2011-08-PATHO-Red Blood Cells and Bleeding Disorders (1)

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Bloodlines

Above: From pluripotent cells arise the WBC and RBC and lymphoid series. Note that some cells will arise from

the same mother cell.

Anemias

Reduction below normal limits of the total

circulating red cell mass

Reduced oxygen transport capacity of the

blood

Reduction below normal in the volume of

packed red cell as measured by hematocrit

or hemoglobin concentration

IOW, the patient will appear pale and weak

from lack of oxygen.

Classification of Anemia According to Underlying

Mechanism

Blood loss

Increased rate of destruction (hemolytic

anemias)

Impaired red cell production

Anemia of Blood Loss

Acute blood loss (microcytic, hypochromatic RBC’s

may not be evident)

Reflect loss of blood volumemay lead to

shock, death

Hemodilutionshift of water from

interstitial fluid compartment into

intravascular space

Erythropoietin productionreticulocytosis

(Immature RBC containing remnants of

nuclei seen only in special stain. Bigger

than usual RBC. Polychromatophilicbluish

– red hue) reaching 10 – 15%

Reticulocyte count normally 0.5 – 1.5%

Chronic blood loss (microcytic, hypochromic RBC’s

are more evident in chronic blood loss)

GIT bleeding: gastric ulcer, hematemesis,

hemorrhoids

o Striking reticulocytosis may not be seen.

Gynecologic causes

Subject: PathologyTopic: RBC’s and Bleeding Disorders Lecturer: Dr. CagampanDate of Lecture: August 9, 2011Transcriptionist: Mopster and Pinay Editor: Mopster and Pinay Pages: 16

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Increased Rate of Destruction (Hemolytic Anemia)

Intrinsic (intracorpuscular) abnormalities of

red cells

o Hereditary

Red cell membrane disorders

Disorders of membrane

cytoskeleton: spherocytosis,

elliptocytosis Disorders of lipid synthesis:

selective increase in membrane

lecithin

Red cell enzme deficiencies

Glycolytic enzymes: pyruvate

kinase deficiency, hexokinase

deficiency

Enzymes of hexose

monophosphate shunt: G6PD,

glutathione synthetase

Disorders of hemoglobin synthesis

Deficient globin synthesis:

thalassemia syndromes

Structurally abnormal globin

synthesis

(hemoglobinopathies): sickle

cell anemia, unstable

hemoglobin

o Acquired

Membrane defect: paroxysmal

nocturnal hemoglobinuria

Extrinsic (extracorpuscular) abnormalities

o Antibody mediated Isohemagglutinins: transfusion

reactions, erythroblastosis fetalis

Autoantibodies: idiopathic

(primary), drug associated, SLE,

malignant neoplasm, mycoplasmal

infections

o Mechanical trauma to red cells

Microangiopathic hemolytic

anemia: thrombotic

thrombocytopenic purpura, DIC

Cardiac traumatic hemolytic anemia Infections: malaria

Chemical injury: lead poisoning

Sequestration in mononuclear

phagocyte system: hypersplenism

Impaired Red Cell Production

Disturbance of proliferation and

differentiation of stem cells: aplastic

anemia, pure red cell aplasia, anemia of

renal failure, anemia of endocrine disorders

Disturbance of proliferation and maturation

of erythroblasts:

o Defective DNA synthesis: deficiency or

impaired use of vitamin B12 and folic

acid (megaloblastic anemia)

o Defective hemoglobin synthesis

Deficient heme synthesis: iron

deficiency

Deficient globin synthesis:

thalassemias

Unknown or multiple mechanisms:

sideroblastic anemia, anemia of

chronic infections, myelophthisic

anemia due to marrow infiltration

Hemolytic Anemia

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

Markedly increased erythropoiesis with

associated reticulocytosis

Accumulation of hemoglobin degradation

products released by red cell breakdown

derived from hemoglobin (e.g., bilirubin)

Pigment stone formation as a result of

hemoglobin degradation.

Tend to produce extravascular hemolysis

although, on occasion, intravascularhemolysis may occur.

Tend to be autosomal dominant

Rare in the Philippines, except Thalassemia.

Intravascular hemolysis (causes):

o Mechanical injury: e.g., prosthetic

cardiac valves, thrombi

o Complement fixation to red cells: e.g.,

mismatched transfusion

o Toxic injury: e.g., malaria

Manifestations of intravascular hemolysis:

o Anemia

o Hemoglobinemia

o Hemoglobinuria

o Jaundice: a small percentage of gall

stones are of hemoglobin origin

o Hemosiderinuria

Extravascular hemolysis

o Occurs in mononuclear phagocytes of

spleen

o Predisposing factors:

Red blood cell membrane injury Reduced deformability

opsonization

o Sequestration of “deformed” or

“foreign” red blood cells followed by

opsonization phagocytosis as red

cells navigate sinusoids

o These sequestered RBC’s are rendered

“palatable” to macrophages due to

hypoxia and ATP depletion.

o Clinical features

Anemia Splenomegaly

Jaundice

Morphology of hemolytic anemias

o Normoblastic hyperplasia in marrow

o Reticulocytosis in peripheral blood

o Pigment gallstones

o Hemosiderosis

o Jaundice, anemia



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Below: Defective RBC’s sequestered outside are

then phagocytized.

Hereditary Spherocytosis Intrinsic defect in RBC membraneankyrin

deficiency and other (usually spectrin)

skeletal membrane components

RBCspheroidal, less deformable,

vulnerable to splenic sequestration and

destruction

Ankyrin deficiencyassociated with

reduced stability and loss of membrane

fragments as cells traverse circulation

Inherited disorder, in Northern Europe

Autosomal dominant

Morphology:

o Spheroidal RBC (normal is biconcave

disc)

o No central pallor noted

o Moderate splenomegaly due to marked

congestion of the cords of Billroth

o Erythrophagocytes in the splenic cords

o Features of hemolytic anemia

Clinical course: treatment is splenomegaly

o Chronic hemolytic anemia mild to

moderate

o Aplastic crisis parvovirus infection o Hemolytic crisis

o Diagnosis: Osmotic Fragility Test

Below: Cell membrane defect leads to formation of

spherocytes, which are sequestered and rendered

palatable to macrophages.

Below: How primary membrane defect leads to

phagocytosis on a chemical basis. This

pathophysiology is common to most hemolytic

anemia and needs to be known by heart.

Below (next 2 photos): Note round shape of RBC’s

and absence of central pallor.

G6PD Deficiency

X – linked

One of the tests for newborn screening

Impaired or deficient enzyme function

which reduce ability of red cells to fight

against oxidative injuries

Abnormalities in Hexose Monophosphate

Shunt pathway or glutathione metabolism

Need reduced glutathione to protect RBC

against oxidants

Oxidant stress:

o Drugs: antimalarials, sulfonamides, etc

o Infection: viral hepatitis, TF,

pneumonia

o Fava bean ingestion



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Pathogenesis: Oxidative stress results in

the oxidation of globin chains which causes

the globin chains to denature and

precipitate to form Heinz Bodies. Heinz

bodies render the RBC palatable to

phagocytes. Sometimes, the Heinz bodies

are so abundant, that intravascular

hemolysis can occur. Extravascular and

intravascular hemolysis can occur.

Below: Not the Bite Cell in the center of the larger

picture. In the smaller picture in the upper left

corner, note the presence of Heinz Bodies under

special stain.

Sickle Cell Anemia

Structurally abnormal hemoglobin

Substitution of valine for glutamic acid at

the 6th position of β globin chain

American blacks:o Heterozygote: 40% HgbS

o Homozygote: 100% HgbS

Under deoxygenation, the RBC will sickle.

At first the sickling is reversible until such

time that the RBC can no longer change its

shape and is sequestered and phagocytized.

Infarction: sickle cells have the unique

feature of having increased adhesion to

each other. This what causes them to

aggregate and form thrombi which can lead

to infarct. Morphology:

o Hyperplastic marrowlead to

resorption of bone

o Extramedullary hematopoiesis

o Sickle red cells

o Initial splenomegaly erythrocytosis

thrombosis and infarction scarring

autosplenectomy

o Infarction in bone, brain, kidney, liver,

and retina

o Leg ulcer, cor pulmonale

o Pigment gallstones

Clinical course:

o Severe anemia: reticulocytosis

o Vasoocclusive complications: acute

chest syndrome

o Chronic hyperbilirubinemia: gallstoneso Increased susceptibility to

infectionsepticemia and meningitis

o CNS hypoxia: seizures, stroke

o Aplastic crisis: triggered by parvovirus

infection

o Sequestration crisis

o Priapism: thrombi lead congestion of

blood vessels which can lead to

persistent, painful erection.

Diagnosis

o PBS, metabisulfite-induced sickling

o Hemoglobin electrophoresis

o Fetal DNA by chorionic biopsy of

amniocentesis

Below: Single point mutation leads to sickle cell

formation which leads to hemolysis in the spleen

and infract in the tissues.

Below: Sickle cell admixed with anisocytosis,

hypochromia, poikylocytosis

Below: Spleen shrunken down to 3 cm.



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Below: Severe congestion because of trapping of

the RBC’s

Thalassemia

α type seen in the Philippines

o There are 2 genetic loci for the α chain,

thus there are 4 alleles. There are 4

types of α thalassemia, each type

coinciding to a loss a allele. Type 1: Loss or mutation of single

allele. Minimal symptomatology

because the other 3 chains are

present.

Type 2: 2 alleles affected. Mild

anemia.

Type 3: 3 alleles affected. Leads to

Hemoglobin H.

Type 4: 4 alleles affected. Hydrops

fetalis. No chance of survival.

Patients with mild forms of the disease are

usually asymptomatic and are noticed to

have anemia when a CBC is ordered. They

are then given iron, which does not improve

the anemia. The astute doctor may suspect

another diagnosis, order an electrophoresis

and this is when thalassemia is diagnosed.

Mendelian disorder characterized by a lack

of or decreased synthesis of either α or β

globin chain of HbA

β Thalassemialack of β globin chains with

excess α chain

o Thalassemia major: both alleles of theβ chain are affected.

o Thalassemia minor: only one allele of

the β chain is affected. Aka, Cooley’s

anemia.

α Thalassemialack of α globin chains,

with excess β, γ, δ

Excess chains will precipitate and result in

phagocytosis

Facie: prominent cheekbones because of

increased blood production

Target cells: typical cells seen inThalassemia but not exclusive to it.

Morphology: same as in all HA

o “Crew-cut” appearance of bone on X-

ray due to marrow expansion with

thinning of cortical bone with few bone

formation on the external aspect

o Hepatosplenomegaly

o Hemosiderosis

Clinical course:

o Growth retardation

o Death at early age of homozygous

patient

o Manifestation depends on severity

o Prone to infection

Below: Typical facie of patient with thalassemia.

Prominent cheekbones are a result of increasedblood production by the facial bones in order to

compensate for RBC loss.

Below: Pathophysiology of β thalassemia. There is

reduced β hemoglobin with a relative excess α

hemoglobin as a compensatory mechanism. The

excess α globin precipitates in RBC. Most die inbone marrow, but some will make it into circulation

where they will be sequestered in spleen and

destroyed. The resulting anemia causes increased

erythropoiesis and increased iron absorption as the

body attempts to correct the anemia. As a result,

bone marrow expansion occurs as does systemic

iron overload. The bone deformities that result in

the facie are a result of bone marrow expansion.

Note that iron overload also comes from

destruction of the erythroblasts within the bone

marrow and from regular blood transfusions that

are required by these patients.



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Below (next 3 pics): Target cells. Note: these are

not exclusive to thalassemias.

Below: “Crew cut” appearance of skull resulting

from increased erythropoiesis.

Below: Hepatic hemosiderosis in Beta Thalassemia

Assignment: Another name for target cell, why

does it happen?

Answer: Codocyte, leptocyte, or Mexican hat cell.

Seen in thalassemia, liver disease, post –

splenectomy patient. What causes targeting is

uneven distribution of hemoglobin.

Paroxysmal Nocturnal Hemoglobinuria

Acquired defect in cell membrane

Somatic mutation of the PIGA gene which is

essential for synthesis of the GPI(glycophosphatidylinositol) anchor

GPI – linked proteinsinactivate

complement

Other cells affected because GPI is found in

all blood cells, so patient can have

pancytopenia.

If patient is subject to an immune reaction

involving complement it can lead to lysis.

Ham’s Test: how it’s diagnosed.

Immunohemolytic Anemia Demonstration of the anti – RBC Ab

Coomb’s Test

Classification of Immune Hemolytic Anemias

Warm Antibody Type

o The antibody is of the IgG type, does

not usually fix complement and is active

at 37° C.

o Primary (Idiopathic)

o Secondary

Lymphomas and leukemias

Other neoplastic diseases

Autoimmune disorders (particularly

SLE)

Drugs

Cold Agglutinin Type

o The antibodies are IgM and are most

active in vitro at 0° C to 4° C.

Antibodies dissociate at 30° or above;

agglutination of cells by IgM and

complement fixation only in peripheral

cool parts of the body (eg, ears, toes,

and fingers)o Acute:

Mycoplasmal infection

Infectious Mononucleosis

o Chronic:

Idiopathic

Associated with lymphoma

Cold Hemolysin type (Paroxysmal

Hemoglobinuria)

o IgG antibodies bind red cells at cold

temperature, fix complement, and

cause hemolysis when the temperatureis raised above 30° C.

Hemolytic Anemia Resulting from Trauma to rBC

1. Prosthetic cardiac valves (mechanical)

2. Microangiopathic Hemolytic Anemia:

abnormally narrowed vessels



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a. In DIC, malignant HTN, SLE, TTP,

Hemolytic-uremic syndrome,

disseminated cancer

b. See schistocytes, burr, helmet cells,

and triangle cells (couldn’t find a

pic, but some explanations basically

say these are RBC remnants that

resemble triangles). Note:

schistocytes are usually a sign of trauma, intravascular or

extravascular.

Below: Schistocyte

Below: Burr cell

Below: Target cell

Below: Helmet cell. Resembles Bite Cell, but Bite

Cell will have 1 bite, Helmet Cell will have >1 bite.

Anemias of Diminished Erythropoiesis

Megaloblastic Anemia

Impaired DNA synthesis leading to defective

nuclear maturation. DNA synthesis is

affected but RNA synthesis does not.

Asynchronism between nuclear and

cytoplasmic maturation. Immature nucleus

with very mature and often huge cytoplasm Due to folate or vitamin B12 deficiency.

o Vitamin B12 must be obtained through

the diet. It is absorbed in the ileum and

requires intrinsic factor.

o These are necessary for DNA synthesis

o RNA synthesis continues

o There is a lag so cell becomes

megaloblastic

Morphology:

o Macro – ovalocytes

o Hypersegmented neutrophils (>6 lobes)

o Bone marrow hypercellular (1:1)

o Megakaryocytes large with bizarre,

multilobate nuclei

o Ineffective

erythropoiesisintramedullary

destruction of megaloblast

o Increased hemolytic destruction of RBC

o Leukopenia and thrombocytopenia

o In short, pancytopenia



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Below: Normal vitamin B12 metabolism. R –

binder is produced by the salivary gland. Vitamin

B12 is digested in the stomach via gastric acids and

binds with R – binder. It is carried through the small

intestine, where the B12 – R-binder complex is

digested by proteases. Vitamin B12 is now bound

to Intrinsic Factor and carried to the ileum, where it

is absorbed into the portal circulation. Intrinsic

factor is the switch by which vitamin B12 isabsorbed. Disruption of the GI tract, loss of R –

binder or Intrinsic Factor can all lead to

malabsorpton of vitamin B12.

Below: Macroovalyctes. Bone marrow would be

hypercellular, composed of RBC series, all

megaloblasts. Because megaloblastic anemia

affects all cell lines, PMN’s will also be affected.

They will appear, as below, as hypersegmented (>5

lobes) because of the asynchrony between DNA and

RNA synthesis. Sometimes, the deficiency is so bad,

RBC’s can be destroyed in the bone

marrowineffective erythropoiesis just likeThalassemia. Again, megaloblastic anemia may

manifest as pancytopenia in the bone marrow.

Below: Bone marrow looks busy, hypercellular.

The cells are very large nucle, hyperchromatic, and

granular. There appears to be maturation of the

cytoplasm with a lag in the nucleus:cytoplasm ratio.

Below (next 3 pictures): Macro – ovalocytes in the

PBS with schistocytes.



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Pernicious Anemia

Autoimmune destruction of gastric mucosa

Chronic atrophic gastritis lack of intrinsic

factor

Presence of autoantibodies against parietal

cellsblocking Ab, Type II Ab and parietal

canalicular Ab

Morphology:

o GIT Atrophic glossitis

Diffuse chronic gastritis. This is

specific to pernicious anemia. If it is

not due to pernicious anemia, you

won’t find this.

Intestinalization of gastric glands

o CNS lesion

Myelin degeneration of the dorsal

and lateral tractssensory motor

deficits

Diagnostic features:o Moderate to severe megaloblastic

anemia

o Leucopenia with hypersegmented

granulocytes

o Mild to moderate thrombocytopenia

o Neurologic changes: “subacute

combined degeneration”

o Achlorydia even after histamine

stimulation. Remember, histamine is

supposed to release gastric acids. The

patient with pernicious anemia will not

do this.

o Inability to absorb oral dose of

cobalamine – “Schilling Test”

o Low serum B12

o Excretion of methylmalonic acid in urine

o Improvement after parenteral B12

o Demonstration of antibody to instrinsic

factor

Below: Atrophic glossitis

Below: Atrophic gastritis

Below: myelin degeneration of the dorsal tracts



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Below: Myelin degeneration of the lateral tracts

Folate Deficiency

Same as B12 deficiency but without

neurologic changes

Iron Deficiency Anemia

Most common nutritional deficiency

Iron is absorbed in the duodenum and can

be recycled. Storage pool of Fe: hemosiderin and

ferritin

Ferritin:

o Protein – iron complex; stored in

parenchymal cells or within RES

o Level is a good indicator of adequacy of

body iron stores

o Iron deficiency

anemia↓iron↓Ferritin

Transferrin:

o Iron – binding glycoprotein whichtransports iron in plasma; deliver iron

to cells including erythroid precursors

(TIBC)

o When iron is deficient↑TIBC

(because the body is scavenging for

iron)

Causes of iron deficiency:

o Dietary lack: in elderly, poor, infants,

and children

o Impaired absorption: in malabsorption

o Increased requirement: growing infants

and children, adolescents,

premenopausal, pregnancy

o Chronic blood loss: hemorrhoids, GIT

Ca, parasitism, menstrual

abnormalities, urinary tract bleeding

Morphology:

o Normoblastic hyperplasia in marrow

o Microcytic, hypochromic RBC

Diagnosis:

o PBS findings, decreased hemoglobin

and hematocrit, low serum Fe and

serum Ferritin TIBC (transferrin

concentration) is high

Below: Microcytic, hypochromic RBC’ssmall and

paler central pallor. The PMN is used as a point of

reference to determine the relative size of RBC.

PMN’s are around 12μm. The RBC’s in the PBS

below are ¼ the size, so around 4 – 5 μm. Normal

RBC’s are usually 6 – 7 μm, or 1/3 the size of a PMN.

Anemia of Chronic Disease

Reduced erythroid proliferation and

impaired Fe utilization

Chronic infection: osteomyelitis, bacterial

endocarditis, lung abscess

Chronic immune disorder: RA, Crohn’s

Neoplasms: Hodgkin’s CA of lung and

breast

Pt. peripheral blood smear may appear like

iron deficiency anemia, but stores are

normal

The failure is in the utilization of iron, not

in the amount.

Diagnosis:

o Low serum Fe, decreased TIBC but

abundant stored iron in marrow

macrophage

o Low erythropoietin levels marrow

hypoproliferation

Aplastic Anemia

Pancytopenia characterized by anemia,

neutropenia, and thrombocytopenia Bone marrow is almost converted to fat.

Cells present are usually lymphocytes.

Normal BM is 50:50.

Morphology:

o Markedly hypocellular marrow – “fatty

marrow”

o Fibrous tissue with scattered

lymphocytes



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Below: Most of the time cause is unknown, but

when it is known, it is usually drug induced.

Below: Pancytopeniaall cells are decreased.

Markedly hypocellular marrow. Sometimes fibrotic

with scattered lymphocytes.

Below: Note the abundance of fat in the marrow.

Other Forms of Marrow Failure

Myelophthisic anemia

o Due to space – occupying lesions in

marrow; metastatic carcinoma; multiple

myeloma, leukemia, Tb

Diffuse liver disease

Chronic renal failure

Below: myelophthisic anemia secondary to

leukemia. Leukemias typically fill up the marrow

with abnormal cells.

Bleeding Disorders

Can be caused by :

o Increased blood vessel fragility/ Vessel

wall abnormality

o Platelet disorders/ abnormality (both in

function and in number)

o Coagulation defects

Evaluation requires laboratory testing:o Bleeding time: tests platelet function

o Platelet counts

o Prothrombin time: tests extrinsic

pathway (Mnemonic: PeT, prothrombin

extrinsic time)

o Partial Thromboplastin time: tests

intrinsic pathway (Remember: PiTT,

partial intrinsic thromboplastin time)

o Specialized tests (e.g., clotting factor

levels)

I. Vessel Wall Abnormality

relatively common but usually do not

cause serious bleeding

typically induce only petechial and

purpuric hemorrhages

Can be caused by infections, drug

reactions, autoimmune diseases, vitamin

deficiency, immune complex deposits, or

hereditary disorders

normal platelet count, BT, PT, and PTT

Conditions which causes increased vascular fragility:1. Infections

a. Meningococcemia (Waterhouse –

Friedrichsen syndrome), gram (-)

septicemia, infective endocarditis,

rickettsiosis

b. Microbiologic damage to vessels

(vasculitis) or DIC (Disseminated

intravascular coagulation) underlying

mechanism

2. Drug reactions – often secondary to

immune complex deposition in vessel wallswith resulting hypersensitivity vasculitis

3. Poor vascular support

a. Abnormal collagen synthesis (Scurvy,

Ehlers- Danlos Syndrome: impaired

collagenous support

b. Loss of perivascular supporting tissue

(Cushing syndrome)

c. Vascular wall amyloid deposition

4. Henoch – Schonlein Purpura: systemic

hypersensitivity reaction of unknown cause

characterized by purpuric rash, abdominal

pain, polyarthralgia, and acute

glomerulonephritis. Associated with

vascular and glomerular mesangial

deposition of immune complexes.

5. Hereditary hemorrhagic telangiectasia

II. Reduced platelet number:

Thrombocytopenia= characterized principally by

petechial bleeding, most often from small vessels of



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skin and mucous membranes. Count is

<100,000/mm3

Normal: 150,000 – 450,000/mm3

Thrombocytopenia: <100,000/mm3

Spontaneous bleeding: <20,000/mm3

***Sometimes patient has <10,000/mm3 and

patients don’t bleed, or has <50,000/ mm3 and

already experienced spontaneous bleeding therefore clinically it really depends on when to

start your management; as physicians we should

know when to act

Causes:

a. Decreased production: due to ineffective

megakaryopoiesis (e.g., megaloblastic

states) or to generalized marrow disease

that also compromises megakaryocyte

number (e.g., aplastic anemia, disseminated

cancer).

b. Decreased survival: due to immune-

mediated platelet destruction, usually with

a compensatory megakaryocytic marrow

hyperplasia

-it can follow drug exposure or

infections

-platelet deficiencies due to

consumption often occur in systemic

coagulopathies (DIC, hemolytic uremic

syndrome, thrombotic

thrombocytopenia purpura).

c. Sequestration: platelets are retained in thered pulp of enlarged spleens

d. Dilution: massive whole blood transfusions

can cause a relative reduction in the

number of circulating platelets because

storage for longer than 24 hours at 4°C

results in rapid hepatic platelet

sequestration upon infusion.

e. HIV: results from immune complex injury,

antiplatelet antibodies, and HIV- induced

suppression of megakaryocytes.

Idiopathic Thrombocytopenic Purpura (ITP)/

Immune Thrombocytopenic Purpura

: antibody- mediated platelet destruction

Acute (children)

o Self-limiting

o Seen most often in children after a viral

infection (e.g., rubella, cytomegalovirus

infection, viral hepatitis, infectiousmononucleosis)

o Platelet destruction is due to transient

antiplatelet autoantibodies.

Chronic (adult<40 y/o), mostly female of

childbearing age

o Long history of easy bruising or

nosebleeds

o Platelet autoantibodies (synthesized in

the spleen) are usually directed toward

one of two platelet antigens (platelet

membrane glycoprotein complexes IIb/

IIIa or Ib/IX).

o Destruction of antibody-coated

platelets occurs in the spleen.

o Splenectomy benefits 75- 80% of

patients

Antiplatelet antibodies

Pathogenesis: opsonized platelet

susceptible to phagocytosis by RES cells (in

spleen)

Morphology: spleennormal in size

o Congestion of sinusoids and enlarged

follicles

o Prominent germinal centers

o Megakaryocytes within sinusoids

o Bone marrowincrease number of

megakaryocytes

Below: Bone marrow in ITPincreased number of

megakaryocytes, because it is a compensatory

mechanism. If ITP count is not increased in the

bone marrow, you can pretty much rule out ITP.



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Below: normal spleen. But there may be

megakaryocytes in the spleen.

Thrombotic Microangiopathies:

-characterized byo Thrombocytopenia

o Microangiopathic hemolytic anemia

o Fever

o Transient neurologic deficits (in TTP)

o Renal failure (HUS)

-most of the clinical manifestations are due to

widespread hyaline microthrombi in arterioles and

capillaries (microcirculation) composed of dense

aggregates of platelets and fibrin

-platelets adhere more to the thrombi

Thrombotic Thrombocytopenic Purpura(TTP)

o Associated with inherited or acquired

deficiencies in ADAMTS13 (a

matalloprotease that limits the size of

von Willebrand factor multimers in the

plasma.

o In adult female

o Pentad of: fever, thrombocytopenia,

microangiopathic hemolytic anemia,

neurologic defects, renal failure

o Probably viral - induced

Hemolytic – uremic syndrome (HUS)

o Commonly follows gastrointestinal

infections with verotoxin-producing

E.coli.

Verotoxin injures endothelial cells

promotes dysregulated platelet

activationaggregation

o Microangiopathic hemolytic anemia,

thrombocytopenia and acute renal

failure o Onset in childhood

o Follow infection with verotoxin –

producing E. coli

Both show widespread formation of hyaline

thrombi in microcirculation

Bleeding Related to Defective Platelet Function

A. Congenital Disorders

1. Defective adhesion

a. “Bernard – Soulier Syndrome” :

caused by deficient platelet

membrane glycoprotein complex

GpIb/ IX- platelet receptor for vWF

and necessary for platelet-collagen

adhesion

b. Inherited deficiency of platelet

membrane glycoprotein

2. Defective aggregation

a. Thrombasthenia: caused by

deficient platelet membraneglycoprotein GpIIb/ IIIa- involved in

binding fibrinogen

3. Defective secretion- platelet will secrete

an enzyme to stabilize the plug

B. Acquired disorders

1. Aspirin ingestion- potent inhibitor of

cyclooxygenase and can suppress the

synthesis of thromboxane A2 – for

platelet aggregation

2. Uremia

III. Bleeding due to Abnormalities in Clotting

Factors

von Willebrand’s Disease

Autosomal dominant

Characterized by spontaneous bleeding

from mucous membranes; excessive

bleeding from wounds, menorrhagia



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Prolonged BT, PTT, normal platelet count,

reduced vWF and Factor VIII levels

May have quantitative or qualitative effect

in VWF

Compound defects involving platelet

function and coagulation pathway

Hemophilia A (Factor VIII Deficiency)

X – linked recessive trait; in male andhomozygous female

Reduction in amount or activity of Factor

VIII

Severity depends on Factor VIII activity;<1%

Factor VIII activity is severe disease

Easy bruising and massive hemorrhage after

trauma or operation

Spontaneous joint hemorrhages –

hemarthrosesrecurrent

bleedingdeformities

Normal BT, platelet count, and PT,prolonged PTT

Below: Easy bruising is common

Below: Bleeding gums is common

Below: Genogram showing the X – linked

inheritance of Hemophilia in the royal families of Europe.

Disseminated Intravascular Coagulation (DIC)

-an important complication= not a disease but a

complication of some other disease

Acute, subacute, and chronic

thrombohemorrhagic disorder occurring as

a secondary complication in a variety of

disease

Characterized by activation of the

coagulation sequence that leads toformation of microthrombi throughout the

microcirculation

Consumption of platelets, fibrin,

coagulation factors with secondary

activation of fibrinolytic

mechanisms”Consumptive

Coagulopathy”

2 major mechanisms which trigger DIC

o Release of tissue factors or

thromboplastic substances

o Injury to endothelial cells

releasingthromboplastic substances, which

causes:

Massive thrombosis

Bleeding to death

***massive thrombosis release of thromboplastic

substancestrigger the coagulation system

consume more factorsbleed spontaneously

death.

***Can be difficult to treat as there are 2 stages:

thrombotic and bleeding. If patient is in the

thrombotic stage, then giving fibrinogen can

potentially worsen the condition because itconsumes more factors to be used. If during the

bleeding stage, giving thrombotic agents can also

hasten the bleeding.

***Thrombi can lead to ischemia tissue damage

Morphology:

o Multiple thrombi in one or several

organs

o ARDS in lungs, microinfarcts in brain,

adrenal hemorrhages

Below: common causes of DIC. Most commoninfective agent is Gram negative sepsis. Whatever,

the cause, it triggers DIC through the release of

coagulation factors.



Below: Pathophysiology of DIC

Below: DIC causes thrombi that can lead to occlusion of the blood vesselsischemia in various organs.

Note: With DIC the patient is usually admitted for another condition, but develops clotting disorders because

DIC is a complication and rarely a primary disorder itself.

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“And God showed His love for us by sending His own Son into the world.” 1 John 4:9-10

2011-08-PATHO-Red Blood Cells and Bleeding Disorders (1)

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