Thrombosis, and Shock Flashcards
Thrombosis
The primary abnormalities that lead to thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood (the so-called Virchow triad)
Virchow’s Triad
Endothelian injury (Hypercholesterolemia)
Abnormal Blood Flow (Stasis, turbulence)
hypercoaguability (Inherited- V leiden, disemminated cancer)
Endothelial Injury
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
cardiac and arterial clots are
rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries.
Why use aspirin in MI and CAD?
cardiac and arterial clots are typically rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries. This insight provides part of the reasoning behind the use of aspirin and other platelet inhibitors in coronary artery disease and acute myocardial infarction
severe endothelial injury may trigger thrombosis by
exposing vWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.
endothelial activation or dysfunction and can be produced by
including physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke. Endothelial activation is believed to have an important role in triggering arterial thrombotic events.
Procoagulant changes.
Endothelial cells activated by cytokines downregulate the expression of thrombomodulin, already described as a key modulator of thrombin activity. This may result in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells. In addition, inflamed endothelium also downregulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, changes that further promote a procoagulant state
Antifibrinolytic effects
Activated endothelial cells secrete plasminogen activator inhibitors (PAIs), which limit fibrinolysis, and downregulate the expression of t-PA, alterations that also favor the development of thrombi.
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
Alternations in Normal Blood Flow
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 the endothelium •
Prevent washout and dilution of activated clotting factors by
Ulcerated atherosclerotic plaques
xpose subendothelial vWF and tissue factor but also cause turbulence
Aortic and arterial dilations called aneurysms result in
local stasis and are therefore fertile sites for thrombosis
Acute myocardial infarctions result in areas of noncontractile myocardium and sometimes in cardiac aneurysms;
both are associated with stasis and flow abnormalities that promote the formation of cardiac mural thrombi
Rheumatic mitral valve stenosis results in
left atrial dilation; in conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for thrombosis
Hyperviscosity
(such as is seen with polycythemia vera; Chapter 13) increases resistance to flow and causes small vessel stasis, and the deformed red cells in sickle cell anemia (Chapter 14) impede blood flow through small vessels, with the resulting stasis also predisposing to thrombosis.
Hypercoagulability
Hypercoagulability (also called thrombophilia) can be loosely defined as any disorder of the blood that predisposes to thrombosis
Hypercoagulability has a particularly important role in
venous thrombosis and can be divided into primary (genetic) and secondary (acquired) disorders
. Of the inherited causes of hypercoagulability, point mutations
in the factor V gene and prothrombin gene are the most common
• Approximately 2% to 15% of Caucasians carry a
single-nucleotide mutation in factor V that is called the factor V Leiden, after the city in The Netherlands where it was discovered
Among individuals with recurrent DVT, the frequency of this mutation is considerably higher, approaching 60%. The mutation results in a glutamine to arginine substitution at amino acid residue 506 that renders factor V resistant to cleavage and inactivation by protein C. As a result, an important antithrombotic counterregulatory pathway is lost (Fig. 4-10)
another common mutation (1% to 2% of the population) associated with hypercoagulability. It leads to elevated prothrombin levels and an almost three-fold increased risk of venous thrombosis.
A single nucleotide change (G20210A) in the 3′-untranslated region of the prothrombin gene
Elevated levels of homocysteine
contribute to arterial and venous thrombosis, as well as the development of atherosclerosis (Chapter 11). The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase
Rare inherited causes of primary hypercoagulability include
deficiencies of anticoagulants such as antithrombin III, protein C, or protein S; affected individuals typically present with venous thrombosis and recurrent thromboembolism beginning in adolescence or early adulthood
factor V Leiden heterozygosity may trigger
DVT
inherited causes of hypercoagulability must be considered in patients younger than
age 50 years who present with thrombosis—even when acquired risk factors are present.
Unlike hereditary disorders, the pathogenesis of acquired thrombophilia is
frequently multifactorial
Hypercoagulability due to oral contraceptive use or the hyperestrogenic state of pregnancy is probably caused by
increased hepatic synthesis of coagulation factors and reduced anticoagulant synthesis. In disseminated cancers, release of various procoagulants from tumors predisposes to thrombosis
hypercoagulability seen with advancing age may be due to
Reduced Endothelial PGI2
Heparin-Induced Thrombocytopenia (HIT) Syndrome
has a distinctive pathogenesis and is of particular importance because of its potential for severe clinical consequences. Thrombocytopenia occurs in about 5% of persons receiving heparin and is of two types: • Type I thrombocytopenia occurs rapidly after the onset of therapy and is of little clinical importance, sometimes resolving despite the continuation of therapy. It most likely results from a direct platelet-aggregating effect of heparin. • Type II thrombocytopenia is less common but of much greater clinical significance. It occurs 5 to 14 days after therapy begins
This severe form of HIT is caused by
antibodies that recognize complexes of heparin and platelet factor 4, which is a normal component of platelet granules. Binding of antibody to these complexes activates platelets and promotes thrombosis, even in the setting of thrombocytopenia. Unless therapy is immediately discontinued and an alternative nonheparin anticoagulant instituted, clots within large arteries may lead to vascular insufficiency and limb loss, and emboli from deep venous thrombosis can cause fatal pulmonary thromboembolism
The risk of severe HIT is lowered, but not completely eliminated, by the use of
low-molecular-weight heparin preparations. Unfortunately, once severe HIT develops even low-molecular-weight heparins exacerbate the thrombotic tendency and must be avoided.
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome
Depending on the vascular bed involved, the clinical presentations can include
PE
LOWER EX THROMB
PUL HYP
Stroke
BOwel infarct
Renovascular Hypertension
Fetal loss does not appear to be explained by thrombosis, but rather seems to stem from
antibody-mediated interference with the growth and differentiation of trophoblasts, leading to a failure of placentation.
Antiphospholipid antibody syndrome is also a cause of renal microangiopathy,
resulting in renal failure associated with multiple capillary and arterial thromboses
Suspected antibody targets include
e β2-glycoprotein I, a plasma protein that associates with the surfaces of endothelial cells and trophoblasts, and thrombin. In vivo, it is suspected that these antibodies bind to these and perhaps other proteins, thereby inducing a hypercoagulable state through uncertain mechanisms
The antibodies also frequently give a false-positive serologic test for syphilis because
the antigen in the standard assay is embedded in cardiolipin
Antiphospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease, such as
systemic lupus erythematosus (
Morphology Thrombi
can develop anywhere in the cardiovascular system and vary in size and shape depending on the involved site and the underlying cause
Arterial or cardiac thrombi vs venous Thrombi
usually begin at sites of turbulence or endothelial injury, whereas venous thrombi characteristically occur at sites of stasis.
arterial thrombi tend to grow
retrograde, while venous thrombi extend in the direction of blood flow; thus both propagate toward the heart.
The propagating portion of a thrombus is often poorly attached and therefore prone to
fragmentation and embolization
lines of Zahn
which are pale platelet and fibrin deposits alternating with darker red cell–rich layers. Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem clots from the bland nonlaminated clots that occur postmortem (see later).
Thrombi occurring in heart chambers or in the aortic lumen are designated
Mural thrombi
promotes cardiac mural thrombi
Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis or catheter trauma)
ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of
aortic thrombi
Arterial thrombi are frequently
occlusive; the most common sites in decreasing order of frequency are the coronary, cerebral, and femoral arteries. They typically consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes
Venous thrombosis (phlebothrombosis)
almost invariably occlusive, with the thrombus forming a long luminal cast. Because these thrombi form in the sluggish venous circulation, they tend to contain more enmeshed red cells (and relatively few platelets) and are therefore known as red, or stasis, thrombi
Venous thrombi are firm, are focally attached to the vessel wall, and contain
lines of Zahn, features that help distinguish them from postmortem clots
The veins of the lower extremities are most commonly involved (90% of cases)
Venous Thrombi
Postmortem clots
can sometimes be mistaken for antemortem venous thrombi. However, clots that form after death are gelatinous and have a dark red dependent portion where red cells have settled by gravity and a yellow “chicken fat” upper portion, and are usually not attached to the underlying vessel wall.
Thrombi on heart valves are called
Vegetations
Bloodborne bacteria or fungi can adhere to previously damaged valves (e.g., due to rheumatic heart disease) or can directly cause valve damage; in either case, endothelial injury and disturbed blood flow can induce the formation of large thrombotic masses
infective endocarditis;
Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states, so-called
Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states, so-called
Less commonly, sterile verrucous endocarditis
(Libman-Sacks endocarditis) can occur in the setting of systemic lupus erythematosus
Fate of the Thrombus
If a patient survives the initial thrombosis, in the ensuing days to weeks thrombi undergo some combination of the following four events:
- Propagation
- Embolization
- Dissolution
- Organization and Recanalization
Propagation.
hrombi accumulate additional platelets and fibrin (discussed earlier).
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. In contrast, the extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis.
This distinction explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis)
is generally effective only when given during the first few hours of a thrombotic event
Organization and recanalization
Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts (Fig. 4-14). Capillary channels eventually form that reestablish the continuity of the original lumen, albeit to a variable degree. Continued recanalization may convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. Eventually, with remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus.
fat embolism occurs in some 90% of individuals with
severe skeletal injuries (Fig. 4-16), but less than 10% of such patients have any clinical findings.
The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation via
a tear in the placental membranes or rupture of uterine veins. Classic findings at autopsy include the presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature (Fig. 4-17). Other findings include marked pulmonary edema, diffuse alveolar damage (Chapter 15), and the presence of fibrin thrombi in many vascular beds due to disseminated intravascular coagulation
