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Blood and Lymph > Week 7 > Flashcards

Week 7 Flashcards

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1
Q

Monoclonal antibodies

A

i. Abs derived from single B cell that has been fused with a multiple myeloma tumor cell → grows forever in culture
- B cell has info on what Ab to make, and myeloma cell is the machine
ii. Very expensive to produce, but promising use as anti-inflammatory agents
- Now trying to grow Ab in plants (cheaper)

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2
Q

Murine monoclonal antibodies

A

monoclonal made using B cells directly derived from immunized mice

i. (-omab)
ii. Can result in immune complex formation
1. HAMA - human anti mouse antibodies → serum sickness
2. Solved this problem with Chimeric and other forms of mAB

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3
Q

Chimeric monoclonal antibodies

A

mABs engineered at the DNA level to have mouse VL and VH domains but human C domains

i. (-ximab)
ii. Less likely to be recognized by patient’s own immune system - can be given several times, but will eventually develop HACA (human anti-chimeric antibody)

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4
Q

Humanized monoclonal antibodies

A

only CDRs of V domains are from the mouse

i.(-zumab)

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5
Q

Human monoclonal antibodies

A

all human, use a humanized mouse with SCID

i.(-umab)

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6
Q

NK cells

A

large granular lymphocytes (LGL), killers (similar mech to CTL)

i. No rearranged V(D)J genes, NOT thymic derived
ii. Have NK receptors which recognize DAMPs from stressed or dysregulated cells
iii. Part of the innate immune system

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7
Q

Antibody-dependent cell mediated cytotoxicity (ADCC)

A
  1. Requires LGL and antibody
  2. Not MHC-restricted the way CTL-mediated killing is
  3. NK cells have receptors for Fc of IgG → ab-dependent way to bind target cell
  4. IgG ab binds target cell → NK cell binds Fc IgG → NK cell triggered, delivers lethal signal to target → target dies via apoptosis
  5. Many mABs work by triggering ADCC
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8
Q

mABs in tumor therapy

A

i. mABs activate complement → tumor lysed or phagocytosed

ii. OR mABs activate ADCC

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9
Q

mABs tagged with radioisotope

A

used in imaging and as highly targeted therapeutic drug depending on which radioisotope is attached

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10
Q

BiTE: Bispecific T cell engager

A

i. Used specifically in lymphoma and non-philadelphia chromosome ALL
ii. CD-19 and CD3 targets

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11
Q

Hemostasis

A

ability of the body to stop bleeding from a damaged blood vessel and repair the defect in the vessel wall so that normal blood flow to and from the involved area can be maintained

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12
Q

Hemostasis components (5)

A

1) Coagulation cascade
2) Anticoagulation regulatory pathways
3) Fibrinolytic system (breaks down formed clots)
4) Endothelial cell lining of blood vessels (prevents clots in resting state, promotes clot formation following injury)
5) Platelets

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13
Q

Coagulation factors are synthesized in the ____

Name 3 exceptions

A

Liver

  1. Tissue Factor: NOT made in liver, expressed on surface of many cell types outside of vasculature
  2. VWF: NOT made in liver, produced by endothelial cells/megakaryocytes
  3. Factor VIII: can be made in liver, but also spleen, lung, and kidney
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14
Q

Most coagulation factors are ____ proteases

A

serine

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15
Q

Serine proteases

A

i. Includes majority of enzymes in coagulation cascade
ii. Serine proteases exist as Zymogens (inactive precursor proteins) → cleaved at arginine residues → active serine proteases
1. Exception: Factor XIII
iii. Factor XII, XI, IX, X, VII, II (prothrombin), and Prekallikrein

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16
Q

Coagulation cofactors (name 4)

A

initiate or accelerate enzymatic reactions (lack enzyme activity themselves)

i.Factor III (Tissue Factor), Factor V, Factor VIII, high molecular weight kininogen (HMWK)

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17
Q

Intrinsic tenase (4 components and what it activates)

A

Factor IXa (serine protease) + Factor VIIIa (cofactor) + phospholipid surface + calcium → activate factor X

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18
Q

Extrinsic tenase (4 components and what it activates)

A

TF (cofactor) + factor VIIa (serine protease) + phospholipid surface + calcium → activate factor IX or X

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19
Q

Prothrombinase complex (4 components and what it activates)

A

Factor Xa (serine protease) + Factor Va (cofactor) + phospholipid surface + Calcium → activate prothrombin (factor II) to Thrombin (IIa)

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20
Q

Vitamin K dependent factors (name 6 and their properties)

A

Factor II, VII, IX, X, anticoagulant protein C and S

  1. All contain Gla domain (9-13 glutamic acid residues) → post-translational modification to y-carboxyglutamic acid residues (Gla Residues)
    a. y-carboxylation carried out by y-glutamyl carboxylase (enzyme)
    b. Vitamin K required to generate precursor
    i. No Vitamin K (reduced form)→ can’t make Gla residues
  2. Gla residues (negatively charged) bind calcium → change shape of protein, allows binding to anionic phospholipid surface
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21
Q

Enzyme that gamma carboxylates the vitamin K dependent factors

A

y-glutamyl carboxylase

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22
Q

Fibrinogen to fibrin (explain the process)

A

Fibrinogen → Fibrin (by Thrombin) → formation of insoluble fibrin network

i.Factor XIII: stabilizes the forming clot

  1. Covalently links fibrin molecules together to form a stable clot
  2. Transglutaminase that forms amide bonds between specific lysine and glutamine residues of fibrin

ii. Fibrinogen: soluble plasma protein, cleaved by thrombin to Fibrin
iii. Fibrin: participates in forming actual blood clot

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23
Q

Structure of fibrinogen

A

Made of 6 polypeptides (2 pairs of 3) - A-alpha, B-beta, gamma

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24
Q

Von Willebrand Factor

A

i. Carrier protein for factor VIII in the plasma
ii. Stored in endothelial cells and platelets
iii. Binds factor VIII in circulating plasma → prolongs half life
iv. Deficiency → bleeding disorder similar to hemophilia A (factor VIII deficiency)

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25
Extrinsic coagulation pathway
Tissue damage → Tissue Factor (TF) binds Factor VIIa → activate factor X ii.Xa + Va → activate factor II → IIa → fibrinogen converted to fibrin
26
Intrinsic coagulation pathway
all necessary components contained in plasma i. Surface contact → contact factors (XII, prekallikrein, HMWK) → activate factor XI → activate factor IX → IXa + VIIIa → activate factor X ii. Xa + Va → activate factor II → IIa → fibrinogen converted to fibrin iii. TENET = twelve, eleven, nine, eight, ten
27
Initiation phase of coagulation cascade
Vascular disruption → expose plasma TF → encounter free factor VIIa on cell surface (in presence of calcium) → TF-VIIa 1. → binds Factor IXa, converts IX to IXa 2. → converts VII to VIIa 3. → activates Xa Xa begins process of clot generation → activate V, bind Va → form prothrombinase complex → activate thrombin
28
Amplification phase of coagulation cascade
occurs on surface of activated platelets adhered to exposed subendothelium i.Thrombin: 1. Amplifies procoagulant signal 2. Activates Factor V and VIII → Va and VIIIa 3. Activates XI → XIa ii.Platelets activated → Va and VIIIa bind platelet surface → Xa forms prothrombinase complex with Va → thrombin formation from prothrombin
29
Propagation phase of coagulation cascade
i. Assembly of procoagulant complexes on cell surface ii. Intrinsic tenase complex (VIIIa+IXa) → activate more factor X on platelet phospholipid surface 1. 50-100x faster than extrinsic tenase 2. → Xa binds Va → prothrombinase complex → converts prothrombin to thrombin 3. → thrombin cleaves fibrinogen to fibrin → form fibrin clot → activate XIII to XIIIa → cross-link/stabilize clot iii. Platelets: surface for coagulation reactions to occur, generate more thrombin 1. Secrete contents of granules containing components of coagulation
30
Thrombin as the central enzyme (5)
i. Prothrombin converted to Thrombin by tissue thromboplastin in the presence of calcium → fibrinogen to fibrin by thrombin ii. Cleaves and activates V and VIII to Va and VIIIa iii. Activates XI to XIa which then generates for IXa iv. Amplifies coagulation response v. Most potent activator of platelets
31
4 steps of primary hemostasis
i. Platelet Adhesion ii. Platelet Activation iii. Platelet Aggregation iv. Fibrin formation and support of local coagulation 1. Locally thrombin converts fibrinogen to fibrin stabilizing clot
32
End goal of primary hemostasis
formation of platelet plug (weak, unstable)
33
End goal of secondary hemostasis
stabilization of platelet plug by fibrin (clotting cascade)
34
Structure of mature platelet
- 2-3 microns in diameter - No nucleus but DO have mitochondria - Surface-Connected Canalicular System: system of internal membrane tunnels, how platelet granules are extruded during platelet aggregation and secretion - Cytoskeleton: allows shape change with activation
35
Life of a platelet
4-5 day maturation time, 7-10 day lifespan 1. BM platelet reserve limited, can be rapidly depleted 2. TPO (Thrombopoietin) - main growth factor 3. Spleen holds ⅓ of platelets
36
Three types of granules within a platelet
1. Dense granules: contain ATP, ADP, serotonin, and calcium 2. Alpha granules: proteins essential for platelet function (fibrinogen, factor V, VWF), platelet activation, and growth factors 3. Lysosomal granules: contain acid hydrolases
37
Four functions of platelets
1) Adhesion to vascular subendothelium at site of injury 2) Activation of intracellular signaling pathway → cytoskeleton change (rounder with legs reaching out)→ release granules 3) Aggregation to form platelet plug 4) Support of thrombin generation (provides phospholipid surface)
38
Describe the process of platelet adhesion to a damaged vessel wall
platelets adhere to damaged vessel wall directly via collagen or indirectly via von Willebrand Factor Vessel injury → expose subendothelial components Circulating vWF adheres to exposed area Platelets adhere to subendothelium via Glycoprotein 1B (GP1b) on platelet surface, binds vWF Stimulated platelets expose membrane GP2b3a → bind fibrinogen and vWF
39
GP2b3a + vWF →
stabilizes platelet adhesion
40
GP2b3a +fibrinogen →
platelet aggregation
41
How to prevent platelet adhesion under normal circumstances (2)
i. Prevent Coagulation with: Heparin-like molecule and Thrombomodulin + thrombin → Protein C and S ii. Prevent platelet aggregation: secrete NO, prostacyclin, inhibitors of platelet activation
42
5 steps of platelet activation
1) Platelet adherence → cytoskeleton activation and shape change 2) Causes release of platelet granules - Thrombin - Thromboxane A2 - Epinephrine - ADP 3) → Calcium mobilization 4) → Ca2+ further promotes thromboxane A2 synthesis and amplifies platelet activation 5) Switch phosphatidylserine from inner to outer membrane leaflet → available for clotting factors to use to make thrombin
43
Process of platelet aggregation
i. GP2B3A binds fibrinogen → lace platelets together into an aggregate ii. Soup of agonists promoting aggregation around growing platelet aggregate - ADP, Thrombin, Collagen, Epinephrine, Thromboxane iii. Thrombin generated through activation of coagulation cascade that converts fibrinogen to fibrin
44
Throbocytopenia
decreased number of platelets i. 20-50,000 platelets → spontaneous hemorrhage, increased hemorrhage ii. Less than 10,000-20,000 → life threatening spontaneous hemorrhage * MUST rule out pseudo-thrombocytopenia*
45
General causes of thrombocytopenia (3)
1. Decreased production of platelets 2. Increased destruction of platelets 3. Distribution disorders
46
Things that cause decreased production of platelets
BM failure, nutritional deficiencies, ETOH, malignancies, drug-induced, radiation, viral infections
47
Things that cause increased destruction of platelets
ITP, autoimmune disorders, drugs, DIC, sepsis, Thrombotic thrombocytopenic purpura (TTP), post-transfusion purpura
48
Distribution disorders
1. Increased sequestration (splenomegaly) 2. ETOH, hematologic disorders, storage diseases, active bleeding/clotting (consumption) 3. Dilution (massive transfusion)
49
Immune thrombocytopenic purpura
Platelets coated with anti-platelet abs → premature removal by spleen
50
Acute ITP (including treatment)
disease of children/young adults following viral infection 1. Sudden onset severe thrombocytopenia 2. Recovery in 2-6 weeks TX: none or steroids
51
Chronic ITP (including treatment)
adults 1.Autoimmune disorders TX: steroids, IVIG, splenectomy, TPO agonists
52
5 common treatments of ITP and their mechanism of action
i. Steroids: inhibit B cell production of auto-ab ii. Rituximab: B cell inhibitor (anti-CD20) iii. Splenectomy: stop removal of platelets iv. IVIG: block splenic Fc receptors v. TPO: enhance TPO production
53
Von Willebrand disease
primary hemostatic bleeding disorder, AD i. vWF key for adhesion of platelets to injured endothelium → lack of vWF causes abnormal platelet/endothelial interaction → Mucosal and skin bleeding Caused by inadequate amount of vWF or mutation in vWF gene ii. vWF = carrier protein for factor VIII 1. Can cause defects in secondary hemostasis
54
Lab tests for VW disease (5)
1. Bleeding time (PFA-100) 2. Factor VIII level 3. vWF antigen test (test amount of vW protein) 4. vWF activity test (ristocetin cofactor activity) 5. Blood Type
55
Treatment of VW disease (2)
1. DDAVP (Arginine vasopressin): enhances release of vWF from endothelial stores (treats type 1, partial quantitative vWF deficiency) a. Does not treat qualitative defects (type 2) or complete absence of vWF (type 3) 2. vWF replacement therapy: a. Intermediate purity factor VIII - Used mostly in type 2 and 3
56
Questions for patient with excessive bleeding
i. Is the bleeding real? ii. Is it platelet type or coagulation factor bleeding? iii. Is it acquired or congenital? iv. What tests do I order and how do I interpret them
57
Brisk bleeding from obvious trauma →
local vascular defect
58
Prolonged/recurrent bleeding →
generalized hemostatic disorder
59
Sudden resumption of bleeding →
excessive fibrinolysis/abnormal fibrin crosslinking
60
Multiple site bleeding →
more severe, generalized hemostatic disorder
61
Mucocutaneous bleeding →
platelet or vWF defect
62
Soft tissue/joint/deep bleeding →
coagulopathy
63
Lab studies for extensive bleeding (5)
1) CBC and peripheral blood spears - -> Platelet count, size granularity 2) Bleeding time (PFA-100 test) (test platelet function, primary hemostasis) - Normal is less than 100,000/uL, qualitative bleeding disorder → prolonged bleeding time - Affected by ASA and NSAIDs - Abnormal values DO NOT predict intraoperative bleeding risk 3) Platelet Aggregation Studies 4) Check LDH, Liver, Renal Function 5) Review old CBCs
64
Antithrombin
serine protease inhibitor, aka Serpin i. Serpin binds serine residue of target protease → form covalent bond - Suicide protease inhibitor, inactivates serpin and target ii. Made in liver iii. Plasma half life = 3 days
65
Targets of antithrombin
thrombin and factor Xa
66
Heparin
Accelerates protease inactivation by 1000x 1. Allosteric activation of antithrombin → more efficient binding of target protease (Xa, NOT Thrombin) by antithrombin 2. Binds antithrombin and serine protease target → close proximity
67
Protein C
vitamin K dependent serine protease i. Circulates as a zymogen ii. Thrombomodulin expressed by endothelial cells binds thrombin → neutralize thrombin procoagulant activity 1. Thrombin-Thrombomodulin → binds and activates protein C 2. Activated protein C (APC) → cleave and inactivate cofactors Va and VIIIa → decreased thrombin generation - Enhance reaction by interaction of Protein C and Protein S iii. Made in liver iv. Plasma half life - 8-10 hrs
68
Protein S
cofactor with activated protein C i. Made in liver ii. Vitamin K dependent
69
Factor V Leiden
mutated Factor V i. Mutation at AA 506 (glutamine → arginine) ii. Factor V resistant to inactivation by APC
70
Tissue factor pathway inhibitor (TFPI)
Expressed constitutively by endothelial cells - Inhibits extrinsic coagulation pathway → inhibit thrombin generation 1. TFPI binds factor Xa → binds and inactivates TF-factor VIIa 2. TFPI binds factor IXa → bind and inactivates TF-factorVIIa
71
Fibrinolysis
process of clot breakdown following clot formation i. Allows eventual repair of damaged blood vessel following injury ii. Begins as soon as clot begins forming
72
Key enzyme of fibrinolysis
Plasmin
73
Plasmin
i. . Plasminogen (zymogen precursor) → Plasmin ii. Cleaves fibrinogen and fibrin and breaks down ECM proteins iii. Made in liver (plasminogen), circulates in plasma and tissues iv. Plasma half life = 2 days
74
Plasmin is activated by
t-PA and u-PA
75
Tissue plasminogen activator (t-PA)
serine protease a. Produced in endothelial cells b. VERY short half life (2.5 minutes) c. Activates plasminogen → plasmin in presence of fibrin
76
Urokinase plasminogen activator (u-PA)
serine protease a.Produced by kidney cells and endothelial cells b. VERY short half-life (5 min) c. Prourikase binds clot → cleave to active u-PA → activate plasmin
77
Plasminogen activation inhibitor 1 (PAI-1)
clears t-PA from blood i. Half life of less than 10 minutes in blood ii. Present in a-granules of platelets iii. Serpin - binds and inactivates t-PA, and binds/inactivates u-PA
78
Alpha 2-antiplasmin
Primary plasmin inhibitor in blood 1. Binds and inactivates free plasmin (1:1) 2. Localizes fibrinolysis to site of the clot
79
Thrombin-activated fibrinolysis inhibitor (TAFI)
zymogen i. Made in liver, circulates in blood in complex with plasminogen ii. Activated by Thrombin-Thrombomodulin complex 1. → exopeptidase → target C-terminal of fibrin molecules 2. Down regulates plasmin, slows clot lysis
80
Anticoagulation mechanisms in endothelial cell lining (3)
1. Heparan sulfate and dermatan sulfate → cofactors for antithrombin and heparin cofactor II respectively 2. Thrombomodulin → cofactor with thrombin for activation of protein C 3. TFPI → inhibit extrinsic Xase complex
81
Antiplatelet mechanisms in endothelial cell lining (2)
1. Prostacyclin (PGI2) and NO → prevent adhesion of activated platelets and cause vasodilation 2. Enzyme metabolism of ADP (platelet agonist) to AMP+adenosine (platelet inhibitor)

Blood and Lymph (9 decks)

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