Midterm 2 Flashcards
1
Q
What are the goals of DVT treatment?
A
- Prevent further clot extension
- Prevent acute PE
- Reduce risk of recurrent thrombosis
- Relieve the symptoms
- Limit development of late complications
2
Q
What is the order of platelet formation?
A
- Proplatelet formation and release
- Preplatelet to proplatelet interconversion
- Platelet release
3
Q
What are the coagulation co-factors?
A
- Factor V- Labile factor
- Factor VIII- Antihemophilic factor
- Tissue Factor
- Von Willebrand Factor (VWF)
4
Q
What is the differential for someone with both prolonged PT and PTT?
A
- Deficiency of common pathway factor
- Supra-therapeutic warfarin
- Supra-therapeutic heparin
- Multiple factor deficiencies (severe liver disease or DIC)
5
Q
What is the mechanism of the Tissue Factor Pathway Inhibitor System?
A
- Works in concert with Factor Xa and Factor VIIa-TF
- Helps “turn off” clotting
6
Q
When should DDAVP not be used for hemophilia?
A
- Not used in B
- Only used in A if some level of FVIII (increases 3-fold, so need something to start with)
7
Q
What labs are disturbed in Hemophilia A?
A
- aPTT is long
- Factor VIII is low
8
Q
What is the usefuleness of D-dimer levels in the clinic?
A
- Evaulation of thrombus formation
- Ruling out deep vein thrombosis
- Monitoring anticoagulative treatment
- Disseminated intravascular coagulation (DIC)
9
Q
Which coagulation proteins are made primarily by the liver?
A
- All vitamin K-dependent proteins (FII, FVII, FIX, FX, Protein C and S)
- FV, FXIII, fibrinogen, antithrombin, alpha2-plasmin inhibitor (alpha2-PI), and plasminogen
10
Q
What is the vitamin K cycle?
A
11
Q
What is the intrinsic pathway of secondary hemostasis?
A
- Begins with factor XII (this activates cleavage cascade)
- Factor XI -> Factor IX -> Factor VIII
- Factor VIIIa and Factor IXa link to activate factor X cleavage
12
Q
What is the common pathway of secondary hemostasis?
A
- Once factor X -> Xa, it binds Factor Va
- Prothrombin converts to thrombin
- Thrombin activates fibrinogen -> fibrin
13
Q
What are the coagulation non-protein cofactors?
A
- Calcium (blood)
- Phospholipid suraces (on cells)
14
Q
What is the mechanism of fibrinolysis?
A
- “Clot lysis machinery”
- Convert fibrin to fibrin degradation products
- Involves plasminogen to plasmin (plasminogen activator inhibitor-1)
- Plasmin inhibitor
- Tissue plasminogen activator (tPA)
15
Q
Where is urokinase (uPA) expressed?
A
Expressed by endoethelial cells, macrophages, and renal endothelial cells
16
Q
What is endomitosis and its significance in megakaryocytes?
A
- DNA divides, but neither the nucleus nor cell do
- Leads to many chromosomes and a huge nucleus
- After this process the MK can undergo cytoplasmic maturation and make platelets!
17
Q
How is thrombopoietin (TPO) concentration regulated?
A
- Static synthesis mainly in the liver
- Regulated by platelet production rates, platelet/MK mass
- Receptors (c-Mpl) binds and clears TPO from circulation
18
Q
What are some causes of acquired Factor VII deficiency?
A
- Vitamin K deficiency
- Vitamin K inhibitors
- DIC
- Liver disease
19
Q
What are some causes of hypercolagulable state?
A
Inherited
- Protein C, S, or AT deficiency
- Factor V Leiden
- Prothrombin 20210 mutation
- Sickle cell
Acquired
- Cancer
- Estrogen, Pregnancy
- HIT, MPN
- Hyperhomocysteinemia
- Antiphospholipid antibody
20
Q
What are the receptor for collagen in platelet activation?
A
- GP Ia/IIa- adhesion to collagen
- GP VI- acts in complex to activate platelets
21
Q
What is the differential diagnosis for red/swollen leg?
A
- Clot
- Baker’s Cyst (build up of synovial fluid)
- Cellulitis
22
Q
What is the difference between warfarin and DOACs in the following?
- Onset
- Dosing
- Food Effect
- Interactions
- Monitoring
- Offset
A
23
Q
When should DVT prophylaxis be used in the hospital (strong risk factors)?
A
- Hip or leg fracture
- Hip or knee replacement
- Major general surgery
- Major trauma
- Spinal cord injury
24
Q
What are common causes of splenomegaly (which leads to splenic sequestarion)?
A
- Cirrhosis and Fatty Liver Disease
- Lymphoma
- Infection (AIDS, endocarditis)
- Congestion/Inflammation
- Primary splenic disease
25
What is a normal platelet count and lifespan?
* Count: 150-450 x 109/L
* Life: 7-10 days
26
What are the 3 types of Von Willebrands Disease (VWD)?
* **Type 1-** quantitative disorder, most common
* **Type 2**- qualitative disorder
* **Type 3**- homozygous type 1 w/ no VWF
27
What should you test if somebody comes in and you are pretty sure they do not have a clot (despite symptoms)?
Run a D-dimer. If it is negative then they don't have a clot!
If it is positive, this does not mean that they do...
28
What are the deep arm veins?
* Brachial
* Axillary
* Subclavian
29
What are IVC filters and when should they be used?
* Mechanical device implanted to "catch" clots
* Only use if there is inability to use anticoagulation
* Only use temporarily, then begin proper therapy
30
What happens in blood clotting before platelet aggregation and coagulation?
Vasoconstriction
31
What is the degradation product of crosslinked fibrin?
* D-dimer (presence reflects ongoing activation of hemostatic system)
* Healthy individuals have minimal D-dimer level
32
What are integrins?
* Heterodimeric transmembrane molecules
* Respond to extracellular matrix proteins
* Lead to signaling within the cell
* Clustering around membrane can amplify signal
* Can also have "inside out" signaling
33
What is the role of Adenine di-Phosphate (ADP) in platelet activation?
* Released by damaged RBC's and acitvated platelets
* Has two GPCRs
* **P2Y12-** bind purine and pyrimidine agonists, target of many antiplatelet drugs
* **P2Y1**- bind purine and pyrimidine agonists
34
What are the three broad categories of thrombocytopenia?
* Underproduction
* Peripheral destruction
* Splenic sequestration
35
What is the mechanism of the protein C system?
* Activated protein C (anticoagulant serine protease), along with protein S as a cofactor
* Activated by thrombin-thrombomodulin complex
* Substrates are Factors Va and VIIIa
36
What is pseudothrombocytopenia?
* Platelet count is artificially low (higher in vivo)
* Platelet clumping due to patients' having substance that can cause blood to clump with EDTA in test tube
* No bleeding consequences
* No treatment
37
What is the significance of the following in secondary hemostasis?
* Fibrinogen
* Factor XIII
* Both are activated by thrombin
* **Fibrinogen**- converted to fibrin, which links platelets
* **Factor XIIIa**- transaminase that cross-links fibrin 3 adjacent domains of fibrin monomers (DDE) through gamma chains
38
What is the extrinsic pathway of secondary hemostasis?
1. Blood flows out of damaged vessel
2. Tissue factor is made by subendothelial cells
3. Factor VII binds tissue factor
4. Cleavage of factor X gives Xa
39
What are some causes of peripheral destruction of platelets?
* Non-immune: DIC and TTP
* Immune: provoked by drugs, HIV, autoimmune disease, idiopathic
40
What factor must be activated along with factor X in order to convert prothrombin to thrombin?
Factor V
41
What coagulation factors are Vitamin K-independent zymogens?
* **Factor XI**- Antihemophilic factor C
* **Factor XII**- Hageman factor
* **Factor XIII**- fibrin stabilizing factor
42
What is the risk of hemophilia and inhibitors?
* Patients can develop neutralizing antibodies to clotting factor concentrates
* More common in A than B
* More common with certain mutations
* More common in non-caucasians
43
What are two of the granule contents release by activated platelets?
* **ADP**- activates more platelets
* **Thromboxane A2-** activates more platelets and increases aggregation
44
What is Virchow's triad?
A representation of the three things needed for venous thrombosis:
1. Venous stasis
2. Endothelial injury
3. Hypercoagulable State
45
What is the general steps in clot formation?
1. Expose collagen
2. Von willebrand factor binds collagen
3. Initial plug formation
4. Platelets stick and activate, release granules
5. More platelets recruited
6. GPIIb/IIIa adheres to fibrinogen
7. Fibrinogen stabilizes the platelet plug
8. Exposed phospholipids catalyze coagulation
9. Generate thrombin and fibrinogen
46
How is thromboxane made?
* Arachidonic acid is converted to thromboxane (TxA2) by COX1
* COX1 is inhibited by NSAIDs and aspirin (irreversible)
* Receptor is a GPCR
47
What is special about factor VIII synthesis?
* Hepatic endothelial cells synthesize factor VIII (liver)
* However, factor VIII levels remain normal or even high in patients with liver disease (all others can be low)
* Due to absence of LRP1 (which usually clears FVIII)
48
Which coagulation factors are Vitamin-K dependent zymogens?
* **Factor II**- prothrombin
* **Factor VII**- stable factor
* **Factor IX-** Christmas factor
* **Factor X**- Stuart factor
* **Protein C and S**
49
What is the order of the coagulation factors in the intrinsic pathway?
(Hint: TENET)
* **T**welve
* **E**leven
* **N**ine
* **E**ight
* **T**en (begins common)
50
What is heparin?
* Polysaccharide containing variable amounts of disaccharide-repeating units
* Variable sulfated within
* Extermely heterogenous population of molecules
51
What are the two main functions of VWF in hemostasis?
* Help platelets stick to injured subendothelium
* Ferry FVIII around circulation (protect from degradation)
52
What is lupus inhibitor?
* Also known as phospholipid dependent inhibitor
* Prolonged aPTT results from autoantibody directed against phospholipid
* Can correct this prolonged time by adding excess phospholipid to the reaction mix
53
What are the 4 main regulatory systems that prevent thrombosis?
* Tissue Factor Pathway Inhibitor System (TFPI)
* Protein C System
* Coagulation Protease Inhibitors
* Fibrinolysis
54
What are the main reasons for acquired platelet disorders?
* Uremia (high wast in blood)
* Drugs (aspirin, NSAIDs, antibiotics)
* Herbs (ginkgo, garlic, vitamin E)
* Myeloproliferative disorders
55
Where is blood flow the slowest in blood vessels?
Capillaries- allows time for exchange of gases and nutrients
56
What cell is responsible for the synthesis of VWF, tissue plasminogen activator (tPA), thrombomodulin, and tissue factor pathway inhibitor (TFPI)?
Endothelial cells
57
What are some causes of venous stasis?
* Old age
* Immobilization
* Stroke (cord injury)
* Anesthesia
* Heart/lung failure
* Hyperviscosity
58
Why are blood vessels considered to be anticoagulant?
Because their negative charge prevents negative cells from sticking to them (most cells in blood are negative)
59
What is the mechanism of Coagulation Protease Inhibitors?
Direct anticoagulant that inhibit the coagulation proteases, antithrombin (AT), heparin cofactor II, protein 2-dependent inhibitor
60
What do we not treat with blood thinners?
* Superficial Venous Clots
* Distal DVTs
\*These rarely embolize or cause long-term symptoms\*
61
What is an INR?
* International Normalized Ratio
* Normal value is 1
* Comes back anytime you order a PT
62
Why will TPO levels remain constant if platelet counts fall due to sequestraion in the spleen?
Because TPO can still bind the platelets in the spleen (functional), so they will continue to be produced. This is obvi very bad
63
What are some causes of underproduction of platelets?
* **Marrow failure**- myelodysplaia, aplastic anemia, vitamin deficiencies (B12 and folate)
* **Marrow infiltration**- tumor, granulomatous diseases, fibrosis, leukemias, lymphomas
* **Marrow toxins**- drugs (chemo), radiation, infections, alcohol (affects MKs)
64
What is a mixing study?
Used two differentiate between the two broad causes of a prolonged aPTT
65
What is the general structure of fibrinogen?
* Formed from three protein molecules (Aalpha, Bbeta, and gamma chains) all present in pairs
* Central part is referred to as E domain, distant ends as D domains
66
What are the general steps in a screening test of coagulation?
1. Blood is collected into tube with citrate (sequesters calcium and prevents clotting)
2. Plasma is sparated by centrifugation
3. Coagulation initiated by adding activating agent
4. Time to clot formation measured in seconds
67
Which anticoagulant is used for prevention of thrombosis on heart valves and artifical hearts?
Warfarin
68
What is the role of thrombopoietin (TPO)?
* Regulator of platelet production
* TPO receptor is on megakaryocytes and platelets
* Binding of TPO prevens apoptosis; increases number, size, and ploidy of MK
69
How does thrombin activate fibrinogen -\> fibrin?
Cleaves two small activation peptides from fibrinogen to form fibrin monomer
70
Why is vitamin K such an essential cofactor for many coagualtion proteins?
* Needed for posttranslational carboxylation of Glu residues to gamma-carboxyglutamates (GLA) on N-terminal regions
* This permits proteins to undergo conformational change (calcium-dependent complexing of proteins to cofactors on phospholipid surfaces)
71
How do we measure anti-Xa level?
* Activate FX to FXa with snake venom
* Add patient's plasma
* Decrease in rate is the Anti-Xa level
72
What 4 interactions is hemostasis dependent on?
* Platelet adhesion and aggregation
* Endothelial cell function
* Blood coagulation system
* Clot lysis (fibrinolysis) system
73
Does lupus inhibitor cause excess bleeding?
* No, it can actually cause abnormal clotting
* Most people who have antibody, do not have lupus
* And most people with lupus, do not have antibody
74
What are the different stages of hemolysis?
* Primary
* Secondary
* Tertiary
* **Primary-** platelet aggregation/endothelium
* **Secondary-** coagulation
* **Tertiary**- fibrinolysis
75
What do the results in a mixing study mean?
* Clotting times remain prolonged= inhibitor
* Clotting times normalized or decreas near-normal= Factor deficiency
76
What causes vitamin K deficiency?
Sources are diet (greens) and gut flora, so:
* Inadequate Dietary Intake
* Antibiotics
* Fat malabsorption
* Newborns (get injection)
* Hepatic disease (impairs uptake/storage)
* Warfarin (Coumadin)
77
What is the receptor for thrombin?
* PAR-1 (GPCR), ligand is its own protelyzed N-terminus
78
Why is VWD distinct from hemophilia?
* Common in both sexes
* Mucosal bleeding (not joints/muscle)
* Bleeding time is longer
79
What are some causes of endothelial injury?
* Surgery
* Prior DVT
* Venous access
* Trauma
* Sepsis
* Vasculitis
80
What is the average plasma concentration and half life of the following?
* Factor VII
* Factor VIII
* **Factor VII**- 0.5 mcg/mL and 3-6 hours
* **Factor VIII**- 0.1-0.2 mcg/mL and 8-12 hours
\*Both of these are much lower than other factors due to need for very intricate control of coagulation\*
81
What is the difference between hemophilia A and B?
* A- Factor VIII deficiency
* B- Factor IX deficiency
* Both are X-linked disorders and essentially indistinguishable in clinic
82
What labs are distrubed in VWD?
* PFA-100 (long)
* Low- Factor VIII, VWF antigen/activity
83
When should we screen for inherited thrombophilia?
* Age less than 50
* Clot in a weird place
* Family history of clot
* Recurrent clots
84
What prevents platelets from sticking to normal, healthy endothelium?
* **Nitric Oxide-** vasodilator
* **Ecto-ADPase (CD39)-** chews up ADP
* **Prostacyclin (PGI2)**- vasodilator and inhibits platelet activation
85
What is Heparin Induced Thrombocytopenia?
* Usually 7-10 days after heparin started (platelets fall by 30-50%)
* Antibodies against heparin/PF4 complex
* IMMEDIATELY STOP HEPARIN
* Can lead to thrombosis too in some patients
86
How does the level of Factor VIII/IX affect severity of hemophilia in patients?
* **\<1%**- **Severe** (spontaneous bleeding)
* **1-5%**- **Moderate (**severe bleeding in surgery/trauma)
* **5-25%**- **Mild** (bleeding with surgery/trauma)
* **25-50%**- presents normal
87
What is the mechanism of Desmopressin (DDAVP)?
* Releases FVIII and VWF from preformed stores in endothelial cells
* Associated with tachyphylaxis
* Can cause hyponatremia (low blood sodium)
88
What is stupid about the Superficial Femoral Vein?
It is actually a deep vein and if a clot forms here it should be treated as DVT
89
What is hemostasis?
The arrest of bleeding following vascular injury
90
What two deficiencies present risk for warfarin use (need to bridge)?
Vitamin K deficiency
Protein C deficiency
91
What is the differential diagnosis for acute chest pain?
* Pulmonary Embolism
* Pneumonia
* Myocardial Infarction
* Costochondritis (ribs inflamed)
* Muscle strain
* Panic attack
92
What is the difference between thromboplastin and partial thromboplastin?
* Thromboplastin provides factor VII and phospholipid
* Partial thromboplastin provides negative charges (no factor VII) and phospholipid
93
What is the significance of moving up the intrinsic pathway factors (in a deficiency)?
* The higher up in the chain you go, there will be a more prolonged PTT
* This does not indicate a clinical significance though!
\*Can have zero FXII and really long PTT, with no bleeding problems\*\*
94
What do integrin is activated in platelets when they bind agonists?
GP IIb-IIIa (bind fibrinogen)
95
What are the 2 main congenital platelet disorders?
* **Bernard-Soulier:** defect in Ib/IX on platelet surface, **no adhesion**
* **Glanzmann's thrombaesthenia:** defect in IIb/IIIa on platelet surface, **no aggregation**
96
What drugs can induce thrombocytopenia?
* Beta-lactam antibiotics
* Trimethoprim-sulfamethoxazole (and other sulfa drugs)
* Quinine/quinidine
* Heparin
* GP IIb-IIIa inhibitors
97
What happens to bleeding in liver failure?
* Hepatocytes make less coagulation factors
* Impaired absorption of vitamin K (biliary obstruction)
* Portal hypertension causes hypersplenism (sequesters platelets)
* Decreased TPO
98
What does heparin need to bind for activity?
Antithrombin (AT or AT3)
99
When should platelet transfusion occur in the following:
* ITP
* TTP
* DIC
* Splenic sequestration
* Hypoproduction
* **ITP**- use only if severe bleeding (will not raise counts)
* **TTP**- NO (contraindicated)
* **DIC**- treat bleeding
* **Splenic sequestration**- severe bleeding (will hone to spleen too)
* **Hypoproduction**- if counts drop to 10K
100
What is the most potent platelet agonist?
Thrombin
101
What is special about GP 1b-IX-V that binds VWF for platelet adhesion?
It is not an integrin, because it is always on. Its main role is just in sticking to VWF, but that depends on VWF availability.
102
What tests are prolonged with the following treatment?
* Warfarin
* UFH
* LMWH
* **Warfarin**- PT (extrinsic)
* **UFH**- PTT, TCT, Anti Xa (all parts!)
* **LMWH**- Anti Xa (only)
103
What clotting factors are low in liver disease, but not in patients on Coumadin?
* These are factors made by the liver, but not Vitamin-K dependent
* Fibrinogen (I), Factor V, Factor XI, Factor XIII
104
Why lab abnormality will result from TPA treatment?
Low fibrinogen level (because TPA lyses fibrin/fibrinogen)
Should administer cryoprecipitate to bring levels back up
105
What levels of Factor VIII in hemophilia indicate that you should use DDAVP as therapy (opposed to active bleeding)?
20% (will increase to over 50%)
