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Heam Onc > Hematology > Flashcards

Hematology Flashcards

1
Q

p53

A

Tumor suppressor gene –> Location: Ch17 –> del: 17p13.1

a. HPV –> E6 –> inactivate p53 –> cervical cancer
b. CML –> p53 + myc are responsible for oncological cells survival.

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2
Q

Hepcidin

A
  • Acute phase reactant –> produced by the liver
  • Key modulator for iron to get into the circulation
  • level is abnormally high such as inflammation –> serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption –> anemia of chronic disease
  • level is abnormally low such as in hemochromatosis, hypoxia, inc EPO –> iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.
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3
Q

Ferroportin

A

Transmembrane protein –> hepcidin attach with it –> downregulation –> dec intestinal absorption + dec release of iron from macrophages.

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4
Q

Ferritin

A

Intracellular protein –> iron binds with it to be stored within the cell.

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5
Q

Transferrin

A

serum protein –> iron binds with it to be circulated within the blood –> interact with transmembrane receptor –> internalized and provide iron to a cell.

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6
Q

RBC

A

a. Source of energy –> Glucose (90% from glycolysis, 10% from HMP shunt via G6PD enzyme)
b. Cl/HCO3 antiporter –> help in transporting CO2 from periphery till lungs.

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7
Q

Thrombocytes (Platelets)

A

a. PLTs + Fibrinogen –> Plug –> Primary hemostasis.
b. 1/3 of pool is stored in spleen
c. DenCe granules –> aDp and Ca++ deposit
Alpha granules –> vWF (Gp Ib receptor) and Fibrinogen (Gp IIb-IIIa receptor).

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8
Q

Leukocytes

A

Granulocytes –> neutrophils, basophils, eosinophil

Mononuclear –> monocytes –differenciate into–> macophages, lymphocytes.

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9
Q

Neutrophils

A

a. Inc means bacterial infections
b. has Alkaline phosphatase –> inc LAP score
c. Azurophilic granules –> lysosomes
d. Hypersegmented i.e. >5 lobes –> B9/B12 deficiency
e. Left shift –> inc. bands –> inflamation v/s CML
f. chemotactic signals: C5a, IL8,

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10
Q

Macrophages

Gamma-Madarchod

A

a. Differentiate from monocytes and activated by INF-g
b. Antigen-presenting via MHC II
c. Granuloma forming
d. Lipid A from bacterial LPS binds with CD14 on macrophages to initiate septic shock.

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11
Q

Eosinophil

A 
Eosinophilia --> NCAAP
N: Neoplasm (mix cellularity cHL)
C: Chronic adrenal insufficiency 
A: Asthma
A: Allergy 
P: Parasitic infection
IL-5 (eoCINCOphil) is chemotactic and produces Histamine and Major Basic Protein(MBP).
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12
Q

Basophil

A

a. Cause allergic reaction in blood
b. Have Heparin, Histamine, Leukotrienes.
c. Basophilia –> Myeloproliferative disorders (CML)

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13
Q

Mast cells

A

a. Allergic reaction in local tissues only and is a cousin of basophil.
b. Fc portion of IgE binds on the surface –> degranulation –> Histamine, Heparin and Eosinophilic chemotactic.
c. Cromolyn and Nedocromil –> mast cell stabilizers –> prevent stimulus independent degranulation –> use as 2nd line prophylaxis.
c. Cause Type I hypersensitivity by recruiting Eosinophils.

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14
Q

APCs (Antigen Presenting Cells)

A

Macrophages
B cells
Dendritic cells
- All 3 have MHC class II expression (dendritic cells have Fc receptors as well) and link innate and adaptive immunity together.

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15
Q

T cells

A
  1. Cytotoxic T cell: CD8 + and MHC I expression (8*1=8)
  2. Helper T cell: CD4 + and MHC II expression (4*2=8)
  3. Regulatory T cell: CD28 +. necessary for T cell activation.
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16
Q

Blood grouping classifications

A

a. ABO: IgM antibodies –> can not cross placenta
b. Rh: IgG antibodies –> cross placenta –> erythroblastosis fetalis. Prevented by giving RhoGAM to Rh- mothers during 3rd trimester, which prevent maternal anti-Rh IgG production.
- O is universal RBC dooooooner
- AB is universal RBC acceptor
- The opposite is true for plasma donation.

17
Q

Blood transfusion

A
  • Citrate cause hypocalcemia and hypomagnesemia

- old RBC ruptures cause hyperkalemia

18
Q

Factors keeping blood in liquid form

A
  1. Endothelial cells: Preventing blood contact with the subendothelial surface and producing NO and prostacyclin (PGI2).
  2. Thrombomodulin (found on endothelial cells surface) functions as a cofactor in the thrombin-induced activation of protein C in the anticoagulant pathway.

The physiologic (endogenous) inhibitors of the coagulation pathways are:

  1. Tissue factor pathway – tissue factor pathway inhibitor (TFPI)
  2. Contact activation pathway – C1 esterase inhibitor (C1-inh)
19
Q

Thrombin v/s Plasmin

A
  1. Thrombin is procoagulant and helps to do hemostasis/thrombus formation via fibrin formation.
  2. Plasmin is anticoagulant and helps to make plasma flow by fibrinolysis.
20
Q

Hemostasis phases (hemostasis is part of normal healing as well)

A

a. Primary hemostasis –> platelet plug formation
b. Secondary hemostasis –> coagulation cascade involvement
c. Clotting cessation –> controlled antithrombotic mechanism
d. Clot clearance –> Fibrinolysis

21
Q

Primary hemostasis comprises of 4 phases

A
  1. Platelet adhesion (weak and direct)
  2. Platelet activation / secretion
  3. Procoagulant function by strong and indirect adhesion
  4. Platelet aggregation
22
Q

Platelet adhesion (weak and direct = Ia)

A

Endothelial cells preventing platelet contact with the subendothelial surface and producing NO and prostacyclin (PGI2) –> injury –> endothelial cell rupture –> subendothelial collagen exposure –> Platelet adhere to collagen via GP Ia/IIa –> weak and direct adhesion –> GP VI on adhesion activate platelet (most potent activator along with thrombin) –> platelet activation.

23
Q

Platelet activation

A

ADP, epinephrine, thrombin, and collagen are 4 activators. Thrombin and collagen are the most potent one.

a. Collagen mediated activation during adhesion via GP VI receptors.
b. Thrombin activates via PARs (1 and 4) receptors. Vorapaxar is an oral PAR-1 antagonist as an antiplatelet agent.
c. ADP activates via P2Y1 and P2Y12 receptors –> Ca++ mobilization, shape change, secretion (alpha and dense granules) and GP IIb/IIIa exposure.

ADP act as paracrine on platelets and activate further platelets and is a potent trigger for aggregation. Clopidogrel blocks P2Y12.

Platelet secretion:

  1. Alpha granules (vWF, Fibrinogen, PDGF, Platelet factor 4).
  2. Dense granules (ADP, ATP, Ca++, histamine, serotonin, TXA2: vasoconstrictor)
24
Q

Platelet adhesion (strong and indirect = Ib)

A

activation –> shape change (provide phospholipid surface for coagulation cascade to run) –> secretion –> platelet receptors GP Ib/IX/V binds with subendothelial collagen via vWF.
Bernard-Soulier disease: GP Ib/IX/V deficiency
Von Willebrand disease: vWF deficiency

25
Q

Platelet aggregation

A

Adhesion –> Activation/Secretion –> Adhesion –> G IIb/IIIa expression –> Fibrinogen and vWF gluing –> Platelet aggregation –> plug formation.
Glanzmann Thrombasthenia: GIIb/IIIa deficiency

26
Q

Procoagulant production site

A

all procoagulants are made in liver except vWF (made in platelets and endothelial cells) and Factor VIII (made in endothelial cells of the liver as well as lymphatics and renal glomeruli). vWF stabilizes factor VIII.

27
Q

Vitamin K dependent factors

A

POST translational vitamin K dependent carboxylation of Glutamic acid, functions as Ca++ binding site and necessary for activation.
Factors: 2790CS (2: Prothrombin / Tissue factor)

28
Q

Clotting times

A
  1. aPTT (activated partial thromboplastin time): intrinsic pathway, starting from a negatively charged surface.
  2. PT (Prothrombin Time): extrinsic pathway, activated by tissue factor (Factor 2/ Prothrombin) exposed on injury site. Most important physiological event and time.
  3. TT (thrombin time): intrinsic and extrinsic pathway merge on factor X which activates prothrombin to thrombin and then thrombin converts soluble fibrinogen to insoluble fibrin.
29
Q

why people with thrombocytopenias remain asymptomatic?

A

Endothelial cells near injury site are more important for coagulation than platelets. And coagulation factors adhere to the edges of endothelial cells near injury more than the platelets and that’s why people with severe thrombocytopenias remain asymptomatic

30
Q

Extrinsic Pathway (EX 270)

A

Endothelial injury –> tissue factor (TF II, Thromboplatin) exposure –> bind with factor VIIa –> activate factor X and factor IX
Xa –> feedback activation of VII to VIIa, VIII to VIIIa and II to IIa. (278)
IXa –> activate X to Xa

Malignant cells also cause thrombosis by tissue factor production.

31
Q

Intrinsic / Contact pathway (COIN)

A

can be activated by 2 ways:

  1. Via extrinsic pathway (27 combination –> activate IX)
  2. Contact of negatively charged surfaces with Hageman(factor i2), prekallikrein (Fletcher factor) and high molecular weight kininogen (HMWK, Fitzgerald factor) –> activate XI –> activate IX and then X and thus merges with extrinsic arm.

PK, XII, HMWK deficiencies do NOT cause any bleeding problems.

32
Q

Cessation of clot

A 
The physiologic (endogenous) inhibitors of the coagulation pathways are followings which maintain the fluidity of blood:
1. Tissue factor pathway – tissue factor pathway inhibitor (TFPI) produced by endothelial cells and circulate in plasma --> inhibit IIa VIIa complex and Xa. Heparin also enhance TFPI secretion and hence anticoagulate.
  1. Contact activation pathway – C1 esterase inhibitor (C1-inh) produced by liver –> inhibit XIIa, PK and C1. Deficiency cause hereditary angioedema.

other important factors are:
serine protease inhibitor (SERPIN), antithrombin (previously called antithrombin III), the protein C pathway. In addition, prostacyclin, thromboxane, and nitric oxide (NO) modulate vascular and platelet reactivity.

33
Q

Antithrombin

A

AT in plasma + Heparin/Heparan (endogenous or exogenous) –> boost in AT activity –> destroy factor 2,9,10,11,12.

34
Q

Protein C and S

A

Thrombin + Thrombomodulin (on endothelial surface) –> activates Protein C –> activate protein S –> cleave factor V and 8. if factor V is mutated then can not be cleaved by Protein C and hence is a hypercoagulable state called F-V leiden mutation.

35
Q

TXA2 and PGI2

A

TxA2 activates platelet aggregation and vasoconstriction, PGI2 blocks platelet aggregation and antagonizes TxA2-mediated vasoconstriction

a. Low dose aspirin irreversibly acetylates and inhibits COX-1 and only weakly inhibits COX-2. Since platelets cannot make new COX-1, the inhibition of TxA2 is permanent for the life of the platelet.
b. In comparison, endothelial cells can make new COX-1 as well as COX-2 and higher doses of aspirin are required for inhibition of PGI2 production

36
Q

Clot dissolution and fibrinolysis

A
  1. Plasmin: tPA (tissue plasminogen activator) and fibrin bind with plasminogen and activate it into plasmin. Plasmin cleaves fibrin mesh work into D-dimers, and inactivate F XIIIa.
    tPA is produced by endothelial cells.
    Urokinase also activates plaminogen but is a major component of extravascular fibrinolysis.
37
Q

Plasminogen activator inhibitors and alpha-2-antiplasmin

A

The PAIs inhibit tPA, while alpha-2-antiplasmin inhibits plasmin.

38
Q

Carboxypeptidase B2 (thrombin-activatable fibrinolysis inhibitor)

A

TAFI is activated by thrombin-thrombomodulin complex and Activated CPB2 functions as a fibrinolysis inhibitor by cleavage of C-terminal lysines from partially digested fibrin, thereby diminishing the incorporation and activation of plasminogen, leading to delayed clot lysis.

Heam Onc (4 decks)

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