Lec 7 and 8 Coagulation Flashcards
What is the action of thrombin?
cleaves soluble fibrinogen to form fibrin clot
What 2 molec secreted by endothelium inhibit thrombossi
- NO
- prostacyclin
both cause vasodilation and inhibit platelet aggregation
What 2 molec secreted by endothelial cells involved in modulating the coagulation cascade?
thrombomodulin: receptor for thrombin; inhibits thrombin action and enhances of activity of protein C
tissue factor pathway inhibitor: inactivates factors VIIa and Xa
What is the action of thrombomodulin?
binds thrombin and inhibits its ability to cleave fibrinogen to fibrin
together thrombin-thrombomodulin complex enhance activity of protein C
What is action of protein C?
inactivates factors Va and VIIIa
What 2 factors does tissue factor pathway inhibitor inactivate?
factors VIIa and Xa
Where are the coagulation factors synthesized?
all synthesized in liver
some factor VIII also made in endothelial cells, megakaryocytes, spleen, kidney
Which coagulation factor is not made exclusively in the liver?
factor VIII
Which are the vit K dependent coagulation factors?
II, VII, IX, X and protein C and S
Where is vit K found?
in leafy plants, vegetable oils, and synthesized by intestinal bacteria
Who is at risk for vit K deficiency?
people with poor nutrition
antibiotic use
malabsorption
biliary obstruction
What is the mech of action vitamin K?
gamma-carboxylases glutamic acid residues on factors II, VII, IX, X, and proteins C and S
What is the mech of action vitamin K epoxide reductase?
recycles vit K so it can be used to gamma carboxylase more coag factors
What is mech of action warfarin?
inhibits vit K epoxide reductase
where is von willebrand factor produced?
by megkaryocytes [stored in platelets] and in ednothelial cells
What are the 2 functions of von willebrand factor?
- mediate platelet adhesion to subendothelial collagen via platelet glycoprotein receptor 1b [GP1b]
- protects factor VIIIf rom degradation
What is action of tissue factor?
exposed to blood following vessel injury –> binds factor VII and activates
What 2 reactions does TF/VIIa complex catalyze?
- activation of factor X to factor Xa = initiation
2. activation of factor IX to IXa = amplification
What is action of activated factor X?
binds cofactor V to form prothrombinase complex and convert prothrombin [factor II] to thrombin
What 2 cofactors are required for the conversion of prothrombin to thrombin by prothrombinase?
Ca and phospholipids from platelet cell membrane
What is function of thrombin? What 4 factors does it activate?
- activates platelets
- activates factors V, VIII, XI, XIII
- cleaves fibrinogen to fibrin
What is action of factor IX?
IXa binds cofactor VIIIa to form tenase complex and convert X –> Xa
Xa then binds Va to convert prothrombin –> thrombin
What activates factor XI?
thrombin
Where is fibrinogen [factor 1] produced?
liver
What is the action of thrombin on fibrin?
- thrombin converts fibrinogen to fibrin
- also activates factor XIII to XIIIa which stabilizes cross-linking of fibrin
What is action of factor XIII?
activated by thrombin to cause cross-linking of fibrin and stabilize fibrin polymer
What is action of platelet plug formation?
- platelets adhere/attach when they see subendothelium matrix proteins exposed
- platelet structure spreads to form tight contacts with matrix
- platelets secrete granules and recruit other platelets for aggregation
What protein regulates von willebrand factor multimers?
ADAMTS13
Does deficiency in factor XII cause bleeding disorder?
no
Does deficiency in factor XI cause bleeding disorder?
yes but not clinically severe
How do you measure prothrombin time [PT]?
add Ca and thromboplastin [TF plus phospholipid] to the plasma –> activates factor VII –> measures the componenets of extrinsic and common paths
What is INR?
normalized ratio of PT
What does long PT/INR mean?
deficiency or abnormality of VII, X, V, II, fibrinogen or inhibitors
= extrinsic or common path problem
How do you measure partial thromboplastin time [PTT]?
add Ca, phospholipid, and contact activator to plasma –> measures components of intrinsic and common paths
What does long PTT mean?
inherited or acquired deficiency of extrinsic path or inhibitor of these factors
What does thrombin time measure?
action of thrombin on fibrinogen to form fibrin clot
What does long thrombin time mean?
- too little fibrinogen
- abnormal fibrinogen
- heparin present
- fibrin degradation products present
What does mixing study tell you?
helps distinguish between factor deficiency and presence of an inhibitor of clotting factors
What does bleeding time tell you?
measures platelet-vessel wall interaction
prolonged if there is quantitative or qualitative defect of platelets OR if there is an abnormality in the vessel wall OR von willebrand disease or other defect of platelet adhesion
How does bleeding time change in clotting factor deficiency?
not changed
What is hemophilia A?
X linked
decreased or absent factor VIII
What is normal action of factor VIII?
cofactor for activation of factor X by IXa
What do you normally see clinically in hemophilia A?
bleeding in joints and muscles
What are some complications of hemophilia A?
chronic arthropathy from repeated joint bleeds
trasnfusion transmitted infection
inhibitor formation to infused factor VIII
What happens to PTT, PT, thrombin time, bleeding time, mixing studies in hemophilia A?
- long PTT
- normal PT, thrombin time, bleeding time
- corrected with mixing studies unless inhibitor present
What are 2 treatments of PTT?
infuse factor VIII
desmopressin [DDAVP] = increases factor VIII levels by stimulating secretion of vWF from endothelial cells
What is hemophilia B [christmas disease]?
X linked
deficiency of factor IX
How can you distinguish hemophilia A from hemophilia B clinically?
you can’t
What happens to PTT, PT, thrombin time, bleeding time, mixing studies in hemophilia B?
- long PTT
- normal PT, thrombin time, bleeding time
- corrected with mixing studies unless inhibitor present
What is treatment for hemophilia B?
give factor IX infusion
What is a unique complication of hemophilia B?
development of thrombosis if give too much exogenous factor IX
What do you see clinically in factor XI deficiency?
seen in ashkenazi jews = hemophilia C
clinically see variable bleeding; usually after trauma/surgery; may have delayed bleeding b/c have normal initiation of thrombin but don’t have the amplification from XI
What happens to PTT, PT, thrombin time, bleeding time, mixing studies in factor XI deficiency?
- long PTT
- normal PT, thrombin time, bleeding time
- corrected with mixing studies unless inhibitor present
What is effect of factor XIII deficiency?
delayed bleeding several days after invasive procedure due to failure of fibrin clot cross-linking –> clot is easily dissolved
What are 3 acquired causes of impaired clotting factor production?
- vit K deficiency
- liver disease
- warfarin
What are x causes of increases consumption of clotting factors?
- DIC [factors consumed in clot formation]
- liver disease [associated w/ DIC]
- transfusion can dilute platelets/coag factors
- nephrotic syndrome [lose factor IX in urine]
What are acquired factor inhibitors? which most common?
spontaneous new antibodies against clotting factors
most common factor VIII
seen in autoimmunity and post-partum
What is lupus anticoagulant?
anticardiolipin antibodies;
in vivo associated with thrombosis [not bleeding]
in vitro causes long PTT
What happens to PTT, PT, thrombin time, bleeding time, mixing studies in vitamin K deficiency?
- long PT and PTT
- corrects with mixing studies
- thrombin time normal
- bleeding time normal
What happens to clotting in liver disease?
- factor deficiencies of all but VIII
- can see abnormal fibrinogen and thus long thrombin time
- tissue factor released from damaged liver –> DIC –> consumption of clotting factors
- thrombocytopenia secondary to hyperplenism
What happens to PTT, PT, thrombin time in liver disease? Other findings?
long PT and usually long PTT [PT affected more b/c factor VII has shortest 1/2 life]
- long thrombin time
- thrombocytopenia
- decreased fibrinogen
- elevated fibrin degradation products
What is DIC?
clotting system activated –> excessive thrombin generation leads to disseminated fibrin deposition in microcirculation –> consumption of clotting facotrs and platelets
What is typical clinical manifestation of DIC?
diffuse bleeding [even though initial event is disseminated thrombosis]
intravascular hemolysis, schistocytes, microagniopathic hemolytic anemia
What happens to PTT, PT, thrombin time in DIC? Other findings?
long PT, PTT long thrombin time consumption of factors + fibrinogen thrombocytopenia elevated fibrin degradation products elevated D-Dimer
What do you see on peripheral smear in DIC?
schistocytes
low platelets
increased neutrophils and bands
nucleated RBCs
What is action of antithrombin?
serine protease inhibitor; made in liver
inactivates II, IX, X, XI, XII
What is role of heparin in thrombosis/fibrinolysis?
on surface of endothelial cells; binds antithrombin and increases its ability to inactivate thrombin
What happens in antithrombin deficiency?
increased risk for developing thromboses
What is the action of protein C?
- activated by thrombin-thrombomodulin complex
- complexes with phospholipid, Ca, and protein S to inactivate factors Va and VIIIa
What is action of tPA?
produced by endothelial cells –> converts plasminogen bound to fibrin to plasmin
What is action of plasmin?
digets fibrin polymers and releases fibrin split products that inhibit clotting
What 2 serine protease inhibitors regulate fibrinolysis?
alpha plasmin inhibitor = inactivates plasmin in circulation
plasminogen activator inhibitor-1 [PAI-1]: produced by endothelial cells and stored in platelets –> inhibits tPA to prevent premature lysis of fibrin clot as it forms
What are the 3 thrombogenic factors of virchows triad?
- vessel wall damage
- static blood flow
- coagulable state of blood
What is thrombophilia?
inherited tendency to develop thrombosis
Where do arterial thrombi form? What are they composed of?
under conditions of high blood flow
composed mainly of platelet aggregates held together by fibrin strands
Where do venous thrombi form? What are they composed of?
in areas of stasis
composed of RBCs with large amount of interspersed fibrin and fewer platelets
What is factor V leiden?
point mutation in factor V –> resistant to inactivation by activated protein C
What are two most common causes of thrombophilia?
- factor V leiden
- prothrombin gene mutation
What happens in prothrombin gene mutation?
increases amount of prothrombin in blood –> increased risk of thrombosis
What is inheritance of protein C or S deficiency?
autosomal dominant
What do you see in homozygous protein C deficiency?
neonatal thrombosis [purpura fulminans] = often fatal
Who is at risk for warfarin skin necrosis? Why?
patients treated with warfarin who have underlying protein C or S deficiencies
this is b/c protein C has shorter half life so declines faster than other vit K dependent clotting factors –> can lead to hypercoagulable state
What do you give to patients to prevent warfarin skin necrosis?
initiate anticoagulation with heparin before giving warfarin
What is inheritance of antithrombin deficiency?
autosomal dominant
What happens in antithrombin deficiency?
increased risk of venous thromboembolism; high risk of thrombosis in pregnant women with AT deficiency
What happens in hyperhomocysteinemia? possible mech?
increased risk of arterial and venous thromboembolism due to:
- direct damage to endothelium
- decreased endothelial expression of heparan sulfate
- inhibition tPA binding
- activation factor V
What are 3 vitamin deficiencies that cause high homocysteine?
- B12, folate, and B6 deficiencies
What are some acquired risk factors for thrombosis?
- pregnancy or post partum
- immobilization
- malignancy
- obesity
- birth control pill
What is heparin induced thrombocytopenia [HIT]? treatment?
paradoxical arterial and venous thrombosis in pts on heparin
treat: stop heparin and anti-coag therapy w/ direct thrombin inhibitors
What happens in anti-phospholipid syndromes?
antiphospholipid antibodies [IgG or IgM] interact with negative charged phospholipids
seen in pts with syphilis, lupus, other collagen vascular diseases
associated with arterial and venous thrombosis
What is a possible complication in people with anti-phospholipid antibodies?
recurrent miscarriages
