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, hemorrhoidso Striking reticulocytosis may not be seen.

Gynecologic causes

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

Increased Rate of Destruction (Hemolytic Anemia) Intrinsic (intracorpuscular) abnormalities of

red cellso 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, intravascular hemolysis 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 Anemiao Hemoglobinemiao Hemoglobinuriao Jaundice: a small percentage of gall

stones are of hemoglobin origino 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 marrowo Reticulocytosis in peripheral bloodo Pigment gallstoneso Hemosiderosiso Jaundice, anemia

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 notedo Moderate splenomegaly due to marked

congestion of the cords of Billrotho Erythrophagocytes in the splenic cords o Features of hemolytic anemia

Clinical course: treatment is splenomegalyo Chronic hemolytic anemia mild to

moderateo Aplastic crisis parvovirus infectiono Hemolytic crisiso 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

Primary

membrane skelet

al defect

Surface to volume ratio

(spherocytosis) Cellular deformity

Membrane instability

Membrane loss

ATP depletionAcid-induceddamage

Macrophageprocessing

Erythrostasis Glucose pH Macrophage contactHemolysis

?phagocytosis?osmotic lysis

???

PATHOPHYSIOLOGY OF HEREDITARY SPHEROCYTOSIS

PATHOPHYSIOLOGY OF HEREDITARY SPHEROCYTOSIS

Oxidant stress:o Drugs: antimalarials, sulfonamides, etco Infection: viral hepatitis, TF, pneumoniao Fava bean ingestion

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% HgbSo 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 boneo Extramedullary hematopoiesis

o Sickle red cellso Initial splenomegaly erythrocytosis

thrombosis and infarction scarring autosplenectomy

o Infarction in bone, brain, kidney, liver, and retina

o Leg ulcer, cor pulmonaleo Pigment gallstones

Clinical course:o Severe anemia: reticulocytosiso Vasoocclusive complications: acute

chest syndromeo Chronic hyperbilirubinemia: gallstoneso Increased susceptibility to

infectionsepticemia and meningitiso CNS hypoxia: seizures, strokeo Aplastic crisis: triggered by parvovirus

infectiono Sequestration crisiso Priapism: thrombi lead congestion of

blood vessels which can lead to persistent, painful erection.

Diagnosiso PBS, metabisulfite-induced sicklingo Hemoglobin electrophoresiso Fetal DNA by chorionic biopsy of

amniocentesisBelow: 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.

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 chaino Thalassemia major: both alleles of the

β 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 in Thalassemia but not exclusive to it.

Morphology: same as in all HAo “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 Hepatosplenomegalyo Hemosiderosis

Clinical course:o Growth retardationo Death at early age of homozygous

patiento Manifestation depends on severityo Prone to infection

Below: Typical facie of patient with thalassemia. Prominent cheekbones are a result of increased blood 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 in bone 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.

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 temperature is raised above 30° C.

Hemolytic Anemia Resulting from Trauma to rBC1. Prosthetic cardiac valves (mechanical)2. Microangiopathic Hemolytic Anemia:

abnormally narrowed vesselsa. 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 synthesiso RNA synthesis continueso There is a lag so cell becomes

megaloblastic Morphology:

o Macro – ovalocyteso Hypersegmented neutrophils (>6 lobes)o Bone marrow hypercellular (1:1)o Megakaryocytes large with bizarre,

multilobate nucleio Ineffective

erythropoiesisintramedullary destruction of megaloblast

o Increased hemolytic destruction of RBCo Leukopenia and thrombocytopeniao In short, pancytopenia

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 is absorbed. 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 like Thalassemia. 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.

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 glandso CNS lesion

Myelin degeneration of the dorsal and lateral tractssensory motor deficits

Diagnostic features:o Moderate to severe megaloblastic

anemiao Leucopenia with hypersegmented

granulocyteso Mild to moderate thrombocytopeniao 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 B12o Excretion of methylmalonic acid in urineo Improvement after parenteral B12o Demonstration of antibody to instrinsic

factor

Below: Atrophic glossitis

Below: Atrophic gastritis

Below: myelin degeneration of the dorsal tracts

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 which

transports 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 childreno Impaired absorption: in malabsorptiono Increased requirement: growing infants

and children, adolescents, premenopausal, pregnancy

Anemias of Diminishe

d Erythropoi

esis

PERNICIOUS ANEMIAMorphology:

GIT atrophic glossitis diffuse chronic gastritis - atrophy of

fundic glands affecting chief and parietal cells

intestinalization of gastric glands- goblet cells

CNS lesion

myelin degeneration of dorsal and lateral tracts

o Chronic blood loss: hemorrhoids, GIT Ca, parasitism, menstrual abnormalities, urinary tract bleeding

Morphology:o Normoblastic hyperplasia in marrowo 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

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 abnormalityo Platelet disorders/ abnormality (both in

function and in number)o Coagulation defects

Evaluation requires laboratory testing:o Bleeding time: tests platelet functiono Platelet countso 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 walls with 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 deposition4. 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 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 the red 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-limitingo Seen most often in children after a viral

infection (e.g., rubella, cytomegalovirus infection, viral hepatitis, infectious mononucleosis)

o Platelet destruction is due to transient antiplatelet autoantibodies.

Chronic (adult<40 y/o), mostly female of childbearing ageo Long history of easy bruising or

nosebleedso 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 sizeo Congestion of sinusoids and enlarged

follicleso Prominent germinal centerso Megakaryocytes within sinusoidso 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.

Below: normal spleen. But there may be megakaryocytes in the spleen.

Thrombotic Microangiopathies:-characterized by

o Thrombocytopeniao Microangiopathic hemolytic anemiao Fevero 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 femaleo 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 childhoodo Follow infection with verotoxin –

producing E. coli

Both show widespread formation of hyaline thrombi in microcirculation

Bleeding Related to Defective Platelet FunctionA. 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 membrane glycoprotein GpIIb/ IIIa- involved in binding fibrinogen

3. Defective secretion- platelet will secrete an enzyme to stabilize the plug

B. Acquired disorders1. 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

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 and

homozygous 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 to formation of microthrombi throughout the microcirculation

Consumption of platelets, fibrin, coagulation factors with secondary activation of fibrinolytic mechanisms”Consumptive Coagulopathy”

2 major mechanisms which trigger DICo Release of tissue factors or

thromboplastic substanceso Injury to endothelial cells releasing

thromboplastic 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 it consumes 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

organso ARDS in lungs, microinfarcts in brain,

adrenal hemorrhages

Below: common causes of DIC. Most common infective 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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