Term
| How does Aspirin/NSAIDs affect clotting? |
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Definition
At platelet plug formation
inhibits COX, which is an enzyme in platelets that makes TXA2, which is a pro-coagulation factor and vasoconstrictor.
Aspirin is irreversible.
Primarily prevents Primary hemostasis (white clot platelet plug arterial system) and is therefore used to prevent atherosclerosis. |
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Term
| How does abciximab impact clotting? |
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Definition
At platelet plug formation
Inhibits Gp2b3a expression, which is needed for platelets to bind to each other through fibrin
It is an antibody to Gp2b3a |
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Term
| How do ticlopidine and clopidogrel impact clotting? |
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Definition
Inhibit ADP from activating platelets to express Gp2b3a
irreversible inhibitor of ADP receptor on platelet |
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Term
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Definition
Venous
Red clot
inhibited by heparin
coag cascade |
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Term
| How does heparin affect clotting? |
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Definition
Inhibits clotting by syndergizing with antithrombin to degrade thrombin and factors 7, 9, 10, 11, 12
(everything except 5 and 8)
Primarily prevents Secondary hemostasis (red clots, venous system) because it degrades thrombin (which is needed to convert fibrinogen into fibrin in the clots) |
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Term
| How does Warfarin affect clotting |
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Definition
| Inhibits epoxide reductase, which activates Vit K, which is needed to make factors 2, 7, 10, 9, C, S |
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Term
| What does kallikrien do and how does it connect to the clotting cascade? |
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Definition
Factor 12 activates Kallikrien
Kallikrien activates Bradykinin, which leads to pain, permeablility, and vasodilation
Kallikrien also increases plasmin (activated by tPA), which breaks down fibrin clots, and activates C3a complement cascade |
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Term
| List hypercoagulable Hereditary dzs |
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Definition
Factor 5 Leiden
Prothrombin gene mutation
Antithrombin def
Protein C or S def |
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Term
| List mixed platelet and coag dz's |
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Definition
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Term
|
Definition
Bernard-Soulier (Gp1b defect)
Glanzmann's (Gp2b3a defect)
Idiopathic TP (anti-Gp2b3a antibody)
TTP (vWF doesn't get degraded)
Heparin induced TP (antithormbin is overactive breaking down clotting factors)
Meds:
COX-1 inhibitors (aspirin and NSAIDs)
Clopidogrel (inhibits ADP receptor)
Abciximab (antibody against Gp2b3a)
Myeloproliferative disorders - abnormal platelets
Uremia - renal dysfunction - accumulated metabolites impair function of circulating platelets |
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Term
|
Definition
Hemophilia (8A, B9) - increase PTT not PT
Vit K def - increase PTT an PT |
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Term
| What factors prevent thrombus formation in small blood vessels? |
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Definition
Heparin like molecules - degrades clotting factors with antithrombin
Prostaglandin (prostacyclin) - vasodilator, inhibits aggregation
Protein C and S - degrade 5 and 8
tPA - activates plasmin to degrade coag factors and lyse fibrin clots
Adenosine diphosphatases - break down ADP
NO
ADAMTS13 - breaks down vWF, therefore downregulating platelet aggregation |
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Term
| Which factors enhance thrombus formation in small vessel injury |
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Definition
TXA2 - synthesized by platelets, inhibited by aspirin/NSAIDs. Vasoconstrict, enhances platelet aggregation (vs PGI2)
vWF - platelet adhesion to collagen, protects factor 8
Tissue thromboplastin (3) - aka tissue factor, activates factor 7 in extrinsic cascade |
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Term
| How is calcium involved in clotting? |
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Definition
| Calcium is a binding agent for vit K dependent factors. It is released from platelet dense bodies. |
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Term
|
Definition
recombinant forms of tPA
give in thrombolytic therapy to activae plasmin to lyse clots |
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Term
| List Plasminogen activators |
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Definition
synthetic: alteplase , reteplase
tPA
streptokinase
urokinase |
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Term
|
Definition
An antifibrinolytic agent
use:
menstruating women with vWF / primary hemostasis problem
mech:
competatively blocks plasminogen activation, inhibiting fibrinolysis |
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Term
Temporary platelet plug vs.
Stable platelet plug |
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Definition
Temporary
correlates with bleeding time
ca be easily dislodged
geld together by fibrinogen (no cross links)
Stable
fibrinogen in temporary plug is converted to fibrin by thrombin
Coagulation cascade needs to be functioning properly to form thrombin and the stable plug |
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Term
| DdX of prolonged bleeding time |
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Definition
Aspirin/NSAID (blocks TXA2 synth via COX)
Bernard-Soulier
Glanzmann's
Genal failure (inhibition of platelet phospholipid by toxic product) - reversed by dialysis and desmopressin acetate
Scurvy (collagen synth defect due to vit C def)
Thrombocytopenia (decreased plt number)
vWD (adhesion defect) |
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Term
| How can you test platelet function? |
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Definition
Platelet count
Bleeding time
Platelet aggregation test
- give aggregating agenst: ADP, epinephrine, collagen, ristocetin
Test for vWF
-Ristocetin cofactor assay (detects Bernard-Soulier and vWD)
-vWF antigen assay (tests presence not function) |
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Term
| How can you test coagulation function? |
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Definition
PT - extrinsic + common
normally 11-15 seconds, INR of 2-3
liver synthetic function, factor 7 def
can be used to follow warfarin therapy
PTT - intrinsic + common
normally 25-40 seconds
can be used to follow heparin therapy |
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Term
Coag disorder vs. Platelet dysfunc
Symptoms |
|
Definition
Platelet disorder:
microhemorrhages because no temporary plug is ever formed
epistaxis (nosebleeds)
petechiae (pinpoint hemorrhage)
small ecchymoses (quarter sized, not palpable, esp in areas of trauma)
bleeding from superficial scratches
Menorrhagia
hematuria
easy bruising
GI and intracradial bleeding
Coag disorders:
macrohemorrhages and late rebleeding because temporary plug is never made into a stable plug. You also get most of the symptoms of platelet disorders too.
Hemoarthroses
retroperitoneal and deep muscular bleeds
ecchymoses, epistaxis, menorrhagia, hematuria, brusing, GI and intracraneal bleeds. |
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Term
| What disorders have PT normal but elevated PTT? |
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Definition
|
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Term
| List Acquired thrombotic syndromes |
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Definition
Malignancy (increased coag factors, increased platelets, procoagulats released from pancreatic tumors)
Postoperative stasis
Folate or vit B12 deficiency (from increased homocysteine levels)
OCPs (estrogen increases coag factor synth and decreases antithrombin)
Hyperviscosity (Polycythemia syndromes, Waldenstrom's macroclobulinemia)
APLS (antiphospholipid syndrome)
- tied to SLE, RA, Sjogrens, HIV
- antiphospholipid antibodies
- cause arterial and venous thrombi
- spontaneous abortions (thrombosis of placenta)
- stroke
- DVT
- False positive sphyilis serology if anticardiolipin antibodies are present
- PTT does not correct with mixing studies
- hepatic vein thromboses |
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Term
Primary hemostasis
vs.
Secondary hemostasis |
|
Definition
Primary hemostasis - Temporary Platelet plug formation
- Platelet aggregation and agglutination
- vWF
- "white clot"
- arterial system
- prevented by aspirin
This is disrupted in diseases of platelets. It results in superficial bleeding (gums, petechiae, bruising). Eg. Thrombocytopenia, vWD, Glanzmann's, Bernard-soulier
Secondary hemostasis
- intrinsic and extrinsic cascade
- conversion of fibrinogen in temporary plug to fibrin by plasmin (end of coagulation cascade)
- fibrin has cross linkages and is more stable, made by factor 13 (activated by thrombin)
- "red clot"
- venous system
- prevented by heparin (antithrombin)
This is disrupted in coagulation defects and factor deficiencies. It results in delayed deep bleeding (hemarthroses). Eg. liver dz, vit K def, warfarin OD, DIC, Hemophilia |
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Term
|
Definition
| Cleaves vWF, downregulating platelet aggregation |
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Term
| What are the main platelet adhesive receptors? |
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Definition
Gp1b --vWF--collagen
Gp2b3a ---fibrinogen---Gp2b3a on other platelets
(aka integrin 2b3beta)
PAR --- thrombin
Protease activated receptors. Bind thrombin, which stabalizes the platelet plug by converting fibrinogen into fibrin. |
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Term
| What are the steps of platelet activation? |
|
Definition
1. Adhesion
to collagen in subendothelium via Gp1b and vWF
2. Granule release
Dense - Ca, ADP, etc
Alpha - adhesion molecules, fibrinogen, etc
3. Aggregation
Encouraged by ADP and TxA2
Shape change of platelets
spherical --> stellate
"inside out signaling"
Conformational change of Gp2b3a, exposing fibrinogen binding pocket
4. Procoagulant Phosphatidylserine is exposed by membrane rearrangement (flip inside out). It has procoagulant activity. |
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Term
|
Definition
| exposed by membrane rearrangement (flip inside out) during platelet activation. It has procoagulant activity. |
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Term
| What drugs cause platelet dysfunction? |
|
Definition
COX-1 inhibitors: no TXA2 made in platelets (pro-aggregation)
Aspirin - irreversible, depends on half-life of platelets (3-5 d)
NSAIDS - depends on half-life of drug
ADP receptor inhibitor: Clopidogrel
irreversible.
Antibody to Gp2b3a receptor: abciximab |
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Term
How do the following factors modify vWF expression/activity?
stress
hypothyroidism
blood type O
exercise
pregnancy/OCPs
desmopressin acetate? |
|
Definition
increase vWF levels (more released)
desmopressin acetate
pregnancy/OCPs
exercise
sress
Decrease vWF levels
hypothyroidism
Blood type O |
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|
Term
|
Definition
PFA 100
Platelet function assay (global primary hemostasis)
VWF:Ag
vWF antigen assay measure amount of vWF with ELISA
VWF:RCo ** best test
Ristocetin cofactor activity, activates Gp1b to bind vWF. Tests function
Collagen binding assay
Factor 8 activity
checks vWF function in carrying factor 8 |
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|
Term
| What are treatment options for defects in primary hemostasis? |
|
Definition
desmopressin acetate
- increases release of vWF
Aminocaproic acid / tranexamic acid
anti-fibinolytic. (menstruating women)
Humate-P / Wilate
Factor 8 products with high vWF conc
12-24 hr halflife
Novoseven - 7a
used for acquired disorders
Platelet transfusion
worry about alloimmunization
Bone marrow transplant |
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|
Term
|
Definition
promotes agglutination by activating Gp1b receptor
tests vWF function with ristocetin cofactor assay, used in vWD dx |
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|
Term
| What are the 3 mechanisms of control preventing a thrombus from growing beyond a clot's edges? |
|
Definition
1.
Tissue factor plasma inactivator
knocks out 7 and 10
2.
Thrombomodulin system (protein C and S)
inhibit factors 8 and 5
3.
Heparin and antithrombin
Inhibit 10, 9, and 2 (thrombin) |
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|
Term
| what promotes tPA? what is its role? |
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Definition
tPA is promoted by thrombin (ironic, as thromin is also what forms a more permanent plug by making fibrin from fibrinogen)
tPA (tissue plasminogen activator) activates plasmin to destroy clots (fibrinolysis) |
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Term
|
Definition
thrombosis. >10% factor 8. "titers up" with factor 8 dilution assay. PT and DRVVT may be changed.
antibodies that inhibit phospholipid dependent coagulation tests
They are neutralized by the presence of excess phosophilids
must be differentiated from hemophilia.
hemophilia:
Bleeding. <10% factor 8. Stable with factor 8 dilution assay. PT and DRVVT normal.
*not related to SLE |
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Term
| Why do you have a brief period of hypercoagulability when you first start warfarin therapy? |
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Definition
| because warfarin depletes protein C and S (anticoagulants) before it depletes factor 7, 9, 10, thrombin (procoagulants). |
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Term
What happens to fibrinogen levels in the following?
pregnancy
liver failure
DIC
L-asparaginase therapy |
|
Definition
pregnancy - increases (hypercoagulable)
liver failure - decreases (liver makes all clotting factores except vWF)
DIC - decreases (clots eat up clotting factors)
L-asparaginase therapy - decreases |
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|
Term
| Which clotting factors are made by the liver? |
|
Definition
|
|
Term
List the 3 ways to activate complement
(ie. get to C3b) |
|
Definition
classical - activated by immune complexes
lectin - activated by bacterial cell walls
alternative - constitutively on at low levels
(predilection for glomerular endothelial cells) |
|
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Term
|
Definition
| suprpresses C3b convertase |
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Term
|
Definition
|
|
Term
Risks for developing DVT?
(Virchow's triad) |
|
Definition
Endothelial injury
Hypercoaguability
Abnormal blood flow |
|
|
Term
| List 5 inherited thrombophilias associated with venous thrombosis. |
|
Definition
Antithrombin deficiency
Protein C deficiency.
Protein S deficiency.
Prothrombin gene mutation. Caucasians.
Factor 5 Leiden mutation. Caucasians.
Hyperhomocysteinemia. |
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