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116 Cards in this Set
- Front
- Back
hemostasis definition
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arrest of hemorrhage following vascular injury
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what are the 2 paths of the coagulation cascade
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1) Intrinsic cascade. FXII contacts thrombogenic surface.
2) Extrinsic cascade: blood is exposed to extravascular (subendothelial) tissue factor (TF) |
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Coagulation, generally
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conversion of soluble plasma fibrinogen to insoluble fibrillar polymer fibrin, catalyzed by thrombin
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What is probably the most important factor in thrombus progression and stabilization?
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Thrombin production
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Steps to know in clotting cascade
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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 |
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What is vWF?
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Von Willebrand factor enhances platelet adhesion by binding both to platelet membrane and fibrinogen
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What do activated platelets do?
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1) release granule contents (ADP, TxA2) that recruits more platelets and promotes aggregation
2) other factors released promote clotting cascade and thrombus formation |
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What does endothelium do to regulate the thrombus?
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releases NO and PGI2 (prostacyclin), which INHIBIT platelet aggregation
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Descibe hemophilia A
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1) inherited coagulopathy
2) MOST COMMON X-linked recessive inherited bleeding disorder 3) absent/low F XIII 4) spontaneous bleeding into joints, muscles, organs |
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Describe hemophilia B
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1) less common X-linked recessive bleeding disorder
2) clinically indistinguishable from type A 3) "Christmas disease" |
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Describe vWD
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1) the MOST COMMON HEREDITARY BLEEDING DISORDER
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 |
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Incidence of acquired coagulopathies
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GREATER than that of the inherited coagulopathies (hemophilia, vWD)
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Vitamin K deficiency
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1) decrease in a bunch of factors (II, VII, IX, X)
2) malapsorption in the gut of stuff |
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Liver disease and coagulopathy
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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 |
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Characteristics of DIC
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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
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General cauases of DIC
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1) tissue injury
2) endothelial cell injury |
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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 |
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what is the most common cause of death in western industrialized countries?
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arterial thrombosis, with the complication of embolization
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what is effusion
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excess fluid in body cavities
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definition of embolism
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vascular obstruction by a non blood mass traveling in the blood stream
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What are some plasma derived mediators of edema?
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1) Hageman factor (triggers clotting system), triggers bradykinin production
2) Complement activation system (C3a, C5a) |
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Materials able to cause embolism
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thrombus air amniotic fluid fat atheromatous debris foreign objects tumor
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What are some cell derived mediators of edema?
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1) Histamine (mast cell degranulation)
2) platelets (serotonin) 3) inlfammatory cells (PAF, PG, Leukotrienes) 4) Endothelium (NO, PAF, PGs) |
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Where can arterial emboli cause infarct
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(usually cardiac source, e.g. mural thrombi)
1) brain 2) intestine 3) lower extremeties 4) kidney 5) heart |
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What is transudate?
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edema fluid with LOW protein content
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Describe amniotic fluid embolism
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1) uncommon but lethal childbirth complication
2) sudden dyspnea, hypertension, SCA 3) ebolization of fetal material/debris 4) associated with DIC and ARDS |
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What is exudate?
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edema fluid with HIGH protein content
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what is fat embolism associated with
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bone fractures
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what cells are responsible for organizing a thrombus? how?
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Phagocytes: injest thrombotic material
Fibroblasts: replace it with fibrosis |
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name some signs of greater thrombus reorganization
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clefts form in the thrombus, line themselves with endothelial cells! meanwhile fewer nucleii are seen inside the thrombus.
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what things can happen to a thrombus after formation (Evolution)?
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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 |
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Simplified clot cascade steps
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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 |
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what does hageman factor activation cause?
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(=factor XII) kinin generation
clot formation anaphylatoxin generation (via complement cascade) fibrin degradation product formation (fibrinolyiss) |
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what does fibrinolysis do w/ vascular permeabilty?
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augments it
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how else does hageman factor increase vascular permeability?
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activates complement cascade, which produces anaphylatoxins (c3a, c5a) generates kinins (bradykinin)
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What is PAF? What does it do?
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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 |
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What are the platelet derived mediators?
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1) serotonin (-->inc vasc perm)
2) TxA2 (AA-->cyclooxygenasepath-->SM constriction 3) cationic proteins ( inc. vasc perm up) 4) histamine |
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What is sarcoidosis? what can be involved
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multisystemic disease of unknown etiology invovling noncaseating granulomatous infection in many organs, including: skin uveal tract hilar/mediastinal nodes bone marrow spleen liver lungs
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what does granulation tissue eventually do
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remodels into dense fibrous tissue
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In addition to sarcoidosis, what can cause granulomatous inflammation?
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fungal infection
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what is a characteristic of keloid microoscopicallly?
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wide, pink, accellular bands of stained collagen
not normal skin/dermis componenets Large, darkly staining fibroblasts |
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what is the major pathological process in viral myocarditis?
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chronic inflammation
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is infiltration with mononuclear leukocytes characteristic of acute, chronic, neither, or both viral myocarditis?
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BOTH
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Dysplasia, def
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1) abnormal appearing cells pleomorphism nuclear enlargment/irregularity hyperchromatism
2) disorderly arranged cells loss of polarity loss of maturation abnormal location of mitotic figures |
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Neoplasia, def
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abnormal growth of tissue excessive growth uncoordinated and autonomous
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histology of benign neoplasms
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resemble normal tissue histologically
well differentiated low mitotic rate generally well circumscribed does not metastasize |
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osteoma is...
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benign bone neoplasm
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chondroma
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benign Cartilage neoplasm
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Adenoma
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benign neoplasm of gland
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what are sarcomas?
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tumors that arise in CT like bone, muscle, fat
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where do carcinomas arise
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epithelium
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what age group are sarcomas more common in?
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kids/teens
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is dysplasia reversible?
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yes
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what is grading
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a HISTOLOGICAL determination of how differentiated tumor cells are compared to the tissue they came from
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what are the 3 parts of a cancer staging?
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tumor (0-4)
nodes (0-4) metastasis (0, +) |
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what is anaplasia
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very poorly differentiated neoplasm
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Rhabdo-
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skeletal muscle-derived
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leimyo-
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smooth muscle derived
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is leiomyoma at risk to turn into leiosarcoma?
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no
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how does tumor get from gut to liver
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hematogenous spread
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what is desmoplasia
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scarring response to tumor
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what is chronic myelogenous leukemia?
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cancer of white blood cells
due to bcr-abl tranlocation targeted by magic bullet gleevec |
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what are the pathological changes associated with coagulative necrosis?
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-General architecture is well preserved
-nuclear changes-pyknosis, karyorrhexis, karyolysis -eosinophilia |
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what is hemosiderin?
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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 |
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describe local hemosiderosis
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- local deposition of hemosiderin
- most often results from hemorrhage into tissue - hemosiderin derived from breakdown of Hb |
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describe systemic hemosiderosis
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- generalized deposition of hemodesirin w/o tissue damage
- may result from hemorrhage multi blood xfusion, excessive iron intake - often accompanied by alcohol consumption |
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describe hemochromatosis
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- 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 |
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what is lipofuscin?
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- 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 |
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coagulative necrosis is the most common underlying cause of infarct in all organs except....
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the brain, in CNS infarcts are due to liquefactive necrosis
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What nuclear changes occur during necrosis?
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karyolysis - fading of stainable chromatin
pyknosis - condensation of nucleus karyorrhexis - nuclear fragmentation |
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What cytoplasmic changes occur during necrosis?
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denaturation of proteins w/ maintenance of cell outlines (coagualtion necrosis)
enzymatic digestion of dead cells (liquefactive necrosis) |
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What are two major differences between necrosis and apoptosis?
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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. |
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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) |
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Describe pyknosis
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a process during necrosis in which the nucleus becomes smaller and stains deeply basophilic as chromatin clumping continues.
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When the rate of dissolution of cells is greater than the rate of repair, it is called ____________ necrosis.
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liquefactive
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What is the pathophysiology behind liquefactive necrosis.
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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.
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What portion of the body does fat necrosis specifically occur? Causes?
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occurs in and around the pancreas and small intestine. Caused by acute pancreatitis or trauma to the area.
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Pathophysiology behind fat necrosis?
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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. |
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What would fat necrosis look like under a microscope?
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basophilic deposits at the periphery of islands of necrotic adipocytes
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What is the mechanism behind caseous necrosis?
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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. |
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Fibrinoid necrosis refers to an alteration of ___________.
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injured blood vessels
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How are apoptotic cells disposed of?
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they are phagocytosed by surrounding cells or macrophages.
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1. what happens to the cell size during apoptosis?
2. what about chromatin? |
1. Shrinks
2. Chromatin condenses |
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this type of necrosis occurs in the brain following artery occlusion.
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liquefactive necrosis. (mechanism unknown)
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What is the most characteristic feature of apoptosis?
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chromatin condensation
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what is an apoptotic body and how is it formed?
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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.
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What happens to the apoptotic bodies?
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they are phagocytosed by resident macrophages or adjacent parenchymal cells.
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What would the cytoplasm of an apoptotic cell look like under the microscope?
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it would be intensely eosinophilic.
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what is a DNA ladder?
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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.
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What role does transglutaminase have in apoptosis?
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transglutaminase crosslinks cytoplasmic proteins and forms a shell under the plasma membrane. In this way it mediates cell shrinkage and body formation.
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What do these 3 genes have in common: caspases, Bcl gene family, Apaf-1?
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they are all genes that are essential in the control of cell death via apoptosis.
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What is so special about caspase-3?
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caspase-3 is a terminal caspase: once it is activated the cell will undergo apoptosis.
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How is the Bcl-2 family involved in apoptosis?
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the balance between pro and anti-apoptotic family members controls the decision on whether to undergo apoptosis or not
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describe (in general) the pathobiology of apoptosis. (4 steps)
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1. protein cleavage
2. protein cross-linking 3. DNA breakdown 4. phagocytosis |
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DNA cleavage during apoptosis is mediated by?
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endonucleases
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TNF-a and fas ligand are great examples of what kind of apoptosis?
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receptor mediated apoptosis
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Where is TNF-a found vs. where fas is found?
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TNF-a is found as a free cytokine. fas is found in the plasma membrane
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How do TNF-a and fas ultimately mediate apoptosis?
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they activate the caspases
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how do killer lymphocytes mediate apoptosis?
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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.
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Where do proteins of the Bcl family reside and why is this crucial?
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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.
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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 |
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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 |
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What are four mechanisms that always result in cell death?
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1. oxygen and ROS
2. intracellular Ca++ 3. ATP depletion 4. defects in membrane permeability |
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How does increased intracellular [Ca++] lead to cell death?
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Ca++ activates:
1. phospholipases (destruction of cell membrane) 2. proteases 3. ATPases (causes ATP depletion) 4. endonucleases |
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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 |
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How does hydrogen peroxide form free radicals?
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via the Fe2+ catylized Fenton reaction
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How is the superoxide anion generated?
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mainly via leaks in the electron transport chain
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What is dangerous about the superoxide anion?
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It goes on to create other ROS
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How are lipid peroxide radicals generated?
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these radicals are produced during lipid peroxidation
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What ROS is generated by macrophages and neutrophils during respiratory burst accompanying phagocytosis?
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Hypochlorous acid (HOCL). Dissociates to yield hypochlorite radical (OCl-)
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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 |
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What are four cellular defenses against ROS?
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1. superoxide dismutase
2. catalase 3. glutathione peroxidase 4. vitamins E, C and retinoids |
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What makes reperfusion so devastating in an I/R injury?
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reperfusion results in an excess of oxygen - this results in lots of ROS.
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What is the role of hypoxanthine/xanthine in ischemic conditions?
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formation of a superoxide anion
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Which ROS can the (NO radical) be converted to? What is "special" about this one?
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peroxynitrite (ONOO) - a major mediator of tissue damage with high oxidative power.
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I/R injury leads to the release of cytokines. What do these cytokines do? (3 things)
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1. promote vasoconstriction
2. stimulate adherence of inflammatory cells and platelets to endothelium. 3. produce a systemic effect. |