Stasis allows platelets and leukocytes to come into contact with the endothelium when the flow is sluggish. #201 | | |
| | |
Stasis also slows the washout of activated clotting factors and impedes the inflow of clotting factor inhibitors. #203 | | |
Turbulent and static blood flow contributes to throm- bosis in a number of clinical settings. Ulcerated athero- sclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations called aneurysms create local stasis and conse- quently are fertile sites for thrombosis (Chapter 9). 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 are more easily formed because of the local blood stasis (Chapter 11). Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial #204 | | |
dilation. In conjunction with atrial fibrillation, a dilated #205 | | |
atrium also produces stasis and is a prime location for the development of thrombi. Hyperviscosity syndromes (such as polycythemia vera, Chapter 12) increase resis- tance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia (Chapter 12) cause vascu- lar occlusions, and the resultant stasis also predisposes to thrombosis. #206 | | |
| | |
Hypercoagulability refers to an abnormally high ten- #208 | | |
dency of the blood to clot, and is typically caused by alterations in coagulation factors. It contributes infre- quently to arterial or intracardiac thrombosis but is an important underlying risk factor for venous thrombosis. The alterations of the coagulation pathways that predis- pose affected persons to thrombosis can be divided into primary (genetic) and secondary (acquired) disorders (Table 4.2). #209 | | |
Primary (inherited) hypercoagulability is most often caused by mutations in the factor V and prothrombin genes: #210 | | |
| | |
Approximately 2% to 15% of whites carry a specific factor V mutation (called the Leiden mutation, after the Dutch city where it was first described). Among those with recurrent deep venous thrombosis (DVT), the fre- quency of this mutation approaches 60%. The mutation alters an amino acid residue in factor V and renders it resistant to proteolysis by protein C. Thus, an impor- tant anti-thrombotic counterregulatory mechanism is lost. Heterozygotes carry a fivefold increased risk for venous thrombosis, with homozygotes having a 50-fold increased risk. #212 | | |
A single-nucleotide substitution (G to A) in the 3′-untranslated region of the prothrombin gene is a fairly common allele (found in 1%–2% of the general population). This variant results in increased prothrom- bin transcription and is associated with a nearly three- fold increased risk for venous thromboses. #213 | | |
| | |
Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as to the development of atherosclerosis (Chapter 10). 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. #215 | | |
| | |
Less common primary hypercoagulable states include inherited deficiencies of anti-coagulants such as anti- thrombin III, protein C, or protein S; affected patients typically present with venous thrombosis and recurrent thromboembolism in adolescence or in early adult life. #217 | | |
Although the risk of thrombosis is only mildly increased in heterozygous carriers of factor V Leiden and the pro- thrombin gene variant, these genetic factors carry added significance for two reasons. First, both abnormal alleles are sufficiently frequent that homozygous and compound heterozygous persons are not uncommon, and these indi- viduals are at much higher risk for thrombosis. More importantly, heterozygous individuals are at higher risk for venous thrombosis in the setting of other acquired risk factors, such as pregnancy, prolonged bed rest, and lengthy airplane flights. Consequently, inherited causes of hyper- coagulability should be considered in young patients (<50 years of age), even when other acquired risk factors are present. #218 | | |
Secondary (acquired) hypercoagulability is seen in many settings (Table 4.2). In some situations (e.g., cardiac failure or trauma), stasis or vascular injury may be the most important factor. The hypercoagulability associated with oral contraceptive use and the hyperestrogenic state of pregnancy may be related to increased hepatic synthesis of coagulation factors and reduced synthesis of anti-thrombin III. In disseminated cancers, release of procoagulant tumor products (e.g., mucin from adenocarcinoma) predisposes to thrombosis. The hypercoagulability seen with advanc- ing age has been attributed to increased platelet aggrega- tion and reduced release of PGI2 from endothelium. Smoking and obesity promote hypercoagulability by unknown mechanisms. #219 | | |
Among the acquired thrombophilic states, two are par- ticularly important clinical problems and deserve special mention: #220 | | |
| | |
Heparin-induced thrombocytopenia (HIT) syndrome. This syndrome occurs in up to 5% of patients treated with unfractionated heparin (for therapeutic anti-coagulation). It is marked by the development of autoantibodies that bind complexes of heparin and platelet membrane protein (platelet factor-4) (Chapter 12). Although the #222 | | |
Hemostasis and Thrombosis 109 mechanism is unclear, it appears that these antibodies #223 | | |
may also bind similar complexes present on platelet and endothelial surfaces, resulting in platelet activa- tion, aggregation, and consumption (hence thrombocy- topenia), 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. #224 | | |
Anti-phospholipid antibody syndrome. This syndrome (previously called the lupus anti-coagulant syndrome) has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve veg- etations, and thrombocytopenia. Depending on the vas- cular bed involved, the clinical presentations can include pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or 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. Anti-phospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses (Chapter 14). #225 | | |
The name anti-phospholipid antibody syndrome came from the detection in patients of circulating anti- bodies that bind to phospholipids. But this name is misleading, as it is believed that the most important pathologic effects are mediated through binding of the antibodies to epitopes on proteins that are somehow induced or “unveiled” by phospholipids. Suspected antibody targets include β2-glycoprotein I, a plasma protein that associates with the surfaces of endothe- lial cells and trophoblasts, and prothrombin. In vivo, it is suspected that these antibodies bind to these and perhaps other proteins, thereby inducing a hypercoag- ulable state through uncertain mechanisms. However, in vitro, the antibodies interfere with phospholipids and thus inhibit coagulation (hence the name lupus anticoagulant, also a misnomer). The antibodies also frequently provide a false-positive serologic test for syphilis because the antigen in the standard assay for syphilis is embedded in cardiolipin. #226 | | |
Anti-phospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease, such as systemic lupus erythema- tosus (Chapter 5), are designated as having secondary anti- phospholipid syndrome (hence the earlier term lupus antico- agulant syndrome). In primary anti-phospholipid syndrome, patients exhibit only the manifestations of a hyperco- agulable state and lack evidence of other autoimmune disorders; occasionally, it appears following exposure to certain drugs or infections. Therapy involves anti- coagulation and immunosuppression. Although anti- phospholipid antibodies are clearly associated with thrombotic diatheses, they have also been identified in 5% to 15% of apparently normal individuals, implying that they are necessary but not sufficient to cause the full-blown syndrome. #227 | | |
Table 4.2 Hypercoagulable States #228 | | |
| | |
Common (>1% of the Population) #230 | | |
Factor V mutation (G1691A mutation; factor V Leiden) Prothrombin mutation (G20210A variant) Increased levels of factor VIII, IX, or XI or fibrinogen #231 | | |
| | |
Anti-thrombin III deficiency Protein C deficiency Protein S deficiency #233 | | |
| | |
Fibrinolysis defects Homozygous homocystinuria (deficiency of cystathione β-synthetase) #235 | | |
Secondary (Acquired) High Risk for Thrombosis #236 | | |
Prolonged bed rest or immobilization Myocardial infarction #237 | | |
Atrial fibrillation Tissue injury (surgery, fracture, burn) Cancer #238 | | |
Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Anti-phospholipid antibody syndrome #239 | | |
Lower Risk for Thrombosis Cardiomyopathy #240 | | |
Nephrotic syndrome Hyperestrogenic states (pregnancy and postpartum) Oral contraceptive use #241 | | |
| | |
| | |
| | |
Thrombi can develop anywhere in the cardiovascular system. #245 | | |
Arterial or cardiac thrombi typically arise at sites of endothelial injury or turbulence; venous thrombi characteristically occur at sites of stasis. Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart; thus, arterial thrombi grow in a retrograde direction from the point of attachment, whereas 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. #246 | | |
Thrombi can have grossly (and microscopically) apparent laminations called 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 therefore usually dis- tinguish 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 shows ill-defined laminations. #247 | | |
Thrombi occurring in heart chambers or in the aortic lumen are designated as mural thrombi. Abnormal myocardial con- traction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis, catheter trauma) promote cardiac mural thrombi (Fig. 4.13A), whereas ulcerated atherosclerotic plaques and aneurysmal dilation promote aortic thrombosis (Fig. 4.13B). #248 | | |
Arterial thrombi are frequently occlusive. They are typically 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 underlying causes. Venous thrombi (phlebothrombosis) are almost invariably occlusive; they frequently propagate some distance toward the heart, forming a long cast within the vessel lumen that is prone to give rise to emboli. Because these thrombi form in the slug- gish 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); however, venous thrombi also can occur in the upper extremities, periprostatic plexus, or ovarian and periuterine veins, and under special circumstances they may be found in the dural sinuses, portal vein, or hepatic vein. #249 | | |
At autopsy, postmortem clots can sometimes be mistaken for venous thrombi. However, the former are gelatinous and because of red cell settling they have a dark red dependent portion and a yellow “chicken fat” upper portion; they also are usually not attached to the underlying vessel wall. By contrast, red thrombi typically are firm, focally attached to vessel walls, and they contain gray strands of deposited fibrin. #250 | | |
