Hematology & Oncology Firecracker

8/12/2019 Hematology & Oncology Firecracker

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Normocytic AnemiaSickle Cell nextOrgan Systems Hematology/Oncology Hematologic Disorders

10 questions

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Definition of hemoglobinopathy: Hb structural abnormality that

causes hemolytic anemia

HbS: - globin gene point mutation substitutes valinefor glutamicacid at codon 6

less

At low O2tension, HbS polymerizes (the substituted Val

residue allows for hydrophobic interactions to occur between Hb

chains) RBCs sickle and cell membranes stiffen, becoming

more likely to hemolyze

Transportation of RBCs through inflamed tissue can also

lead to occlusion of microvasculature.

Inflammatory cells release mediators adhesion molecules

slowing of RBC passage through capillary beds sickling and

occlusion.

Sickled RBCs also obstruct microvasculature splenic

autoinfarction, painful crises

Confers malarial resistance in parts of Africa, 1/3 of

population carries HbS gene

Sickle cell disease: homozygousHbS, severe hemolytic anemialess
https://med.firecracker.me/topics/824https://med.firecracker.me/topics/824https://med.firecracker.me/topics/479https://med.firecracker.me/topics/824https://med.firecracker.me/topics/479


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Sickled shape is due to spontaneous polymerization of HbS

in deoxygenated state.

Painful crises during dehydration, infection, temperature

extremes, or sudden decreases in ambient O2tension (e.g. high

altitude)

Autosplenectomy increased risk of disseminated

infections from encapsulated bacteria (pneumococcus,

meningococcus, H. flu)

Viral infection (esp. parvovirus B19) aplastic crises with

major in hemoglobin concentration

Patients with sickle cell disease are at increased risk for

renal papillary necrosis andSalmonellaosteomyelitis Splenic sequestration occurs in children who have normal,

in tact spleens. Entrapment of sickled RBCs rapid

enlargement of the spleen. This can lead to hypovolemia and

shock and can be fatal.

Sickle cell patients may undergo extramedullary

hematopoeisis. Can often see the same characteristic "crew cut"

skull X-ray that occurs in other conditions with extramedullary

hematopoeisis (e.g., - thalassemia) Treatment: hydroxyurea (causes increased HbF synthesis,

used in severe cases)

Common Complications of Sickle Cell Anemia can be

summarized by the MNEMONIC :

Sickle cell anemia affects different AREASof the body:

Autosplenectomy, acute pain crisis

Renal papillary necrosis

Encapsulated organism infection (S. pneumo, Haemophilus, etc)

Aplastic anemia from Parvovirus B19

Salmonella osteomyelitis, Splenic sequestration

Sickle cell trait: heterozygous HbS, largely asymptomatic


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HbC: same codon is mutated as in HbS ( - chain, codon 6),

except lysine(not valine) is substituted for the glutamic acidless

HbC homozygotes have milder disease than HbS

homozygotes.

HbSC patients (heterozygous HbS and HbC) also have

milder disease vs. HbS homozygotes

Normocytic AnemiaAplastic Anemia nextOrgan Systems Hematology/Oncology Hematologic Disorders

3 questions

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Toxin exposure hypocellular bone

marrow pancytopenia(including reticulocytopenia,

thrombocytopenia, and severe neutropenia)

Specific toxins that can produce aplastic anemia include:benzene, chloramphenicol, gold salts (old Tx for RA),

sulfonamides, phenytoin. It can also result from radiation and

chemotherapy.

Also in parvovirus infections (sickle cell patients at risk)

Labs: reticulocytopenia, normal MCV (in severe cases

macrocytosis, i.e., MCV > 100, may be seen).

Bone marrow aspiration shows hypocellularity.

If chronic and severe, hemosiderosis (systemic iron deposition)

can occur


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Microcytic AnemiaThalassemias nextOrgan Systems Hematology/Oncology Hematologic Disorders

37 questions

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Thalassemias are anemias that are due to defects in synthesis

of - or - globinchains of hemoglobin.

less - Thalassemiais most prevalent in Asian and African

populations.

- Thalassemiais most prevalent in Mediterranean and

African populations.

Thalassemia carriers are protected againstPlasmodium

falciparummalaria.

Clinically significant thalassemias are inherited in

anautosomal recessivefashion.- Thalassemia results from deletionsof entire - globin genes.

less

There are 4copies of the - globin gene, two on each copy

of chromosome 16.

If 1 allele is deleted, the patient is asymptomatic.

If 2 alleles are deleted, this is known as - thalassemia trait.

The patient will develop a mild hypochromic anemia with

increased RBC count. This is not a clinically significant anemia.

Cis-deletions of 2 alleles are prevalent in Asian

populations.

Cis-deletions of 2 alleles increase the risk of hydrops fetalis

and severe - thalassemia in offspring.


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Trans-deletions of 2 alleles are prevalent in African

populations.

If 3 alleles are deleted, the patient will develop a severe

microcytic, hypochromic anemia.

If 3 alleles are deleted, - globin chains form

tetramers (HbH)which precipitate and damage RBCs. Note,

HbH is detectable by electrophoresis.

If 4 alleles are deleted,hydrops fetaliswill develop which

is lethal in-utero.

If 4 alleles are deleted, - globin chains form tetramers (Hb

Barts)which precipitate and damage RBCs. Note, Hb Barts is

detectable by electrophoresis.- thalassemiaresults from mutationsin - globin genes.

Common genetic mechanisms include point mutations or small

deletions within promoter regions or splice sites.less

There are 2 copies of the - globin gene, one on each copy

of chromosome 11.

Mutations can result in absent ( 0) production of - globin

chains. Mutations can also result in decreased(B+) production of -

globin chains.

- thalassemiaminorhas a genetic signature of / + , or

one normal allele and one under producing allele, leading to an

overall decrease in - globin.

- thalassemia minor ( / +) is the mildest form and is

usually asymptomatic.

Blood smear shows microcytic, hypochromic anemia with

increased RBC count and target cells.

Hb electrophoresis shows slightly decreased HbA with

increased HbA2 (>3.5%) and increased HbF.


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- thalassemia majorhas a gene signature of ( 0/ 0), meaning

that both - thalassemia alleles are non-functioning. As a result,

there is zero - globin production.less

- thalassemia major ( 0/ 0) presents with severe anemia

approximately 6 months after birth because the HbF (fetal

hemoglobin) does not require - globin.

In - thalassemia major, - globinchains form tetramers

which precipitate and damage RBCs. These damaged RBCs

then undergo extravascular hemolysis.

In - thalassemia major, ineffective erythropoiesis results in

extramedullary hematopoiesis in the liver, spleen, and otherbones (e.g. skull).

Extramedullary hematopoiesis in the liver and spleen

results in hepatosplenomegaly.

Extramedullary hematopoiesis in the skull results

in crewcutappearance on x-ray.

Extramedullary hematopoiesis in the facial bones results in

characteristic chipmunk facies.

Extramedullary hematopoiesis results in increasederythroid precursors leading to an increased risk of aplastic crisis

from parvovirus B19 infection.

Blood smear shows microcytic, hypochromic RBCs with

target cells and nucleated RBCs. Note, extramedullary

hematopoiesis results in nucleated RBCs.

Hb electrophoresis shows little or no HbA with increased

HbA2 and increased HbF.

Hypersplenism, from extramedullary hematopoiesis and

increased extravascular hemolysis, can result in splenic

infarction and abdominal pain. Note, the increased hemolysis

can also lead to bilirubin gallstones leading to RUQ pain.


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Hb electrophoresis is the diagnostic test of choice for

thalassemias.

Severe thalassemias generally require chronicblood

transfusions.less

Chronic blood transfusions increase the risk of secondary

hemochromatosis. Note, hemachromatosis can be treated with

iron chelation therapy using deferoxamine.

Overview of Anemia nextOrgan Systems Hematology/Oncology Hematologic Disorders

10 questions

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MCV (mean corpuscular volume): One of the best lab values

used for categorizing anemias.

100 = macrocytic. 80-100 = normocyticMicrocytic Anemias: Thalassemias, Anemia of chronic

disease, Iron deficiency, Lead poisoning.

Can be remembered with mnemonic TAILless

Thalassemias will also show target cells, basophilic

stippling Sideroblastic anemia is associated with myelodysplastic

syndrome ("pre-leukemia") as well as chronic alcoholism and

lead poisoning.


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Anemia of Chronic disease commonly presents as

microcytic anemia

The best way to differentiate microcytic anemias is

by serum ferritin levels.

Thalassemia: Normal iron studies. (There is no deficiency of

iron.)

Anemia of Chronic disease: Ferritin, % saturation of

transferrin, serum iron.

Why?

- Inflammatory state (from chronic infection, immune disorders or

neoplasms) IL-6 production release of iron from iron

stores.

- Because iron stores are normal or elevated, ferritin

is increased.- However, circulating iron in the blood is low % saturation

of transferrin and serum iron.

Iron Deficiency Anemia: Ferritin because of deficient iron

stores.

TIBC can also be used to differentiate iron deficiency anemia

from anemia of chronic disease.

Recall that TIBC is inverselyproportional to the bodys iron

stores

- When iron stores are low(as in iron deficiency)


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TIBC is increased

- When iron stores are adequate (as in anemia of chronic

disease) TIBC isdecreased.

Macrocytic (megaloblastic) Anemias: B12and folate deficienciesless

B12(cobalamin) deficiency: associated neurologic defects

Folate deficiency: no neurologic defects

In both B12& folate deficiency, look for hypersegmented

neutrophils

Other lab findings:

- hyperhomocysteinemia (seen in both B12and folate deficiency)

- methylmalonylacidemia: seen in only B12deficiency

Drug induced (DNA synthesis inhibition): AZT, phenytoin

Normocytic Anemias pretty much everything else, but notable

examples:less

Anemia of chronic disease can also cause a normocytic

anemia. Leukemias and aplastic anemia

Enzyme defects (G6PD deficiency)

Hemoglobinopathies (HbC, sickle cell), look for target cells

Haptoglobin: binds free serum hemoglobinless

serum haptoglobin suggests intravascular hemolysis

(more Hb released into serum)

haptoglobin can suggest liver disease (liver cannot

produce normal levels of haptoglobin)

LDH (lactate dehydrogenase): abundant in RBCsless


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serum LDH can suggest hemolysis, but this is

nonspecific (need more evidence for hemolysis to make the

diagnosis)

Direct Coombs Testless

The direct Coombs test (aka direct antiglobulin test) is used

to detect antibodies that are bound directlyto the surface of

RBCs.

RBCs are exposed to anti-humanglobulin. If anti-

RBC antibodies are present on the surface of RBCs, the anti-

human globulin will cause agglutination, thus constituting a

positive test. A positive Direct Coombs Test suggests autoimmune

hemolysis.

Indirect Coombs Test: detects free-floating antibodiesin serumless

A serumsample is incubated with RBCs with known

antigens

RBC agglutination = positive Indirect Coombs Test

Used to cross-match blood for transfusion and in antenatalantibody screening (anti-Rh antibodies against a RH+fetus)

Megaloblastic Anemias nextOrgan Systems Hematology/Oncology Hematologic Disorders

8 questions

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B12/folate deficiency DNA synthesis RBCs grow larger

than normal before dividing


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A Quick Review of B12/Folate Metabolism:

*Folate is absorbed in the jejunum. The enzyme intestinal

conjugase(which is inhibited by phenytoin) is required for

absorption.

*Vitamin B12 is absorbed in the terminal ileum. B12 absorption is

slightly more complicated:

-B12 is bound by R-factor which protects it from gastric acidity

-In the duodenum, pancreatic enzymes hydrolyze the R-factor

bond and B12 is bound by IF (which is synthesized by gastric

parietal cells).

-The B12-IF complex is absorbed in the terminal ileum.

*Folate and B12 are required for the synthesis of dTMP.

B12 deficiency causes neurological symptoms:

-Loss of dorsal column function ( vibration and position sense)

-Loss spinocerebellar tracts proprioception

-Demyelination of the lateral corticospinal tract spasticity,

weakness

Neurological symptoms are due to failure of Methylmalonyl CoA

Succinyl CoA.

Methylmalonyl CoA causes an Propionyl CoA (the

precursor) replacement of acetyl CoA with Propionyl CoA

demyelination.

Note: Megaloblastic anemia caused by B12 deficiency canbe corrected by folate administration, but the neurological

symptoms can not!

Laboratory Findings:

-Hypersegmented neutrophils


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- serum homocysteine (B12 deficiency and Folate deficiency)

and serum methylmalonic acid (B12 only)

Pernicious anemia: autoimmune gastritis leading to IF

(intrinsic factor)less

Also look for achlorhydria, antibodies against IF

(pathognomonic) and parietal cells, pancytopenia,

hypersegmented neutrophils

Schilling Test, part 1:

- patient is given an oral dose of radiolabeled B 12followed by an

intramuscular injection of nonradiolabeled B12

- positiveif < 5% of the radiolabeled B12is detected in urine after

24 hours (indicates pernicious anemia or malabsorption)

Schilling Test, part 2 (perform if part 1 is positive):

- give oral IF+ labeled B12, followed by IM injection of nonlabeled

B12.

- If urine B12 then its pernicious anemia. If urine B12doesnt ,its malabsorption (e.g. Crohns disease, the fish

tapeworm Diphyllobothrium latum)

Explanation of Schilling Test:

The Schilling test is done when a GI cause for B12 deficiency is

suspected. Under normalcircumstances, radioactive B12 should

be absorbed in the gut and excreted in the urine. When there is a

defect in the absorption pathway, lessB12 is seen in the urine.

At that point, the potential causes of B12 malabsorption can be

individually ruled out. What are the causes of B12

malabsorption?

-Pernicious Anemia IF deficiency


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-Bacterial overgrowth B12 breakdown

-Pancreatic insufficiency absorption

-Intestinal tapeworm (diphyllobothrium)

-Terminal ileal disease inability to absorb B12

By replacing missing enzymes (IF or pancreatic) or giving

antibiotics (for bacterial overgrowth) the urine can be analyzed

for an increasein the amount of B12 signifying that B12 has

been absorbed normally.

Folate deficiency: Similar to B12 deficiency in presentation,

except there are NO neurological symptoms.less

Commonly seen in :-Alcoholics

-Pregnancy

-Celiac sprue

-Giardiasis

-Phenytoin use

-Chemotherapeutic agents (e.g. methotrexate)

-TMP-SMX (TMP is a dihydrofolate reductase inhibitor)

-Valproic acid (folate deficiency causes neural tube defects)-Zidovudine

Normocytic AnemiaEnzyme

eficiency nextOrgan Systems Hematology/Oncology Hematologic Disorders

6 questionsTop of Form

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G6PD: X-linked recessive


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less

G6PD deficiency NADPH formation via the Hexose-

Monophosphate Shunt.

NADPH is responsible for regenerating the reduced form of

glutathione from its oxidized form. Glutathione fights oxidative

stress in the cell.

Without NADPH, Glutathione is not regenerated the cell is

more vulnerable to oxidative stress hemolysis

10% incidence in African Americans and persons of

Mediterranean heritage

Exposure to oxidative stress acute, self-limited

intravascular hemolysis hemoglobinuria (dark urine),

hemoglobinemia and jaundice

Oxidative stressors: infection, primaquine, sulfas, nitros,

fava beans

Heinz Bodies:intracytoplasmic aggregates of precipitated

hemoglobin.

Bite Cell:Splenic macrophage will attempt to phagocytose theHeinz body formation of bite cells.

Pyruvate Kinase deficiency: autosomal recessiveless

Chronic lack of ATP leads to membrane damage

extravascular hemolysis.

Pyruvate kinase is an ATP-producing enzyme in the

glycolytic pathway. Since RBCs can only

produce ATP viaglycolysis, this deficiency severely effects theability of RBCs to produce energy. Decreased ATP production in

the RBC altered membrane integrity hemolysis

!olycythemia


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nextOrgan Systems Hematology/Oncology Hematologic Disorders

13 questions

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Polycythemia: Hct, Hb, and RBC count.

Absolute polycythemia: total RBC mass.

Appropriate polycythemia: RBC count increase in response to

chronic hypoxia.

less Hypoxic stimuli O2saturation due to:

- High altitude

- Primary lung disease

- Cyanosis (due to heart disease or CO exposure)

RBC count, RBC mass, and EPO.

Plasma volume (PV)= normal.

Inappropriate polycythemia: RBC count increase withouthypoxic stimulus.

less

No hypoxic stimuli normal O2saturation.

Ectopic EPO production (e.g. from RCC)

RBC production RBC mass and RBCcount

The normal O2saturation distinguishes inappropriate from

appropriate polycythemia.

Plasma volume (PV) can be normal orincreased.

Inappropriate absolute polycythemia from

ectopic EPO production normal PV.


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Inappropriate absolute polycythemia from polycythemia vera

increased PV.

Relative polycythemia: Decreased plasma volume increased

Hct, Hb, and RBC countrelativeto total plasma volume.less

Due to volume depletion:

- Sweating

- Diarrhea

- Burns

Corrected by fluid replacement add whatever was lost.

Usually due to sweating hyposomotic fluid loss replace with

hypotonic salt solution (i.e. Gatorade or Powerade).

Summary of lab findings in polycythemialess

Polycythemia SaO2 RBC Mass PV EPO

Relative polycythemia Normal Normal Normal

Appropriate polycythemia Normal

Inappropriate polycythemia Normal Normal

P. vera Normal

Polycythemia vera: Due to acquired mutations to myeloid stem

cells.


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Microcytic AnemiaAnemia of

Chronic isease nextOrgan Systems Hematology/Oncology Hematologic Disorders

6 questions

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Anemia of chronic disease occurs in the setting of a chronicinfectious or inflammatory process. It is one of the most

common causes of anemia in hospitalized patients.less

Common causes include :

- Chronic infectious processes (TB, osteomyelitis, lung abscess)

- Malignancy (breast, lung, Hodgkins lymphoma)

- Autoimmune disease (SLE, RA)

Pathophysiology of anemia of chronic disease is related to thepersistent release of inflammatory mediators.

less

Inflammatory state IL-6 production release of iron

from iron stores by upregulating synthesis of hepcidin.

Hepcidin is a hepatic protein which inhibits transport of

ironfrom bone marrow macrophages to developing RBCs. Thus, RBCs production takes place in a state of perceived

iron deficiency (despite the fact that iron stores are in fact

adequate).

Laboratory examination is crucial for differentiating anemia of

chronic disease from iron deficiency anemia.


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less

Because iron stores are normal or elevated, ferritin

is increased.

However, circulating iron in the blood is low % saturation of

transferrin and serum iron.

RBCs are generally microcytic and hypochromic, however

they can also be normocytic and normochromic.

Summary of Labs in Anemia of Chronic Disease :

- Ferritin

- MCV

- Serum Iron

- % Saturation of Transferrin

- TIBC

Comparison of Labs in Anemia of Chronic Disease and Iron

Deficiency Anemia:

"ron eficiency Anemia of Chronic isease Ferritin Ferritin

MCV MCV

% Sat % Sat

TIBC TIBC

Treatment of underlying inflammatory condition is paramount.

Do NOTgive iron!

Microcytic Anemia"ron eficiency nextOrgan Systems Hematology/Oncology Hematologic Disorders

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Iron deficiency anemia is most commonly the result of chronic

blood loss: menorrhagia, gastrointestinal bleeding (e.g. colonicpolyp or cancer, Meckels diverticulum in children).

less

Can also occur in breast fed infants; human milk has low

iron.

Also, note that iron is absorbed in the duodenum, so any

disease process of the small bowel (i.e. Crohns, celiac) thataffects the duodenum may compromise iron absorption.

Plummer-Vinson Syndrome: Triad of anemia, glossitis and

esophageal webs. Be suspicious if a patient presents with

symptoms of dysphagia and has concurrent anemia.less

Patients with Plummer Vinson syndrome may have

increased risk of developing esophageal squamous cell cancer.

Labs: serum iron, ferritin, and TIBCless

Ferritin is the intracellular protein that stores iron.

Serum ferritin is correlated to intracellular iron stores

serves as an excellent way to differentiate iron deficiency anemia

( ferritin) from anemia of chronic disease ( ferritin)

The increase of TIBC is due to a decrease in the total

number of binding sites occupied by iron. Rememberthat TIBC and Transferrin always change in the same direction!

The change in transferrin is due to a negative feedback process.

When the body senses a decrease in total iron upregulation of

Tf synthesis


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MCV (microcytic)

Iron deficiency anemia is treated by replenishing iron stores.less

Oral Iron :

- Oral iron is the mainstay therapy for iron deficiency anemia.

- Oral iron tablets should not be taken with tea, coffee or calcium

supplements as these will decreasethe absorption.

- Conversely, acidity (Vitamin C or orange juice) will increasethe

absorption of iron.

- Side effects of oral iron include: nausea, vomiting and

constipation. Additionally, iron tablets will cause the stool to

appear black, but this is NOT because of GI bleeding.

Parenteral Iron :

- IV iron is used in patients who are unable to absorb iron

enterally (small bowel resection, inflammatory bowel disease,

etc.)

- It must be administered in the hospital.- Generally well tolerated, however one formulation, iron dextran,

can cause life-threatening anaphylaxis.

Blood Transfusion :

- Blood products are generally reserved for patients who are

unstable (either hypotensive due to bleeding or hypoxic due to

anemia).

- The threshold for transfusion varies based on the patients co-

morbid conditions, but is generally considered to be hemoglobinof 7 for healthy patients and hemoglobin of 10 for patients

with CAD.


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Normocytic Anemia#emolytic

Anemias nextOrgan Systems Hematology/Oncology Hematologic Disorders

9 questions

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Warm autoimmune hemolytic anemia: positive Direct CoombsTestless

Most common immune hemolytic anemia

IgGautoantibodies (most active at 37C, hence "warm")

Associated with underlying diseases: SLE, Hodgkin/non-

Hodgkin lymphomas, chronic lymphocytic leukemia

Associated with some drugs, e.g., - methyldopa

stimulates production of autoantibodies against Rh antigens Commonly results in extravascular hemolysisby splenic

macrophages splenomegaly

Cold agglutinin disease: RBCs clump when placed on ice but

disaggregate when re-warmedless

IgMantibodies, usually against I group antigen

Can be triggered by EBV or Mycoplasma

pneumoniaeinfections

"The 3 Ms" mnemonic: IgM, Mycoplasma, Mononucleosis

Mnemonic for remembering cold vs warm

agglutination: Georgia is warmer than Maine.


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CD59 attachment. The corresponding gene

is PIGA(phosphatidylinositol glycan class A), on the X

chromosome.less

CD55 and CD59 inactivate complement. The GPI anchor

deficiency leads to complement mediated hemolysis.

Patients occasionally (paroxysmally) wake up with

hemoglobinuria (nocturnal)

Sxs: anemia, thrombosis, pancytopenia, hypercoagulable

state

#o$gkin%s &ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies

10 questions

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Malignancy that usually affects young malesless

All subtypes of Hodgkins lymphoma are more common in

males except nodular sclerosingtype, which affects young

women greater than men.

The identification of Reed-Sternberg (RS) cells is requiredfor

diagnosis of Hodgkin lymphoma.less

RS cells are classically seen as a cell with 2 nucleisurrounded by clear cytoplasm.

Reed-Sternberg cells are of B cell origin and are CD15 and

CD30 positive


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less

Associated with EBV infection in approximately 40% of

cases good prognosis

Lymphocyte-depleted: Least common form (


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B cells that have undergone somatic hypermutationto become

plasma cells.

Malignant cells readily seen on bone marrow

biopsy/aspiration, which is requiredfor diagnosis.

MM is generally considered a disease of the elderly, with peak

incidence occurring between ages 65-70.less

Common features can be remembered with mnemonic :

MM patients can be crabby CRABBI

HyperCalcemia

Renal insufficiency

AnemiaBence-Jones proteinuria

Bone lesions (lytic)

Infections

Because immunoglobulin production is compromised, the

most common cause of death isrecurrent infection.

Bence Jones proteinuria: Ig light chains in urine.

This causes renal insufficiency 2nd most common cause of

death.

Peripheral smear: rouleaux, a stacking of RBCs which is a

sign of inflammation.

Amyloidosis(AL type) often occurs because of the

excessive production of light chains.

Tumors produce lytic lesionsof bone severe bone pain,

spontaneous fracturesless

Skull & axial skeleton most commonly involved

Excessive bone resorption can precipitate hypercalcemia,

which can present with neurological manifestations such as


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confusion and weakness, as well as polyuria, constipation and

bone pain (recall: bones, stones, groans and psychic

overtones).

Since a plasma cell can only produce 1 antibody and this is a

clonal population massive quantities of one immunoglobulin

M protein. NOTE: This is not the same M-protein associated

with strep pyogenes!less

Single, sharp spike on electrophoresis

Usually IgG or IgA

Normal antibody synthesis can be impaired infection

(e.g. pneumococcus, Hemophilus)MGUS(monoclonal gammopathy of undetermined significance

(5-10% of healthy older persons)less

Monoclonal M protein spike w/o Bence Jones proteinuria

Asymptomatic, benign

No concentration of normal immunoglobulins

Waldenstrm macroglobulinemia: neoplastic B cells

in lymphoplasmacytic lymphomaproduce monoclonal IgMless

No bony lesions

Waldenstrm macroglobulinemia is most commonly

characterized by a hyperviscosity syndrome.

1) Neurologic symptoms: Visual impairment, headaches, deafness,

lethargy.

2) Cryoglobulinemia: Precipitation of macroglobulins at low

temperatures (may require plasmapheresis).

3) Bleeding: Consumption of clotting factors into large complexes with

macroglobulins can interfere with the coagulation cascade.


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Approximately 10% of patients have autoimmune hemolytic

anemia caused by IgM (cold agglutinins).

Non(#o$gkin &ymphomaOverview nextOrgan Systems Hematology/Oncology Hematologic Malignancies

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Non-Hodgkins Lymphoma (NHL) is a malignant neoplasm, oftenoriginating from lymph nodes/lymphoid tissues

less

B-cell Lymphoma: originate from B-cells within the

germinal follicle and include:

-Burkitts Lymphoma

-Diffuse large B-cell lymphoma (DLBCL)

-Follicular lymphoma

-Small lymphocytic lymphoma (SLL)-MALToma

T-cell lymphoma:

-Mycosis fungoides and Sezary syndrome

Periaortic nodes often involved

Noncontiguous spread observed

There are several infections and predisposing conditions

associated with the pathogenesis ofNHL

less

Bacterial Infections

-H. pylori: MALToma a low grade lymphoma found in the

gastric mucosa-associated lymphoid tissue (i.e. MALT)


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Viral Infections

-HTLV-1 (Human T-cell leukemia virus type I): adult T-cell

lymphoma

-EBV: Burkitts lymphoma, DLBCL, CNS lymphoma

-HCV: B-cell lymphoma

Hashimotos thyroiditis predisposes to thyroid lymphoma

Diffuse large cell lymphoma (DLBCL): most common non-

Hodgkins lymphoma. 80% are B-cell in origin, remaining 20%

are T-cell in origin.less

Presentation: Typically presents as rapidly enlarging mass

that can present anywhere in the body. Can be found in nodalor extranodal tissue. Associated with an aggressive, widespread

dissemination rapidly fatal if untreated.

CD19+ and CD20+

Non(#o$gkin &ymphoma)'rkitt

&ymphoma nextOrgan Systems Hematology/Oncology Hematologic Malignancies

3 questions

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Burkitt's lymphoma is linked to EBV infection

less

Burkitts lymphoma (small non-cleaved non-Hodgkin's

lymphoma): B-cell lymphoma

-African form: maxilla/mandible involvement

-American form: abdominal organ involvement


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"8urkitt's" (8 looks like a B):

t(8;14) translocation c-mycproto-oncogene moved next to Ig

heavy chain gene c-myc overexpression cell proliferation

(high grade)

Can also be caused by t(2;8) or t(8;22)

Starry sky appearance: normal macrophages ingest cellular

debris from rapid cell turnover

Because Burkitt lymphoma exhibits a very high mitotic rate

and rapid turnover of cells with high levels of apoptosis, it

inherently can NOT express Bcl-2. Contrast this with follicular

lymphoma where translocation causes overexpression of Bcl-2.

Non(#o$gkin &ymphomaT(Cell


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Precursor T-cell lymphoblastic leukemia/lymphoma commonly

presents with a mediastinal mass.less

Formerly "lymphoblastic lymphoma", but the WHO now

classifies it as a form of ALL Thymic lymphocyte origin

Usually occurs in children

Rapid progression (b/c its an ALL variant)


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Mycosis fungoides and Sezary syndrome are neoplastic

conditions of CD4+ Helper T cellsless

Mycosis Fungoidespresents as a cutaneous rash which

spreads to lymphoid tissue, liver and lungs.

Sezary Syndromeoccurs when CD4+ T cells invade the

blood leukemia. The circulating cells are called Sezary cells

Non(#o$gkin &ymphomaSmall

&ymphocytic &ymphoma

nextOrgan Systems Hematology/Oncology Hematologic Malignancies

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Small lymphocytic lymphoma (SLL) is a neoplasm of mature

(peripheral), small, monoclonal B-cells.less

SLL is considered the same disease as chronic

lymphocytic leukemia (per WHO) but SLLis limited to lymph node

involvement.

Men, older than 60 years of age are most commonly

affected.

SLL is preceded by monoclonal B-cell lymphocytosis, which

results from cytogenetic abnormalities leading to an abnormal

response to antigen stimulation and thus proliferation of the

mutated B-cell.less


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Affected B-cells express mutated B-cell receptors, which

allow antigen-independent, autonomous signalling promoting cell

survival.

The diagnosis of SLL relies on excisional lymph node biopsy

along with analysis of a bone marrow biopsy and aspirate.less

SLL most commonly runs an indolent course, and patients

are often asymptomatic.

Physical exam can show generalized painless

lymphadenopathy, and hepatosplenomegaly.

Coombs test will show warm antibody hemolytic anemia

(IgG mediated). CBC will show mild lymphocytosis. And flowcytometry shows B-cells expressing CD19/20/23 and 5 (normally

a T-cell marker).

Nodal biopsy will show nodal architecture effacement, small

lymphocytes, and some larger lymphoid cells arranged

in pseudo follicles (pathognomonic).

Genetic abnormalities are most commonly of chromosomes

11, 12, or 13.

SLL monoclonal B-cell proliferation leads to defects of thecellular and humoral immune systems.

less

Patients are at increased risk of infection by encapsulated

bacteria (Streptococcus pneumoniae, Staphylococcus

aureus, Haemophilus influenzae), and reactivation of latent

Herpesvirus infections.

Patients may also have an increased risk for: anemia,

thrombocytopenia, other cancers (hematologic and solid tumor),

leukostasis, and tumor lysis syndrome.

Treatment of early, asymptomatic SLL is observation.less


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show neutropenia or thrombocytopenia. Pancytopenia is present

in up to 50% of patients at time of diagnosis.

The blood smear in myelodysplastic syndrome will show

dysplastic red and white cells. Ovalomacrocytosis is the best-

recognized abnormality of the red cells, and neutrophils may

have increased size, abnormal lobation, and abnormal

granularity. Ringed sideroblasts, basophilic stippling, Howell-Jolly

bodies, or megaloblastoid nucleated RBCs may also be seen.

Bone marrow aspirate/biopsy in myelodysplastic syndrome

may show increased myeloid precursors (though, by definition,

less than 20% blasts) and dysplastic features. Bone marrow is

usually hypercellular; this, combined with peripheralpancytopenia, indicates high rates of intramedullary cell death.

Many patients are asymptomatic and myelodysplastic

syndrome is found incidentally on routine CBC.

Physical exam findings are nonspecific and include pale

complexion, petechiae/purpura, recurrent infections, bruising, or

abnormal bleeding. Sweet syndrome (neutrophilic dermatosis)

may also be seen.

Complications of myelodysplastic syndromes are due to theabnormalities in blood and bone marrow cell morphology and

number.less

These complications (of myelodysplastic syndrome) include

anemia (RBC), bleeding/bruising/petechiae/purpura

(thrombocytopenia), and recurrent infections (neutropenia).

Myelodysplastic syndrome can progress to acute myeloid

leukemia (AML), which is diagnosed when blast counts rise

above 20%, or if myeloid sarcoma (solid tumor composed of

myeloblasts) is present.


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Blood smear for a patient with myelofibrosis may show

poikilocytosis (red-blood cells (RBCs) with different shapes),

anisocytosis (RBCs of different sizes), nucleated RBCs,

polychromasia, and teardrop shaped RBCs.

Bone marrow aspirate from a patient with myelofibrosis

may show a dry tap. It may also show neutrophilic and

megakaryocytic hyperplasia.

Bone marrow biopsy is essential for appreciation of the

marrow fibrosis seen in almost all patients with myelofibrosis.

A hallmark finding in the bone marrow of myelofibrosis

patients is hypervascularity, believed to be caused by the

increased amount of secreted endothelial growth factor. MRI Imaging of a patient with myelofibrosis will show

changes in the bone marrow from fatty to fibrotic.

In myelofibrosis, the increased numbers of megakaryocytes

secrete increased amounts of cytokines and growth factors,

which leads to activation of fibroblasts and fibrosis of bone

marrow.less

Once the bone marrow becomes fibroticinmyelofibrosis, hematopoiesis becomes extramedullary. This can

be seen in any body tissue; soft tissue, body cavities, serosal

surfaces, CNS, skin, etc, and is picked up on CT scan or MRI.

Myelofibrosis can progress to acute leukemia.

Treatment for myelofibrosis is mostly supportive, directed at

correcting abnormal blood cell counts.less

Allogeneic hematopoietic cell transplantation is the only

treatment with curative potential.

Myelofibrosis patients may also receive pharmacologic

therapy including chemotherapy, hydroxyurea (for


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thrombocytosis), JAK2 inhibitors, interferon alpha, androgens, or

thalidomide.

Splenectomy is often performed for patients with

myelofibrosis.

!olycythemia *era nextOrgan Systems Hematology/Oncology Hematologic Malignancies

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Polycythemia vera: Absolute polycythemia without hypoxic

stimulus, usually due to mutation on JAK2 gene of chromosome

9.less

Clonal expansion of myeloid stem cell.

Same mutation found in myelofibrosis, myeloid metaplasia,

and essential thrombocythemia. Increased production of:

- RBCs

- Granulocytes

- Mast cells

- Platelets

Symptoms due to hyperviscosityand vessel congestion.less

Hepatosplenomegaly: Engorgement with blood cells.

Burning pain in the hands due to micro thrombi occlusion of

vessels. Also seen in essential thrombocythemia.

Ruddy face (plethoric): Due to vessel congestion.

Thrombosis: Due to hyperviscosity.


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CNS involvement: Due to hyperviscosity.

- Headache

- Blurred vision

- Retinal vein engorgement

- Vertigo

- Transient ischemic attack

- Stroke

Increased histamine: Peptic ulcers and itching after

bathing.

Gout: Due to increased cell turnover with release of nucleic

acids.

Decreased erythropoietin (EPO) with increased hematopoiesisless

EPO and normal O2sats (>92%).

RBC mass, RBC count, and plasma volume.

May see leukocytosis, thrombocytosis.

Leukocyte alkaline phosphatase > 100.

B12> 900 pg/mL or B12binding protein.

Treatment used to reduce red blood cell proliferation

(chemotherapy), reduce hematocrit (phlebotomy), and prevent

thrombosis (aspirin).less

Perform phlebotomy, hydroxyurea, or aspirin.

Thrombotic complications are a major cause of morbidity

and mortality

&e'kemias nextOrgan Systems Hematology/Oncology Hematologic Malignancies

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Leukemic cells often infiltrate the marrow, disrupting normal

hematopoiesis:less

Leukopenia infection risk Anemia

Thrombocytopenia hemorrhagic complications

Acute leukemiasless

Clinical findings generally abrupt in onset.

Fever, bleeding and fatigue are commonly found.

Laboratory findings-Thrombocytopenia

-Hypercellular bone marrow with >20% blasts

-Usually an elevated WBC count

Acute leukemias have a bimodal distribution, and occur in

children and adults >60 years of age.

The acute leukemias are often tatal within 6 to 12 months if

there is no intervention.

ALL (Acute lymphoblasticleukemia)less

Most common malignancy in children, also the most

responsive to therapy

There are 2 general types: B-ALL and T-ALL

B- ALL :

-Presents as blood disorder, will generally metastasize to CNS

-Surface Markers: CD10 (aka CALLA), CD19, CD20 and CD22-Translocation: t(12;21) is commonly asked

T- ALL:

-Presents commonly as anterior mediastinal mass


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2 questions

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mant11e:

t(11;14)translocation bcl-1 (cyclin D1) overexpression

cell cycle high grade; terrible prognosis with average survival

of 3 yearsless

Mantle cell (zone) lymphoma: B-cellsform the mantle zone

of lymphoid follicles Morphology is similar to SLL/CLL (SLL is considered a

phase of CLL)

Mantle cell NHL vs. CLL (chronic lymphocytic leukemia):

- both express CD5, CD19, CD20

- Mantle cell NHL is CD23-vs. CLL is CD23+

Incurable. Often aggressive, disseminated, affects older

men

Non(#o$gkin &ymphoma+ollic'lar


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Follicular Fourteen:

t(14;18)translocation juxtaposition of bcl-2(an oncogene that


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inhibits apoptosis) next to the IgH locus. This leads

to overexpression of BCL2 apoptosis.less

Follicular lymphoma: B-celllymphoma, second most

common non-Hodgkin lymphoma

Classically presents in adults with waxing and waning

lymphadenopathy

Predominantly centrocytes (small cleaved cells)

expressing:

- CD10+, CD19+, CD20+

- BCL2+, BCL6+

Lymph nodes are obliterated by characteristic neoplasticnodules: uniform, round, and isolated. These nodules are

comprised of B-cells recapitulating the germinal centers of

lymphoid follicles

#ematopoiesis nextOrgan Systems Hematology/Oncology Hematopoiesis

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Primary lines: myeloid vs. lymphoid

During hematopoeisis, cytokines and growth factors direct

commitment of progenitor cells into and through specific

lineages.

Platelet productionless


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Production of megakaryocytes and platelets is primarily

regulated by thrombopoietin, a glycoprotein hormone produced

by the liver and kidneys.

IL-6 stimulates the assembly of platelets from

megakaryocytes.

Erythropoiesisless

Controlled by erythropoietin(EPO), a glycoprotein

hormone produced in kidneys and liver.

Mast cell productionless

Primarily regulated by Stem Cell Factor (SCF, aka c-Kitligand)

Cofactors: IL-3, IL-6, thrombopoietin, nerve growth factor

Granulopoiesisless

Basophils:

- granulocyte-macrophage colony-stimulating factor (GM-CSF):

basophil growth and differentiation, mast cell differentiation

- IL-3

- TGF- (suppresses eosinophil lineage, stimulates production of

basophils)

Neutrophils:

- GM-CSF

- granulocyte colony-stimulating factor (G-CSF)

Eosinophils:

- GM-CSF


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nextOrgan Systems Hematology/Oncology Hematopoiesis

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Biconcave to maximize surface area for gas exchange

Lack organelles: no nuclei, no mitochondria

Glucose is the sole fuel (glycolysis only)less

Also uses glucose for NADPH via HMP shunt to preventoxidative damage

Average survival: 120 daysevery 120 days, the

entire RBC population is replaced

,ran'locytes nextOrgan Systems Hematology/Oncology Hematopoiesis

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Subclass of leukocytes; includes: basophils, neutrophils, and

eosinophils

Basophil granules contain:

less

Bilobed nucleus. Intracellular granules stain well with basic

dyes, hence "basophilic"

Heparin

Histamine key role in mediating allergic reactions
https://med.firecracker.me/topics/3386https://med.firecracker.me/topics/3386https://med.firecracker.me/topics/709https://med.firecracker.me/topics/124https://med.firecracker.me/topics/124https://med.firecracker.me/topics/710https://med.firecracker.me/topics/3386https://med.firecracker.me/topics/709https://med.firecracker.me/topics/124https://med.firecracker.me/topics/710


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Leukotrienes and cytokines are synthesized on demand

Neutrophil granules contain myeloperoxidase, lactoferrin,

hydrolytic enzymesless

Most common WBC, highly motile

2-5 nucleus lobes; can become hypersegmented in vitamin

B12 or folate deficiency

Phagocytic, but also has granules

Phagocytosed molecules/cells are exposed to respiratory

burst: NADPH oxidase produces superoxide, which is converted

to H2O2. H2O2 is then converted to OCl- byMPO.

Eosinophils contain bilobed nucleus. Intracellular granules stainwell with acid (e.g. eosin) dyes, hence "eosinophilic"

less

Granules contain cytotoxins: major basic protein, eosinophil

peroxidase, histaminase and arylsulfatase.

Defends against parasites: e.g., helminths eosinophilia is

a marker for some parasitic infections (note that protozoa and

noninvasive metazoa usually do not elicit eosinophilia)

Major basic protein is a toxic component of the lysosomal

granules and is an important mediator in the death of parasites

and protozoa.

Also upregulated in allergic reactions (esp. drug reactions)

and collagen vascular diseases (e.g. rheumatoid arthritis, Churg-

Strauss vasculitis)

Causes of eosinophilia can be remembered with

mnemonic: CCHINA

Connective tissue diseases

Cortisol deficiency

Helminthic infections

Idiopathic hypereosinophilic syndrome


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Neoplasia

Allergies

Monocytic &ineage nextOrgan Systems Hematology/Oncology Hematopoiesis

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Subclass of leukocytes; includes: monocytes and macrophagesMonocyte: Large, with a kidney-shaped nucleus

less

Following migration from bloodstream into tissues, they

differentiate into macrophages and dendritic cells

Macrophagesless

Phagocytose bacteria, cellular debris, damaged cells (e.g.

old RBCs), often via pseudopods Digested material in a phagosome is fused to a lysosome

phagolysosome

Antigen-presenting cells: during breakdown of foreign

material, MHC-II binds to antigens inside the macrophage

lysosomes, the complex translocates to the cell surface, and

theMHC-II presents antigens to CD4 receptors on T-cell surfaces

Plays a key role in atheroma formation

Epithelioid macrophages are the principal constituent of

granulomas

Dendritic cells are antigen-sampling and -presenting cells.less


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Express toll-like receptors, pattern recognition

receptors, MHC II, and Fc receptor

Induce naive T-cells, B-cells

&ymphocytes nextOrgan Systems Hematology/Oncology Hematopoiesis

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3 types: T cells, B cells/plasma cells, NK cells

T and B lymphocytes have small amounts of cytoplasm but a

round, dense nucleus

T cellsless

Mature in the thymus and differentiate into cytotoxic,

helper, and suppressor T cells

Major component of cellular immunity; comprise 80% ofcirculating lymphocytes

Cytotoxic T-cells express CD8 receptors; these interact

with MHC-I molecules that present antigen fragments to the CD8

receptors. Cytotoxic T-cells destroy infected cells and tumor cells

Helper T-cells express CD4 receptors; these interact

with MHC II molecules on antigen presenting cells

Helper T-cells secrete cytokines, activate B cells, and serve

as memory cells for future exposures to the same antigen

Suppressor T-cells are responsible for

immunologic tolerance they prevent T-cells from attacking the

body

B cells


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less

Produced in bone marrow

Mediate humoral immunity via antibody production

Activated by APCs but can also recognize antigens

independently. Maximal antibody production requires

immunological synapse with an activated helper T cell.

Differentiate into plasma cells and memory B cells

)loo$ ,ro'ps nextOrgan Systems Hematology/Oncology Hematopoiesis

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A & B oppose each other:less

A antigen B antibody

B antigen A antibody

Type A blood group: risk for gastric adenocarcinoma

A & B are codominantless

AB blood type: both A & B antigens noblood group

antibodies "universal recipient"

i is recessive. Thus Blood types A, B and O:

- Type A: Ai or AA- Type B: Bi or BB

- Type AB: AB only

- Type O: ii only


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O blood type: neither A nor B antigens both A and B antibodiesless

"Universal donor" because the RBCs arent immunogenic

(no surface ABO antigens)

Both A & B antibodies can only receive O blood type

Rh is another antigen found on RBC surfacesless

People who are Rh- do not develop antibodies against Rh

antigen until they are exposed (as during delivery of an

Rh+baby)

Example: Rh-mother exposed to Rh+fetal blood (via

placenta) will develop IgGanti-Rh antibodies Subsequentpregnancies where fetus is Rh+ hemolytic

disease of the newborn (aka erythroblastosis fetalis)

Fetus develops hepatosplenomegaly with ascites, and

cardiac hypertrophy from hypoxia

ABO incompatibility is actually protectiveagainst Rh

incompatibility. This is because when fetal cells are detected by

the maternal anti-A or anti-B IgM antibodies, complement is

activated and the RBC is lysed before sensitization to Rh antigencan occur.

)loo$ Composition nextOrgan Systems Hematology/Oncology Hematopoiesis

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Blood contains plasma, platelets, leukocytes, and red blood

cells.


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Plasma: Fluid portion of blood, contains proteins.less

Albumin: maintains oncotic pressure of the blood.

Clinical Correlate: Burn victims and patients with

nephrotic syndrome lose albumin (through their skin and urine,

respectively), resulting in edema due to loss of oncotic pressure.

Gamma and beta globulins: transport hormones, metal

ions, and lipids.

Blood coagulation proteins, including fibrinogen fibrin is

the reaction that forms the fibrin clot.

Plasma without fibrinogen is serum.

Platelets: Degranulate to form blood clots.Leukocytes: White blood cells, include:

less

Neutrophils

Eosinophils

Basophils

Monocytes

Natural killer cells

T lymphocytes

B lymphocytes and plasma cells

Red blood cells:less

Hematocrit: Percent blood volume occupied by RBCs.

Normal = 45%.

In a centrifuged blood sample, plasma is the top

layer, leukocytes and platelets are in the middle layer,and RBCs are in the bottom layer.

Myeloi$ Tiss'e nextOrgan Systems Hematology/Oncology Hematopoiesis


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Myeloid tissue (bone marrow)is the main site of

hematopoiesis.less

Bone marrow cell types:

- Stromal (1%)

- Myeloid (granulocytes, 65%)

- Erythroid (20%)- Lymphoid (14%)

Present in:

- Vertebrae

- Sternum

- Ribs

- Skull

- Pelvis

- Proximal femur

Clinical Correlate: Bone marrow aspirates are taken from

the superior iliac crest, sternum, or upper end of the tibia.

The myeloid to erythroid ratio (M:E)is the ratio of myeloid

precursor cells (immature white blood cell) to erythrocyte

precursor cells (immature erythrocytes). Useful in diagnosis of

blood dyscrasias. Normal: 3:1 to 5:1.less

Clinical Correlate: After severe hemorrhage the body

should stimulate erythropoiesis to compensate for blood loss

the M:E ratio will be decreased.


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Clinical Correlate: In cases of aplastic anemia (bone

marrow failure), the bone marrow is unresponsive to EPO

inappropriately high M:E ratio.

Myeloid tissues also phagocytize aged and defective red blood

cells (as do the spleen and liver) and are the sites of B

lymphocyte formation.

!latelets nextOrgan Systems Hematology/Oncology Hematopoiesis

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Platelets: Mediators of hemostasis.less

Not actual cells, but cell fragments of megakaryocytes.

Platelets bud off from megakaryocytes in the bone marrow

and enter the circulation. Life span: 9 " 10 days.

Express surface proteins that mediate platelet aggregation and

clot formation.less

Surface protein GpIbbinds to vWF on injured endothelial

tissue.

Surface protein GpIIb-IIIabinds to fibrinogen to cross-link

platelet plug.

Contain granules of pro-coagulant mediators. Degranulation

primary hemostasis.less


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Thrombosthenin: Contractile internal structure for clot

retraction.

Alpha-granulescontain: platelet factor 4, PDGF (platelet-

derived growth factor), factor V, vWF and fibrinogen.

Delta-granulescontain: serotonin, Ca2+, ADP.

For information on the mechanism of platelet degranulation

and plug formation, reviewPrimary Hemostasis.

For information on platelet dysfunction, review Platelet

Dysfunction

-)C Morphology nextOrgan Systems Hematology/Oncology Hematopoiesis

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Poikilocytosis = abnormally shaped RBCs

less Occurs when RBCs are traumatized (DIC, TTP/HUS) or

have membrane abnormalities (spherocytes, elliptocytes, Burr

cells)

Anisocytosis = normal-shaped RBCs but with variation in

size

Spherocytes occur in hereditary spherocytosis

Elliptocytes occur in hereditary elliptocytosis (membrane defects)less

RBCs become elliptical (deform) when passing through

capillaries

Target cells: surface area-to-volume ratio due to

RBC volume and/or RBC membrane.


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less

Target cells are associated with:

- Thalassemia

- Iron deficiency anemia

- Structurally aberrant hemoglobin disease: HbS, HbC which

also characteristically have the HbC crystal

- Splenectomy

- Liver disease

- Hereditary LCAT (lecithin-cholesterol acyl transferase)

deficiency

HbC patients have mild hemolytic anemia

Sickle cells are found in sickle cell anemia.

HbS molecules aggregate and form long filamentous fibers that

cause sickling of the RBC.less

Hypoxemia, acidosis and dehydration are common

precipitants.

Bite cells are formed when the spleen removes a Heinz bodyfrom an RBC

less

Heinz bodies form in G6PD deficiency

Basophilic stippling: ribosomal aggregatesless

Classic for lead poisoning; also occurs in severe anemias:

megaloblastic anemia, thalassemia

Echinocyte (burr cell): Seen in pyruvate kinase deficiency andrenal insufficiency

Schistocyte ("helmet cell"): RBC fragment, seen in any hemolytic

anemia, formed in cases of mechanical trauma, can be an

intrinsic abnormality of erythrocytes

Acanthocytes: irregularly spaced projections


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less

Found in abetalipoproteinemia and severe liver disease

Teardrop cells (Dacrocytes): found in myelofibrosis (replacement

of bone marrow by fibrous tissue aka myelophthistic anemia) and

thalassemia major

Erythropoiesis nextOrgan Systems Hematology/Oncology Hematopoiesis

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Erythropoiesis: Production of new red blood cells.less

Regulated by EPO (erythropoietin).

EPO is a glycoprotein secreted by interstitial fibroblasts in

the kidney.

Takes place in myeloid tissue (bone marrow).less

Clinical Correlate: The presence of precursor cells, which

normally reside in the bone marrow, in the peripheral blood is a

useful marker for disease states.

Reticulocyte count can be used to gauge the ability of the

marrow to respond to anemic states. It is particularly useful for

differentiating anemia caused by increased destruction ofRBCsfrom anemia caused by decreased production of

RBCs.

For example, in cases of hemolytic anemia, the bone marrow

responds by increasingRBC production, as such reticulocytes


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are released at a higher rate into the peripheral blood. Thus,

reticulocyte count is increasedin states of RBC destruction.

In contrast, in cases of decreased production, such as iron or

B12 deficiency or aplastic anemia, the marrow is not able to

adequately respond by releasing reticulocytes into the blood,

thus reticulocyte count will be decreased.

Maturation of erythrocytes.less

Proerythroblast: RBC precursor cell, extrudes nucleus and

nucleoli to become a reticulocyte.

Reticulocyte: Non-nucleated, red, hemoglobin-containingcytoplasm. The final stages of maturation to RBCs (extrusion of

mitochondia and polyribosomes occur in the peripheral blood)

"C .isseminate$ "ntravasc'lar

Coag'lation/ next

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DIC is a consumptive coagulopathycharacterized by

generation of fibrin clots consumption of clotting factors and

platelets hemorrhage and often death.

Note: DIC is NOTa primary disorder, rather It is

a complicationof several different disease processes. You must

always look for an underlying cause.


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Common precipitating conditions include:Mnemonic:

ATTOMS

-Acute pancreatitis

-Trauma

-Transfusion reaction

-Obstetric causes such as abruptio placentae and amniotic fluid

embolism

-Malignancy

-Sepsis

Microthrombi can cause mechanical trauma to circulating RBCs

schistocytes aka helmet cells

Consumption of all hemostatic components leads to:

-Microangiopathic hemolytic anemia

-Thrombocytopenia

- Bleeding time

- PT and PTT

-Because it is a consumptive coagulopathy, coagulation

factors (Factor V, Factor VIII)

less Fibrin split products (D-dimers) as the excessive clotting

activates fibrinolysis(plasmin)

In addition to consumption of coagulation proteins, plasminogen

is activated hemorrhage.less

Activated plasmin cleavage of fibrin, factors V and VIII.

This exacerbates the hemorrhagic diathesis caused by

consumption of the factors.

Coag'lation Tests nextOrgan Systems Hematology/Oncology Hemostasis

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Prothrombin Time (PT) evaluates the extrinsic system:

Factors VII, X, V, II and Iless

The normal PT is between 10-12 seconds.

INR (International Normalized Ratio) is a standardized

value for PT that is often quoted when

following warfarintherapy. The normal value is set at 1.

An elevated INR indicates relative increasein anti-coagulation (i.e. INR = 2-3)

PT can be seen with warfarin therapy, or any process

affecting the synthesis or consumption of coagulation factors (i.e.

liver disease and DIC (Disseminated Intravascular Coagulation);

respectively).

PTT (Partial Thromboplastin Time) evaluates the intrinsic

system: Factors XII, XI, IX, VIII, X, V, II and I.less

The normal PTT is between 25-40 seconds.

PTT is used to follow heparin but not LMWH (i.e.

enoxaparin)therapy.

PTT is seen with factor deficiencies, DIC, vWD and anti-

phospholipid syndrome (associated with SLE).

!latelet ysf'nction nextOrgan Systems Hematology/Oncology Hemostasis

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Qualitative defects: Platelet count, PT and PTT are normal.

BT.less

Bleeding is not due to lack of platelets, instead there is a

problem with platelet function. This can be caused by several

different defective surface proteins or COX inhibition, clopidogrel

Adhesion defects: vWD, Bernard-Soulier diseaseless

vWD (von Willebrands Disease): usually autosomal

dominant, however some types of vWD are autosomal recessive:

- Type 1: autosomal dominant; production of vWF; treat

with DDAVP (desmopressin, an ADH analog), which releases

vWF from Weibel-Palade bodies of endothelial cells

- Type 2: autosomal dominant; abnormal vWF multimers

- Type 3: autosomal recessive; severe vWF deficiency

Bernard-Soulier: glycoprotein Ibis absent (autosomal

recessive). Note that despite being characterized as

a qualitativeplatelet defect, BSS is associated

withthrombocytopenia and giant platelets in the blood.

Think St. Bernard(a giant dog) to remember the giant plateletsin

Bernard-Soulier.

Aggregation defects: Glanzmann thrombasthenia, COX inhibitors

less Glanzmann thrombasthenia: autosomal recessive GPIIb-

IIIa deficiency, so neighboring platelets cant form fibrinogen

bridges to each other.


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Note the similarity between the pathogenesis of Glanzmann

thrombasthenia and ITP.

COX (cyclooxygenase) inhibitors TXA2. Examples:

aspirin, celecoxib

Coag'lation Casca$e efects nextOrgan Systems Hematology/Oncology Hemostasis

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Unlike defects of primary hemostasis, defects of secondary

hemostasis cause large vessel bleeding hemarthroses, large

ecchymoses

PT is caused by deficiency of fibrinogen (factor I) or II, V, VII,

X ("1752")

PTT is caused by deficiency of all factors exceptVII and XIII

Hemophilia A (Factor 8 deficiency)less

X-linkedrecessive with variable severity

PTT but allother labs are normal: normal bleeding time,

normal PT

Hemophilia B (Factor 9 deficiency)less

S/Sx are identical to Hemophilia A, including laboratory

results demonstrating isolated PTTprolongation. Like hemophilia

A, hemophilia B is also X-linked recessive.

Keys to differentiating bleeding disorders:

1.Coagulation cascade defects will have a history of hematoma,

hemarthrosis and bleeding at circumcision


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Labs: PTT, normal BT. Normal PTis often found

in hemophiliabut PT prolongation can occur with factor II, V

or VII deficiency.

2.Platelet defects: patients will have history of mucosal

bleedingwith recurrent epistaxis, petechiae and small

ecchymoses and purpura

Labs: BT, PTT (in vWD because

of VIII deficiency), normal PT.

Also look at the platelet count as it will tell you if the

problem is due to platelet number or platelet function.

3.Bleeding caused by Vit K dependent factor deficiency, liver

disease, coumadin therapy PT, PTT, normal BT

Vitamin K deficiencyless

"1972": Factors 10, 9, 7, 2

Both PT and PTT are

Neonates: breast milk is vit K deficient and GI tract isnt

colonized yet with vit K-producing bacteria hemorrhagic

disease of the newborn

Cirrhotics: all coagulation factors except vWF are

synthesized in the liver. Factor VIII is synthesized in sinusoidal

endothelial cells and Kupffer cells of the liver as well as tubular

epithelial cells in the kidney. Recent research shows that FVIII is

actually increasedin cirrhosis.

Remember: vWF is made in endothelial cells and

megakaryocytes, and stored in platelets and endothelial cells.

When it is released complexes with VIII.

#ere$itary Thrombophilia


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nextOrgan Systems Hematology/Oncology Hemostasis

4 questions

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Hypercoagulability is also known as thrombophilia.less

There are hereditary (primary) and acquired (secondary)

causes of thrombophilia.

Inherited causes become especially apparent in patientswho have a few acquired risk factors as well (prolonged

immobilization, endothelial damage, etc).

The most common cause or hereditary thrombophilia is

the Factor V Leiden mutation.less

The Leiden mutation is a single NT mutation in the Factor V

gene which causes Arg Gln substitution.

The mutant form of Factor V is resistant tocleavageby protein C.

Heterozygotes have a 5x higher risk of venous thrombosis

compared to 50x higher risk seen in homozygotes.

Another common cause of hereditary thrombophilia is a

mutant prothrombingene.less

The mutation is in the 3-UTR and leads to increased

expression of prothrombin and therefore increased risk of

venous thrombosis.

Elevated homocysteine levels can lead to venous and arterial

thrombosis.less


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The most common mutation causing

hyperhomocysteinemia is in the

enzyme MTHFR(methylenetetrahydrofolate reductase) but it can

also be due to inherited cystathione - synthetase deficiency.

Rarer causes of inherited thrombophilia includes:less

Protein C/S deficiency

Antithrombin III deficiency

von 0illebran$%s isease nextOrgan Systems Hematology/Oncology Hemostasis

4 questions

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339

Bottom of Form

Most commonly inherited as autosomal dominant

A combined primary and secondary hemostatic defect,

involving von Willebrand factor (vWF), which:less

1) vWF is made chiefly in endothelial cellsand to some

extent also in megakaryocytes.

a) The vWF that is synthesized in megakaryocytesis stored

in - granulesinside the platelets.

b) The vWF synthesized in endothelial cellsis storedin Weibel-Palade bodies.

Mediates platelet adhesion between subendothelial

collagen and platelet receptor GpIb


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In the blood, vWF binds to and stabilizes factor VIII

half-life of factor VIII.

Therefore, vWF deficiency causes both platelet

adhesion (prolonged bleeding time) and functional

efficiencyof Factor VIII (PTT is prolonged). PT/INR times are

normal.

vWD generally presents with mucosal type bleeding (similar to

other platelet defects) as well as menorrhagia. It

does NOTpresent with hematoma and hemarthrosis that is

typical of the hemophilias.Treatment of vWD generally consists of ddAVP (Desmopressin,

a Vasopressin analog) which causes release of vWF from

endothelial cells. Note this would not work in the subtype of vWD

which completely lacks vWF.

#enoch(Schonlein !'rp'ra next

Organ Systems Hematology/Oncology Hemostasis1 question

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339

Bottom of Form

A small vessel vasculitis that commonly affects the skin, GI tract,

kidneys and joints.

Also characterized by IgA-anti-IgA immune complex deposition.

Generally follows a viral respiratory infection.


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Clinical symptoms:

-Hematuria, proteinuria (renal sxs)

-Abdominal pain (GI sxs)

-Palpable purpura (skin sxs)

-Arthralgia (joint sxs)

Thrombocytopenia nextOrgan Systems Hematology/Oncology Hemostasis

22 questions

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Three basic causes of thrombocytopenia:less

1. platelet production:characterized by decreased

megakaryocytesin the bone marrow.

For example:

- Aplastic anemia- Alcohol

- Antineoplastic drugs

- Malignancy (e.g., myelofibrosis; metastatic spread of cancer to

bone marrow)

2. platelet destruction: peripheral destruction

associated with increased megakaryocytesin bone marrow.

For example:

- Bernard-Soulier syndrome- DIC (disseminated intravascular coagulation)

- Drug-induced thrombocytopenia (i.e., heparin, penicillin,

quinidine, methyldopa)

- HUS (hemolytic uremic syndrome) / TTP (thrombotic


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thrombocytopenic purpura)

- ITP (idiopathic / immunologic thrombocytopenic purpura)

3. platelet sequestration: platelets are retained in the

spleen.

For example: portal HTN hypersplenism

Clinical features are much different than coagulation defects!

Petechiae (small pinpoint hemorrhages) and purpura (small

ecchymoses) are common. Bleeding typically occurs from

mucosal surfaces (i.e. epistaxis, menorrhagia, bleeding gums),

GI bleeds.Laboratory investigation should take place when a bleeding

disorder is suspected.

Platelet count are decreased (< 150,000/mm3) in cases of

platelet destruction. bleeding time, while PT & PTT are

unchanged.

ITP (Idiopathic thrombocytopenic purpura): autoimmune

conditionless

Caused by auto-antibody against receptor GpIIbIIIa on the

platelet surface

In children, usually follows a viral infection and is self-

limited (vs. chronic course in adults)

Antiplatelet antibodies coat platelets which are then

removed by splenic macrophages

Look for thrombocytopenia with megakaryocytesin

the absenceof splenomegaly (to rule out splenic sequestration)

Clinical features: petechiae, menorrhagia

Dx: platelet count, bleeding time, megakaryocytes

in the bone marrow.


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TTP (Thrombotic thrombocytopenic purpura)less

Rare, life-threatening emergency characterized by

a classical pentadof symptoms:

1) Microangiopathic hemolytic anemia produces schistocytes

2) Thrombocytopenia

3) Renal failure (generally look for an BUN:Cr ratio)

4) CNS changes (i.e. mental status)

5) Fever

High Yield Fact: TTP/HUS are differentiated

from DIC by normalPT and PTT.

Due to a deficiency in the vWF multimer cleaving

protease ADAMTS-13. This deficiency can be acquired (e.g.

auto-antibodies against ADAMTS-13)

The deficient/defective protease larger multimers of vWF

persist. These have a higher propensity for aggregating and

forming whitemicrothrombi in the vasculature

White microthrombi in microvasculature organdysfunction, notably neurologic (stroke-like sx or altered mental

status) and renal failure (hematuria and BUN:Cr)

The thrombi also shear RBCs, causing a microangiopathic

hemolytic anemia schistocytesare present but not

pathognomonic

Tx: plasma exchange to remove auto-

antibodies; FFP transfusions

HUS (Hemolytic Uremic Syndrome)less

Most common cause of renal failure in children

Presents with classic triadof:

1) Thrombocytopenia


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2) Microangiopathic hemolytic anemia

3) Acute renal failure

Usually preceded by O157:H7 (Shiga-like toxin producing)

E. coli infection

Endothelial cells are damaged, predominantly in the kidney

platelets aggregate, forming microthrombi renal injury

uremia

Clot formation consumes platelets thrombocytopenia

Thrombi shear RBCs schistocytes, anemia

HIT (Heparin Induced Thrombocytopenia)less

Heparin binds to platelet antigen (Platelet Factor 4) Autoantibody formed against the Heparin/PF4 complex.

This is an example of Type II Hypersensitivity

These immune complexes induce activation of platelets

patients becomeprocoagulantand are at risk for

thromboembolic events

Note: the presence of heparin is required to trigger platelet

activation. Thus, all heparin administration should be

immediately stopped in patients suspected of having HIT

Ac1'ire$ Thrombophilia nextOrgan Systems Hematology/Oncology Hemostasis

7 questions

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339

Bottom of Form

Hypercoagulability is also known as thrombophilia.


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less

There are hereditary (primary) and acquired (secondary)

causes of thrombophilia.

Antiphospholipid antibody syndrome(also known as lupus

anticoagulant syndrome) is a commonly tested acquired

thrombophilia.less

In the blood stream, antibodies directly activate platelets

and complement hypercoagulable state.

Patients commonly present with a history of

recurrent DVT and miscarriages.

In vitro, the antibodies interfere with phospholipids (henceantiphospholipid) and inhibitcoagulation PTT.

Additionally, antiphospholipid antibodies can cause a false

positivefor syphilis.

Other causes of acquired thrombophilia include:less

Immobilization (bed rest, long plane flights)

Major surgery (especially orthopedic)

Oral contraceptive pills and pregnancy estrogendriven synthesis of coagulation factors

Malignancy tumor release of procoagulant mediators

Smoking (possibly endothelial damage, but true etiology is

unknown)

Obesity

Prosthetic valves

!rimary #emostasis nextOrgan Systems Hematology/Oncology Hemostasis

9 questions

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Platelet plug formation is primary hemostasis

Endothelial injury collagen exposed platelets adhere to vWFin the subendothelium (adhesion)

less

vWF (synthesized in megakaryocytes and endothelial cells)

binds GpIb on the platelet a dhesion

There is also a brief arteriolar vasoconstrictionmediated

by the local factorendothelin.

Binding of platelets also activates them to release their granules

which contain key molecules: ADP, Ca2+, and serotonin.

Thromboxane A2 (TXA A2) ia generated by the membrane

enzyme phospholipase A2.less

TXA2 activates more platelets ( aggregation)

ADP increases glycoprotein IIb/IIIas binding

of fibrinogen plug is strengthened

Serotonin enhances overall platelet procoagulability;mechanisms still being elucidated.

Role of ADP in platelet activation: ADP binds receptors on

platelet surface, causing insertion of GpIIb/IIIa (fibrinogen

receptor) allows aggregation of plateletsless

Antiplatelet agents ticlopidine and clopidogrel

block ADP receptors and thus inhibit expression of GpIIb/IIIa

Aggregationis mediated by fibrinogen, which binds GpIIb/IIIaon adjacent platelets

Aggregation is inhibited by endothelial cells that

release PGI2(prostacyclin) and NO


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Secon$ary #emostasis .Coag'lation

Casca$e/ nextOrgan Systems Hematology/Oncology Hemostasis

10 questions

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Goal: generate fibrin for the clotMany coagulation factors are secreted as zymogens. Upon

activation, they become serine proteasesthat can activate

downstream factors

Bradykinin, cleaved from HMWK (high molecular weight kinin),

vasodilates and increases vascular permeabilityless

It is short: 9 amino acids in length

Many reactions in the cascade require Ca2+and plateletphospholipid as cofactors

Factors X, IX, VII, II (mnemonic "1972") are vitamin K-dependentless

Their synthesis is inhibited by warfarin, a vitami

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