Hematology

Bernard-Soulier syndrome

(1) Autosomal recessive disease of platelet adhesion due to deficiency of GPIb-IX; (2) On PBS, platelets are abnormally large; (3) Platelet count Is mildly low low or normal PC, high BT low GP Ib-IX causes defect in platelet to vWf adhesion

hematocrit formula

(Red Blood Cell Level/Total Blood Level) x 100= Percent Red Blood Cell Volume= Hematocrit. ~40% = females ~45% = males ~55% = newborns

Apixaban

Eliquis DIRECTLY inhibits factor Xa; prevents clots & strokes Used to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE)

Fibrinolysis

Breakdown and removal of a clot

Coagulation factors that contain Gla residues

Factor 2, 9, 10, 2

Which factor holds fibrin together

Factor XIII (ca2+ dependent)

normal blood hemoglobin levels

Females: 14 g/dL Males: 15.5 g/dL

46 year old woman receives a non-T lymphocyte depleted, allogenic bone marrow transplant from a matched, unrelated donor. Immunosuppressive therapy with cyclosporine is started. One month later, she has a fever. Cytolytic destruction of the skin, GI tract and liver is seen, with associated dermatitis, enteritis and hepatitis. Which of the following best explains these findings? A. C3b deposition B. Cytomegalovirus infection C. Graft vs. host disease D. Tolerance induction E. Type I hypersensitivity

C. Graft vs. host disease

B cells

Cells manufactured in the bone marrow that create antibodies and immunoglobulins for isolating and destroying invading bacteria and viruses.

Blood is what type of tissue?

Connective

Factors/ condition that can cause eosinopenia

Cushing syndrome, corticosteroids

What drives the support and differentiation of stem cells in bone marrow?

Cytokines

Human Leukocyte Antigens (HLA)

-class I is expressed on all nucleated cells (everything but RBCs) -class II is a subset of immune--showing antigens to T cells -polygenic-multiple genes encode for class I and II -6 different HLA I molecules per individual

Plerixafor

-drug that allows for autologous bone marrow transplant -targets CXCR4--keeps hematopoietic stem cells within bone marrow -releases CXCR4:CXCL12 lock on stem cells--mobilized into peripheral circulation -target stem cells -eliminates concerns of GVHD--no donor T cells in bone marrow graft

Why is HLA polymorphism critical?

-ensures population won't succumb to new or mutated pathogen--if we had same, would all be wiped out -HLA molecules teach T cells

What hematopoietic defects can bone marrow correct?

-immune system disorders--Severe combined immunodeficiency (SCID) -sickle cell anemia -leukemias and lymphomas--ALL, CML

Blood function:

-transport and distribute--oxygen, nutrients, waste products, and hormones -maintenance and regulation--body temp and pH -protection--infection and loss of blood

Eosinophils make up ____% of leukocytes

1 - 3% of leukocytes

steps of primary hemostasis

1 vasoconstriction, 2 platelet adhesion to vWF on exposed collagen (GPIb receptor), 3 platelet degranulation (ADP/TXA2), 4 platelet aggregation (GPIIb/IIIa)

Clinical manifestations of bone marrow graft

1+ months post transplant -bright red rash -fever -diarrhea -swelling of abdomen, skin around eyes -hepatitis

Coagulation involves which 3 pathways

1. Extrinsic pathway 2. Intrinsic pathway 3. Common pathway

two causes of anemia?

1. underproduction of RBC (reticulocyte count < 2.5%) 2. destruction of normal RBC (reticulocyte count > 2.5%)

RBC lifespan

120 days

Normal platelet count

150,000-450,000 cells/uL ~10 day lifespan

Hemoglobin A2

2 alpha, 2 delta (2-3% of Hb found in adults) is elevated in beta-thalassemia as beta-globin chain underproduction leads to decreased hemoglobin A levels.

calcium dependent factors

2, 10, 13

Which factors are activated by thrombin?

5,7,8,11,13

HbF is replaced how many weeks after birth?

6 weeks post birth HbF is 2 alpha 2 gamma

Blood is how much of total body weight?

8%

RBCs are ________% hemoglobin

97% each RBC can bind 1 billion oxygen molecules

Granulocytes

A group of leukocytes containing granules in their cytoplasm; neutrophils, eosinophils, basophils (& closely related mast cells).

Agranulocytes

A group of leukocytes without granules in their nuclei; lymphocytes (B & T-cells), monocytes (macrophages).

Hypoxia-inducible factor (HIF)

A transcription afctor that activates genes for EPO (HIF can only survive in hypoxic environment)

ReoPro

Abciximab GP IIaIIIa antagonist. This is the only one with irreversible blockade (binds GP IIaIIIb for weeks due to high affinity); used after angioplasty to prevent blood clot Antibody therapy

lymphopenia

Absolute lymphocyte count < 1500 cells/mm3 [<3000 in children]

What proteins are in blood?

Albumin, immunoglobulins, clotting factors, and globins

Coumadins

Anticoagulants that inhibit vitamin K reductase enzymes Ex: Warfarin, Dicoumarol *not for use in placenta (teratogenic)

ATIII

Antithrombin III; inhibits Xa and II (thrombin)

Drugs that inhibit platelet activation by blocking thromboxane A2 production

Aspirin (irreversible NSAID) and reversible NSAID (e.g. ibuprofen, naproxen)

Factors/ condition that can cause lymphopenia

HIV, DiGeorge syndrome, SCID, corticosteroids, radiation, sepsis, postoperative

Only identical twins have the exact same set of:

HLA molecules

Ristocetin cofactor assay

In vitro platelet agglutination test for vWF. Ristocetin enhances vWF interaction with platelet GP Ib/IX. If ABNORMAL, no platelet aggregation occurs in assay

Thalassemia

Inherited defect in the ability to produce hemoglobin

Von Willebrand Disease

Intrinsic pathway coagulation defect: low vWF --> high PTT (vWF acts to carry/protect factor VIII). Defect in platelet plug formation: low vWF --> defect in platelet-to-vWF adhesion. 2 types: hereditary (Autosomal dominant) & acquired Mild but most common inherited bleeding disorder (mixed platelet/coagulation disorder). No platelet aggregation with ristocetin cofactor assay. Treatment: desmopressin, which releases vWF stored in endothelium & prednisone (with patients w/autoimmune diagnosis)

Aspirin

Irreversible COX inhibitor; long lasting anti-thrombotic; inhibit platelet activation

Immunoglobulin classes

MAGED mu, alpha, gamma, epsilon, delta

what electrolytes are in blood?

Na+, K+, Cl-, and HCO3-

Thromboxane synthase

PGH2 --> TXA2

Drug that inhibits platelet activation by blocking ADP receptors (preventing contact activation)

Plavix (clopidogrel)

Agents that inhibit coagulation by decreasing Ca2+

Prostacyclin (in vivo)- released by endothelium in vitro: EDTA chelates calcium sodium citrate forms insoluble Ca2+ salts

Anti-coagulation factors that contain Gla residues

Protein C and S

Phospholipase A2

Releases arachidonic acid from phospholipid membrane

Which Rh classification makes anti-D (Rh) IgG antibodies?

Rh negative

Erythropoiesis steps

ST-HSC-->CMP-->MEP-->BFU-E--> Proerythroblast (CFU-E) --> Basophilic erythroblast --> Polychromatic erythroblast --> Orthochromatic erythroblast --> Reticulocyte --> Erythrocyte

Koilonychia

Spoon nails; characteristic of iron deficient microcytic anemia

Normal RBCs

The number of RBCs in a whole uL of blood. 4.8 x 10^6/ uL = females 5.5 x 10^6/uL = males

Heparin inactivates

Thrombin (IIa), IXa, Xa, XIa

___________ is an essential co-factor for the production of amino acid gamma-carboxyglutamate (Gla)

Vitamin K

Agglutination test

What immunologic test checks for a reaction between Abs and a particular Ag? (hint: ABO typing)

Angina

a condition of episodes of severe chest pain due to inadequate blood flow to the heart

Hemophilia

a group of hereditary coagulation disorders in which a blood-clotting factor is missing (results in high PTT)

Endothelin-1 (ET-1)

a vasoconstrictor secreted by endothelial cells and triggered by thrombin

Thromboxane A2

a vasoconstrictor that is released from platelet granules; major product of COX-1 metabolism in platelets

eosinopenia

absolute eosinophil count <30 cells/mm^3

Neutropenia

absolute neutrophil count < 1500 cells/mm3

CD4 helper T cells

activate Ag-specific B cells that stay in the T cell areas

When are remaining organelles lost on an immature erythrocyte

after reticulocyte stage

Plavix

aka Clopidogrel blocks GP IIb/IIIa activation inhibits aggregation to exogenous ADP prevents amplification by othe ragonists non effect on cyclooxygenase (COX)

Celiac disease

an inherited autoimmune disorder characterized by a severe reaction to foods containing gluten, results in decrease of iron absorption

Heparin activates?

antithrombin (AT III)

Glanzmann's thrombasthenia

autosomal recessive disorder, Defect in platelet plug formation ⇓ GpIIb/IIIa → defect in platelet to platelet aggregation via fibrinogen Labs: blood smear shows NO platelet clumping. ⇑ BT, normal PC AVOID aspirin

neutrophil number increases during...

bacterial infections

rarest leukocyte

basophil (0.5 - 1%)

important for parasitic infections and allergies

basophils

Heme is broken down into this pigment, which is secreted in bile and excreted in urine.

bilirubin

GP Ia/IIa binds to

binds collagen beneath the vascular bed; binding activates platelets

GP Ib/IX

binds von Willebrand factor

At what stage of erythropoiesis is all hemoglobin finished being synthesized?

by end of orthochromatic stage (stage were nucleus is lost)

CXCL12/CXCR4

chemokine and receptor pair that keeps hematopoietic stem cells within bone marrow

Agents that decease Ca2+ inhibit ______________

coagulation

Protein S

cofactor of protein C

Thrombomodulin

complexes with II (thrombin) and keeps it from being activated into IIa Thrombin-throbomodulin complex activates protein C

intrinsic pathway is activated by

contact activation (e.g. activated platelets, collagen, basement membrane, negatively charged surface like glass)

COX 1

converts arachidonic acid to prostaglandin H2

Cytopenia

decrease in WBC numbers

hypovolemia

decreased blood volume; leakage of blood into vasculature due to not enough clotting

Alpha Thalassemia

deletions in alpha globins, leading to an excess of beta chains in adults or gamma chains in fetus

hemolytic reaction

destruction of RBCs when patient receives mismatched blood transfusion

Allogenic graft

donor & recipient differ genetically, similar HLA haplotype

Syngenic graft

donor & recipient identical twins, matched HLA haplotype

What do monocytes do?

eat invading pathogens, clean up dead neutrophils & RBCs

critical for defense against helminths and bacteria

eosinophils

Integrillin

eptifibatide antiplatelet agent, GP IIb/IIIa inhibitor shorter half-life than ReoPro given to patients with angina

Clotting cascade starts which which pathway

extrinsic pathway

Hemophilia B

factor IX deficiency x linked recessive prevalent in European royal families

Hemophilia A

factor VIII deficiency x linked recessive

Hemophilia C

factor XI deficiency; autosomal recessive disorder primarily affecting the Ashkenazi Jewish population

Secondary hemostasis begins with

fibrin aggregation at platelet plug

spleen function

filters and removes old erythrocytes

best time to measure peripheral blood smear

first thing in the morning (b/c counts may be elevated after meals)

SCID (severe combined immunodeficiency)

genetic disorder in which T cells and B cells are absent or inactive

Prednisone

given to patients with autoimmune vWD

Graft vs. Host Disease (GVHD)

graft recognizes pt's cells as foreign and tries to attack them; some GVHD indicates successful engraftment; try limit activity of donor T-cells w/ drugs w/o suppressing them to the extent that new cells stop grafting

G-CSF

granulocyte colony stimulating factor, promotes neutrophil differentiation

GM-CSF

granulocyte-monocyte colony stimulating factor -promotes neutrophil and monocyte differentiation

leukocytes divided into

granulocytes and agranulocytes

Basophils secrete

histamine, serotonin, and heparin

Desmopressin

hormone that stimulates production of vWf

Events that trigger EPO synthesis

hypoxia, severe anemia, high altitude hormones Hb that have high affinity for O2 (not deposited in tissues)

Sites of bone marrow harvest

iliac crest and sternum

Protein C

inactivates co-factors Va and VIIIa

Unfractionated Heparin

injected under skin or through intravenous infusion; anticoagulant -long, high MW

Transferrin

iron transport protein that controls level of free iron in blood fh

Where is EPO produced?

kidneys (90%) and liver (10%)

WBC and platelets make up ______% of total blood volume

less than 1%

Causes of iron deficiency

low dietary intake (vegetarians), malabsorption (celiac disease, gastrectomy - decreased acid production), increased demands (pregnancy and infancy), chronic loss of blood (heavy menstruation), peptic ulcer disease, colon cancer/polyps, hookworm infection)

MCHC

mean corpuscular hemoglobin concentration-the amount of hemoglobin per unit volume in a single red blood cell (avg. concentration of Hb in a packed volume of RBCs normal = 35 g/dL or RBCs The difference between MCH and MCHC is that the MCHC measurement takes the volume or size of the red blood cell into account while MCH does not.; when MCHC is low, the cell is hypochromic

MCH

mean corpuscular hemoglobin-average amount of hemoglobin per cell (avg. mass of each cell); RBCs are mostly Hb normal = 30 picograms/cell

MCV

mean corpuscular volume-average volume or size of a single red blood cell; when MCV is high, the cells are macrocytic, and when low, the cells are microcytic normal = 80 - 100 femtoliters/cell

M-CSF

monocyte colony stimulating factor, promotes monocyte differentiation

first responders to damaged/infected tissues

neutrophils

most abundant leukocyte

neutrophils aka polymorphonuclear leukocyte 10^11 produced daily

GP IaIIa and GP IbIX are found

on the surface of platelets

All hemoglobin synthesized by the end of what stage

orthochromatic stage

PTT

partial thromboplastin time, time it takes for blood to clot (intrinsic & common pathway); tests for abnormalities in blood clotting 30 - 50 seconds; defect results in high PTT determines if blood thinning treatment is effective (monitors effect of heparin)

Where is bone marrow found?

pelvis, femur, sternum, ribs, and tibia

At what stage of erythropoiesis does globin synthesis begin?

pro-erythroblast stage (CFU-E)

Globin synthesis starts at what stage

pro-erythroblast stage (CFU-E)

Vitamin K deficiency causes

problems with coagulation & bleeding increase in PT & PTT; bleeding time= normal, decrease in activity of factors 10,9,7,2

PT

prothrombin time, time it takes for blood to clot (extrinsic & common pathway) 11 - 13 seconds; defect results in high PT most common test used to follow patients on warfarin (tests vitamin K status in blood) measures warfarin dosage

neutrophils are the major component of:

pus

GP Ia/IIa

receptor for collagen (beneath vascular bed)

Anemia

reduced oxygen flow to the body's organ & tissues

Thrombopoietin

required for platelet (megakaryocyte) development

Immature erythrocytes have no nucleus

reticulocyte

NSAIDs

reversible COX inhibitors; include ibuprofen and naproxen; inhibit platelet activation

Factors/ condition that can cause neutropenia:

sepsis, drugs (chemo), aplastic anemia, radiation

Platelets release

serotonin, thromboxane A2, ADP

these induce vasoconstriction

serotonin, thromboxane A2, endothelin-1

Function of fibrin

stabilizes platelet plug (clot)

SCF

stem cell factor, keeps stem cells pluripotent

low molecular weight heparin drugs

subcutaneous injection; anticoagulant; does not cross the placenta (good for use during pregnancy) delteparin, enoxaparin, nadroparin, tinzaparin (DENT)

IL-3

supports committed stem cells

Erythropoietin

supports differentiation and growth of RBCs

gastrectomy

surgical removal of part or all of the stomach

___________ activates intrinsic pathway

thrombin

TT

thrombin time; time it takes for clot to form in plasma containing anti-coagulant after excess of thrombin is added ; indicates abnormalities in conversion of fibrinogen to fibrin 12 - 19 seconds

Activation factors for platelets

thromboxane A2, ADP, thrombin, other activated platelets, collagen, vWf, serotonin

Extrinsic pathway is activated by

tissue factor

TFPI

tissue factor pathway inhibitor extrinsic pathway inhibitor; blocks protease activity of VIIa TFPI binds to and inhibits factor Xa. After binding o factor Xa, TFPI undergoes a conformation change. The TFPI/factor Xa complex then mediates feedback inhibition of tissue factor/factor VIIa

tPA

tissue plasminogen activator; a clot-dissolving drug used as therapy for stroke tPA released from endothelial cells

Thrombosis

too much fibrinogen causes blood clots to form in the bloodstream = bad

Integrins are

transmembrane proteins/receptors that attach cell cytoskeleton to ECM (e.g. GP IaIIa, GP IbIX)

What metabolites are in blood?

urea, bilirubin, and creatinine

VIII activity assay

vWf is a carrier protein for factor 8 & protects it from protease digestion; assay used to test for vWD Because factor VIII circulates in the body attached to vWF, a decreased amount of factor VIII can also mean a decreased amount of vWF

GP Ib/IX binds to

vWf on extra-vascular smooth muscle cells; binding activates platelets

The body contains how much blood?

~5 L of blood