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116 Cards in this Set

  • Front
  • Back
hemostasis definition
arrest of hemorrhage following vascular injury
what are the 2 paths of the coagulation cascade
1) Intrinsic cascade. FXII contacts thrombogenic surface.

2) Extrinsic cascade: blood is exposed to extravascular (subendothelial) tissue factor (TF)
Coagulation, generally
conversion of soluble plasma fibrinogen to insoluble fibrillar polymer fibrin, catalyzed by thrombin
What is probably the most important factor in thrombus progression and stabilization?
Thrombin production
Steps to know in clotting cascade
1) TF combines with VII
2) TF:VIIa catalzyses X-->Xa and IX--IXa
3) These steps are inhibited by TFPI tho
4) Meanwhile, THROMBIN Activates XI to XIa.
5) Thrombin also activates V and VIII and XIII.
6) these precursors help the steps in 2 progress better
7) this all leads to more creation of thrombin from prothrombin
8) finally, thrombin converts fibrinogen to soluble fibrin, and then soluble fibrin converst to insoluble fibrin via activated XIIIa
What is vWF?
Von Willebrand factor enhances platelet adhesion by binding both to platelet membrane and fibrinogen
What do activated platelets do?
1) release granule contents (ADP, TxA2) that recruits more platelets and promotes aggregation

2) other factors released promote clotting cascade and thrombus formation
What does endothelium do to regulate the thrombus?
releases NO and PGI2 (prostacyclin), which INHIBIT platelet aggregation
Descibe hemophilia A
1) inherited coagulopathy
2) MOST COMMON X-linked recessive inherited bleeding disorder
3) absent/low F XIII
4) spontaneous bleeding into joints, muscles, organs
Describe hemophilia B
1) less common X-linked recessive bleeding disorder

2) clinically indistinguishable from type A

3) "Christmas disease"
Describe vWD
2) AUTOSOMAL DOMINANT (cf hemophilias, X-linked recessive)
3) abnormal/deficient vWF
4) also associated with reduced F XIII levels, since vWF is a carrier for F XIII
5) excessive blood loss from superficial injuries, operative and post traumatic injuries
Incidence of acquired coagulopathies
GREATER than that of the inherited coagulopathies (hemophilia, vWD)
Vitamin K deficiency
1) decrease in a bunch of factors (II, VII, IX, X)

2) malapsorption in the gut of stuff
Liver disease and coagulopathy
1) can cause impaired vit K absorption, leading to vit K deficiency-type coagulopathy

2) thrombocytopenia due to hypersplenism

3) reduced synthesis of clotting factors, fibrinogen
Characteristics of DIC
an acquired coagulopathy characterized by widespread thrombosis AND hemorrhage secondary to the consumption of all of the platelets and coag factors elsewhere. Also widepsread ischemia due to thrombosis
General cauases of DIC
1) tissue injury

2) endothelial cell injury
what are the major factors predisposing to thrombosis?
(Virchow's triad)
1) changes in blood constituents (hypercoagulability)

2) endothelial injury or damage

3) stasis or turbulent blood flow
what is the most common cause of death in western industrialized countries?
arterial thrombosis, with the complication of embolization
what is effusion
excess fluid in body cavities
definition of embolism
vascular obstruction by a non blood mass traveling in the blood stream
What are some plasma derived mediators of edema?
1) Hageman factor (triggers clotting system), triggers bradykinin production

2) Complement activation system (C3a, C5a)
Materials able to cause embolism
thrombus air amniotic fluid fat atheromatous debris foreign objects tumor
What are some cell derived mediators of edema?
1) Histamine (mast cell degranulation)
2) platelets (serotonin)
3) inlfammatory cells (PAF, PG, Leukotrienes)
4) Endothelium (NO, PAF, PGs)
Where can arterial emboli cause infarct
(usually cardiac source, e.g. mural thrombi)

1) brain
2) intestine
3) lower extremeties
4) kidney
5) heart
What is transudate?
edema fluid with LOW protein content
Describe amniotic fluid embolism
1) uncommon but lethal childbirth complication
2) sudden dyspnea, hypertension, SCA
3) ebolization of fetal material/debris
4) associated with DIC and ARDS
What is exudate?
edema fluid with HIGH protein content
what is fat embolism associated with
bone fractures
what cells are responsible for organizing a thrombus? how?
Phagocytes: injest thrombotic material

Fibroblasts: replace it with fibrosis
name some signs of greater thrombus reorganization
clefts form in the thrombus, line themselves with endothelial cells! meanwhile fewer nucleii are seen inside the thrombus.
what things can happen to a thrombus after formation (Evolution)?
1) lysis: dissolution by nzms fom trapped leukocytes; fibrinolytic system
2) can be replaced by fibrous tissue/reorganized
3) Embolization
4) Partial calcification; phleboliths
5) vegetations in cardiac valves
6) infection of thrombus
Simplified clot cascade steps
1) vascular/endothelial injury releases TF
2) TF combines with VII to make TF:VIIa, which activates IX and X
3) IX and XIIIa activates X
4) Xa and Va catalzye prothrombin-->thrombin
5) thrombin converts fibrinogen to fibrin
what does hageman factor activation cause?
(=factor XII) kinin generation
clot formation
anaphylatoxin generation (via complement cascade)
fibrin degradation product formation (fibrinolyiss)
what does fibrinolysis do w/ vascular permeabilty?
augments it
how else does hageman factor increase vascular permeability?
activates complement cascade, which produces anaphylatoxins (c3a, c5a) generates kinins (bradykinin)
What is PAF? What does it do?
1) generated by activated inflammatory cells (neutros, masts), endo cells, injured cells
2) induces platelet aggregation
3) enhances platelet release of serotonin
4) increase vascular permeability
5) recruits leukocytes
6) vasodilator
7) enhances phagocytosis
8) stimulates synthesis of AA pathways
What are the platelet derived mediators?
1) serotonin (-->inc vasc perm)

2) TxA2 (AA-->cyclooxygenasepath-->SM constriction

3) cationic proteins ( inc. vasc perm up)

4) histamine
What is sarcoidosis? what can be involved
multisystemic disease of unknown etiology invovling noncaseating granulomatous infection in many organs, including: skin uveal tract hilar/mediastinal nodes bone marrow spleen liver lungs
what does granulation tissue eventually do
remodels into dense fibrous tissue
In addition to sarcoidosis, what can cause granulomatous inflammation?
fungal infection
what is a characteristic of keloid microoscopicallly?
wide, pink, accellular bands of stained collagen

not normal skin/dermis componenets

Large, darkly staining fibroblasts
what is the major pathological process in viral myocarditis?
chronic inflammation
is infiltration with mononuclear leukocytes characteristic of acute, chronic, neither, or both viral myocarditis?
Dysplasia, def
1) abnormal appearing cells pleomorphism nuclear enlargment/irregularity hyperchromatism

2) disorderly arranged cells loss of polarity loss of maturation abnormal location of mitotic figures
Neoplasia, def
abnormal growth of tissue excessive growth uncoordinated and autonomous
histology of benign neoplasms
resemble normal tissue histologically

well differentiated

low mitotic rate

generally well circumscribed

does not metastasize
osteoma is...
benign bone neoplasm
benign Cartilage neoplasm
benign neoplasm of gland
what are sarcomas?
tumors that arise in CT like bone, muscle, fat
where do carcinomas arise
what age group are sarcomas more common in?
is dysplasia reversible?
what is grading
a HISTOLOGICAL determination of how differentiated tumor cells are compared to the tissue they came from
what are the 3 parts of a cancer staging?
tumor (0-4)

nodes (0-4)

metastasis (0, +)
what is anaplasia
very poorly differentiated neoplasm
skeletal muscle-derived
smooth muscle derived
is leiomyoma at risk to turn into leiosarcoma?
how does tumor get from gut to liver
hematogenous spread
what is desmoplasia
scarring response to tumor
what is chronic myelogenous leukemia?
cancer of white blood cells

due to bcr-abl tranlocation

targeted by magic bullet gleevec
what are the pathological changes associated with coagulative necrosis?
-General architecture is well preserved

-nuclear changes-pyknosis, karyorrhexis, karyolysis

what is hemosiderin?
Hb derived golden to yellow brown, granular or crystalline pigment in which form iron is strored in cells

consists of aggregates of ferritin and accumulates pathalogically in tissues

when there is a systemic or local excess of iron ferritin forms hemsiderin

*RBC breakdown leads to hemosiderin accumulation
describe local hemosiderosis
- local deposition of hemosiderin
- most often results from hemorrhage into tissue
- hemosiderin derived from breakdown of Hb
describe systemic hemosiderosis
- generalized deposition of hemodesirin w/o tissue damage
- may result from hemorrhage multi blood xfusion, excessive iron intake
- often accompanied by alcohol consumption
describe hemochromatosis
- excessive accum of hemodesirin w/ tissue destruction and organ disfxn
- hepatic cirrhosis and fibrosis of pancreas ensue
- inc. melanin pigmentation
- may be hereditary causes or due to multi. blood xfusions
what is lipofuscin?
- yellowish, fat soluble pigment
- derive from peroxidation of membrane lipids, indicate FR damage --> "wear n' tear" pigment
- in hepatocytes and cardio myocytes of elderly w/ accompanying atrophy
coagulative necrosis is the most common underlying cause of infarct in all organs except....
the brain, in CNS infarcts are due to liquefactive necrosis
What nuclear changes occur during necrosis?
karyolysis - fading of stainable chromatin

pyknosis - condensation of nucleus

karyorrhexis - nuclear fragmentation
What cytoplasmic changes occur during necrosis?
denaturation of proteins w/ maintenance of cell outlines (coagualtion necrosis)

enzymatic digestion of dead cells (liquefactive necrosis)
What are two major differences between necrosis and apoptosis?
1. Necrosis results in loss of a large area of cells, whereas apoptosis results in loss of specific, individual cells. (Necrosis is messy, Apoptosis is neat)

2. Necrosis results in an inflammatory response, Apoptosis does not.
1. What do cellular proteins look like in necrosis?

2. What would this look like under the microscope?
1. cellular proteins are denatured

2. the cytoplasm would be more eosinophilic (denatured proteins have incr. affinity for eosin)
Describe pyknosis
a process during necrosis in which the nucleus becomes smaller and stains deeply basophilic as chromatin clumping continues.
When the rate of dissolution of cells is greater than the rate of repair, it is called ____________ necrosis.
What is the pathophysiology behind liquefactive necrosis.
polymorphonuclear leukocytes appear in a bacterial infection and produce rapid cell death - they then digest the dead cells completely. this frequently results in an abscess.
What portion of the body does fat necrosis specifically occur? Causes?
occurs in and around the pancreas and small intestine. Caused by acute pancreatitis or trauma to the area.
Pathophysiology behind fat necrosis?
1. ruptured pancreas/small intestine releases activated digestive enzymes.
2. phospholipases and proteases attack the plasma membrane of adipose cells, releasing triglycerides.
3. pancreatic lipase hydrolyzes the TAGs producing free fatty acids.
4. free fatty acids precipitate as calcium soaps.
What would fat necrosis look like under a microscope?
basophilic deposits at the periphery of islands of necrotic adipocytes
What is the mechanism behind caseous necrosis?
1. granuloma is formed on a platform of dead mononuclear cells,mycobacterium and cell debris.

2. Due to the waxy cell walls of the mycobacterium the necrotic debris is not removed. Forms a greyish-white lesion.
Fibrinoid necrosis refers to an alteration of ___________.
injured blood vessels
How are apoptotic cells disposed of?
they are phagocytosed by surrounding cells or macrophages.
1. what happens to the cell size during apoptosis?

2. what about chromatin?
1. Shrinks

2. Chromatin condenses
this type of necrosis occurs in the brain following artery occlusion.
liquefactive necrosis. (mechanism unknown)
What is the most characteristic feature of apoptosis?
chromatin condensation
what is an apoptotic body and how is it formed?
apoptotic body is formed by a "blebbing" which resulted in a separation from the apoptotic cell. These bodies are membrane bound and contain cytoplasm and packed organelles.
What happens to the apoptotic bodies?
they are phagocytosed by resident macrophages or adjacent parenchymal cells.
What would the cytoplasm of an apoptotic cell look like under the microscope?
it would be intensely eosinophilic.
what is a DNA ladder?
DNA in the apoptotic cell is cleaved in specific areas by a calcium dependant endonuclease. these fragments are all approx. the same length and appear as a ladder in an electrophoretic gel.
What role does transglutaminase have in apoptosis?
transglutaminase crosslinks cytoplasmic proteins and forms a shell under the plasma membrane. In this way it mediates cell shrinkage and body formation.
What do these 3 genes have in common: caspases, Bcl gene family, Apaf-1?
they are all genes that are essential in the control of cell death via apoptosis.
What is so special about caspase-3?
caspase-3 is a terminal caspase: once it is activated the cell will undergo apoptosis.
How is the Bcl-2 family involved in apoptosis?
the balance between pro and anti-apoptotic family members controls the decision on whether to undergo apoptosis or not
describe (in general) the pathobiology of apoptosis. (4 steps)
1. protein cleavage

2. protein cross-linking

3. DNA breakdown

4. phagocytosis
DNA cleavage during apoptosis is mediated by?
TNF-a and fas ligand are great examples of what kind of apoptosis?
receptor mediated apoptosis
Where is TNF-a found vs. where fas is found?
TNF-a is found as a free cytokine. fas is found in the plasma membrane
How do TNF-a and fas ultimately mediate apoptosis?
they activate the caspases
how do killer lymphocytes mediate apoptosis?
killer lymphocyte recognizes a cell as foreign. It binds to the cell membrane and uses a perforin to punch a hole in the plasma membrane. It then releases granzyme-B into the cell, granzyme goes on to activate the caspase-8.
Where do proteins of the Bcl family reside and why is this crucial?
They reside in the mitochondrial inner membrane. When balance leans towards the pro-apoptotic members they activate the caspase cascade inside the mitochondrion. Damage to the mitochondrial membrane for sure results in cell death.
1. mitochondria can mediate apoptosis by releasing what?

2. What is a classic activator of mitochondrial mediated apoptosis via this pathway?
1. cytochrome-c, once released, activates Apaf-1, which activates caspase-9.

2. ROS
1. What is the function of p53?

2. what happens when there is a mutation in p53?
1. p53 functions to identify mutations in DNA. If the mutation cannot be repaired p53 signals the cell to undergo apoptosis.

2. defective p53 drives the development and progression of cancer
What are four mechanisms that always result in cell death?
1. oxygen and ROS

2. intracellular Ca++

3. ATP depletion

4. defects in membrane permeability
How does increased intracellular [Ca++] lead to cell death?
Ca++ activates:
1. phospholipases (destruction of cell membrane)

2. proteases

3. ATPases (causes ATP depletion)

4. endonucleases
Activation of...
1. ATPases
2. Phospholipases
3. proteases
4. endonucleases
...results in?
1. ATP depletion

2. loss of plasma membrane integrity

3. disruption of membrane and cytoskeletal proteins

4. nuclear chromatin damage
How does hydrogen peroxide form free radicals?
via the Fe2+ catylized Fenton reaction
How is the superoxide anion generated?
mainly via leaks in the electron transport chain
What is dangerous about the superoxide anion?
It goes on to create other ROS
How are lipid peroxide radicals generated?
these radicals are produced during lipid peroxidation
What ROS is generated by macrophages and neutrophils during respiratory burst accompanying phagocytosis?
Hypochlorous acid (HOCL). Dissociates to yield hypochlorite radical (OCl-)
1. What is the most reactive ROS molecule?

2. What are the 3 ways it damages a cell?
1. Hydroxyl radical

2. lipid peroxidation
protien alteration
DNA damage and repair
What are four cellular defenses against ROS?
1. superoxide dismutase

2. catalase

3. glutathione peroxidase

4. vitamins E, C and retinoids
What makes reperfusion so devastating in an I/R injury?
reperfusion results in an excess of oxygen - this results in lots of ROS.
What is the role of hypoxanthine/xanthine in ischemic conditions?
formation of a superoxide anion
Which ROS can the (NO radical) be converted to? What is "special" about this one?
peroxynitrite (ONOO) - a major mediator of tissue damage with high oxidative power.
I/R injury leads to the release of cytokines. What do these cytokines do? (3 things)
1. promote vasoconstriction

2. stimulate adherence of inflammatory cells and platelets to endothelium.

3. produce a systemic effect.