Unit IV Flashcards
1
Q
What clotting factor has the shortest plasma half life?
A
Factor V II
4-6 hours
2
Q
What are zymogens?
A
inactivated precursor proteins that are activated through cleavage
3
Q
Which factors are serine proteases?
A
factor XII prekallikrein factor XI factor IX factor X factor VII factor II
4
Q
Which proteases are vitamin k dependent factors?
A
II VII IX X anticoagulant protein C
5
Q
Which factor is vitamin k dependent and is a cofactor?
A
Protein S
6
Q
What domain do all vitamin k dependent factors share?
A
A gluatmic acid residue domain
7
Q
Which factor covalently links fibrin together to form a stable clot?
A
Factor XIII
transglutaminase that can form cross linked amide bonds
8
Q
What are the cofactors in the coagulation cascade?
A
tissue factor
Factor VIII
Factor V
High molecular weight kininogen
9
Q
How does thrombin cause activation of fibrinogen?
A
It cleaves off two small peptides, fibrinopeptide A and B. The release of A exposes a site on the E domain that can now non-covalently bond to the D domain of another fibrin molecule
10
Q
What is the role of cofactor XIIIa?
A
it covalently cross links adjacent D domains
11
Q
What factor is the carrier protein for factor VIII in the plasma?
A
Von Willebrand factor VWF
12
Q
What factors are not associated with a bleeding tendency?
A
Factor XII, prekallikrein, HMWK, and lesser extent XI
13
Q
Define immunomodulation?
A
the use of drugs, alone or in combination with other maneuvers, to change the function of all, or part of the immune system
14
Q
Describe the method to make a monoclonal antibody?
A
fuse a progeny line of a single B cell with a multiple myeloma tumor cell so the hybrid can grow FOREVER in culture.
15
Q
Describe what a murine monoantibody is.
A
Derived directlyfrom immunized mice.
100% mouse
16
Q
Describe what chimeric monoantibody is
A
The VL and VH chains are mouse but the C domains are human
17
Q
Describe what humanized monoantibody is
A
The CDR (complementarity determining region) is mouse and the rest is human
18
Q
Describe what fully human monoantibody is
A
straight human antibody yo!
19
Q
What are large granular lymphocytes?
A
Natural Killer cells that make up 5-10% of blood lymphocytic cells
20
Q
What is ADCC?
A
Antibody-dependent cell-mediate cytoxicity
IgG binds to tumor cells. Large granular lymphocytes (NK cells) bind to the Fc portion and signal that cell to undergo apoptosis
21
Q
What is the significance of antibody to tumor associated antigens?
A
They can activate complement and the tumor will be lysed or phagocytosed
**more often invokes ADCC
22
Q
What are immunotoxins?
A
modified antibodies that can be tagged with poison or radioisotopes
**Can be used for imaging or killing a bad cell
23
Q
Define biological response modifiers?
A
a loose class of substances targeted mostly at cytokines or their receptors.
Can be genetically engineered receptor antagonists or mass produced normal gene products.
A lot of these agents are antibodies to components of the immune or inflammatory system.
24
Q
What does HAMA stand for?
A
Human anti-mouse antibody
25
What are key differences between NK cells and T cells?
NK cells do not have a V(D)J region and they have NK RECEPTORS
26
What platelet receptor binds to von willebrand factor?
GP1b
27
What platelet integrin receptor binds to fibrinogen and increases its affinity for VWF?
GPIIb
28
What do dense granules in platelets contain
non protein platelet agonists: serotonin, calcium, ADP, ATP
29
What do alpha granules in platelets contain?
adhesion and procoagulant factors (vWF, fibrinogen, factor V)
Platelet Derived Growth Factor (PDGF)
30
What pathway do platelets use to recruit other platelets?
cyclooxygenase pathway to release thromboxane A2
31
What drug inhibits thromboxane A2?
aspirin
32
What is the most common congenital bleeding disorder?
Von Willebrand Disease
33
What is the role of von willebrand disease?
it helps with platelet adhesion and aggregation
Also that carrier protein for factor VIII
34
Does von willebrand disease affect primary hemostasis or secondary hemostasis?
Both! It leads to abnormal platelet/endothelial interaction and non functional carrier protein for factor VIII
35
How do you treat von willebrand disease?
desmopressin (DDAVP) enhances release of vWF from endothelial stores
it is only effective for type 1 vwd (partial quantitative deficiency)
Can also use factor replacement
36
What is Bernard Soulier syndrome?
rare autosomal recessive disorder where expression of GP1b on platelets is reduced --> decrease platelet adhesion
37
What is an alternative name for vWF?
ristocetic cofactor
38
What is gray platelet syndrome?
deficiency of alpha granules
39
What is afibrogenemia?
lack of fibrinogen leas to primary (GPIIb/IIIa has nothing to bind to) and secondary hemostatc defect (fibrin cross linking defect)
40
What is the clinical presentation for afibrogenemia?
mucosal and cutaneous bleeding
| deep muscle hematomas (coagulation defect)
41
What is glanzmann thrombasthenia?
rare autosomal recessive bleeding disorder caused by absent or defective GPIIb / IIIa
42
What is the clinical presentation for glanzmann thrombasthenia?
platelets can adhere but unable to aggregate --> petechiae and easy bruising
43
What is immune thrombocytopenic purpura (ITP)?
autoantibodies develop against platelet antigens leading to their removal by macrophages and reticuloendothelial system of liver and spleen
44
When is acute immune thrombocytopenic purpura typically seen?
In children or young adults, often preceded by viral infection
45
What are the clinical presentations of immune thrombocytopenic purpura?
petechiae and nosebleeds
can resolve on its own
46
When is chronic immune thrombocytopenic purpura typically seen?
in adults and typically concurrent with autoimmune disorders like lupus and rheumatoid arthritis, lymphoma, or HIV
usually requires treatment
47
Best way to treat chronic immune thrombocytopenic purpura?
1. corticosteroids (dampens proliferation of B cell clones making antibody)
2. intravenous immunoglobulin (IVIG) - blocks the splenic Fc receptor to prevent binding to antibody coated platelet,
3. splenectomy (removes site of autoantibody induced platelet removal)
48
What is alloimmune thrombocytopenia?
When a patient develops antibodies to plateelet antigens NOT on their own platelets.
Relevant during platelet transfusions / neonate and placenta
49
What are non immune mediated causes of thrombocytopenia?
DIC
sepsis
thrombotic thrombocytopenic purpura
hemolytic uremic syndrome
**all due to increase platelet consumption
50
What are the clinical presentations of thrombotic thrombocytopenic purpura?
fever, renal insufficiency, microangiopathic hemolytic anemia, mental status changes, and thrombocytopenia
51
What causes thrombotic thrombocytopenic purpura?
absence of metalloprotease ADAMTS13 the leads to abnormally large vWF complexes
52
What are distinguishing features associated with hemolytic uremic syndrome (HUS)?
more often associated with renal failure, occurs more often in children
usually caused by bacterial toxin that damages endothelial lining.
53
What are basic screening tests for excessive bleeding?
platelet count and blood smear to evaluate thrombocytopenia
bleeding time or platelet function analyzer (PFA-100)
APTT intrinsic coagulation pathway
PT/INR extrinsic coagulation pathway
Thrombin clotting time (TCT)
fibrinogen level
54
What is a safe platelet count for surgery?
>50,000
55
What is the normal platelet count?
150,000 - 400,000
56
How would you treat type 2 and 3 von willebrand disease?
“Intermediate purity” factor VIII
57
How does a platelet function analyzer work?
upgraded version of bleeding time
Measures the time it takes for patient's blood to block membrane coated with either collagen/epinephrine or collagen/ADP (platelet agonists)
58
What are the most physiological relevant factors that antithrombin acts on?
Factor II and Factor X
59
which molecule cleaves plasminogen into plasmin?
tissue plasminogen activator (t-PA) or urokinase plasminogen activator (U-PA)
60
what is the role of alpha2-macroglobulin?
nonspecific proteinase inhibitor that inhibits thrombin, kallikrein, and plasmin
61
What are the inhibitors of fibrinolysis?
Thrombin Activatable Fibrinolysis Inhibitor
alpha 2 macroglobulin
alpha 2 plasma
plasminogen activator inhibitor
62
What are the activators of fibrinolysis?
plasminogen
Tissue plasminogen activator
Urokinase plasminogen activator
63
What are the anticoagulation activators?
C1 inhibitors
Tissue Factor Pathway Inhibitor (TFPI)
Anti-thrombin
Active Protein C
64
What are the cofactors for anticoagulation?
Protein S and Thrombomodulin
65
What cofactor is needed for thrombin activatable fibrinolysis inhibitor (TAFI)?
Thrombomoduline
66
How does warfarin work?
treats/prevents blood clots by in inhibiting vitamin k dependent factors VII, X, and II
67
What is the prothrombin T (PT)
measures procoagulant factors VII, X, V, and II
68
What drug can prolong the PT time?
warfarin
69
What is the activated partial thromboplastin time (APTT)?
measures the procoagulant activity of the entire pathway.
| MOST sensitive to deficiencies of the higher numbered factors: XI, IX, VIII (INTRINSIC)
70
What coagulant factor is not accounted for in the activated partial thromboplastin time?
Factor VII
71
What drugs can prolong the APTT?
heparin
72
What is the normal PT?
9-12 seconds
73
What is the normal APTT?
25-32 seconds
74
What is the thrombin time (TT)?
measures coagulation activity of fibrinogen
12-18 seconds
Prolonged with heparin
75
What is the bleeding time BT?
The bleeding time measures the platelet and vessel interaction, as well as the number and the function of platelets
76
How is a platelet function analyzer performed?
in vitro
77
What is hemophilia A?
defect in cofactor VIII and is the most common cause of severe bleeding disorders
causes a prolonged PTT
78
What is hemophilia B
Only noticeable upon major trauma or surgery. Need factor replacement upon surgery
defect in cofactor IX and causes a prolonged PTT
79
What is considered severe hemophilia
80
What is considered mild hemophilia
>10% activation
Only noticeable upon major trauma or surgery where you would need factor replacement upon surgery
81
symptomatic hemophilia carriers?
females that have 30% factor activity
| can range anywhere from 30-100% (asymptomatic)
82
What type of blood disorder is typically seen in Ashkenazi Jews?
Factor XI deficiency
83
What is the typical clinical presentation of Factor XI deficiency
post operative hemorrhage
84
What is prolonged in factor VII deficiency?
only PT time
85
What is prolonged in von willebrand disease?
PTT because it carries Factor VIII
86
clinical presentation of von willebrand disease?
patients often bleed from mucosal membranes, and nose bleeds, GI bleeds and menorrhagia (heavy menstruation) are major clinical problems
often bleed after surgery if not treated
87
How is type I von willebrand treated
desmopressin
88
What is type I von willebrand disease?
deficiency in nomal von willebrand factor. Treat with desmopressin!
89
How would you assess platelet function?
bleeding time or platelet function analyzer (PFA)
90
What is acquired Factor VIII inhibitor?
when a patient makes antibodies against factor VIII
has a prolonged PTT
91
what is the clinical presentation of factor VIII inhibitor?
soft tissue and muscle bleeding, and usually marked hematomas of their skin or mucosal bleeding.
92
What is the prognosis for factor VIII inhibitor?
excellent long term prognosis since most patients respond to immunosuppressors
93
What causes PTT to be more prolonged than protime
disseminated intravascular coagulation
94
what is the coagulation pattern seen with a patient that has liver disease?
prolonged protime with a relatively less prolonged PTT.
remember liver produces vitamin k dependent factors for the extrinsic pathway
95
What causes vitamin k deficiency in these blood disorders?
no oral intake of vitamin K and/or gut flora killed by broad spectrum antibiotics
96
what is an artificial way to stop vitamin k production --> death?
long acting fat soluble rat poison
97
What laboratory findings are consistent with disseminated intravascular coagulation?
low fibrinogen levels and low platelet count
98
Abnormalities in DIC:
```
Prolonged PT
Greatly prolonged PTT
Prolonged thrombin time
Low platelet count
Low fibrinogen level
Increased fibrin split products
Increased D-dimer
```
99
what are Hypercoagulable states?
when there is chronic damage to vessel walls, excess of
| procoagulant factors or a deficiency of anticoagulant factors or fibrinolytic activity.
100
What is lupus anticoagulant?
when you make IgG antibodies against platelets.
**Even though this is an anticoagulant process this is NOT bleeding disorder but rather a THROMBOTIC DISORDER
101
What is prolonged in lupus anticoagulant?
PTT
102
If you mix lupus anticoagulant with normal plasma will the PTT correct?
NO
103
What are the four most common familial
| congenital conditions which cause a hypercoagulable syndrome?
deficiencies in antithrombin, protein C, protein S, or resistance to protein C activation (Factor V Leiden)
104
What is an important factor that explains why we can do blood transfusions?
Red blood cells do not have MHC antigens
105
What is bombay phenotype?
people do not express the H antigen so there is no substrate for the A or B glycosyltransferase to modify
106
What blood type would a bombay individual present as?
Type O
107
Which blood type does not make antibodies against other blood types?
AB
108
Which blood type is a universal recipient?
AB
109
Which blood type is a universal donor?
O
110
What class of antibodies are isohemagglutinins?
IgM we dont want it to cross the placenta!
111
What is blinatumomab used for?
Bite cell that has two single chain antibodies linked together. One CD19 that can bind to antibodies specifically bound to a tumor cell and the linkings side with a CD3 side chain that can bind to T cells (mostly CTL) to kill the tumor cells
112
What is immunohistochemistry?
uses afinal antibody labeled with an enzyme.
113
How would you test for common variable hypogammaglobulinemia?
CVH not making antibodies against specific antigen
Get a test tub with the antigen in question and add in the patients serum and look for precipitation
114
How is a simple ELISA tes done?
antigen coupled to plate then add the serum and if there is antibody it will bind to antigen. Use an enzyme coupled antibody to see if the specific class of expected serum antibody
115
When would you use a sandwich or capture ELISA?
if antigen is divalent
you're testing for the ANTIGEN so you have premade antibodies sitting in the test tube that you add antigens to
116
Where are double positive T cells found?
only in the thymus
117
Does blood have more T cells or B cells?
T cells! They do all the searching and finding
118
What are the requirements for seropositive HIV?
you make antibody against HIV
symptoms of opportunisitic infection
kaposis sarcoma
CD4+ count below 200
119
How many people in the US are living with HIV?
1,100,000
120
What are lentiviruses?
cause slow ultimately fatal illness
include: HIV, equine infectious anemia virus, feline immunodeficiency virus
121
Explain why HIV is the probably te most antigenetically variable pathogen?
its reverse transcriptase is highly error prone
122
Which virus is HIV most closely related to?
Simian Immunodeficiency Virus
123
What is kaposi sarcoma>
tumor of endothelial cells lining lymphatics and is caused by human herpesvirus8
124
What are the classes of drugs used to treat HIV?
nucleoside reverse transcriptase inhibitor (NRTI) which is a competitve inhibitor and chain terminator
Non-nucleoside reverse transcriptase inhibitor
protease inhibitor for gag,pol and env polyprotein
fusion inhibitor to gp41 (Enfuvirite)
CCr5 antagonist (Maraviroc)
integrase inhibitor to DNA
125
What is the standard antiretroviral therapy?
combines to nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase
126
What are broadly neutralizing antibodies for HIV?
antibodies that can block infection by almost all HIV strains and mutant forms. its usually binds to gp120 and this site cant mutate much.
about 20% of HIV + people make this. How can we get them to make more?
127
Undre what conditions do arterial thrombi occur?
high shear stress
**aggregated platelet
128
Under what condition do venous thrombi typically occure?
low shear stress/slow blood flow
**aggregated fibrin
129
What is phlegmasia cerulean dolens?
extremely swollen, blue, painful leg
130
What is saddle embolus?
clot involving both pulmonary arteries
131
What type of DVT is more likely to result in symptomatic and fatal PE?
clot in popliteal or more proximal leg veins
132
What test would you use to test for DVT?
D-dimer
| ultrasound
133
What test would you use to test for PE?
CT scan of chest and ventilalation/perfusion (V/Q) scans
134
How do you treat acute arterial thrombi?
heparin and fibrinolytic agent:tPA
135
How do you prevent arterial thrombi in the future?
anti-platelet agents: aspirine, thienopyridines (Ticlid and clopidodrel), and glycoprotein IIb/IIIa inhibitors such as abciximab
136
ipilimumab
antibody that blocks CTLA-4 from binding and sending a negative feedback to T cell activation
137
nivolumab and pembrolizumab
creates antibodies against PD 1 so it doesnt receive inhibitory signal from PD1L
