Exam 1 (Chapters 1-4) Clinical Scenarios and Notes Flashcards
1
Q
Linkage Disequilibrium
A
Neutral and non-neutral SNPs causing the genetic factor
2
Q
Difference between SNP and CNV
A
SNPs are single nucleotide positions, but CNV can involve 1000-1 million base pairs
3
Q
Epigenetics
A
Heritable changes in gene expression not caused by alterations in DNA sequence
4
Q
Chromatin Writer Complexes
A
Methylation, Acetylation, and Phosphorylation
“Mark” the histones
5
Q
Naked DNA is ____ long, packed down to be ____
A
1.8 m
7-8 micrometers
6
Q
Pathway of miRNA
A
MiRNA –> pri-miRNA –> pre-miRNA (exits the nucleus) –> DICER –> miRNA –> splits and joins RISC complex
Always causes gene silencing
7
Q
Actions of the Long Noncoding RNA (lncRNA)
A
Gene activation
Gene suppression
Promote chromatin formation
Assembly of protein complexes
8
Q
XIST is an example of:
A
LncRNA actions
Inactivated X chromosomes physiologically
9
Q
Phosphatidylserine is responsible for:
A
- changing platelet shape
- flips to extracellular surface during apoptosis
10
Q
Phosphatidylinositol is responsible for:
A
- scaffolding on the inner membrane
- generates secondary signals like DAG and IP3
11
Q
What is flippase responsible for?
A
Maintains asymmetry of the plasma membrane
12
Q
Insertion of proteins into the membrane may happen with these types of anchors?
A
Glycosylphosphatidylinositol (GPI) anchors
13
Q
Glycocalyx
A
Chemical and mechanical barrier between cells - made up of carbohydrates
14
Q
Caveolae-mediated endocytosis:
A
SMALL molecules taken up by invagination
Major protein: calveolin
Subset: POTOCYTOSIS
15
Q
Receptor mediated endocytosis:
A
BIG molecules taken by binding surface receptors and internalized
Major protein: clathrin proteins –> form a clathrin coated pit –> clathrin coated vacuole –> bind to an endosome, then lysosome
Subset: PINOCYTOSIS
16
Q
Which receptor-mediated pathway aides in increased vascular permeability?
A
Transcytosis
17
Q
Process of Phagocytosis
A
Invagination of membrane (to engulf microbe, etc)
Formation of phagosome
Combines with lysosome –> phagolysosome
Dumps out digested material
18
Q
Actin Microfilaments
A
G-actin is the MOST ABUNDANT cytosolic protein
Muscle cells: myosin binds to actin
Non-muscle cells: controls shape and movement
19
Q
Intermediate Filaments
A
Mainly: Structural proteins (hair and skin)
20
Q
Lamin A, B, C
A
Important for nuclear transcription
21
Q
Vimentin
A
Fibroblasts and other mesenchymal cells
22
Q
Desmin
A
Muscle cells, form the scaffold for myosin/actin
23
Q
Neurofilaments
A
Axons of neurons, giving strength and rigidity
24
Q
Glial fibrillary acidic proteins
A
Glial cells around neuron
25
Microtubules
Alpha and beta tubulin with positive and negative ends
Serves as connecting cables for motor proteins
26
Different Types of Desmosomes
Spot Desmosome: (macula adherens) rivet-like adhesion, small
Hemidesmosome: spot des that attaches basement membrane
Belt Desmosome: broad bands of attachment
27
Transmembrane Glycoproteins b/t Desmosomes
All fall under the category of cadherins:
1. Spot: desmogleins and desmocollins
2. Belt: E-cadherins **
3. Hemi: integrins
28
Focal Adhesion Complexes
Associated with hemidesmosomes and generate signals in response to increased shear stress
29
Communicating (or gap) Junctions rely on:
Connexons (pores) and Connexins (transmembrane proteins)
**especially important for cardiac myocytes**
30
In which cells are the Golgi most prominent?
Goblet cells, bronchial epithelium, and plasma cells
31
What part of the mitochondria is responsible for ATP synthesis?
Inter membrane space (between the two membranes)
32
Thermogenin
Inner membrane protein that creates heat and energy production
33
Warburg Effect
Makes it so that mitochondria doesn't need ATP
Up regulates glucose/glutamine uptake and decreases production of ATP
34
Examples of Receptor Tyrosine Kinases:
RAS, RAF, MAPK
35
Examples of Non-Receptor Tyrosine Kinases:
JAK/STAT, Src Family
36
Notch Family Receptors responsible for:
Proteolytic cleavage of the receptor and translocation to the nucleus
37
Wnt Protein Ligands responsible for:
Attached to Frizzled receptors --> regulates B-catenin
| Recruits Disheveled --> prevents degradation of B-catenin
38
Transcription Factors and Genes related to growth:
MYC and JUN: needed for growth
| P53: needed for growth arrest
39
Which growth factors are involved in angiogenesis?
VEGF and FGF-2 (basic)
40
TGF-beta is most important for:
Scar formation - production of collagen
| Anti-inflammatory
41
Components of Basement Membrane
Type 4 collagen, laminin, proteoglycan
42
Components of Interstitial Matrix
Fibrillar collagens, elastin, proteoglycan/hyaluronan
43
Marfan Syndrome
Caused by defects in fibrillin --> skeletal abnormalities and weakened aortic walls
44
What two checkpoints are in the cell cycle?
G1 --> S: no bad DNA into cell cycle
| G2 --> M: no bad DNA out of the cell cycle and into mitosis
45
Two important properties of stem cells?
Self-renewal and asymmetric division
46
Hypertrophy Example and Definition
Increase in cell SIZE
Ex: muscle cells, *uterus during pregnancy*, caridac hypertrophy
47
Steps of Cardiac Hypertrophy
1. Mechnical sensors
2. Signal transduction --> PI3K/AKT Pathway and GPCR
3. Transcription Factors --> GATA4, NFAT, MEF2
48
Hyperplasia Example and Definition
Increase in cell NUMBER
Ex: Physiologic --> hormonal and liver hyperplasia
Pathologic --> endometrial (may lead to cancer)
49
Atrophy is caused by:
Decreased protein synthesis AND increased protein degradation
50
Proteins are degraded (in atrophy) by:
Ubiquitin-proteasome pathway
51
Metaplasia Example and Definition
Reprogramming of cells to a different cell type
Ex: *most* go from columnar --> squamous BUT Barrett's Esophagus goes from squamous --> columnar due to GERD
52
What parts of cell death are reversible?
All features of cellular swelling and reduced oxidative phosphorylation
53
Changes you can see under a light microscope:
Cellular swelling and fatty change
54
Gross morphologic changes:
Apoptosis and Necrosis
55
Basic steps of necrosis:
1. Membrane breaks down and releases contents --> inflammation
2. Enzymes from lysosome digest the cell
3. Increased eosinophilia (pinker cells)
4. Nuclear changes
5. Tissue necrosis
56
Nuclear Changes in Necrosis
Pyknosis (shrinking) --> karyorrhexis (fragments) --> karyolysis (loss of DNA)
57
Coagulative Necrosis
Tissues keep their shape but lose their nucleus
Caused by ISCHEMIA
Ex: vegetations, infarcts, can happen almost anywhere (except brain)
58
Liquefactive Necrosis
Cells turn to liquid mass due to hypoxic death - from bacterial/fungal infection
Ex: BRAIN
59
Gangrenous Necrosis
Caused by loss of blood supply (usually due to diabetes or infection)
Wet vs dry gangrene (hard to tell them apart...)
60
Caseous Necrosis
Typically seen in tuberculosis in the lung (cheese-like, white)
Necrotic area may appear as a granuloma
61
Fat Necrosis
Due to release of activated pancreatic lipases
Happens on the OUTSIDE of the pancreas (chalky white, saponification)
62
Fibrinoid Necrosis
Seen in immune reactions involving blood vessels
Ex: malignant hypertension and vasculitis, pre-eclampsia
63
Hallmark of irreversible damage:
Plasma membrane damage!
64
Dystrophic Calcification
If necrosis doesn't include phagocytosis, becomes calcium deposition
Ex: psammomas, saponification
65
Structural protein responsible for further opening the mitochondrial pore?
Cyclophilin D --> this can be stopped by cyclosporine (immunosuppressive)
66
What does Cytochrome C do?
Works in the mitochondria and activates caspases (increases permeability)
67
How do you remove free radicals from the body?
1. Antioxidants
2. Free iron and copper
3. Associated enzymes
68
Pathologic effects of free radicals:
1. Lipid peroxidation (membrane damage)
2. Oxidative modification (structural damage)
3. Lesions in DNA (oncogenesis)
69
Hypoxia Inducible Factor 1
- In cells to protect against hypoxia
- Uses endothelial growth factor
- promotes angiogenesis
70
Treatment for Ischemia?
Transient induction of hypothermia to reduce metabolic demands
71
Where does chemical injury usually take place?
LIVER
72
Physiologic situations of apoptosis
1. Destruction during embryogenesis
2. Upon withdrawal of hormone on tissues (endometrium, breasts)
3. Maintaining homeostasis
4. Elimination of lymphocytes
73
Pathologic situations of apoptosis
1. DNA damage
2. Misfolded proteins
3. Infections causing cell death
4. Atrophy after duct obstruction
74
Important features of the intrinsic apoptotic pathway:
MITOCHONDRIAL - major mechanism!
Genes: anti-apoptic (prevents cytochrome C from leaking out) --> BCL2, BCL-XL, MCL1
pro-apoptotic (promote permeability) --> BAX/BAK
Cytochrome C --> binds APAF-1 --> activates caspase 9
75
Important features of extrinsic apoptotic pathway:
PLASMA MEMBRANE - death receptors
Due to TNF/FasL binding to FADD (death domains) --> activates caspase 8 and 10 --> execution phase
76
What caspases are activated in the execution phase of apoptosis?
Caspase 3 and 6
| DNase cleaves DNA
77
Diseases that cause unfolded protein response:
```
Cystic fibrosis - loss of CFTR
Hypercholesteremia - loss of LDL
Tay-Sachs - lysosomal storage disease
Alpha-1 antitrypsin - storage nonfunctional protein
Creutzfeldt-Jacob - prions
Alzhemiers - AB peptides
```
78
Steps of Autophagy
1. Atgs work under starvation
2. Nucleation causes phagophore
3. LC3 requires ubiquitin to make the autophagosome
4. Fuses with endosomes, then lysosomes, to make the autophagolyosome
5. degraded by lysosomal enzymes
79
Autophagy happens in these diseases:
Cancer, neurodegenerative, infections, and IBD
80
Storage Diseases
Caused by enzyme deficiency so metabolites cannot be degraded
81
How are Russell Bodies formed?
Proteins accumulate in excess with the synthesis of immunoglobulins and causes the ER to produce eosinophilic inclusions
82
Alpha-1 antitrypsin is caused by:
Slow, misfolding proteins aggregate in the ER in liver
Not having these in circulation causes emphysema
83
Exogenous Pigments
Most common is carbon --> causes anthacosis, coal worker's pneumoconiosis
Tattooing
84
Endogenous Pigments
Lipofuschin --> pigment of aging, seen in autophagy
Melanin --> black pigment
Hemosiderin --> excess gets taken up by macrophages
85
Metastatic calcification is caused by:
Hypercalcemia due to:
- PTH
- Resorption of bone
- Vitamin D disorders
- Renal failure
86
Werner Syndrome
Premature aging due to defective DNA helicase
87
Bloom Syndrome and Ataxia-Telangiectasia
Mutated genes encode proteins involved in double stranded DNA breaks
88
Job of the telomerase?
Somatic cells: absent most times
| Cancer cells: reactivated so that cells proliferate
89
Sirtuins
Promote expression of genes to increase longevity
| done by reducing caloric intake
90
How does IGF-1 relate to longevity?
Reduced IGF-1 and insulin increases longevity
| can do this by reducing caloric intake
91
Acute Inflammatory Disorders
ARDS, Asthma, Glomerulonephritis, Septic Shock
92
Chronic Inflammatory Disorders
Asthma, Arthritis, Atheroscleroisis, Pulmonary Fibrosis
93
What did John Hunter do?
Said inflammation itself is not a disease, just a response to a disease
94
Who discovered phagocytosis?
Elie Metchnikoff
95
What did Sir Thomas Lewis discover?
Chemical substances mediate inflammation
96
Receptors that detect microbes?
TLRs (recognize PAMPs) on Macrophages and DCs
Trigger production of inflammatory cytokines and adhesion molecules
97
Receptors that detect cell damage?
Detect things like uric acid, ATP, and reduced K+
Activate the inflammasome complex to trigger inflammatory cytokines
98
Autoinflammatory Syndromes
Caused by hyper-sensitive receptors for IL-1
Treated with IL-1 inhibitors
99
Which protein does the opsinization?
Mannose-binding lectin
100
Primary stimulator of vasodilation in inflammation?
Histamine
101
Common cause of death secondary to severe burns?
Excessive fluid loss due to increased vascular permeability
102
Difference between lymphagitis and lymphadenitis?
Lymphagitis - inflammation of lymphatic vessels
Lymphadenitis - inflammation of lymph nodes
BOTH are secondary to infection
Presents with RED STREAKS around the wound
103
What two proteins come from Weibel-Palade Bodies?
vWF and P-Selectin
*think about the W and P in the name!*
104
What activates all of the integrins?
TNF and IL-1
| and also LTB4 and C5a
105
Which molecule in responsible for diapedesis/migration of leukocytes?
PECAM-1
106
Which enzyme is used for leukocytes to break through vascular wall?
Collagenase
107
What types of cells do you see with bacteria/virus/allergies?
B: neutrophils
V: lymphocytes
A: eosinophils
108
Most frequently targeted molecule for drugs against chronic inflammation?
TNF
109
Different types of receptors on phagocytes:
Mannose: detect bacteria
Scavenger: LDLs, microbes
Opsonin: detects IgG, C3b, MBL
TLRs: LPS on bacteria
110
Once bound to the receptor, the phagocyte wraps around the microbe forming a _____ which then forms ____
Pseudopod --> vacuole --> phagolysosome
111
What substances do phagocytes use to kill/degrade?
ROS, reactive nitrogen species, and lysosomal enzymes
112
What reaction is myeloperoxidase (MPO) responsible for?
Converting hydrogen peroxide + Cl --> HOCl- (hyperchlorite)
This is an antimicrobial agent and only happens in the neutrophil
113
Most efficient system for killing bacteria?
H2O2-MPO-halide System in neutrophils
114
Which AA is primarily responsible for NO production?
Arginine
115
Process of using a Neutrophil Extracellular Trap (NET)?
Neutrophils use their own chromatin to form the NET and trap pathogens and inflammatory mediators
Neutrophils will die after this process
116
What is the consequence of frustrated phagocytosis?
Phagocytes release all of their lysosomal enzymes causing severe inflammation
117
How do urate crystals cause inflammation?
They can break open phagolysosomes and have them release their enzymes
118
Anti-inflammatory cytokines?
IL-10 and TGF-beta
119
Important things about Histamine
Actions: vasodilation and increased vascular permeability
*First to be released during inflammation*
Activated by C3a and C5a, Substance P, IL-8/IL-1
120
What stimulates production of Arachidonic Acid?
C5a and Phospholipase A2
121
Which prostaglandin is responsible for producing pain and fever?
PGE2
122
What is LTB4 specifically responsible for?
Chemotaxis of leukocytes (adhesion and activation)
123
What are lipoxins responsible for?
These will inhibit inflammation (LXA4 and LXB4)
124
Local vs Systemic effects of cytokines?
Local: adhesion molecules
Systemic: IL-1 and TNF produce fever
125
Generally, what is Platelet Activating Factor used for?
Vasodilation and Increased Vascular Permeability
**at high levels, can cause vasoconstriction**
126
Actions of bradykinin?
Increases vascular permeability, vasodilation, and PAIN
127
What do Protease Activated Receptors (PARs) do?
Activate platelets in the clotting response
| activated by thrombin
128
Thromboxane A2 (TxA2)
VASOCONSTRICTION
Causes platelet aggregation
129
Examples of COX inhibitors and what they do:
Ibuprofen and Aspirin
MOA: Inhibits both COX-1 and 2
130
Problems with COX-2 inhibitors?
Good because they prevent side effects like gastric ulcers but bad because they can increase chance for strokes
131
What are lipoxygenase inhibitors used for?
Asthma (Zileuton inhlaers)
132
Mechanisms of Corticosteroids
Broad-spectrum, anti-inflammatory drugs
Reduce the transcription of genes for mediators
133
What does TNF do?
Increase endothelial adhesion
Increase secretion of cytokines
Causes cachexia (muscle wasting and decreased appetite)
134
Acute inflammation cytokines:
TNF, IL-1, IL-6, Chemokines, IL-17
135
Chronic inflammtion cytokines:
IL-17, IL-12, IFN-gamma
136
Which cytokine is responsible for the initiation of acute or chronic inflammation?
IL-17
137
3 pathological effects of too much TNF?
Low cardiac output
Formation of thrombus/increased permeability
Insulin resistance
138
CXC Chemokines
Primarily act on neutrophils, produce IL-8
139
Examples of CC Chemokines?
MCP-1, Eotaxin, MIP-1-A, RANTES
140
Examples of C Chemokines?
Lymphotactin (lymphocytes only)
141
Examples of CX3C Chemokines?
Fractalkine (mono and T cells) for adhesion and chemotaxis
142
Difference in the 3 complement pathways:
Classic: C1 binds to IgM or IgG (*GM makes classic cars*)
Alternative: microbe binds directly to C3
Lectin: MBL attaches to microbe and activates C1
In all of these, C3 is cleaved
143
Congenital abnormalities related to the complement system:
No C1 inhibitor (C1 INH): hereditary angioedema - body can't downregulate C1
No GPI anchor proteins: results in excessive C3 and MACs --> paroxysmal nocturnal hemoglobinuria (PNH) which destroys RBCs
144
Classic example of fibrous inflammation?
Heart! Due to extreme vascular permeability and pro-coagulant stimulus
Leads to scarring and organization of fibrin
145
Morphology of an Abscess
**acute inflammation**
Core of necrotic leukocytes
Outer ring of neutrophils
Surrounded by healing vascularized tissue
146
Causes of chronic inflammation?
Infection, hypersensitivity, and exposure to toxins
147
3 roles of the macrophage in chronic inflamamtion?
Secrete: cytokines, growth factors
Destroy: microbes and healthy tissue
Activate: T cells
148
Which lymphocyte most important for inflammatory response?
CD4+ T Cell
149
What chemical do eosinophils release when stimulted?
Major Basic Protein (lysis of parasitic cells and healthy cells)
150
2 inflammatory mediators that come from mast cells?
Histamine and Prostaglandins
151
Neutrophils are recruited by what?
C5a, LBT4, IL-8, and bacterial products
152
In what conditions do neutrophils play a role in chronic inflammation?
Osteomyelitis and Lungs of Long-tern Smokers
**this is called the acute-on-chronic response**
153
What do Th1 produce?
IFN-gamma to activate M1 macrophages
IL-2 to activate CD8+ T cells
Responds to intracellular pathogens
154
What do Th2 produce?
IL-4, 5, 13 to activate M2 macrophages
IL-5 also helps B cells
IL-10 to inhibit M1 formation
Important for Eosinophils to kill helminthes/allergies
155
Examples of foreign body granulomas?
```
Talc granulona (drug users)
Sutures with surrounding granuloma
```
**no T-cells in these**
156
Most important caseating necrosis granuloma?
Tuberculosis - if you see a granuloma, need to rule this out!
157
How does cat scratch fever present?
With a round/stellate granuloma, usually around the neck
158
Most common granuloma in the US?
Chrohn's Diseasei
159
Which cytokines produce the acute phase response?
TNF, IL-1, IL-6, Type 1 Interferons
160
Production of a Fever
Microbial products (LPS) --> IL-1 and TNF from M1's --> increase COX-1 and 2 --> PGE2
161
Types of Acute Phase Proteins
CRP --> predictor of heart attack
Fibrinogen --> form rouleaux --> ESR
Serum amyloid (SAA) --> secondary amyloidosis
Hepcidin --> binds iron, leads to anemia
162
What is an acute phase response?
Systemic response to infection or trauma
163
Of the stable tissues, which organ is best at regenerating?
Liver
| but the kidney can do some regenerating too - mostly hypertrophy
164
Types of permanent tissues:
Neurons, cardiac, and skeletal muscle
These will scar extensively
165
Phases of Liver Regeneration
1. Kupffer cells release IL-6
2. TGF-alpha and HGF push hepatocytes into cell cycle
3. Hepatocytes return to quiescence
166
Liver repopulation from progenitor cells:
These cells are called oval cells - in the Canal of Hering
| Only happens if the hepatocytes are damaged
167
When can't the liver regenerate?
When the whole liver is damaged or there is a liver abscess
168
Scar Formation 1: Angiogenesis
Growth factors needed: VEGF, FGF-2, PDGF, and TGF-B
Pericytes separate from the abluminal surface to allow new vessel to sprout
Notch pathway ensures proper spacing
169
Scar Formation 2: Granulation Tissue
Includes migration/proliferation of fibroblasts and the deposition of ECM proteins
Mediators: ***TGF-B***, PDGF, FGF-2 (from M2)
170
What causes a scar to contract?
Myofibroblasts - fibroblasts that have acquired muscle features
**this only happens in secondary union**
171
Scar Formation 3: Connective Tissue
```
Scar loses vascularization
MMPs (membrane metalloproteinase) - NEED ZINC
- Collagenases
- Gelatinases
- Stromelysins
```
172
How are MMPs activated/inhibited?
Activated by plasmin cofactor
| Inhibited by TIMPs (tissue inhibitors of MMPs)
173
Dehiscence means:
Tearing open of a wound due to mechanical factors (often happens in abdominal procedures)
Happens because of inadequate granulation or scar formation
174
When does healing by primary union/first intention take place?
Shallow injurys only involving the epithelial layer - used for suturing - causes minimal scarring
175
When does healing by secondary union/second intention take place?
More extensive injuries - involves parenchyma and ischemic necrosis
Examples: abscess, ulceration, and infarction
176
Wound strength stops increasing after how long?
3 months - usually about 70-80% of the strength returns
177
Hypertrophic Scar vs Keloid
Hypertrophic scar: any raised scar, made up of type I collagen
Keloid: much larger, type III collagen (African Americans are predisposed to this)
178
Proud Flesh Disorder
Occurs when there is excess granulation and has a red color to the epithelium
May occur due to excessive action of fibroblasts --> Desmoids or Agressive Fibroblasts
179
Causes of impaired venous return:
CHF, pericarditis, ascites, venous obstruction
180
Causes of arteriolar dilation:
Heat, neurohumoral dysregulation
181
If you have decreased albumin synthesis or loss of albumin, it leads to:
Reduced plasma osmotic pressure
Caused by: severe liver disease (reduced albumin) or nephrotic syndrome (albumin loss)
182
Most important cause of renal hypoperfusion:
Congestive Heart Failure
183
What happens when lymphatics are obstructed?
Lymphedema
Caused by: elephantiasis, breast cancer
184
Characteristic sign of renal disease:
Periorbital Edema (swelling of the eyelids)
185
Hyperemia vs Congestion
Hyperemia: ACTIVE -increased blood flow
Congestion: PASSIVE - reduced outflow of blood from a tissue - appears red/blue
186
Chronic Passive Hepatic Congestion causes:
Nutmeg Liver - due to centrilobular hemorrhage
| **will also see hemosiderin-laden macrophages**
187
Steps of Hemostasis:
1. Vasoconstriction
2. Primary hemostasis
3. Secondary hemostasis
4. Clot stabilization and resorption
5. Thrombus and antithrombolytic events
188
Where do platelets come from?
Anucleated cell fragments from megakaryocytes which are NOT found in blood
189
Alpha granules release:
P-selectin
190
Delta (or dense) granules release:
ADP, ATP, calcium, serotonin, epinephrine
191
Disorders in Platelet Adhesions
Problems with vWF: Von Willebrand Disease
Problems with GpIb: Bernard-Soulier Syndrome
Problems with GpIIb/IIIa: Glanzmann Thrombasthenia
192
Prothrombin Time (PT) measures:
EXTRINSIC PATHWAY
Needs tissue factor, calcium, and phospholipids
193
Partial Thromboplastin Time (PTT) measures:
INTRINSIC PATHWAY
Needs negative charged particles, calcium, and phospholipids
194
Factor XI Deficiency
Mild bleeding
195
Factor XII Deficiency
NO bleeding - susceptible to thrombosis
196
Actions of thrombin:
Conversion of fibrinogen to fibrin
Platelet activation
Pro-inflammatory effects
197
Most common factor to be inhibited:
Factor VIII!
198
Vitamin K is required for which factors?
"1972": X, IX, VII, and II
199
Fibrinolysis
Needs plasmin to break down fibrin into fibrinogen and D-dimers (breaks down formed clots)
Gets plasmin from tPA
200
Anticoagulant Effects on the Endothelium
1. Thrombomodulin and Protein C will bind to thrombin along with Protein S --> inhibits thrombin --> no clotting
2. Heparin-like molecules activates anti-thrombin III to inhibit thrombin
3. Tissue factor pathway inhibitor (TFPI) blocks the clotting cascase and uses Protein S
201
Defects of Primary Hemostasis
Caused by platelet defects or vWF disease
Presents with petechiae, purpura, and sometimes epistaxis, GI bleeding, menorrhagia
202
Defects of Secondary Hemostasis
Caused by coagulation factor defects
Presents with soft tissue bleeds --> hemarthrosis
203
Consequences of turbulence and stasis:
Promote endothelial activation --> procoagulation
Disrupt laminar flow
Prevent dilution/washing away
204
Primary Disorders causing Hypercoagulability
Factor V Leiden Mutation --> inactivated Protein C
Prothrombin Mutation --> increased prothrombin in circulation so more clotting
Homozygous Homocystinuria --> cystathione B-synthase deficiency
205
Heparin-Induced Thrombocytopenia (HIT)
Caused by unfractionated heparin --> antibodies bind to heparin/platelet complex causing clots and thrombocytopenia
Commonly presents with PE
Need low MW heparin
206
Antiphospholipid Antibody Syndrome
Presents with recurrent clots, miscarriages, cardiac valve vegetations
Can be primary (hypercoagulable state) or secondary (to autoimmune)
Treatment: anticoagulation and immunosuppresion
207
Mural Thrombi
Most likely found in the heart or the aorta
Prone to embolization
208
Red Thrombi refers to:
Venous thrombi (they have more RBCs)
Can be either superficial (saphenous v) or deep (DVT)
209
Cardiac Valve Vegetations
Thrombi located on the heart valves - often due to bacterial infection
210
Steps of Thrombus Fate:
1. Propagation: accumulates platelets and fibrin
2. Embolization: dislodges and travels
3. Dissolution: fibrinolysis
4. Organization and recanalization: older thrombi can grow into the endothelium (first vessels will form, then it will just become connective tissue)
211
Disseminated Intravascular Coagulation (DIC)
Presents with increased PT, PTT, and D-dimers
Begins as a clotting disease until the factors are consumed and it turns to hemorrhaging
Important: may see oozing from an IV, schistocytes on a slide, sepsis
212
95% of Pulmonary Embolism come from where?
DVTs!
Most are clinically silent, but can lead to pulmonary hypertension and right ventricular failure if there are multiple
213
Where do most (80%) of systemic emboli arise from?
Intracardial Mural Thrombi (most of which are associated with left ventricular wall infarcts)
Most end up in the lower extremities (75%) and result in tissue infarction
214
Fat and Marrow Embolism
Mostly comes from vigorous CPR that breaks a rib bone and sends marrow into the blood
10% of people have fat embolism syndrome and presents with pulmonary insufficiency, neurologic symptoms, anemia, thrombrocytopenia
215
What results from decompression sickness?
Can get the bends (nitrogen coming out of solution creating air bubbles) or the chokes (respiratory distress with edema, hemorrhage, and atelectasis)
216
Caisson Disease
Gas emboli in the skeletal system leading to ischemic necrosis
Chronic form of decompression sickness
217
Amniotic Fluid Embolism
Mostly occurs either during labor or right after
NOT caused by obstruction, it is caused by immune system and infusion of fetal tissue into maternal circulation
218
Red vs White Infarcts
Red - named for it's color, usually happens with venous obstruction (torsion) and in organs with dual supply
White - mostly arterial occlusions, in organs with end-arterial circulation
219
Septic Infarctions
Caused by infected cardiac valve vegetations embolized
These infarcts are converted to abscesses and have a large inflammatory response
220
Factors that Influence Infarcts
1. Amount of vascular supply
2. Rate of occlusion (slow is better for survival)
3. Tissue vulnerability to hypoxia
4. Hypoxemia
221
Shock associated with systemic inflammation is caused by?
Bacterial infection or superantigens
222
Septic Shock caused mainly by:
Gram-positive bacterial infection
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Factors of Septic Shock
Endothelial activation --> becomes leaky
Procoagulant state --> may see DIC in 50%
Metabolic --> insulin resistance and hyperglycemia to inhibit neutrophils
Organ failure --> ARDS
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Three Stages of Shock
1. Nonprogressive stage - sympathetic discharge (catecholamines), compensatory mechanisms
2. Progressive stage - tissue hyperperfusion, lactic acidosis, anaerobic metabolism
3. Irreversible stage - survival is not possible because of extensive damage
