General Principles of Hemostasis Hemostasis is a balancing act! pro-clotting plugs up holes in blood vessels anti-clotting keeps clotting under control Hemostasis
Opposite of hemorrhage = stops bleeding Too little hemostasis = too much bleeding Too much hemostasis = thrombi/emboli Three major steps: 1. Vasoconstriction 2. Platelet plug Temporarily blocks the hole Platelet-derived cytokines further the
process 3. Coagulation cascade = clot formation seals hole until tissue repaired Steps of Hemostasis 1. Two coagulation pathways converge onto common pathway 1. Intrinsic Pathway. Collagen exposure. All factors needed are present in blood. Slower. 2. Extrinsic Pathway. Uses Tissue Factors released by injured cells and a shortcut. 2.
3. Usually both pathways are triggered by same tissue damaging events. The different factors can be subject to a variety of problems 1. Hemophilia 2. Hypercoagulable states Steps of Hemostasis Vessel damage exposes collagen fibers Platelets adhere to collagen & release factors + feedback loop
local vasoconstriction & platelet aggregation decreased blood flow platelet plug formation Pro-Clotting clot Pro-Clotting vessels platelets
cascade http://www.mhhe.com/biosci/esp/2002_ge neral/Esp/folder_structure/tr/m1/s7/trm1s 7_3.htm Pro-Clotting Blood vessel constricts. Blood loss decreases Platelets and factors meet Pro-Clotting Platelets form a plug. Proteins are exposed
Platelets adhere Granules release contents Platelets aggregate Phospholipids are exposed Pro-Clotting Fibrin seals up plug. Tissue factor is exposed Cascade begins Cascade makes fibrin Fibrin solidifies plug Structure of Blood Clot Plasmin, trapped in clot, will dissolve
clot by fibrinolysis Clot formation limited to area of injury: Intact endothelial cells release anticoagulants (heparin, antithrombin III, protein C). SEM x 4625 Platelets Tissue factor Fibrin Platelets
Platelet activation Coagulation Cascade Intrinsic Extrinsic thrombin XII exposed TF XIIa XIa
XI IX VIII TF VIIa IXa VII VIIIa Final common pathway X
V Xa Va prothrombin thrombin fibrinogen fibrin clot
Intrinsic Extrinsic thrombin exposed TF XIa XI IX VIII TF VIIa
IXa VII VIIIa X V Xa Va prothrombin fibrinogen thrombin
fibrin clot Intrinsic Extrinsic thrombin exposed TF XIa XI IX VIII
TF VIIa IXa VII VIIIa X V Va Xa
prothrombin fibrinogen thrombin fibrin clot Intrinsic Extrinsic thrombin XI
exposed TF XIa IX VIII TF VIIa IXa VII VIIIa X V
Va prothrombin Xa thrombin fibrinogen fibrin clot Intrinsic Extrinsic
thrombin exposed TF XIa XI IX VIII TF VIIa IXa VII
VIIIa X V Va prothrombin Xa thrombin fibrinogen fibrin
clot Intrinsic Extrinsic thrombin exposed TF XIa XI IX VIII
TF VIIa IXa VII VIIIa X V Xa Va prothrombin
thrombin fibrinogen fibrin clot Where do tissue factors come from? Hidden cells exposed during injury Microparticles floating in blood Endothelial cells and monocytes (during inflammation)
Intrinsic Extrinsic thrombin XI exposed TF XIa IX VIII TF VIIa
IXa VII VIIIa X V Va Xa prothrombin fibrinogen
thrombin fibrin clot Intrinsic Extrinsic thrombin XI exposed TF XIa
IX VIII TF VIIa IXa VII VIIIa X V Va
prothrombin Xa thrombin fibrinogen fibrin clot Intrinsic Extrinsic
thrombin XI exposed TF XIa IX VIII TF VIIa IXa VII
VIIIa X V Va Xa prothrombin fibrinogen thrombin fibrin clot
Intrinsic Extrinsic thrombin XI exposed TF XIa IX VIII TF
VIIa IXa VII VIIIa X V Va Xa prothrombin fibrinogen
thrombin fibrin clot Extrinsic Intrinsic TF VII IX VIII
X V thrombin fibrin clot tissue factor fibrin clot Anti-Clotting clot
Anti-Clotting fibrinogen fibrin clot Anti-Clotting fibrinogen fibrin clot
plasminogen plasmin t-PA Clot Busters & Anticoagulants Dissolve obsolete or unwanted clots Prevent coagulation by blocking 1 or more steps in fibrin forming cascade Enhance fibrinolysis
Inhibit platelet adhesion plug prevention Urokinase, Streptokinase & t-PA Examples: Examples: Coumadin (warfarin) blocks Vit K EDTA chelates Ca2+ Aspirin prevents platelet plug
Coumadin and warfarin block Vit K action (Vitamin K is a cofactor in the synthesis of several coagulation factors). Ca chelators (EDTA and citrate) only in vitro Heparin inhibits activity of thrombin (produced by basophils) Aspirin prevents platelet plug formation Hemostasis Outline The big picture Laboratory tests
Platelet Lab Tests Count Done by particle counter 150 450 x 109/L Morphology Size Granulation Platelets Normal Platelets Bleeding Time
Why? Evaluate platelet response to vascular injury Some platelet disorders have a long bleeding time How? Inflate blood pressure cuff Make incision Time how long it takes to stop bleeding Careful! Lots of things affect the test! Some consider the test unreliable. Coagulation Lab Tests
Draw blood into citrate tube Spin tube, decant plasma Add reagents to plasma Watch for formation of fibrin Prothrombin Time Plasma + thromboplastin Measures extrinsic pathway Extrinsic
Intrinsic TF VII IX VIII X V thrombin fibrin clot
Extrinsic Intrinsic TF VII IX VIII X V thrombin fibrin
clot Extrinsic Intrinsic TF VII IX VIII X V
thrombin fibrin clot PT increased VII, X, V, II, I Coumadin Heparin DIC When should you order a PT?
Never! Order an INR instead. What is an INR? Just a corrected PT. When should you order an INR? To assess liver function To monitor Coumadin therapy
To diagnose DIC* To assess pre-op status * Disseminated intravascular coagulation Partial Thromboplastin Time Plasma + phospholipid Measures intrinsic pathway APTT = same thing Intrinsic
Extrinsic IX TF VII VIII X V thrombin fibrin
clot Intrinsic Extrinsic TF VII IX VIII X V thrombin
fibrin clot Intrinsic Extrinsic TF VII IX VIII X PTT increased:
hemophilia A hemophilia B DIC heparin V thrombin fibrin clot When should you order a PTT?
To investigate a history of abnormal bleeding To monitor heparin therapy To diagnose DIC To assess pre-op status Fibrin Degradation Product Assay Measures FDPs (including D-dimers) VERY sensitive! Anti-Clotting
clot Thrombin fibrinogen XIII fibrin cross-linked fibrin fibrinogen cross-linked fibrin
fibrin plasmin FDPs D-dimers Anti-Clotting clot FDPs increased: Thrombi Minor clotting
When should you order an FDP assay? rule in a clot... but to rule out a clot. Not to Intrinsic Extrinsic thrombin exposed TF
XI XIa IX VIII TFPI TF VIIa IXa VII VIIIa
X protein C V Va prothrombin ATIII Xa thrombin fibrinogen
fibrin clot
