle Cell Disease
Increased susceptibility to infections
 Crises

– Vaso-oclusive =pain crises
– Acute chest syndrome
– Sequestration crises
– Aplastic crises
Thalassemia Syndromes
Heterogenous group of disorders caused
by inherited mutations that decrease the
synthesis of adult hemoglobin, HbA
 Alpha-globin genes on chromosome 16
 Beta-globin gene on chromosome 11
 Table 14-3 – clinical and genetic
classification of thalassemias

Beta-Thalassemias

Mutations that diminish the synthesis of
beta-globin chains
– Beta0 mutations – absent beta-globin
synthesis
 Chain terminator mutations
– Beta+ mutations – reduced beta-globin
synthesis
 Splicing mutations
 Promoter region mutations
Beta-Thalassemias

Two mechanisms leading to anemia
– Hypochromic, microcytic anemia with
decreased oxygen transport capacity
– Diminished survival of red cells and precursors
 Membrane damage
 Ineffective erythropoiesis
 Extravascular hemolysis
 Extramedullary hematopoiesis
 Excessive absorption of iron
Beta-Thalassemias

Clinical syndromes
– Beta-thalassemia major
– Beta-thalassemia minor or trait
– Beta-thalassemia intermedia
Alpha-Thalassemias


Inherited deletions that result in reduced or absent
synthesis of alpha-globin chains
Clinical syndromes – determined and classified by the
number of alpha-globin genes that are deleted
– Silent carrier – deletion of one gene
– Alpha-thalassemia trait – deletion of two genes
– Hemoglobin H disease – deletion of three genes
– Hydrops fetalis – deletion of all four genes
Paroxysmal Nocturnal
Hemoglobinuria
Acquired mutations in the phosphatidylinositol
glycan complementation group A gene ( PIGA),
an enzyme that is essential for the synthesis of
certain cell surface proteins
 Intravascular hemolysis caused by the C5b-C9
membrane attack complex
 Thrombosis is the leading cause of diseaserelated death because of dysfunction of platelets
 5-10% develop AML or myelodysplastic
syndromes

Immunohemolytic Anemia
Caused by antibodies that bind to red
cells, leading to their premature
destruction
 Direct Coombs antiglobulin test
 Indirect Coombs antiglobulin test
 Table 14-4 Classification

– Warm Antibody type
– Cold agglutinin type
– Cold hemolysin type
Anemias of Diminshed
Erythropoiesis
Megaloblastic anemias
 Iron deficiency anemia
 Anemia of chronic disease
 Aplastic anemia
 Pure red cell aplasia
 Other forms of marrow failure

Megaloblastic Anemias
Caused by an impairment of DNA synthesis that
leads to distinctive morphologic changes,
including abnormally large erythroid precursors
and red cells
 Table 14-5 Causes of megaloblastic anemias
 Macrocytic oval cells, hypersegmented
neutrophils, giant metamyelocytes and band
forms

Vitamin B12 Deficiency

Pernicious anemia
– Autoimmune gastritis leading to failure of
intrinsic factor production leading to vitamin
B12 deficiency
– Atrophy of the fundic glands, intestinalization,
atrophic glossitis, CNS – demyelination of the
dorsal and lateral tracts leading to spastic
paraparesis, sensory ataxia, severe
paresthesias in the lower limbs
Folate Deficiency

Three major causes
– Decreased intake – chronic alcoholics, elderly,
indigent
– Increased requirements – pregnancy, infancy
– Impaired utilization – folic acid antagonists
Iron Deficiency anemia
Most common nutritional disorder in the
world
 Iron in the body is recycled extensively
between the functional and storage pools

– Transferrin
– Ferritin

Iron balance is maintained largely by
regulating the absorption of dietary iron in
the proximal duodenum, hepcidin
Iron Deficiency

Causes
– Dietary lack
 Infants, impoverished,elderly, teenagers
– Impaired absorption
– Increased requirements
– Chronic blood loss-most common cause in the
Western world – GI bleed until proven
otherwise
Iron Deficiency
Hypochromic, microcytic anemia
 Low serum iron and ferritin
 Elevated TIBC
 Disappearance of stainable iron in the
macrophages of the bone marrow

Anemia of Chronic Disease
Chronic microbial infections, such as
osteomyelitis, endocarditis, lung abscess
 Chronic immune disorders, such as RA
 Neoplasms, lung and breast, non-Hodgkin
lymphomas
 Iron sequestration
 Increase iron in marrow macrophages,
high ferritin, decreased TIBC

Aplastic Anemias





Chronic primary hematopoietic failure and
attendant pancytopenia
Major causes – table 14-7
Most common known etiology drugs and
chemicals also infections, whole body irradiation,
Fanconi anemia
Pure red cell aplasia
Other forms – myelophthisic anemia, chronic
renal failure, hepatocellular liver disease,
endocrine disorders ( hypothyroidism)
Polycythemias

Table 14-8
Bleeding Disorders

Increased fragility of the vessels

Platelet deficiency or dysfunction

Derangement of coagulation
Laboratory Screening Tests in Selected Hemorrhagic Disorders
Disorder
Bleeding
time
Platelet
Count
PT
PTT
Thrombin
Time
Fibrinogen
Assay
Vascular
Bleeding
Usually
prolonged
Normal
Normal
Normal
Normal
Thrombocytopenia
Prolonged
Decreased
Normal
Normal
Normal
Qualitative
Platelet
Defects
Prolonged
Normal
Normal
Normal
Normal
Platelet
Aggregation/sp
ecial
studies
Classic
Hemophilia
Normal
Normal
Normal
Prolonged
Normal
Factor
VIII
Assay
Christmas
Disease
Normal
Normal
Normal
Normal
Factor IX
Assay
Von
Willebrand
Disease
Prolonged
Normal
Normal
Prolonged
Normal
vWF
assay
DIC
Prolonged
Decreased
Prolonged
Prolonged
Prolonged
Fibrin
and FDP
Prolonged
Confirmatory
Testing
Coagulation Cascade
PTT
PT
Coagulation Cascade
www.hopkinsmedicine.org/hematology/coag
ulation.swf
Bleeding Disorders:
Hemorrhagic Diatheses





Bleeding disorders caused by vessel wall abnormalities
Bleeding related to platelet number: thrombocytopenia
– Chronic immune thrombocytopenia purpura
– Acute immune thrombocytopenia purpura
– Drug-induced thrombocytopenia
– HIV-associated thrombocytopenia
– Thrombotic microangiopathies
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremia syndrome
(HUS)
Bleeding disorders related to defective platelet functions
Hemorrhagic Diatheses related to abnormalities in clotting factors
– The factor VIII-vWF complex
– Von Willebrand disease
– Hemophilia A (factor VIII deficiency)
– Hemophilia B (Christmas disease, Factor IX deficiency
Disseminated intravascular coagulation
Vessel Wall Abnormalities
Infections (e.g. meningococcemia)
 Drug reactions
 Scurvy, Ehlers-Danlos, Cushing
 HSP
 Hereditary hemorrhagic telangiestasia
(Weber-Osler-Rendu)
 Perivascular amyloidosis

Thrombocytopenia
Count <20,000 = spontaneous bleeding
 Decreased production = bone marrow
issue
 Decreased platelet survival = immunologic
or nonimmunologic
 Sequestration = hypersplenism
 Dilution = transfusions
 Table 14-9 Causes of Thrombocytopenia

Chronic Immune Thrombocytopenic
Purpura ( ITP)
Cause – autoantibodies to platelets act as
opsonins, primary (diagnosis of exclusion) or
secondary ( e.g SLE, HIV, B-cell neoplasms)
 Spenectomy helps – site of removal of opsonized
platelets, site of plasma cells that produce
autoantibodies
 Megakaryocytes – increased number and size in
marrow
 Most common – women over 40 years of age,
petechiae, echymoses, risk of intracranial bleeds

Other Causes of
Thrombocytopenia
Acute ITP – children, following a viral
illness, usually self-limited
 Drug-induced – heparin-induced (HIT)severe form – thrombosis, even in setting
of low platelets
 HIV-associated – megakarocytes infected

Thrombotic Microangiopathies
Caused by insults that lead to excessive
activation of platelets, which deposit as
thrombi in microcirculatory beds –
microangiopathic hemolytic anemia, organ
dysfunction, thrombocytopenia – Table
14-10
 Thrombotic thrombocytopenic purpura
(TTP)
 Hemolytic-uremic syndrome (HUS)

Defective Platelet Dysfunctions




Defects of adhesion – Bernard-Soulier syndrome –
inherited deficiency of platelet membrane glycoprotein
complex (receptor for vWF)
Defective platelet aggregation – Glanzmann
thrombasthenia – AR - deficiency or dysfunction of
glycoprotein Iib-IIIa (integrin that participates in “bridge
formation” between platelets)
Defects of platelet secretion – storage pool disorders
Acquired – aspirin and other NSAIDs, uremia
Abnormalities in Clotting Factors
Most commonly manifest as large posttraumatic ecchymoses or hematomas or
prolonged bleeding after a laceration or
surgical procedure
 Hereditary – usually single clotting factor
 Acquired – usually multiple factors
simultaneously (e.g. vitamin K deficiency)

Von Willebrand Disease






Most common inherited bleeding disorder of humans (
1% of adults in US)
20 variants
Type 1 and Type 3 are associated with a reduced
quantity of circulating vWF
Type 2 is characterized by qualitative defects in vWF
Defects in platelet function despite a normal platelet
count leading to secondary abnormalties in platelet
adhesion and clot formation
Clinically – Epistaxis, excessive bleeding from wounds,
menorrhagia
Hemophilia A (Factor VIII
Deficiency)
Most common hereditary disease
associated with life-threatening bleeding
 X-linked recessive
 Clinical severity correlates well with level
of factor VIII activity
 Petechiae are characteristically absent
 Prolonged PTT, normal PT

Hemophilia B (Christmas
Disease, Factor IX Deficiency)

Clinically indistinguishable from hemophilia
A – factors VIII and IX function together
to activate factor X
Disseminated Intravascular
Coagulation (DIC)
Acute, subacute, or chronic
thrombohemorrhagic disorder
characterized by the excessive activation
of coagulation, which leads to the
formation of thrombi in the
microvasculature of the body
 Consumption of platelets, fibrin, and
coagulation factors and activation of
fibrinolysis
 Not a primary disease

DIC




Two major mechanisms trigger DIC - Table 14-27
– Release of tissue factor or thromboplastic substances into the circulation
– Widespread injury to endothelial cells
Most likely associated with:
– Obstetric complications
– Malignant neoplasms
– Sepsis
– Major trauma
Possible consequences
– Widespread deposition of fibrin – ischemia, microangiopathic hemolytic anemia
– Hemorrhagic diathesis
Clinical Features
– Microangiopathic hemolytic anemia
– Dyspnea, cyanosis, respiratory failure
– Convulsions and coma
– Oliguria and renal failure
– Shock
– Only definitive treatment is to remove or treat the inciting cause