Path 10- Hemodynamics 1b Flashcards
What are the three primary abnormalities that lead to thrombus formation (called Virchow’s triad):
(1) endothelial injury,
(2) stasis or turbulent blood flow, and
(3) hypercoagulability of the blood
Endothelium does not need to be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothrombotic and antithrombotic effects of endothelium can influence clotting locally.
How does turbulence contribute 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 factor in the development of venous thrombi.
Under conditions of normal laminar blood flow, platelets (and other blood cells) are found mainly in the center of the vessel lumen, separated from the endothelium by a slower-moving layer of plasma. By contrast, stasis and turbulent (chaotic) blood flow have the following deleterious effects:
- Both promote endothelial cell activation and enhanced procoagulant activity, in part through flow-induced changes in endothelial gene expression.
- Stasis allows platelets and leukocytes to come into contact with the endothelium when the flow is sluggish.
- Stasis also slows the washout of activated clotting factors and impedes the inflow of clotting factor inhibitors.
T or F. Hypercoagulability contributes infrequently to arterial or intracardiac thrombosis but is an important underlying risk factor for venous thrombosis.
When are people hypercoaguable ?
T. It is loosely defined as any alteration of the coagulation pathways that predis- poses affected persons to thrombosis, and can be divided into primary (genetic) and secondary (acquired) disorders
people are hyper coagulable in cancer and late pregnancy, and while taking oral contraceptives (=low antithrombin), and OLD AGE (=low PGI2 release)
Primary (inherited) hypercoagulability most often is caused by mutations in the ___ and ___ genes
Factor V (Leiden) and prothrombin (20210A)
think venous thrombosis with hypercoaguability
Among the acquired (secondary) thrombophilic states, two are particularly important clinical problems and deserve special mention:
- Heparin-induced thrombocytopenic (HIT) syndrome. This syndrome occurs in up to 5% of patients treated with unfractionated heparin (for therapeutic anticoagulation). It is marked by the development of autoantibodies that bind complexes of heparin and platelet membrane protein (platelet factor-4). Although the mechanism is unclear, it appears that these antibodies may also bind similar complexes present on platelet and endothelial surfaces, resulting in platelet activation, aggregation, and consumption (hence thrombocytopenia), as well as causing endothelial cell injury. The overall result is a prothrombotic state, even in the face of heparin administration and low platelet counts. Newer low-molecular-weight fractionated heparin preparations induce autoantibodies less frequently but can still cause thrombosis if antibodies have already formed.
- Antiphospholipid antibody syndrome. This syndrome has protean manifestations, including recurrent thrombosis, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia; it is associated with autoantibodies directed against anionic phospholipids (e.g., cardiolipin) or—more accurately—plasma protein antigens that are unveiled by binding to such phospholipids (e.g., prothrombin). In vivo, these antibodies induce a hypercoagulable state, perhaps by inducing endothelial injury, by activating platelets or complement directly, or by interacting with the catalytic domains of certain coagulation factors. In vitro (in the absence of platelets and endothelium), however, the antibodies interfere with phospholipid complex assembly, thereby inhibiting coagulation (hence the designation lupus anticoagulant). In patients with anticardiolipin antibodies, serologic testing for syphilis will yield a false-positive result, because the antigen in the standard assays is embedded in cardiolipin.
Patients with antiphospholipid antibody syndrome
fall into two categories. Many have secondary antiphos- pholipid syndrome due to a well-defined autoimmune A disease, such as systemic lupus erythematosus. The remainder of these patients exhibit only the man- ifestations of a hypercoagulable state without evidence
of another autoimmune disorder (primary antiphospho-
lipid syndrome). Although antiphospholipid antibodies
are associated with thrombotic diatheses, they also occur
in 5% to 15% of apparently normal persons; the implica-
tion is that their presence may be necessary but not sufficient to cause full-blown antiphospholipid antibody syndrome.
Thrombi can develop anywhere in the cardiovascular system. Arterial or cardiac thrombi typically arise at sites of ___ and ___; venous thrombi characteristically occur at sites of ___.
endothelial injury or turbulence
stasis
T or F. Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart
T. thus, arterial thrombi grow in a retrograde direction from the point of attachment, while venous thrombi extend in the direction of blood flow.
The propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation and migration through the blood as an embolus.
What are lines of Zahn?
these represent pale platelet and fibrin layers alternating with darker red cell–rich layers. Such lines are significant in that they are only found in thrombi that form in flowing blood; their presence can there-fore usually distinguish antemortem thrombosis from the bland nonlaminated clots that form in the postmortem state. Although thrombi formed in the “low-flow” venous system superficially resemble postmortem clots, careful evaluation generally reveals ill-defined laminations.
Thrombi occurring in heart chambers or in the aortic lumen are designated ____.
mural thrombi.
Arterial thrombi are typically relatively rich in ____.
platelets, as the processes underlying their development (e.g., endothelial injury) lead to platelet activation. Although usually superimposed on a ruptured atherosclerotic plaque, other vascular injuries (vasculitis, trauma) can also be causal.
An increase in the activity of coagulation factors is involved in the genesis of most ____ thrombi, with platelet activation playing a secondary role
venous. Because these thrombi form in the sluggish venous circulation, they tend to contain more enmeshed red cells, leading to the moniker red, or stasis, thrombi. The veins of the lower extremities are most commonly affected (90% of venous thromboses)
If a patient survives an initial thrombotic event, over the ensuing days to weeks the thrombus evolves through some combination of the following four processes:
- Propagation. The thrombus enlarges through the accretion of additional platelets and fibrin, increasing the odds of vascular occlusion or embolization.
- Embolization. Part or all of the thrombus is dislodged and transported elsewhere in the vasculature.
- Dissolution. If a thrombus is newly formed, activation of fibrinolytic factors may lead to its rapid shrinkage and complete dissolution. With older thrombi, extensive fibrin polymerization renders the thrombus substan- tially more resistant to plasmin-induced proteolysis, and lysis is ineffectual. This acquisition of resistance to lysis has clinical significance, as therapeutic administration of fibrinolytic agents (e.g., t-PA in the setting of acute coronary thrombosis) generally is not effective unless given within a few hours of thrombus formation.
- Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus. In time, capillary channels are formed that—to a limited extent—create conduits along the length of the thrombus, thereby reestablishing the con- tinuity of the original lumen. Further recanalization can sometimes convert a thrombus into a vascularized mass of connective tissue that is eventually incorporated into the wall of the remodeled vessel. Occasionally, instead of organizing, the center of a thrombus undergoes enzymatic digestion, presumably because of the release of lysosomal enzymes from entrapped leukocytes.
Thrombi are significant because they cause obstruction of arteries and veins and may give rise to emboli. Which effect is of greatest clinical importance depends on the site of thrombosis. Thus, while venous thrombi can cause conges- tion and edema in vascular beds distal to an obstruction, they are most worrisome because of their potential to embolize to the lungs and cause death. Conversely, while arterial thrombi can embolize and cause tissue infarction, their tendency to obstruct vessels (e.g., in coronary and cerebral vessels) is considerably more important.
Thrombi are significant because they cause obstruction of arteries and veins and may give rise to emboli. Which effect is of greatest clinical importance depends on the site of thrombosis. Thus, while venous thrombi can cause conges- tion and edema in vascular beds distal to an obstruction, they are most worrisome because of their potential to embolize to the lungs and cause death. Conversely, while arterial thrombi can embolize and cause tissue infarction, their tendency to obstruct vessels (e.g., in coronary and cerebral vessels) is considerably more important.
Most venous thrombi occur where?
in either the superficial or the deep veins of the leg.
Superficial venous thrombi usually arise in the saphenous system, particularly in the setting of varicosities; these rarely embolize but can be painful and can cause local congestion and swelling from impaired venous outflow, predisposing the overlying skin to development of infections and varicose ulcers. Deep venous thromboses (“DVTs”) in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they are prone to embolize. Although such DVTs may cause local pain and edema, the venous obstruction often is circumvented by collateral channels. Consequently, DVTs are entirely asymptomatic in approximately 50% of patients and are recognized only after they have embolized to the lungs.
Superficial venous thrombi usually arise in the saphenous system, particularly in the setting of varicosities; these rarely embolize but can be painful and can cause local congestion and swelling from impaired venous outflow, predisposing the overlying skin to development of infections and varicose ulcers. Deep venous thromboses (“DVTs”) in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they are prone to embolize. Although such DVTs may cause local pain and edema, the venous obstruction often is circumvented by collateral channels. Consequently, DVTs are entirely asymptomatic in approximately 50% of patients and are recognized only after they have embolized to the lungs.
What is Disseminated intravascular coagulation (DIC)?
the sudden or insidious onset of widespread thrombosis within the microcirculation.
It may be seen in disorders ranging from obstetric complications to advanced malignancy. The thrombi are generally microscopic in size, yet so numerous as to often cause circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys. To complicate matters, the widespread microvascular thrombosis consumes plate- lets and coagulation proteins (hence the synonym con- sumption coagulopathy), and at the same time, fibrinolytic mechanisms are activated. Thus, an initially thrombotic disorder can evolve into a bleeding catastrophe. A point worthy of emphasis is that DIC is not a primary disease but rather a potential complication of numerous conditions associ- ated with widespread activation of thrombin.
