path - hemostasis etc

transient response to vessel injury

vasoconstriction

how does initial vasoconstriction occur when a vessel is damaged

damaged endothelium rel-eases endothelin

endothelin

vasoconstrictor produced by endothelium in response to injury

important components of platelet granules

fibrinogen (factor I)

factors V and VIII

histamine and serotonin

ADP ATP and Ca++ (for binding to the wound site and other platelets)

process of clot formation

initial vasoconstriction (endothelin)

primary hemostasis

secondary hemostasis

primary hemostasis

Formation of platelet plug

vWF

von Willebrand factor; mediates binding and adhesion of platelets to exposed collagen at site of injury

vWF produced by

endothelial cells

binding of platelet cells to vWF triggers

degranulation (to promote platelet aggregation)

TXA2 produced by

platelets

TXA2

platelet aggregation and vasoconstriction

ADP (platelets)

potent platelet aggregate and attractant

secondary hemostasis

coagulation cascade

tPA

tissue plasminogen activator

tPA converts

plasminogen to plasmin

plasmin role

breaks down fibrin

activates MMPs

important regulator of clot formation

plasmin

in primary hemostasis, how do platelets adhere to the exposed collagen

through binding GpIb to vWF

GpIb

platelet receptor for von Willebrand factor

(stick to collagen 1st)

GpIIb-IIIa

platelet receptor for fibrinogen, allows platelets to "stick to each other"

how do platelets adhere to each other during primary hemostasis

binding fibrinogen on their GpIIb-IIIa receptors

GpIIb-IIIa deficiency

Glanzmann thrombasthenia - deficient platelet aggregation

GpIb deficiency

Bernard-Soulier syndrome, impaired platelet adhesion

vWF deficiency

von Willebrand disease, impaired platelet adhesion

Glanzmann thrombasthenia

GpIIb/IIIa deficiency

Bernard-Soulier syndrome

GpIb deficiency

common coagulation cascade pathway

Xa and Va activate II to IIa

IIa activates I to Ia, and XIII to XIIIa

XIIIa crosslinks Ia

intrinsic coagulation cascade

binding to collagen activates XII to XIIa

XIIa activates XI to XIa

XIa activates IX to IXa

IXa and VIIIa activate X to Xa

extrinsic coagulation cascade

tissue factor (III) binds VII to form VIIa-III complex

VIIa-III complex activates X

test for extrinsic clotting pathway

PT

Play Tennis outside (Extrinsic)

test for intrinsic clotting pathway

PTT

Play Table Tennis inside (Intrinsic)

which clotting factors are produced by platelets

fibrinogen (I)

V and VIII (cofactors)

clotting cascade cofactors

V (common pathway)

VIII (intrinsic pathway)

first step of intrinsic pathway

binding to collagen activates XII (Hageman factor) to XIIa

XIIa activates

XI to XIa

2nd step of intrinsic pathway

XIIa activates XI to XIa

3rd step of intrinsic pathway

XIa activates IX to IXa

4th step of intrinsic pathway

IXa and VIIIa activate X (required Ca++)

factor VIII activated by

thrombin (IIa)

1st step of extrinsic pathway

tissue injury releases stored tissue factor

2nd step of extrinsic pathway

tissue factor binds and activates factor VII to form VIIa-III complex

3rd step of extrinsic pathway

tissue factor (III/thromboplastin) - VIIa complex activates X

factor V activated by

thrombin (IIa)

1st step of common pathway

Xa and Va (activated by thrombin) activate II (prothrombin) to IIa (thrombin), requiring Ca++

prothrombin activated by

Xa/Va

factor IIa

thrombin

factor II

Prothrombin

2nd step of common pathway

factor IIa (thrombin) activates factor I (fibrinogen) to factor Ia (fibrin)

factor IIa activates factor XIII to XIIIa

factor I

fibrinogen

factor Ia

fibrin

crosslinking of fibrin is accomplished by

factor XIIIa

3rd step of common pathway

factor XIIIa crosslinks fibrin

which clotting factors are made by the liver

2, 7, 9, 10

which clotting factors require calcium for binding

2, 7, 9, 10 (liver produced clotting factors)

how does calcium bind clotting factors 2, 7, 9, 10

Ca++ on the PHOSPHOLIPID surface binds carboxyl groups on the clotting factor's glutamic acid residues

how are the glutamic acid residues of factors 2, 7, 9, 10 carboxylated

vitamin K

role of vitamin K epoxide reductase in clotting

reactivate vitamin K to continue carboxylation of liver produced clotting factors (2, 7, 9, 10) which is necessary to bind calcium

warfarin MOA

Inhibits vitamin K epoxide reductase (prevents carboxylation of liver produced factors: 2, 7, 9, 10)

which clotting factors are affected by warfarin

2, 7, 9, 10

protein C

Cleaves Clotting Cofactors (Va and VIIIa)

- inactivates

TF-VIIa complex

important for activating factor IX and factor X

when plasmin degrades fibrin it produces

D dimers

if clotting is suspected, what product in the blood can be tested for

D dimers (plasmin breaking down fibrinous clots would release D-dimers)

thrombus vs embolus

thrombus: clot that forms within a blood vessel (usually the result of a ruptured atherosclerotic plaque), attached to vessel wall

embolus: clot that broken free and is moving in the blood stream, not attached

Virchow's triad

factors that contribute to thrombosis:

1. hypercoagulability

2. hemodynamic changes (stasis, turbulence)

3. endothelial injury

factor V mutation

Leiden

- increased resistance to protein C inactivation

- creates a hypercoagulable state

- prone to clotting

mural thrombus

large thrombus in the cardiac chambers or aorta

trousseau's syndrome

paraneoplastic syndrome involving increased production of mucins by tumor cells creating a hypercoagulable state

mucins activate platelets

thrombosis most commonly occurs following

rupture of atherosclerotic plaque

thrombus vs postmortem clot

thrombus: attached to vessel wall

- alternating layers of fibrin/platelets/rbc = lines of zahn

postmortem unattached

- no lines of zahn

lines of zahn

Alternating layers of platelets/fibrin and RBCs seen in a thrombus

NOT seen in postmortem clots

arterial thrombi are often due to (think virchow's triad)

endothelial injury (rupture of atherosclerotic plaque or turbulent flow = bifurcations)

venous thrombi are often due to (think virchow's triad)

stasis (seen in immobilization)

widow maker artery

LAD

- bifurcation increases risk for turbulent endothelial damage which predisposes thrombus formation

arterial thrombi tend to grow

retrodgrade (from point of attachment)

venous thrombi tend to grow

direction of blood flow

most common sites of arterial thrombi

coronary, cerebral, and femoral arteries

most common sites of venous thrombi

veins of the lower extremities

composition of arterial thrombi

primarily fibrinous platelet aggregate

- layers of fibrin, platelets rbcs

composition of venous thrombi

composed primarily of RBCs

most important consequence of arterial thrombi

occlusion

- primarily coronary and cerebral

most important consequence of venous thrombi

distal edema

potential for emboli

major plasma protein

albumin

hypoalbuminemia

may be caused by hepatic insufficiencies or nephrotic syndrome

results in edema (decreased oncotic pressure of the vasculature increases filtration pressure)

major causes of reduced plasma oncotic pressure

hypoproteinemia (primarily albumin)

sodium retentia in renal insufficiency (leading to water excess)

filariasis

Wuchereria bancrofti

lymphatic obstruction produces lymphedema with potential elephantiasis

ascites

accumulation of fluid in the peritoneal cavity

dependent edema

influenced by gravity

prominent in CHF

edema seen in left sided heart failure

pulmonary

edema seen in right sided heart failure

systemic/dependent edema

pitting edema

right sided CHF

pulmonary edema is most common in

left sided heart failure

hyperemia

increased blood flow

causes red tissue

does not cause ischemia

congestion

decreased outflow

associated with cyanosis/hypoxia

edema

chronic pulmonary congestion

thickened fibrous septa

"heart failure" cells

- hemosiderin-laden macrophages in the alveolar spaces

heart failure cells

hemosiderin laden macrophages in the alveolar spaces

nutmeg liver

Chronic passive congestion of liver due to RHF

centrilobular necrosis

most common cause of chronic passive congestion of the liver

right sided heart failure (increases CVP and backs up blood into the liver)

purpura

multiple pinpoint hemorrhages (similar to petechiae just larger)

- trauma, vasculitis

ecchymoses

larger subcutaneous hematomas

usually following trauma