Hemostasis and Thrombosis Overview

Normal Hemostasis

• Maintains blood in a fluid state in normal vessels
• Forms a localized hemostatic plug at the site of vascular injury

Thrombosis

• Pathologic counterpart of hemostasis
• Formation of a blood clot (thrombus) within intact vessels

Hemostasis and Thrombosis

• Both involve vascular wall, platelets and coagulation cascade

Normal Hemostasis

• Starts with arteriolar vasoconstriction
• Allows platelets to adhere and be activated
• Activated platelets change shape from small rounded disks to flat plates
• Release of secretory granules recruits additional platelets resulting in a hemostatic plug
• This is known as primary hemostasis

Tissue Factor

• Exposed at the site of injury
• Acts in conjunction with factor VII to activate the coagulation cascade
• Leads to thrombin generation, cleaving circulating fibrinogen into insoluble fibrin forming a meshwork
• This is secondary hemostasis
• Thrombin also induces further platelet recruitment and granule release
• Fibrin and platelet aggregates form a solid permanent plug to prevent further hemorrhage

Endothelial Cells and Coagulation

• Intact normal endothelial cells prevent platelet and coagulation factor activation
• Damaged or inflamed endothelial cells upregulate expression of procoagulant factors that promote clotting
• Decrease expression of anticoagulant factors
• Loss of endothelial integrity exposes subendothelial vWF and collagen, stimulating platelet adhesion, activation and clot formation

Platelet Adhesion, Activation, and Aggregation

• Endothelial injury exposes underlying basement membrane ECM
• Platelets adhere to ECM through platelet GpIb receptors binding to vWF
• Adhesion leads to platelet activation, which involves secretion of platelet granule contents, including calcium and ADP
• Platelet activation also results in dramatic changes in shape and membrane composition and activation of GpIIb/IIIa receptors
• GpIIb/IIIa receptors on activated platelets form bridging crosslinks with fibrinogen leading to platelet aggregation
• Concomitant activation of thrombin promotes fibrin deposition, cementing the platelet plug in place

Thrombosis

• Influenced by three primary factors (Virchow's triad):
  • Endothelial injury
  • Stasis or turbulence of blood flow
  • Blood hypercoagulability

Endothelial Injury

• Important cause of thrombosis, particularly in the heart and arteries
• Ex: thrombosis occurs in cardiac chambers after myocardial infarction and over ulcerated plaques in atherosclerotic arteries
• Physical loss of endothelium exposes subendothelial ECM, releases tissue factor, and reduces local production of PGI2 and plasminogen activators
• Endothelial dysfunction occurs in hypertension, bacterial products, radiation injury, hypercholesterolemia, and toxins absorbed from cigarette smoke

Alterations in Normal Blood Flow

• Turbulence contributes to thrombosis by causing endothelial injury or dysfunction, and by forming local stasis
• Stasis is a major contributor to the development of venous thrombi
• Normal blood flow is laminar, with platelets flowing centrally in the vessel lumen and separated from the endothelium by a clear zone of plasma

Hypercoagulability

• Any alteration of the coagulation pathways that predisposes to thrombosis
• Divided into primary (genetic) and secondary (acquired) disorders

Primary (inherited) hypercoagulable states

• Ex: mutations in the prothrombin gene

Causes of Secondary Hypercoagulable states

• Cardiac failure and trauma in both stasis or vascular injury
• Oral contraceptive use and hyperestrogenic state of pregnancy, related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III
• Advanced age due to increasing platelet aggregation
• Smoking and obesity promote hypercoagulability

Morphology

• Thrombi can develop anywhere in the cardiovascular system
• Size and shape depend on site of origin and cause
• Arterial or cardiac thrombi typically begin at sites of endothelial injury or turbulence
• Venous thrombi characteristically occurring at sites of stasis
• Thrombi are focally attached to the underlying vascular surface
• Arterial thrombi tend to grow in a retrograde direction
• Venous thrombi extend in the direction of blood flow
• Propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation, generating an embolus
• Thrombi can have grossly (and microscopically) laminations called lines of Zahn, representing pale platelet and fibrin layers alternating with darker red cell–rich layers
• Important to note that lines of Zahn are only found in thrombi that form in flowing blood, usually distinguishing antemortem thrombosis from postmortem clots

Postmortem Clotting of blood

• Blood separates:
  • Upper plasma layer: translucent, like chicken fat
  • Lower red blood cell layer: very red and resembles red current jelly

Difference between post/ante mortem clotting:

• Post mortem: no damage to inner surface of vessel and clot can be easily removed
• Ante mortem: firmly attached to underlying vascular endothelium, has a white interior and is layered

Fate of the Thrombus

• Propagation: thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction
• Embolization: thrombi dislodge or fragment and are transported elsewhere in the vasculature
• Dissolution: thrombi are removed by fibrinolytic activity
• Organization and recanalization: thrombi induce inflammation and fibrosis (organization)
  • This can eventually recanalize (re-establishing some degree of flow)
  • Or be incorporated into a thickened vessel wall