- Hemorrhagic disorders, characterized by excessive bleeding, hemostatic mechanisms are either blunted or insufficient to prevent abnormal blood loss.
- Thrombotic disorders. Blood clots form within intact blood vessels or within the chambers of the heart.
Hemostasis is precisely orchestrated process involving platelets, clotting factors and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding. Sequence of events leading to hemostasis at a site of vascular injury:
- Arteriolar vasoconstriction reduces blood flow to the injured area. Mediated by local secretion of factors such as endothelin.
- Primary hemostasis: the formation of the platelet plug. Disruption of the endothelium exposes the subendothelial von Willebrand factor (vWF) and collagen, which promote platelet adherence and activation. Activation of platelets results in shape change and release secretory granules, which recruit additional platelets to undergo aggregation to form a primary hemostatic plug.
- Secondary hemostasis: deposition of fibrin. At the site of injury exposed tissue factors binds and activates factor VII, setting in motion a cascade of reactions that culiminates in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin. Secondary hemostasis consolidates the initial platelet plug.
- Clot stabilization and resorption. Platelet and fibrin undergo contraction to form solid permanent plug that prevents further hemorrhage At this stage counter regulatory mechanisms are set into motion that limit clotting to the site of injury and eventually lead to clot resorption and tissue repair.
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| Hemostasis - plug formation |
Platelets play a critical role in hemostasis by forming the primary plug that initially seals vascular defects and by providing a surface that binds and concentrates activated coagulation factors. Platelet membranes contain proteins involved in coagulation such as fibrinogen, coagulation factor V and vWF as well as protein factors that may be involved in wound healing.
After a traumatic vascular injury, platelets encounter contituents of the subendothelial connective tissue such as vWF and collagen. On contact with these proteins, platelets undergo a sequence of reactions:
- Platelet adhesion is mediated largely via interactions with vWF, which acts as bridge between the platelet receptor (glycoprotein Ib) and exposed collagen. Genetic deficiencies of VWF (von Willebrand disease) or GpIb (Bernard-Soulier syndrome) result in bleeding disorders.
- Platelets rapidly change shape following adhesion with greatly increased surface area.
- Secretion of granule contents occurs along with change in shape; these two events are referred to together as platelet activation. Platelet activation is triggered by a number of factors including coagulation factor thrombin and ADP. Activated platelets also produce the prostaglandin thromboxane A2 (TxA2), a potent inducer of platelet aggregation. Aspirin inhibits platelet aggregation and produces a mild bleeding defect by inhibiting a platelet enzyme that is required for TxA2 synthesis.
- Platelet aggregation follows the activation. The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen. The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating definitive secondary hemostatic plug. Inherited deficiency of GpIIb-IIa results in a bleeding disorder called Glanzmann thrombasthenia.
The coagulation cascade is series of amplifying enzymatic reactions that leads to the deposition of an insoluble fibrin clot. Each reaction step involves an enzyme a substrate and a cofactor. Based on assays carried out in clinical laboratories, the coagulation cascade has traditionally been divided into the extrinsic and intrinsic pathways.
- Prothrombin time (PT) assays assesses the function of the proteins in the extrinsic pathways (factors VII, X, V, II and fibrinogen)
- Partial thromboplastin time (PTT) assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VII, X,V, II and fibrinogen)
Among the coagulation factors, thrombin is the most important, in that its various enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair.
- Conversion of fibrinogen into cross-linked fibrin
- Platelet activation
- Pro-inflammatory effects
- Anticoagulant effects
- Simple dilution; blood flowing past the site of injury washes out activated coagulation factors.
- Requirement for negatively charged phospholipids, which are mainly provided by platelets matrix
- Counter regulatory mechanisms expressed by intact endothelium adjacent to the site of injury.
! An elevated level of breakdown products of fibrinogen, most notably fibrin derived D-dimers, are a useful clinical markers of several thrombotic states.
Endothelium
The balance between the anticoagulant and procoagulant activities of endothelium often determines whether clot formation, propagation or dissolution occurs. The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors and fibrinolysis.
- Platelet inhibitory effects. Intact endothelium obviously serves as barrier between platelets and subendothelial vWF and collagen. Normal endothelium also releases a number factors such as prostacyclin, nitric oxide and adenosine disphosphatase that inhibit platelet activation and aggregation. Finally endothelial cells bind and alter the activity of thrombin.
- Anticoagulant effects. Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation (thrombomodulin, protein C receptor, heparin like molecules, tissue pathway inhibitor)
- Fibrinolytic effects.
- Defects of primary hemostasis (platelet defects or von Willebrand disease) often present with small bleeds in skin or mucosal membranes - petechiae or purpura. A feared complication of very low platelet counts (thrombocytopenia) is intracerebral hemorrhage, which maybe fatal.
- Defects of secondary hemostasis (coagulation factor defects) often present with bleeds into soft tissues (muscles) or joins.
- Generalized defects involving small vessels often present with "palpable purpura" and ecchymoses (bruises, hemorrhages of 1-2cm)
The primary abnormalities that lead to thrombosis are endothelial injury, stasis of turbulent blood flow and hypercoagulability of the blood flow - Virchow triad.
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| Virchow Triad |
Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation/ Obviously severe endothelial injury may trigger thrombosis. However inflammation and other stimuli (infectious agents. metabolic abnormalities) also promote thrombosis by shifting the pattern of gene expression in endothelium - also known as endothelial activation/dysfunction:
- Procoagulant changes. Activated/dysfunctional endothelial cells down regulate the expression of thrombomodulin, proteins C and tissue factor protein inhibitor.
- Antifibrinolytic effects. Activated endothelial cells secrete plasminogen activator inhibitors (PAIs) which limit fibrinolysis.
Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents that contribute to local pockets of stasis. Stasis is a major contributor in the development of venous thrombi. Normal blood flow is laminar such that the platelets flow centrally in the vessel lumen, separated from endothelium by a slower moving layer of plasma. Stasis and turbulence therefore:
- Promote endothelial activation, enhancing procoagulant activity and leukocyte adhesion, in part through flow-induced changes in the expression of adhesion molecules and pro-inflammatory factors.
- Disrupt laminar flow and bring platelets into contact with endothelium
- Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors.
Hypercoagulability
Hypercoagulability (thrombophilia) can be loosely defined as any disorder of the blood that predisposes to thrombosis. Hypercoagulability can be divided into primary (genetic) and secondary (acquired) disorders.
- Factor V leiden. Factor V cannot be inactivated by anticoagulant protein "protein C"
- Prothrombin mutation (G20210A)
- Elevated levels of homocysteine contribute to arterial and venous thrombosis, aswell as the development of atherosclerosis.
- Deficiency of anticoagulants such as anti thrombin II, protein C or protein S.
Heparin-Induced Thrombocytopenia (HIT) syndrome
HIT occurs following the administration of unfractionated heparin, complexes of heparin and platelet factor 4 bind to antibodies resulting in platelets activation and aggregation. This effect on platelets and endothelial damage induced by antibody binding leads to prothrombotic state, even in the face of heparin administration and low platelets counts.
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| Heparin-induced thrombocytopenia |
It is suspected that antibodies bind to proteins such as beta2-glycoprotein I (on the surfaces of endothelial cells and trophoblasts) and thrombin, thereby inducing a hypercoagulable state. Antiphospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease such as systemic lupus erythematous (SLE) are designated as having secondary. In primary patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders.
Fate of the thrombus
- Propagation. Thrombi accumulate additional platelets and fibrin
- Embolization. Thrombi dislodge and travel to other sites in the vasculature.
- Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi.
- Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells and fibroblasts
Atherosclerosis is a major cause of arterial thrombosis because it is associated with loss of endothelial integrity and with abnormal blood flow. Myocardial infarction can predispose to cardiac mural thrombi and rheumatic heart disease to atrial mural thrombi, both are prone to embolization. The brain, kidney and spleen are particularly likely targets.
Disseminated Intravascular Coagulation
DIC is a pathological process characterized by the widespread activation of the clotting cascade that results in formations of blood clots in the small blood vessels throughout the body. This leads to compromise of tissue blood flow and can ultimately lead to multiple organ damage. In addition as the coagulation process consumes clotting factors and platelets, normal clotting is disrupted and severe bleeding can occur from various sites. DIC is not a specific disease but rather a complication of a large number of conditions associated with systemic activation of thrombin.
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