Important regulator for DIC is Hageman factor gram negative organisms have the ability to activate Hageman factor

r which functions on different pathways o activation of coagulation and fibrinolytic pathway DIC o complement o kinin system cleaves HMWK to bradykinin vasodilation, increased vascular permeability, pain like histamine + pain o regulators of pain are PGE2 and bradykinin o pain is caused by PGE2 and bradykinin sensitize the sensory nerve endings o rubor (redness) and warmth (calor) mediated by vasodilation vasodilation mediated by histamine, bradykinin, PGs o fever macrophages release IL-1 and TNF which will cause the expression of COX in the perivascular cells of the hypothalamus the COX will take arachidonic acid and convert it into PGE2 which will stimulate the hypothalamus to change the body neutrophil arrival and function acute inflammation can be broken down into 3 phases o fluid phase (first), neutrophil phase (peak at 24 hrs), then macrophage phase (peak 23days) o neutrophil rolling via sialyl lewis x on PMN binding to p-selectin and e-selectin on the endothelial cells p-selectin is located in the weibel-palady bodies with vWF and is stimulated by histamine e-selectin is expressed by release of IL-1 and TNF o TNF and IL-1 will also stimulate the upregulation of cellular adhesion molecules (CAMs) o Integrins on the PMNs and also macrophages will be upregulated by C5a and LTB4 Leukocyte adhesion deficiency AR disease of CD18 (subunit of integrin) Key finding is delayed separation of umbilical cord o After the placenta has been detached there is no more blood flow necrosis of umbilical cord mast cells to release histamine and start the inflammatory process If the neutrophils cannot cross into the tissue there will be no destruction of the umbilical cord Increased circulating PMNs o Marginated pool Which is 50% of PMNs in the body located in the lungs Normally its a pool of PMNs that are premade and attached to the endothelial cells of the lungs by adhesion molecule

If they are needed they can get called into the circulation In LAD there is a defect in Integrins that result in the marginating pool being released o Recurrent bacterial infections w/o pus Once macrophages come into tissue (2-3 days later) there can be 4 resulting processes o Resolution and healing (mediated via IL-10 and TGF-beta) o Increased acute inflammation Recruitment of more PMNs via IL-8 o Abscess formation (via INF-gamma) o Or chronic inflammation Ingestion of organism by macrophages will result in exogenous presentation of antigens via MHC II to Th cells Depending on the cytokines produced by macrophages will stimulate the T-helper cells to differentiate into Th1 or Th2 cells o If macrophages release IL-12 and NK cells release INF-gamma then the differentiation will be towards the Th1 side o If there is antigens is present extracellularly and there is little macrophage or NK cells stimulation then there will be differentiation of Th0 cells toward the Th2 response (via IL-4) 3 signals for activation of T-cells o TCR binds MHC o CD28 on T cell binds B7 on APC (CD4+ cells) IL-2 from CD4 cells will bind IL2R on CD8 cells o cytokines Chronic inflammation o Broken down into granulomatous and non-granulomatous o Determined by the presence of lymphocytes The macrophages will stimulate the lymphocytes to come into the tissue o This is determined by persistent infection o Viruses, mycobacterium, fungi, and parasites o Autoimmune diseases o Foreign material o Some cancers Granulomas o Key cell is epitheloid histiocyte (macrophages w/ abundant pink cytoplasm)

Activated macrophage by INF-gamma Aggregate o Usually giant cells are also seen and a rim of lymphocytes Defining feature is an epitheliod histiocyte Ddx of granulomas o Noncaseating (histiocytes still contain their nuclei) Rxn to foreign material, sarcoidosis, beryllium exposure, crohn disease, cat scratch disease (bartonella henselle causing stellate shaped granulomas) o Caseating granuloma (w/ central necrosis) TB and fungal infections (histo, blasto, coccidiodes, aspergillus) TB = AFB stain (acid-fast bacillus stain) Fungus = GMS stain (grocotts methenamine silver stain)

Immunodeficiencies o SCID 3 etiologies Adenosine deaminase def o Build up of adenosine and deoxyadenosine is toxic to lymphocytes Cytokine receptor defect Bare lymphocyte (no MHC II on cells) o X-linked agammaglobulinemia Defect in bruton tyrosine kinase (signaling molecule to convert immature B-cells into plasma cells) Present w/ a B-cell def after 6 mos of life resulting in recurrent bacterial, enterovirus, and giardia infections o Bacterial infections bc there an inability to opsonize (no IgG produced) o Enteroviruses bc IgA protects mucosal surfaces and enteroviruses infect the mucosal surface of the SI Also avoid live vaccines o Common variable immunodef Low Ig levels due to B-cell or helper T-cell defect Present in teens w/ giardia, enteroviruses, and bacterial infections increased risk for autoimmune disease and lymphomas o IgA def Presents w/ low serum and mucosal IgA Most common Ig def Increased risk for mucosal infections esp viral Can be present in celiac disease o Hyper IgM Defect in CD40-L or receptor Two ways a B-cell can get activated A nave B-cell can have an antigen bind to the IgM receptor

o Results in the B-cell becoming an IgM secreting plasma cell B cell can be an APC and present antigen to the T-cell via MHC II o The T-cell can then give the secondary signal and cytokines IL4/IL-5 to cause isotype switching resulting in plasma cells that secrete IgA, IgG, or IgE o This interaction is mediated by CD40-CD40L (second signal) Defect will result in low levels of IgG, IgA or IgE But IgM will be high because the 1st mechanism is still functioning o Wiskott-aldrich syndrome Triad of thrombocytopenia, recurrent infections, and eczema Increased risk of bleeding (petechia on the skin, mucosal membrane bleeding) o Variety of infections (B-cell and T-cell defect) X-linked o Mutation in WASP gene Autoimmune diseases o Affect 1% of the population o Etiology: Environmental trigger in a genetically susceptible person o SLE (systemic lupus erythematosus) Pt develops abs against tissue Abs bind directly to tissue (type II HSR) o The abs will activate complement which will recruit PMNs and cause tissue damage Abs-antigen complexes (type III) o Will deposit in tissues s/s: fever, weightloss malar butterfly rash especially on exposure to sunlight arthritis, pleuritis an pericarditis (all 3 due to immune complex depo) CNS psychosis Renal damage Most common cause of death in SLE pts o Present w/ any kind of glomerulopathy but most commonly diffuse proliferative glomerulonephritis Cardiac abnormalities Endocarditis, myocarditis, pericarditis (epicardium and pericardium involved) o SLE = LSE (libman-sacks endocarditis) Endocarditis = vegitations of heart valve LSE have vegitations on both sides of valves (noninfectious) Abs against cells in the blood RBCs = anemia, platelets = thrombocytopenia, WBCs = leucopenia o Increased risk of infection death Dx: ANA, anti-dsDNA (anti-smith) ANA is sensitive (screening)

Anti-dsDNA is specific A drug rxn can also lead to lupus in slow-acetylators Hydralazine, procanamide, isoniazid The antibodies for drug induced SLE will be anti-histones o Removal of drug remission of disease Antiphospholipid abs Antiobodies against proteins bound to phospholipids Anti-cardiolipin and lupus anticoagulants will present w/ a false-positive syphilis test o There will also be a falsely elevated PTT because a person is actually in a hypercoagulable state Leading to thrombosis and clots in arteries and veins DVTs, hepatic vein thrombosis (budd-chiari syndrome), placental thrombosis (recurrent pregnancy loss) and stroke Need to be anticoagulated for life Sjogren syndrome Autoimmune destruction of lacrimal and salivary glands Typically by lymphocyte mediated (type IV HSR) w/ fibrosis s/s: sicca (dry eyes, dry mouth) recurrent dental carries in an older woman cant chew a cracker and always feels like they have dirt in their eyes dx: screening test is ANA specific test is anti-ribonucleoprotein antibody o anti-ssa and anti-ssb sequelle associated w/ other autoimmune diseases o common for all autoimmune diseases in this case its associated w/ rheumatoid arthritis increased risk for B-cell lymphoma o bilateral swelling of the parotids, but the pt will come in w/ a new complaint of a unilateral enlargement of one of the parotids late in disease course scleroderma autoimmune tissue damage w/ activation of fibroblasts and deposition of collagen (fibrosis) w/I the skin divided into diffuse and localized diffuse: o exhibits skin and early visceral (organs) involvement o any organ can be involved but the esophagus is most commonly affected results in disordered motility (difficulty with solids and liquids)

characterized by ANA and specificly anti-DNA topoisomerase I (Scl-70) abs localized o skin involvement which is local and late visceral involvement CREST syndrome Calcinosis/ anti-centromere Raynauds phenomenon Esophageal dysmotility Sclerodactyly Telangiectasias of the skin (typically of the eye) Mixed connective tissue disease Auto-immune mediated tissue damage w/ mixed features of SLE, systemic sclerosis, and polymyositis (autoimmune disease involving proximal muscles (combing hair and walking up stairs)) Characterized by serum antibodies against U1 ribonucleoprotein

Wound healing Regeneration or repair o Regeneration occurs when the cells of a specific type have the ability to go through the cell cycle and replicate Examples are labile cells and stabile cells Labile: skin (basal cells), intestinal cells, hematopoietic stem cells Stabile cells: liver cells and Proximal tubule cells of the kidney o Repair is for terminally differentiated tissue who have cells that cannot go into the cell cycle, or when stem cells are lost (myelofibrosis) Myocardium, skeletal muscle, neurons Result will be the formation of a fibrous scar o Repair phases Initial phase is granulation tissue Consists of fibroblasts (deposit type III collagen), capillaries (provide nutrients), myofibroblasts (contract wound) Eventually the end result will be a scar o Type III collagen is replaced by type I o Collagenase removes type III Requires cofactor of zinc (only rxn in the body that requires zinc) o Type III collagen is found in BVs, granulation tissue, embryonic tissue (skin of babies) Extremely pliable o Regeneration/ repair is mediated by factors that are released in a paracrine fashion attach to receptors TGF-alpha Epithelial and fibroblast GF TGF-beta Inhibits inflammation, important in fibroblast growth PDGF Endothelium, SM, and fibroblast GF Released from platelets and causes healing of all the parts of the BV

o FGF

Endothelial cells, smooth muscle, and fibroblasts (for repair)

Angiogenesis, skeletal development Helps grow GFs VEGF Angiogenesis Cutaneous healing o Primary or secondary intentions Primary: Wound edges are brought together (via sutures) o Minimal scar formation Secondary Edges are not approximated (not stitched together) o Granulation tissue fills in the defect Get big scar and the granulation tissue will cause contraction of the wound Myofibroblasts will cause the contraction Delayed wound healing o Infection most common cause Continued inflammation will impair healing o vitC def hydroxylation of the procollagen (once its secreted from the cells) so that crosslinking can occur -GLY-x-y (x/y normally proline, lysine) o The Y will get hydroxylated (-OH) For cross-linking o Copper (Cu) def Used for lysyl oxidase Enzyme that cross-links the OH groups of lysine or proline molecules o Zinc def Used by collagenase to convert type III collagen to type I o Foreign body, ischemia, diabetes, and malnutrition Dehiscence o Rupture of wound Most commonly seen after abdominal surgery Hypertrophic scar o Excess production of scar tissue that is localized to the scar o Predominantly made of type I collagen Keloid o Excess production of type III collagen o Way out of proportion to the wound o More commonly seen in African Americans and effects the earlobes