PT (Prothrombin time): extrinsic pathway. PT is a test of extrinsic coagulation pathway (also called the tissue factor pathway)

-Includes factors VII, X, V and II

-Extrinsic is coming from the tissue itself

PTT: Intrinsic pathway. PTT measures the integrity of the intrinsic system (factors XII, XI, VIII, IX) and common clotting pathways

-Increased levels in a person with a bleeding disorder indicated a clotting factor may be missing or defective

-Intrinsic pathway is a intravascular event

-Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen which causes it to polymerize

-The polymerized fibrin, together with platelets forms a hemostatic plug or clot over a wound

-The fibrinolytic cascade: the plasminogen activators (PAs), tPA, uPA, scuPA (or uPA) or scuPA/uPAR complex (among others), activate proenzyme plasminogen to the powerful proteolytic enzyme plasmin.

-Plasmin cleaves the insoluble network of fibrin, converting it into soluble fibrin degradation products (SFDPs)

-VWD is the most common hereditary blood clotting disorder in humans

-An acquired form can sometimes result from other medical conditions

-It arises from a deficiency in the quality or quantity of VWF, a multimeric protein that is required for platelet adhesion

-It is known to affect several breeds of dogs (Dobermans) and humans

-Three forms of VWD are hereditary, acquired, and pseudo or platelet type

-3 types of hereditary VWD are VWD type 1, VWD type 2 and VWD type 3

1. Endothelial injury

2. Exposure

3. Adhesion

4. Activation

5. Aggregation

Describe steps of Primary Hemostasis

1. Endothelial injury involved damaged endothelium

2. Exposure occurs when damaged endothelium exposes underlying collagen. Underlying collagen releases von Willebrand's factor (vWF) protein that binds to collagen.

3. Adhesion: Circulating platelets bind to the vWF via circulating proteins (GPIB)

4. Activation occurs when platelets become active after binding to vWF. Platelet changes shape and membrane forms tentacle like arms allowing it to grab onto other platelets. Platelets release more vWF and serotonin (a tiny molecule that attracts more platelets to the area). Platelets also release adenosine diphosphate (ADP) and thromboxane A2 (TXA2)---> leads to platelet expression of GPIIB/IIIA which leads to aggregation

5. Aggregation: each platelet expresses multiple GPIIB/IIIA which bind to fibrinogen. When two platelets attach to the same fibrinogen protein they are linked together and a large platelet plug can form.

DRUG INVOLVEMENT EXAMPLE: Aspirin is an NSAID that blocks synthesis of thromboxane A2. Acetylation occurs and thromboxane A2 can no longer be produced. Prevents clots from worsening.

• Studies show a failure to heal with steroids and anti-macrophage serum
• Studies have shown healing without inflammatory infiltrate (knock out)
• Exaggerated inflammation is detrimental to healing
• Fetal cells are less permissive to neutrophil diapedesis than adult cells

-IL8

-Gro

-Kallikrein

-FDP's and fibrinopeptides

-Platelet released cytokines

-Bacterial proteins (bacterial cleavage)

-Activation of Hageman factor leads to the generation of bradykinin fragments which initiates the complement cascades

-Complement cascades release C3a and C5a which call neutrophils and monocytes and increase vessel permeability

-Neutrophils, macrophages and mast cells further attract more

-Reconstitution of laminin within the BMZ

-Large glycoprotein, prevent direct contact between KC's and collagens within BMZ and dermis

-Keratinocytes and platelets (vascular endothelial growth factor (VEGF and TGF-alpha)

-Macrophages and platelets (bFGF, TGF-B1)

-ECM/fibroblasts (fibronectin)

-Mast cells (heparin)

-Substance P enhances the release of IL-1 and TNF-alpha from mast cells

-Substance P and K stimulate DNA synthesis in cultured skin fibroblasts

-Vasoactive intestinal peptide (VIP) enhances KC migration

-Substance P and calcitonin gene-related peptide (CGRP) are increased in hypertrophic scars

-TGF-B1 is increased and induces general protein synthesis- this does not occur in keloids (in keloids TGF-B1 induces a 12-fold increase in ECM matrix formation but not general protein synthesis)

-Invasive and lack epithelial cover (unlike keloid)

-Various studies looking at anti-TGF-B1 and B3 serum application to these wounds

-IL-4 

-Collagen and proteoglycans (RER production)

-required for all protein synthesis (collagen, elastin, cellular replication)

-needed for cell movement

-also required for NO synthesis- regulation of angiogenesis

-Superoxide anion radical is the one-electron reduction product of oxygen

-Drives endothelial cell signaling such as required during angiogenesis

-H202-breakdown product- supports cell migration and proliferation through redox reactions as well as mediate the formation of hypochlorous acid in neutrophils

-NADPH oxidases represent one major source of superoxide anion radicals at the wound site- oxidases in phagocytic cells help fight infection

-Abundance of collagen III

-Black individuals predisposed

-Invasive

-Problem with proliferative phase

-Decreased collagen lysis- an abundance of collagen 1

-Genetic factors- but not clearly defined

-Do not tend to be invasive

-Problem with remodeling phase

-MMP's are primary enzymes

-Study showed distal limb wounds have a significantly decreased MMP-1 (collagenase 1) and increased TGF-B1 protein and mRNA as well as increased myofibroblasts and collagen 1

-TGF-B1 is no longer produced but is still present in the wound as the contraction begins

-Fibroblasts assume myofibroblast phenotype

(Large actin bundles, cell-cell links with adherens jxns, cell-matrix link with integrins (α5β1 to fibronectin and α2β1 to collagen)

1) CD44- widely distributed- involved in attachment, uptake, and breakdown of HA. Fibroblasts from hypertrophic scars and scleroderma shown to have increased CD44 on their membranes

2) RHAMM- found on macrophages and fibroblasts- essential for motility of macrophages and fibroblasts

-Collagen 1 and 3 are the primary collagens in wound repair

-Collagen 3 is first present and synthesized and increased in granulation tissue

-Collagen 1 is made later starting at about day 5

-Type V collagen increased during angiogenesis and is highly vascular scars

-Calcium and sodium salts of alginic acid found in brown seaweed: Phaeophyceae (some are 100% calcium, some are 80:20 calcium: sodium, all rich in mannuronic or guluronic acid

-When contact wound fluid forms hydrophilic gel

-Can be washed off (mannuronic acid) easily or peeled (glucuronic) off

-Absorb 15 to 20 times their weight in fluid (excellent for exudative wounds)

-Colloids (Carboxymethylcellulose, Gelatin, Pectin, Elastomers)

-Forms gel on wound surface (gel may be mistaken for pus)

-Water/air permeable- rehydrate wounds/eschars

-Good for highly exudative wounds

• Causes anagen induction
  • Proinflammatory cytokines
  • Decrease of BMP4
• Refractory telogen
  • No anagen induction