RBCs and Bleeding Disorders
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Transcript RBCs and Bleeding Disorders
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