Coagulation Pre-work Mauro Flashcards
What does endothelin release cause?
vasoconstriction at the site of vessel injury
What provides the initial tethering of platelets to form a platelet plug (platelet adhesion)?
Glycoprotein1b/ IX complex
- binds platelets to the vWF in the exposed subendothelium
What do platelets granule release after they undergo a shape change?
ADP, serotonin, TXA2, fibrinogen, platelet derived growth factor
What do ADP and serotonin do upon release?
recruit additional platelets
What does TXA2 do upon release?
promotes vasoconstriction
What links platelets together
Fibrinogen through GP11b/IIIa complex
What does the GP2IIb-IIIa complex do?
platelets aggregate when linked with fibrinogen to eachother through this complex
What cell released platelets?
megakaryocytes
What initiates hemostasis?
exposure of tissue factor to blood which activates proenzymes
Where are all of the coenzymes for the clotting cascade synthesized?
liver except for VWF
Where is VWF synthesized
megakaryocytes and endothelial cells
What does tissue factor bind upon its release in the extrinsic pathway?
factor VIIa which activates factor X which enters the common final pathway
What plasma factors are activated first in the intrinsic pathway?
kininogen, kallikrein, and factor XIIa
What does factor XIIa activate?
Factor XI which activates factor IX
What does factor IXa complex with to activate factor X?
in complex with factor VIIIa
What releases factors VIII
VWF
What is factor Va released by
platelet alpha granules
What binds together as the first step in the final common pathway?
Factors X and Va to form thrombin from prothrombin
What does thrombin convert in the final common pathway?
fibrinogen to fibrin
What factor stabilizes and cross links the overlapping fibrin monomers?
factors XIIIa
What starts the clotting cascade?
the extrinsic pathway when tissue factor is released from the endothelium which forms factors Xa
What is the role of factor Xa
activates platelets = exposure of phospholipids on platelet surface which supports assembly of enzyme complexes
What leads to increased production of factor VIII and factor IX
more factor X and thrombin formation
What does factor Xa cleave?
FVIII from vWF to activate platelet to expose phospholipid on its surface
What does thrombin activate?
FIX, FXI, FVIIII which starts the intrinsic pathway
What is the role of antithrombin
circulating plasma protease inhibitor
- neutralizes thrombin, Xa, IXa, XIIa, XIa by forming irreversible complexes
Heparin
binds to anti-thrombin and increases its rate of inactivation by 1000x fold and can bind to thrombin simultaneously to inactive it
Protein C and S system
as more thrombin is formed, thrombin will bind to thrombomodulin causing a structural change and then this complex with Ca2+ can activate protein C which is attached to endothelial surface via EPCR and activated protein C with protein S inactivates factor Va and VIIIa so it impairs the final common pathway from moving forward
What does protein S do?
increased the cleaving rate of protein VIIIa by protein C
What would a deficiency of protein S or C lead to?
impairment of termination of clotting and lead to an increase of hyper coagulable states
What is the role of TFPI
circulates in the plasma and inhibits factor Xa directly and factor VIIa
What does TFPI inhibit directly?
FXa and then when bound to Fxa it inhibits tissue factor:FVIIa impairing the triggering method of extrinsic pathway
What leads to an increase in TFPI
heparin
What initiates fibrinolysis
when plasminogen via a lysine residue binds to the fibrin clot with tPA which leads to the conversion of plasminogen to plasmin which can then cleave fibrin and fibrinogen and clotting factors and releases fibrin degradation productions
What is tPA released by?
the endothelial cells
What does PAI-1 inhibit
tPA
What does a deficiency of PAI-1 lead to?
bleeding problems because no check to fibrinolytic pathway
Where is alpha-2-antiplasmin made
liver
What does alpha-2-antiplasmin inhibit
plasmin
TAFI
circulates in the plasma and is activated by thrombin
- removes the lysine residues from the fibrin clot to impair the ability of plasminogen and tPA to bind leads to a delay
What does thrombin activate in fibrinolysis
TAFI
What initiates the extrinsic pathway to initiate the whole clotting cascade?
tissue factor
What are the 4 pro-thrombotic properties of endothelium
- synthesizes vWF and FVIII
- releases tissue factor
- produces PAI
- contains phospholipids that facilitate clot formation
When endothelium is intact how does it impair clot formation and binding of platelets
- not conducive to binding
- prostacyclin and nitric oxide inhibit platelet binding
What are the general bleeding symptoms for platelet defects
mucocutaneous bleeding: oral cavity, nasal, GI, GU
Which type of defect will cause excessive bleeding from minor cuts?
primary hemostasis - platelet defects
What type of defect will have petechia
primary hemostasis - platelet defect
- small capillary hemorrhages on the legs
- asymptomatic
Which type of defect will have small and superficial ecchymoses
primary hemostasis - platelet defects
Which type of defect will have hemarthroses and muscle hematomas
secondary hemostasis - coagulation disorder
- common in severe deficiency or mild/moderate factor deficiency
Which type of defect will lead to immediate bleeding with surgery?
primary hemostasis, platelet defect
- usually delayed with secondary hemostasis
Which type of defect will have large subcutaneous and soft tissue hematomas
secondary hemostasis coagulation disorders
What is a normal platelet count
150,000 - 400,000 platelets per microliter
What level is prolonged bleeding seen at
less than 100,000
What is a platelet less than 50,000 a concern for
bleeding with surgery
What is the concern if platelets are less than 10,000
concern for spontaneous bleeding
What is a normal bleeding time
7.5 minutes
When is bleeding time prolonged?
thrombocytopenia, qualitative platelet disorders, and von Willebrand disease
What is prothrombin time looking at?
extrinsic and common pathways
factors VII, X, V, prothrombin and fibrinogen
What does a coagulation test measure for
factor VII deficiency - liver disease
vitamin K deficiency
or factor deficiencies
what is the partial thromboplastin time looking at
factors XII, XI, IX, X, V, prothrombin and fibrinogen
- intrinsic pathway
mixing study
on any patient with prolonged PT or PTT
- patients blood is mixed with equal amounts of normal blood and the prolonged test is repeated
What will you expect to see in a factor deficiency if a patient’s blood has 0% of the factor level and is mixed with normal blood that has 100% of the factor level
this will lead to product having 50% normal factor level if there is a deficiency
What does thrombin time measure
conversion of fibrinogen to fibrin which is the final step in clotting cascade
What would cause prolonged TT
- heparin
- direct thrombin inhibitors
- hypofibrinogenemia
- circulating light chains or paraproteins
What is a D-dimer test
- elevated in presence of clot turn over
- marker of fibrinolysis
- marker of blood clotting
In which primary hemostasis problems will you have a normal PT and PTT
thrombocytopenia, qualitative platelet defect and von willebrand disease
In which secondary hemostasis problem will you have normal PT and PTT
factor XIII deficiency - helps cross link fibrin monomers into fibrin polymer
What type of vascular problem do you see a normal PT and PTT
-vascular purpuras = structural problems with vessels, vasculitis, collagen problems
What does an isolated prolonged PT tell you
extrinsic pathway problem
- FVII deficiency
- if mixing study is correct you can have a factor deficiency, vitamin K deficiency, liver deficiency
- if mixing doesn’t correct , you have a factor VII inhibitor
What does an isolated prolonged PTT tell you
intrinsic pathway problem
- if mixing study doesn’t correct
What does a patient with prolonged PTT that corrects with mixing that has no bleeding have a deficiency of?
factor XII, pre-kallikrein, kininogen deficiency
What does a patient with prolonged PTT that corrects with mixing that has bleeding have a deficiency of?
factor XI, IX, VIII deficiency
- VWD
What does a patient with prolonged PTT that doesn’t correct with mixing have an inhibitor of?
factor inhibitor: factor VIII, IX, XI
- heparin - binds to antithrombin to increase inactivation
- Lupus anticoagulants
What do patients with prolonged PT and PTT have deficiencies of?
- deficiency final common pathway factors
- severe vitamin K deficiency
- severe liver disease
- disseminated intravascular coagulation
Which factor is deficient in hemophilia A
FVIII
Which factor is deficiency in hemophilia B
FIX
Are women affected by hemophilia
no, they are carriers if their father has hemophilia
- only males are affected
What percent of factor levels is present in patients with severe hemophelia?
less than 1%, they have spontaneous bleeding
What percent of factor levels is present in patients with moderate hemophelia?
1-5%, bleed after slight trauma
What percent of factor levels is present in patients with mild hemophelia?
5-30%, bleed after surgery or moderate trauma
What PT and PTT will patients with hemophelia have
prolonged PTT and normal PT
What are symptoms of hemophelia
- hemarthrosis - joint bleeding
- muscle bleeds
- mucocutaneous bleeding
- intracranial bleeds
- post-dental bleeding
- post-surgical bleeding can be delayed by days
Do patients with hemophelia bleed after minor cut or abrasions?
NO, their platelets are working normally
What is a treatment for hemophelia
- give factor VIII or IX
- give DDAVP (in mild hemophelia A) which stimulates the release of factor VIII
What is DDAVP used for?
mild hemophelia A, stimulates the release of FVIII from endothelium
What do you do for a patient that comes in with an acute bleed with hemophelia
give appropriate factor to try and get 30% of normal factor levels
Von Willebrand disease
- most common inherited bleeding disorder
- vWF = huge molecule involved in primary and secondary hemostasis
- binds platelets to exposed subendothelium
- carrier for FVIII
What can deficiencies in vWF lead to
mucocutaneous bleeding
What is type 1 VWD
- partial deficiency of VWF
- AD
- vWF antigen low and vWF activity low
- FVIII level low
What is type 2 VWD
- usually AD
- activity lower than antigen level with normal or low FVIII
What is type 3 VWD
- total deficiency of vWF
- rare, severe, AR
- decreased or absent vWF antigen and activity
What is a treatment for type 1 VWD
DDAVP to release vWF and FVIII
- intermediate purity FVIII concentrates that contain VWF
What is a treatment for type 2 or 3 vWD
- intermediate purity FVIII concentrates that contain vWF
What clotting factors are synthesized by the liver?
all clotting factors except FVIII and vWF
What will the PT and PTT look in a patient with liver disease
PT will prolong because FVII is affected the most
- PTT is prolonged in severe disease
Which factors require vitamin K
post translational modification of factors II, VII, IX, X, protein C and protein S
What can cause a vitamin K deficiency
biliary tract disease/fat malabsorption, drugs (abx, cholestyramine), severe malnutrition
Which factor is most sensitive to vitamin K deficiency
FVII so you get a prolonged PT first
FVIII inhibitors - alloantibodies
alloantibodies in 25% of patients with severe hemophelia after numerous exposures to foreign FVIII
FVIII inhibitors - autoantibodies
patients were not born with deficiency in factor VIII
- acquired inhibitor to their own FVIII
- occurs in post-partum, lupus, RA, malignancy, allergic rxn, lymphoproliferative disease
What are the symptoms of FVIII inhibitors
ecchymoses, epistaxis, GI, hematuria, intracranial, rare themarthroses (unlike hemophelia)
What is the diagnostic test for FVIII inhibitors
prolonged PTT that doesn’t correct with mixing
What is the treatment for FVIII inhibitors
- can’t use factor to treat because of inhibitors
- use immunosuppresion
- FEIBA = factor 8 bypassing agent
- NovoSeven
What is the first step of DIC
diffusion activation of coagulation (uncontrolled production of thrombin) leading to arterial and venous clotting and tissue ischemia
What causes bleeding in DIC
- consumptive coagulopathy (platelets, fibrinogen, prothrombin, factors get used tup)
- secondary fibrinolysis to break clots down - large amount of fibrin degradation products can impair normal platelet aggregation
What causes DIC
- thromboembolism
- AML
- sepsis
- placental abruption
- severe liver failure
What are the symptoms of DIC
bleeding, renal and liver dysfunction, pulm dysfunction, shock, thromboembolism
What are the diagnoses for DIC
prolonged PT, PTT, low fibrinogen, low platelets, increased FDP and DDimer
What is the treatment for DIC
- treat underlying disease
- supportive care (platelet, FFP, cryofibrinogen transfusion)
Does the venous system consist of muscular vessels?
no the venous system is non-muscular with valves, the artery system has muscular vessels
Which system has a lower rate of blood loss associated with trauma?
venous system
Which system uses platelets for critical rapid response?
arterial system
The generation of what is critical in the venous system?
the clotting cascade, rate of thrombin generation is critical i the venous system but secondary in the artery system
What is the treatment for venous problems
anticoagulants to impair clotting cascade
What happens with problems in the arterial system
MI, CVA, PVD
What is the treatment for anti-platelet agents?
Asprin and plavix
What is venous stasis
decreased blood flow throughout the venous system
What causes vascular injury
trauma, surgery, infection, hypotension
What are inherited risk factors for thrombophilia
FVL deficiency - homozygous = increased risk for VTE compared to heterozygous
PT gene mutation = increases risk of VTE
Protein S and C deficiency - increase risk of clotting
Factor V Leiden
most common inherited cause for thrombophilia
- point mutation that abolishes cleaving site of activated protein C
- slower degradation time because activated protein C isn’t able to inactive it
- extended thrombogeneration
Prothrombin gene mutation
- point mutation
- causes a 30% increase in prothrombin levels = increased clot formation
Protein C and S deficiency
- deficiency = sustained movement through the clotting cascade
- increased clotting risk by 8 fold
What does activated protein C inactive?
inactives FVa and FVIIIa
What does protein S inactivate?
increases rate of inactivation of APC
- deficiency = decreased APC = increased FVa and FVIIIa
Antithrombin deficiency
circulating plasma protease inhibitor that neutralizes thrombin
- deficiency leads to increased amount of activating clotting factors
What are acquired transient risk factors for VTE
orthopedic surgery, trauma and serious accidents, central lines, acute medical illness, immobility, prolonged travel
What are acquired persistent risk factors for VTE
obesity, cancer, myeloproliferative neoplasms, paralysis, nephrotic syndrome
What can cause arterial clotting in addition to venous clotting?
DIC, MPN (myoproliferative neoplasms, antiphospholipid syndrome)
What is the effect of hormones on clotting
increased estrogen increases the risk of clotting = birth control
- pregnancy deliveries and postpartum
- hormone replacement therapy
- infertility treatment
PE/DVT treatment
2 or more unprovoked events = indefinite anticoagulation
1 unprovoked life threatening event = indefinite anticoagulation
1 unprovoked event with APLS, AT, combined thrombophilia = indefinite anticoagulation
1 provoked event (paralysis, MPN, metastatic cancer) = indefinite anticoagulation
1 provoked event with transient risk factor = 3-6 months of anticoagulation
Anti-phospholipid syndrome
can be primary with no underlying cause or secondary to immune disease, medications, infections, malignancy
What does the antiphospholipid antibody increase in the body?
increases pro-coagulants and vascular tone
What is the clinical diagnosis for APLS
arterial or venous thrombosis OR significant pregnancy morbidity (premature birth less than 34 weeks, embryonic miscarriages)
What is the laboratory criteria for APLS
one or more of the following present on two occasions atleast 12 weeks apart:
anticardiolipin Ab or
Beta 2 glycoprotein Ab or
Lupus anticoagulant
What is the treatment for APLS if the clinical diagnosis is thrombosis
anticoagulation for 6 months if not indefinite
Prolonged dRVVT assay
- venom is added to the blood and activates factor X directly = looks at clotting pathway below that and it is prolonged by lupus coagulants
What is the treatment for APLS if the clinical diagnosis is pregnancy morbidity
LMWH (heparin) and baby aspirin during pregnancy and post partum
