Thrombosis

Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad):
(1) endothelial injury (2) stasis or turbulence of blood flow. (3) blood hypercoagulability .

Virchow's triad

1 Endothelial Injury
This is a dominant cause of thrombosis as endothelial loss by itself lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a function of endothelial injury

Thrombosis in Endothelial Injury 1

physical loss of endothelium leads to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators. dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogen activator inhibitors) or may synthesize fewer anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA).

Thrombosis in Endothelial Injury 2

Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur with
hypertension ._ turbulent flow over scarred valves ._ by the action of bacterial endotoxins. homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke, may be sources of endothelial dysfunction

Alterations in Normal Blood Flow 1

Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi. Normal blood flow is laminar, such that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma. Stasis and turbulence therefore: Disrupt laminar flow and bring platelets into contact with the endotheliumPrevent dilution of activated clotting factors resulting in local thrombosis and leukocyte adhesion.

Alterations in Normal Blood Flow 2

Turbulence and stasis contribute to thrombosis in several clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations, called aneurysms, create local stasis and consequently a fertile site for thrombosis . Acute myocardial infarction results in focally noncontractile myocardium; ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases cardiac mural thrombi form more easily because of the local blood stasis Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation .

Alterations in Normal Blood Flow 3

Hyperviscosity syndromes such as
polycythemia; increase resistance to flow cause small vessel stasis . sickle cell anemia with the deformed red cells cause vascular occlusions, with the resultant stasis also predisposing to thrombosis.

Hypercoagulability
alteration of the coagulation pathways that predisposes to thrombosis . It can be divided into
primary (genetic) . inherited causes of hypercoagulability, mutations in the factor V gene and the prothrombin gene are the most common. secondary (acquired) disorders : the pathogenesis of acquired thrombotic diatheses is frequently multifactorial and is therefore more complicated.

secondary (acquired) Hypercoagulability

oral contraceptive use the hyperestrogenic state of pregnancy, probably related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III. In disseminated cancers, release of procoagulant tumor products predisposes to thrombosis. advancing age has been attributed to increasing platelet aggregation and reduced endothelial PGI2 release. Smoking and obesity promote hypercoagulability by unknown mechanisms.

Hypercoagulability

Heparin-Induced Thrombocytopenia (HIT) syndrome

5% of the population the HIT syndrome occurs when administration of unfractionated heparin for therapeutic anticoagulation induces autoantibodies to complexes of heparin and a platelet membrane protein (platelet factor 4) . This antibody binds to similar complexes present on platelet and endothelial surfaces, resulting in platelet activation and endothelial cell injury, and a net prothrombotic state. The occurrence of HIT syndrome can be reduced by using low-molecular-weight heparin preparations that retain anticoagulant activity but do not interact with platelets; these preparations have the additional advantage of a prolonged serum half-life.

Morphology of thrombi
Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker erythrocyte-rich layers. Antemortem thrombosis is distinguished from the bland nonlaminated clots that occur in the postmortem state.

Morphology and types of thrombi 1

Arterial thrombi are frequently occlusive and are produced by platelet and coagulation activation; friable meshwork of platelets, fibrin, erythrocytes, and degenerating leukocytes. Although arterial thrombi are usually superimposed on an atherosclerotic plaque, other vascular injury (vasculitis, trauma) can be involved Venous thrombosis (phlebothrombosis) occlusive, and the thrombus can create a long cast of the lumen; venous thrombosis is largely the result of activation of the coagulation cascade, and platelets play a secondary role. Because these thrombi form in the sluggish venous circulation, they also tend to contain more enmeshed erythrocytes and are therefore called red, or stasis, thrombi. The veins of the lower extremities are most commonly affected (90% of venous thromboses) however, venous thrombi can occur in the upper extremities, periprostatic plexus, or ovarian and periuterine veins; under special circumstances they may be found in the dural sinuses, portal vein, or hepatic vein.

Morphology and types of thrombi 2

Postmortem clots : postmortem "thrombi" are gelatinous, with a dark red dependent portion where red cells have settled by gravity, and a yellow "chicken fat cover, and they are usually not attached to the underlying wall. In contrast, red thrombi are firmer and are focally attached, and sectioning reveals strands of gray fibrin. vegetations :Thrombi on heart valves. Bacterial or fungal blood-borne infections can cause valve damage, subsequently leading to large thrombotic masses (infective endocarditis .Sterile vegetations can also develop on noninfected valves in hypercoagulable states, so-called nonbacterial thrombotic endocarditis

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). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall.

Clinical Correlations: Venous versus Arterial Thrombosis

Thrombi are significant because they cause obstruction of arteries and veins and are potential sources of emboli. Which effect is most important depends on the site of thrombosis. Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are most worrisome for their capacity to embolize to the lungs and cause death . Conversely, while arterial thrombi can embolize and even cause downstream tissue infarction their role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much more significant clinically.

Venous Thrombosis (Phlebothrombosis)

Most venous thrombi occur in the superficial or deep veins of the leg. Superficial venous thrombi usually occur in the saphenous system, particularly when there are varicosities. Such superficial thrombi can cause local congestion, swelling, pain, and tenderness along the course of the involved vein, but they rarely embolize. Nevertheless, the local edema and impaired venous drainage do predispose the overlying skin to infections from minor trauma and to the development of varicose ulcers. Deep thrombi in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they may embolize . deep venous thromboses are entirely asymptomatic in approximately 50% of patients and are recognized in retrospect only after they have embolized.