General Pathology. Hemostasis (Web)

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1 General Pathology Hemostasis (Web) Paul Hanna Feb 2015

2 Hemostasis HEMOSTASIS = refers to the arrest of bleeding well-regulated process to: keeps blood fluid (clot free) within a normal vessel rapid clot formation (hemostatic plug) occurs when vessel injured a hemostatic clot is normal in cases of vessel injury thrombosis refers to an inappropriate activation of the hemostatic process

3 Hemostasis Three General Components Vascular wall - endothelium Platelets Coagulation Cascade

4 Normal Hemostasis Sequence of Events 1. Arteriolar Vasoconstriction reflex neurogenic mechanism local secretion of endothelin

5 Normal Hemostasis Sequence of Events 1. Arteriolar Vasoconstriction 2. Primary Hemostasis - PLATELET platelets respond to exposure of subendothelial ECM by: Adhesion Shape Change Granule Release Recruitment Platelet aggregation (1 o hemostatic plug)

6 Normal Hemostasis Sequence of Events 1. Arteriolar Vasoconstriction 2. Primary Hemostasis - PLATELET 3. Secondary Hemostasis - COAGULATION Tissue factor release Phospholipid complex expression Thrombin activation Fibrin polymerization (2 o hemostatic plug)

7 Normal Hemostasis Sequence of Events 1. Arteriolar Vasoconstriction 2. Primary Hemostasis - PLATELET 3. Secondary Hemostasis - Coagulation 4. Antithrombotic Counter- Regulation Factors released to limit the size of the hemostatic plug

8 Normal Hemostasis Sequence of Events 1. Arteriolar vasoconstriction - VASCULAR WALL 2. Primary hemostasis PLATELET 3. Secondary Hemostasis COAGULATION 4. Antithrombotic Counter- Regulation

9 Endothelial Cells injury to endothelium is the major initiating event for thrombosis & coagulation endothelium modulates many aspects of normal hemostasis Antithrombotic Prothrombotic

10 Endothelial Cells Antithrombotic Properties Antiplatelet barrier to ECM PGI 2 and NO ADPase Anticoagulant Heparin-like molecules (- ATIII) Thrombomodulin Tissue factor pathway inhibitor Fibrinolytic Plasminogen activators (tpa)

Endothelial Cells Prothrombotic Properties - activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury Von Willibrand

11 Endothelial Cells Prothrombotic Properties - activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury Von Willibrand factor (vwf) - synthesize / stores / releases Tissue factor (TF) - injured endothelium secrete TF Plasminogen activator inhibitors - fibrinolysis (counteract PA s)

12 Endothelial Cells Vascular Repair Numerous growth factors are secreted by endothelial cells Platelet Derived Growth Factor (PDGF) stimulates smooth muscles and fibroblasts Fibroblast Growth Factor (FGF) stimulates fibroblasts and angiogenesis Transforming Growth Factor β (TGF- β) modulates vascular (& fibrous) repair

13 Platelets derived from megakaryocytes; circulate as round, smooth discs play central role in hemostasis contain mostly procoagulants form the 1 o hemostatic plug covers and seals a small damaged area Figure (Mescher) Platelets. Platelets are cell fragments 2 4 µm in diameter derived from megakaryocytes of bone marrow. Their primary function is to rapidly release the content of their granules upon contact with collagen (or other materials outside of the endothelium) to begin the process of clot formation and reduce blood loss from the vasculature. (a): In a blood smear, platelets (arrows) are often found as aggregates. Individually they show a lightly stained hyalomere region surrounding a more darkly stained central granulomere containing membrane enclosed granules. X1500. Wright. (b): Ultrastructurally a platelet typically shows a system of microtubules and actin filaments near the periphery to help maintain its shape and an open canalicular system of vesicles continuous with the plasmalemma. The central granulomere region contains glycogen and secretory granules of different types.

14 Platelets For information only

15 Platelet Response Adhesion and Shape Change Vascular injury Exposure of ECM VWF bridge for platelets to ECM

16 Platelet Response Secretion Dense granules (Ca 2+ + ADP) Surface expression of phospholipid complexes (binding site for Ca 2+ and coagulation factors)

17 Platelet Response Aggregation TXA 2 + ADP enlarging platelet aggregate 1 o haemostatic plug

18 Platelet Disorders THROMBOCYTOPENIA Definition: platelet numbers are low (<100 x 10 9 /L is a thrombocytopenia in many species) Diagnosis: history of bleeding low platelet counts Mechanisms: Deficient formation of platelets (eg, estrogen toxicoses) Excessive utilization (eg, consumptive coagulopathies) Premature destruction (eg, antibodies to platelets) THROMBOCYTOPATHY Definition: Mechanisms: Defective platelet function Defect in adhesion (eg, von WIllebrand s disease) aggregation release of granules

19 Coagulation Cascade 3 rd arm of hemostasis an enzymatic cascade a reaction pathway: enzyme (previously activated coagulation factor) + substrate (next non-activated coagulation factor) activated coagulation factor reaction typically occurs on platelet phospholipid complex held together by Ca 2+

20 Coagulation Cascade coagulation cascade forms thrombin bound to platelet surface thrombin converts soluble fibrinogen to fibrin anchor / stabilize the hemostatic plug

21 Coagulation Cascade Intrinsic Pathway all factors in plasma exposure of collagen for activation Extrinsic Pathway TF from injured vessel wall TF + VII TF/VIIa X to Xa Common Pathway fibrin formation Result contraction of fibrin-platelet clot reduces size of clot (restores flow) draws damaged vessels edges closer (for healing)

22 Coagulation Cascade

23 Fibrinolytic System fibrinolytic cascade limits the size &/or dissolves thrombus (temporary patch) primarily by the generation of plasmin (from plasminogen) plasminogen activated by tpa s &/or intrinsic coagulation (XIIa-kallirein) FDP s have anticoagulant activity & used as measure of thrombotic states

24 COAGULATION DISORDERS For information only In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality

25 COAGULATION DISORDERS For information only In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality INHERITED DEFICIENCIES OF COAGULATION numerous (See Box 2-5 McGavin)

COAGULATION DISORDERS For information only In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or

26 COAGULATION DISORDERS For information only In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality INHERITED DEFICIENCIES OF COAGULATION numerous (See Box 2-5 McGavin) ACQUIRED DEFICIENCIES OF COAGULATION (can be production or use) Accompany many severe diseases - transitory depression of factor synthesis - excessive utilization or consumption of factors Acquired disorders may be general or specific - severe trauma or deep burns - snake venoms and plant toxins - vitamin K deficiency (required for factors II, VII, IX, X and proteins C and S) Liver failure - site of synthesis of many coagulation factors - acute destruction of hepatocytes or chronic liver disease may result in coagulopathy

Platelet Review July 2012. Thomas S. Kickler M.D. Johns Hopkins University School of Medicine

Platelet Review July 2012. Thomas S. Kickler M.D. Johns Hopkins University School of Medicine Platelet Review July 2012 Thomas S. Kickler M.D. Johns Hopkins University School of Medicine Hemostasis Hemostasis is the process that leads to the stopping of bleeding Hemostasis involves blood vessels,