3 - Hemostasis/Coagulation Flashcards
Hemostasis is achieved through four main mechanisms:
- Vasoconstriction
- Platelet Plug
- Blood clot
- Fibrous tissue to close the hole permanently
How do platelets contribute to vasoconstriction in small vessels?
release thromboxane A2, which is a vasoconstrictor
Very small holes are closed with what type of plug?
Almost always platelet, and rarely blood
Platelets are formed in the _____ from _____
bone marrow
Megakaryocytes
What is the half life of a platelet?
8-12 days
Why does thrombocytopenia cause petechiae?
Normally very small wounds would be closed off with platelets adhering the endothelium to itself. When platelets are absent, the only other option is a blood clot, hence the bruised appearance
There are three essential steps to blood clotting:
- Production of prothrombin activator in response to vessel damage
- prothrombin activator catalyzes the conversion of prothrombin to thrombin
- thrombin acts as an enzyme to convert fibrinogen into fibrin, which forms the clot
In the presence of sufficient ____, prothrombin activator converts ____ to _____
calcium
Prothrombin
thrombin
What is the rate limiting factor in the coagulation cascade?
the formation of prothrombin activator
Prothrombin is formed continually by which organ?
The liver
Where is fibrinogen formed?
The liver
What is thrombin?
A proteolytic enzyme
Breaks fibrinogen into four fibrin monomers
initial fibrin fibers are weak and not cross linked. What changes this?
fibrin stabilizing factor from platelets
acts as an enzyme to form covalent bonds between the monomers and cross linkage with other fibrin fibers
The extrinsic pathway begins _______
The intrinsic pathway begins _______
with trauma to the vascular wall and surrounding tissues
in the blood in response to the presence of collagen
What’s the difference between factor VIII and factor VIIIa?
The “a” denotes the activated form
What is GpIIb/IIIa?
Glycoprotein 2b/3a
protein on the membrane of the platelet that binds fibrin linkages between platelets and facilitates aggregation
What is GpIa?
Glycoprotein 1A
Protein on the platelet membrane that binds with vWF
When platelets bind with vWF secreted by endothelial cells, they produce:
ADP, Thromboxane A2, Serotonin
All of these promote platelet aggregation and/or vasoconstriction
The first step of the extrinsic pathway is:
the release of Factor III (tissue factor) from damaged endothelial cells
What activates factor XII?
Contact with polyanions
Activated platelets secrete polyphosphates (polyanions) which activate factor XII
The first step of the intrinsic pathway is:
Activation of Factor XII and release of platelet phospholipids
The common pathway of coagulation is:
the activation of factor X
What are the growth factors produced by platelets?
What do they do?
VEGF: vascular regrowth
PDGF: collagen and muscle regrowth
What is tPA?
tissue plasminogen activator
it’s an enzyme that converts plasminogen to plasmin, which digests fibrin
What are the byproducts of fibrinolysis?
fibrin
D-Dimer
Someone with hemophilia would have a breakdown where in the coagulation cascade?
In the activation of factor X
Calcium is required for which stages of the coagulation cascade?
All of them, except the first two steps of the intrinsic cascade
Which is faster: extrinsic or intrinsic
the extrinsic, activated in about 15 seconds
intrinsic takes 6-10 minutes
What prevents intravascular coagulation?
- the smoothness of the endothelium
- the glycocalyx repels clotting factors and platelets
- thrombomodulin binds with thrombin, removing it from circulation and activating plasma protein C
- Plasma protein C inactivates factors 5 and 8
Intact endothelial cells produce ____ and ____ which inhibit platelet aggregation
NO
PGI2
There are two substances that remove thrombin from circulation:
- the fibrin fibers that are forming a clot
- antithrombin III
By itself heparin has no anticoagulant properties, but when it binds with ______, its effectiveness increases exponentially
Antithrombin III
Why does exogenous heparin prevent clotting?
In the presence of excess heparin, free thrombin is instantaneously removed from the blood by antithrombin III
Endogenous heparin is mostly produced by:
basophilic mast cells
Why do the lungs and the liver have an abundance of mast cells?
They receive lots of minor embolic clots that need to be broken down
______ causes fibrinolysis
plasmin
very similar to trypsin, which makes sense since it’s eating proteins
Spontaneous major bleeding episodes generally occur when platelets are less than:
20,000
The state of platelet activation is primarily under the control of:
the endothelium
Platelets adhere when _____ binds to _____
platelet surface receptor FP1b
vWF in the subendothelial matrix
What happens when platelets are activated?
- reorganizes the platelet cytoskeleton from sphere-like to spiky
- degranulation, releasing various biochemicals
Platelets contain three types of granules.
What are their roles?
dense bodies (ADP, serotonin, calcium)
alpha granules (fibrinogen, factor V, VEGF, PDGF)
lysosomes (degrade extracellular matrix and remodel the vasculature)
Once activated, platelet aggregation is induced by:
platelet release of TXA2
_____ and ____ initiate the extrinsic pathway
Tissue Factor
Factor VII
____ and ____ initiate the intrinsic pathway
Factor XIIa (activated by HK)
Prekallikrein (PK)
The intrinsic pathway is activated in the ____ by contact with _____
blood vessels
negatively charged molecules
How do intrinsic pathway deficiencies effect hemostasis?
They generally don’t, except for hemophilia C (only causes mild bleeding)
The intrinsic pathway is not a significant pathway for normal hemostasis
pg. 915
What factor is responsible for blood clots in ECMO or CRRT circuits?
Factor XII
exogenous artificial surfaces activate factor XII
The major regulatory factors that control hemostasis reside where the greatest probability of clotting would occur:
on the endothelial cell surface
p. 916
What are the three types of primary anticoagulant mechanisms?
- Thrombin inhibitors
- tissue factor inhibitors
- mechanisms for degrading activated clotting factors
______ binds with endogenous heparan or exogenous heparin to prevent thrombosis
Antithrombin III
How does tissue factor pathway inhibitor effect coagulation?
Produced by endothelial cells and platelets
forms complexes with and inhibits Xa
The TFPI/Xa complex goes on to inhibit TF/VIIa and prothrombinase
How does heparin impact TFPI?
About 20% of TFPI circulates in the bloodstream on lipoproteins
Heparin increases the plasma levels of TFPI
What happens when thrombomodulin on the surface of endothelial cells binds to thrombin?
When thrombin binds to thrombomodulin, it is inactivated
Protein C binds to this thrombomodulin-thrombin complex and is rapidly activated
Activated protein C interacts with protein S to inactivate factors Va and VIIIa
Inherited hypercoagulation is caused by deficiency of _____ (3)
AT-III
Protein C
Protein S
If the body needs to clot or become inflamed, how does it overcome the body’s natural anticoagulants?
Cytokines and inflammatory mediators down regulate expression of thrombomodulin and protein C receptors
decreased expression leads to decreased protein C production, which leads to coagulation
How does the fetus tolerate the hypoxic environment of the placenta/uterus?
polycythemia
A newborn infant would be expected to have high levels of ______ on a CBC
reticulocytes
Why is there an increased incidence of VTE in the elderly?
platelet adhesiveness is elevated
Higher levels of factors V, VII, and IX and vWF
thrombin generation and platelet activation enhanced
p. 922
Which is worse: insufficient platelets or a clotting cascade abnormality?
Clotting cascade abnormalities tend to cause more serious internal bleeding than platelet defects
Define thrombocytopenia and thrombocythemia
T-cytopenia: decrease platelets
T-cythemia: too many platelets
Why is a manual differential done for patients with low platelets?
to rule out pseudothrombocytopenia
happens with the automated cell counter misreads clumps of platelets and gives a falsely low platelet count
Which is more common: acquired or congenital thrombocytopenia?
Acquired
What are some common causes of acquired thrombocytopenia?
Viral infection (EBV, rubella, CMV, HIV)
Drugs (thiazides, estrogens, quinines, chemo, ethanol)
Nutritional (B12, folate)
Chronic renal failure
bone marrow cancer/hypoplasia
HIT is mediated by which antibodies?
IgG antibodies against the heparin-platelet factor 4 complex that leads to platelet activation
The hallmark sign of HIT is:
thrombocytopenia
Which is more common in HIT: bleeding or clotting?
Clotting
High risk for VTE and arterial thromboses
bleeding is uncommon, even with low platelet counts
HIT begins after _____ days of heparin administration
5-10
Why should coumadin not be used in patients with HIT?
Increased incidence of skin necrosis
Which drugs should be used to decrease the chance of thrombosis in a patient with HIT?
Thrombin inhibitors (argatroban etc)
Hit decreases the platelet count by increasing platelet _____
activation (consumptive)
Immune thrombocytopenia purpura decreases platelet count by ______
destroying platelets
What usually causes acute Immune thrombocytopenic purpura (ITP)?
secondary to a disease (usually viral infection) that leads to large amounts of antigen in the blood (can also be SLE or drug allergies)
Immune complexes bind to platelet receptors, and then that platelet is destroyed by the spleen
What is the treatment for acute ITP?
Usually resolves with the illness (as immune complex load decreases)
What causes chronic ITP?
Autoantibodies against platelet antigens
In chronic ITP, auto-antibodies are usually of the _____ class
IgG
What are the initial manifestations of ITP?
petechiae and purpura, which progress to epistaxis, hematuria, bleeding gums etc.
If a woman develops ITP during pregnancy, what are the implications for her infant?
newborn will also be thrombocytopenic
The IgG antibody cross the placenta
What are the symptoms of ITP?
weight loss
headache
fever
What is the treatment for chronic ITP?
glucocorticoids
IVIG
These are transient, and don’t fix the problem permanently. Some patients may need splenectomy
What is thrombotic thrombocytopenia purpura?
a.k.a Moschcowitz disease
combination of severe thrombocytopenia AND thrombotic microangiopathy caused by platelet aggregation
What is the difference in clots formed by DIC and clots formed by TTP?
TTP clots are mostly composed of platelets and RBCs with minimal fibrinolysis
In DIC, there is a massive amount of fibrinolysis
What causes TTP?
dysfunction in the protein that breaks down vWF
Causes an excess of vWF on the endothelium, which attracts clumps of platelets
These clumps can detach and cause microemboli
The classic pentad of TTP symptoms is:
extreme thrombocytopenia (<20)
intravascular hemolytic anemia
ischemic s/s in the CNS
kidney failure
fever
DO NOT NEED ALL FIVE TO DIAGNOSE
A blood smear of a patient with TTP will show:
schistocytes (fragmented RBCs)
elevated LDH
What is the death rate for TTP if left untreated?
90%
What is the treatment for TTP?
infusion with FFP, which replenishes functional ADAMTS13 (vWF proteinase)
When does secondary thrombocythemia often occur?
After a splenectomy
The spleen is a storage site for platelets, so after splenectomy all those platelets are circulating instead of sequestered
What causes reactive thrombocythemia?
infections and inflammatory conditions (RA in particular)
excessive production of cytokines induces increased production of thrombopoietin in the liver, causing increases megakaryocyte proliferation
What is the most severe form of thrombocythemia?
primary / essential
What causes primary thrombocythemia?
excess platelet production d/t defective bone marrow megakaryocyte progenitor cells
What is common in thrombocythemia: bleeding or clotting?
clotting
microvasculature thrombosis, BUT they are also at risk for large vessel thrombi
Bleeding can occur more rarely
The primary presenting symptoms of essential thrombocythemia are:
erythromelalgia (hot burning hands and feet)
headache
paresthesias
Which is more common with thrombocythemia: venous or arterial clotting?
arterial
Vitamin K is necessary for the synthesis of:
prothrombin
Factor 7, 9, 10
Proteins C and S
What is the most common cause of Vit K deficiency?
Parenteral Nutrition and Abx that wreck the gut
Liver disease can cause complications in three aspects of coagulation:
- coagulation system decreased factor production
- fibrinolysis system decreased plasminogen production
- platelet function decreased thrombopoietin and ADAMTS13 and sequestration in spleen due to portal HTN
Factor ____ is most sensitive to liver damage due to its short half life
VII
For patients with liver disease, what is the optimal way to treat hemostatic alterations?
FFP
Contains all the aspects absent in liver failure (clotting, fibrinolysis and platelets)
TTP causes ____ clots
DIC causes ____ clots
Platelet
Fibrin
What is the most common condition associated with DIC?
sepsis, usually from gram (-) endotoxins causing endothelial damage
The common pathway to DIC is _____
excessive and widespread exposure to TF due to vascular injury
Why do inflammatory disorders lead to DIC?
Normally, endothelial cells and monocytes don’t express surface TF, but they do in response to cytokines
a large majority of the cells produced in response to inflammatory cytokines have TF on their cell surfaces
In DIC, TF binds to factor ______. What happens next?
VII
leads to conversion of prothrombin to thrombin and formation of fibrin clots
Inhibition of _____ or _____ completely halts the path of DIC
TF
Factor VIIa
List the coagulation problems present in DIC:
- Extensive activation of the clotting cascade
- Anticoagulants (TFI, ATIII and protein C) are profoundly diminished
- Fibrinolysis is diminished d/t increased production of plasminogen inhibitor (PAI1)
- Activation of clotting causes activation of complement which induces platelet destruction
Besides consumption of clotting factors and platelets, what are other reasons hemorrhage occurs in DIC?
Fibrin degradation products (FDPs) are natural anticoagulants
DIC will continue until:
whatever started it stops
What things are you looking for on a blood panel to determine DIC?
platelet count
PT/PTT
D-Dimer
pg. 596
Treatment of DIC is directed toward three goals:
- Removing the underlying cause
- controlling thrombosis
- maintaining organ perfusion
Once the stimulus for DIC is gone, how long does it take for plasma to normalize?
24-48 hours
Why is heparin not the drug of choice for septic DIC?
It acts by binding to and activating AT-III, which is deficient in DIC
Arterial thrombi form under conditions of ______ blood flow
Venous thrombi form under conditions of _____ blood flow
High, composed of platelets
Low, composed of red cells
What is Virchow’s triad?
- Vessel Injury
- Abnormal blood flow
- Hypercoaguability
Why does turbulent flow lead to thrombi?
Turbulent flow platelets and endothelial cells activated
Why does stasis lead to thrombi?
platelets remain in contact with the endothelium longer than normal
clotting factors aren’t as diluted as normal and become activated when they come into contact with one another
What are three disorders that cause both stasis and turbulent flow?
Myocardial infarction
polycythemia
sickle cell
Which two inherited thrombophilias pose the greatest risk of developing an MI or stroke?
F2 gene mutation Prothrombin (G20210A)
Factor V Leiden
What happens when a Factor V leiden mutation takes place?
Its binding site for protein C (which normally inactivates Factor Va) is altered and it becomes resistant
results in high levels of factor Va and prolonged clot formation
What does an F2 gene mutation cause?
causes too much prothrombin to be produced
increased prothrombin → increased thrombin → increased clotting
Antiphospholipid Syndrome is an example of a ______ disease
acquired hypercoaguability
What is antiphospholipid syndrome?
autoimmune syndrome
autoantibodies against plasma membrane phospholipids and phospholipid-binding proteins
What are the implications of having APS in pregnancy?
Autoantibodies attack the placental surface
Leads to pregnancy loss, pre-E or eclampsia
What is the treatment for Antiphospholipid syndrome in pregnancy?
unfractionated or LWMH with low-dose aspirin
Deficiencies of which three coagulation factors account for 95% of hemophilias?
VIII
IX
XI
What is the most common hemophilia?
Hemophilia A (Factor VIII deficiency)
Mutations in the F8 gene cause hemophilia ____
Mutations in the F9 gene cause hemophilia ____
A
B
pg. 1007
Hemophilia B is a deficiency of factor:
IX
How are hemophilia A and B inherited?
X-linked recessive
Normal hemostasis is achieved in hemophilia without excessive bleeding. How?
The extrinsic coagulation cascade does not rely on factors VIII, IX or XI
In Hemophilia A or B, the PT will be __ and the PTT will be __
normal
prolonged
What is the primary goal of administering rFVIII/IX to hemophiliacs?
Prevent joint bleeding
Why is von Willebrand disease sometimes said to be a factor VIII deficiency?
Because vWF binds factor VIII and platelets to the blood vessel wall as part of the clotting process
Factor VIII activity is decreased in individuals with von Willebrand disease. Not factor VIII quantity
What are the two types of protein C deficiency?
Type 1: quantitative deficiency
Type 2: qualitative deficiency
What causes neonatal purpura fulminans?
presence of both types 1 and 2 protein C deficiency
What is the treatment for protein C deficiency?
Long term or short term anticoagulation, depending on severity
Which thrombocytopenia has a high probability of neonatal death?
neonatal alloimmune thrombocytopenic purpura (NATP)
Which neonatal thrombocytopenia is relatively benign?
autoimmune neonatal thrombocytopenia
