• Thrombosis = formation of a clot inside the vascular system.
• The three major causes are the Virchow triad (Fig. 3.12):
  • Endothelial injury
  • Stasis or turbulent blood flow
  • Hypercoagulability of blood
• Thrombosis is important because it underlies many serious and common cardiovascular diseases.

Endothelial Injury

• Endothelial injury → platelet activation → thrombus formation, especially in the heart and arteries.
• In arteries, rapid blood flow normally makes clot formation difficult.
• Therefore, platelet adhesion and activation are especially important for thrombus formation under high shear stress.
• Cardiac and arterial thrombi are therefore usually platelet-rich.
• This explains why aspirin and other platelet inhibitors are used in:
  • coronary artery disease
  • acute myocardial infarction
• Severe endothelial injury promotes thrombosis by exposing:
  • vWF → promotes platelet adhesion
  • tissue factor → activates coagulation
• Endothelium may also become activated or dysfunctional without major physical disruption.
• This changes endothelial activity from normally antithrombotic toward a prothrombotic state.
• Causes of endothelial activation/dysfunction include:
  • physical injury
  • infections
  • abnormal blood flow
  • cytokines and inflammatory mediators
  • hypercholesterolemia
  • homocystinemia
  • toxins from cigarette smoke
• Endothelial activation is particularly important in arterial thrombosis.
• Procoagulant changes:
  • Activated endothelium decreases normal coagulation inhibitors:
    • thrombomodulin
    • endothelial protein C receptor
    • tissue factor pathway inhibitor
  • It also increases tissue factor.
  • Result → more coagulation.
• Antifibrinolytic effects:
  • Activated endothelium increases plasminogen activator inhibitors (PAI).
  • PAI inhibits t-PA and urokinase.
  • Therefore → less fibrinolysis → clot persists more easily.

KEY CONCEPT

• Virchow triad = endothelial injury + abnormal blood flow + hypercoagulability.
• In arteries, endothelial injury and platelet activation are especially important.
• Activated endothelium becomes prothrombotic by:
  ↑ tissue factor + ↓ anticoagulant factors + ↑ PAI → ↓ fibrinolysis.

CONCEPTUAL EXAMPLES

• Arterial endothelial damage → vWF exposed → platelets adhere and activate → platelet-rich thrombus.
• Endothelial activation → ↓ thrombomodulin + ↑ tissue factor → coagulation increases.
• ↑ PAI → t-PA is inhibited → fibrin is removed less effectively → clot remains and can enlarge.

Abnormal Blood Flow

• Turbulence = chaotic blood flow → promotes arterial and cardiac thrombosis by:
  • causing endothelial injury/dysfunction
  • creating countercurrents and local areas of stasis
• Stasis = slowed or stopped blood flow → especially important in venous thrombosis.
• Normally, laminar blood flow keeps platelets and other blood cells mainly in the center of the vessel, separated from endothelium by a slower-moving plasma layer.
• Stasis and turbulence promote thrombosis because they:
  • activate endothelium → ↑ procoagulant activity
  • allow platelets and leukocytes to contact endothelium
  • reduce washout of activated clotting factors
  • reduce inflow of coagulation inhibitors
• Important clinical settings:
  • Ulcerated atherosclerotic plaque → exposes subendothelial ECM + produces turbulence → thrombosis.
  • Aneurysm → abnormal arterial dilation → local stasis → thrombus formation.
  • Acute myocardial infarction → noncontracting myocardium → local stasis → mural thrombus.
  • Previous infarction may cause ventricular aneurysm → more stasis → mural thrombus.
  • Mitral stenosis → left atrial dilation.
  • Left atrial dilation + atrial fibrillation → stasis + turbulence → thrombus formation.
  • Hyperviscosity, such as polycythemia vera → ↑ resistance to flow → small-vessel stasis → thrombosis.

Hypercoagulability

• Hypercoagulability = abnormally increased tendency of blood to clot.
• It usually results from abnormalities in coagulation factors.
• It is especially important in venous thrombosis, but may also contribute to arterial or intracardiac thrombosis.
• Causes are divided into primary (genetic) and secondary (acquired) disorders (Table 3.2).
• Primary inherited hypercoagulability is most commonly caused by mutations involving factor V or prothrombin.

• Factor V Leiden mutation:
  • Factor V becomes resistant to breakdown by protein C.
  • Therefore, an important anticoagulant mechanism is lost.
  • Heterozygotes → about 3–4× increased risk of venous thrombosis.
  • Homozygotes → about 25–50× increased risk.
  • It is common among patients with recurrent DVT.
• Prothrombin gene variant:
  • Causes ↑ prothrombin production.
  • Associated with about 3× increased risk of venous thrombosis.
• Less common inherited causes include deficiency of:
  • antithrombin
  • protein C
  • protein S
• These patients often develop venous thrombosis and recurrent thromboembolism at a young age.
• Markedly ↑ homocysteine, such as with inherited cystathionine β-synthetase deficiency → increased risk of arterial and venous thrombosis.
• More modest elevations of homocysteine may also increase venous thromboembolism risk.
• Genetic risk becomes more important when combined with acquired risks such as:
  • pregnancy
  • prolonged bed rest
  • long airplane flights
• Therefore, inherited hypercoagulability should be considered especially in patients younger than 50 years with thrombosis.
• Most patients with DVT have no known genetic abnormality, and most people with factor V Leiden never develop DVT.
• Genetic testing is therefore mainly considered in:
  • strong family history of DVT
  • DVT at a young age without an obvious acquired risk factor
• Secondary acquired hypercoagulability occurs in many conditions.
• Important mechanisms include:
  • Trauma or cardiac failure → vascular injury or stasis.
  • Oral contraceptives and pregnancy → ↑ hepatic coagulation-factor synthesis + ↓ antithrombin synthesis.
  • Disseminated cancer → tumor products such as mucin promote coagulation.
  • Increasing age → ↑ platelet aggregation + ↓ endothelial PGI₂.
  • Smoking and obesity → promote hypercoagulability by uncertain mechanisms.
• Heparin-induced thrombocytopenia (HIT):
  • May occur after unfractionated heparin treatment.
  • Autoantibodies form against heparin–platelet factor 4 (PF4) complexes.
  • Antibody complexes bind platelet Fc receptors → platelet activation + aggregation + removal from blood.
  • Result → low platelets but increased thrombosis.
  • Low-molecular-weight heparin causes this less often but can still cause thrombosis.
• Antiphospholipid antibody syndrome may cause:
  • recurrent thrombosis
  • repeated miscarriages
  • cardiac valve vegetations
  • thrombocytopenia
• Depending on the vessels involved, it may produce:
  • DVT → pulmonary embolism
  • recurrent pulmonary emboli → pulmonary hypertension
  • stroke
  • bowel infarction
  • renovascular hypertension
  • renal microangiopathy with renal failure
• Fetal loss appears to result mainly from antibody interference with trophoblast growth and placentation, rather than simply thrombosis.
• The name “antiphospholipid antibody” is somewhat misleading.
• The antibodies probably act against proteins associated with phospholipids, especially β₂-glycoprotein I.
• In the body, these antibodies promote a hypercoagulable state.
• In laboratory tests, however, they interfere with phospholipid-dependent clotting assays and therefore behave like “anticoagulants.”
• They may also cause a false-positive syphilis test because the test antigen contains the phospholipid cardiolipin.
• Antiphospholipid antibody syndrome may be:
  • Secondary → associated with an autoimmune disease such as systemic lupus erythematosus.
  • Primary → hypercoagulability occurs without another recognized autoimmune disease.
• Treatment involves anticoagulation and immunosuppression.
• Antiphospholipid antibodies may also occur in healthy people, so their presence alone is not sufficient to produce the full syndrome.

KEY CONCEPT

• Turbulence → mainly arterial/cardiac thrombosis.
• Stasis → mainly venous thrombosis.
• Abnormal flow promotes clotting by:
  endothelial activation + platelet contact + retained clotting factors + reduced anticoagulant inflow.
• Hypercoagulability = excessive tendency to clot.
• Major inherited causes → Factor V Leiden + prothrombin mutation.
• Important acquired causes → pregnancy, oral contraceptives, cancer, age, smoking, obesity, HIT, antiphospholipid syndrome.
• HIT = thrombocytopenia + paradoxical thrombosis.
• Antiphospholipid syndrome = thrombosis despite laboratory “anticoagulant” activity.

CONCEPTUAL EXAMPLES

• Atrial fibrillation → chaotic flow + atrial stasis → atrial thrombus.
• Aneurysm → blood stagnates inside dilated vessel → thrombus forms.
• Factor V Leiden → protein C cannot inactivate factor V normally → clotting persists longer.
• Heparin → anti-PF4 antibodies activate platelets → platelets fall but thrombosis increases.
• Antiphospholipid antibodies → hypercoagulable state → recurrent thrombosis or pregnancy loss.

MORPHOLOGY

• Thrombi can form anywhere in the cardiovascular system.
• Arterial/cardiac thrombi usually form where there is:
  • endothelial injury, or
  • turbulent blood flow.
• Venous thrombi usually form where there is stasis.
• Thrombi are attached to the vessel wall and tend to propagate toward the heart:
  • Arterial thrombi → grow backward (retrograde) from the attachment point.
  • Venous thrombi → grow in the direction of blood flow.
• The growing end of a thrombus is often poorly attached → may break off → travel in blood as an embolus.
• Thrombi may show visible layers called lines of Zahn:
  • pale layers = platelets + fibrin
  • dark layers = red blood cells
• Lines of Zahn form only in flowing blood → therefore indicate antemortem thrombosis.
• Postmortem clots are usually nonlaminated, although venous thrombi may sometimes resemble them.
• Thrombi inside heart chambers or the aorta are called mural thrombi.
• Cardiac mural thrombi are promoted by:
  • arrhythmias
  • dilated cardiomyopathy
  • myocardial infarction
  • myocarditis
  • catheter injury (Fig. 3.13A).
• Ulcerated atherosclerotic plaques and aneurysmal dilation promote aortic thrombosis (Fig. 3.13B).
• Arterial thrombi:
  • are frequently occlusive.
  • are usually platelet-rich because endothelial injury activates platelets.
  • commonly form over a ruptured atherosclerotic plaque.
  • may also follow vasculitis or trauma.
• Venous thrombi (phlebothrombosis):
  • are almost always occlusive.
  • often extend toward the heart as a long cast of the vessel.
  • are prone to producing emboli.
  • contain many trapped red cells because they form in sluggish blood → called red or stasis thrombi.
• About 90% of venous thromboses occur in the lower-extremity veins.
• They may also occur in upper-extremity veins, periprostatic plexus, ovarian and periuterine veins.
• In hypercoagulable states, thrombi may also occur in dural sinuses, portal vein, or hepatic vein.
• Postmortem clots may resemble venous thrombi but:
  • are gelatinous
  • are not attached to the vessel wall
  • have a dark red dependent part from settled RBCs
  • have a yellow upper “chicken fat” portion.
• In contrast, true red thrombi are:
  • firm
  • focally attached to the vessel wall
  • contain gray strands of fibrin.

KEY CONCEPT

• Arterial/cardiac thrombus → injury or turbulence → platelet-rich.
• Venous thrombus → stasis → RBC-rich (“red thrombus”).
• Lines of Zahn → clot formed during life in flowing blood.
• Poorly attached thrombus tail → may detach → embolus.
• Postmortem clot = gelatinous + unattached; true thrombus = firm + attached.

CONCEPTUAL EXAMPLES

• Ruptured atherosclerotic plaque → platelet activation → arterial thrombus.
• Slow venous blood in the leg → RBC-rich clot → venous/stasis thrombus.
• Part of a venous thrombus breaks off → travels through blood → embolus.
• Firm attached clot with lines of Zahn → formed before death.
• Gelatinous unattached “chicken-fat” clot → formed after death.

• Thrombi that form on heart valves are called vegetations.
• Bacterial or fungal bloodstream infection → valve damage → large thrombotic vegetations → infective endocarditis.
• Vegetations can also occur without infection.
• In hypercoagulable states:
  • sterile vegetations may form on normal, noninfected valves.
  • This is called nonbacterial thrombotic endocarditis.
• Less commonly, systemic lupus erythematosus (SLE) may cause sterile verrucous endocarditis (Libman-Sacks endocarditis) (eFig. 3.4).

KEY CONCEPT

• Valve thrombus = vegetation.
• Infection → infective endocarditis.
• Hypercoagulability → sterile nonbacterial thrombotic endocarditis.
• SLE → sterile Libman-Sacks endocarditis.

CONCEPTUAL EXAMPLES

• Bacteria in blood → valve injury + thrombotic mass → infective endocarditis.
• Hypercoagulable state + no infection → sterile valve vegetation → nonbacterial thrombotic endocarditis.
• SLE → sterile verrucous valve vegetations → Libman-Sacks endocarditis.

Fates of Thrombi

• If a patient survives the initial thrombotic event, the thrombus can undergo four possible changes over days to weeks:
• Propagation:
  • More platelets + fibrin accumulate on the thrombus.
  • Thrombus enlarges → ↑ chance of vessel occlusion and embolization.
• Embolization:
  • Part or all of the thrombus breaks free.
  • It travels through the circulation to another site.
• Dissolution:
  • A newly formed thrombus can be rapidly broken down by activation of fibrinolytic factors.
  • It may shrink or completely disappear.
  • As a thrombus becomes older → extensive fibrin polymerization makes it increasingly resistant to plasmin-mediated breakdown.
  • Therefore, fibrinolytic drugs such as t-PA are generally most effective when given within the first few hours of acute coronary thrombosis.
• Organization and recanalization:
  • Older thrombi are invaded by:
    • endothelial cells
    • smooth muscle cells
    • fibroblasts
  • This process is called organization (Fig. 3.14).
  • Small capillary channels then develop through the thrombus.
  • These channels partially restore blood flow through the original vessel → recanalization.
  • Further organization may convert the thrombus into vascularized connective tissue that becomes incorporated into the vessel wall.
  • Occasionally, instead of organization, the center of the thrombus undergoes enzymatic digestion, probably from lysosomal enzymes released by trapped leukocytes.

KEY CONCEPT

• Remember the 4 fates of a thrombus:

Propagation → Embolization → Dissolution → Organization/Recanalization

• Propagation = clot gets bigger.
• Embolization = clot breaks off and travels.
• Dissolution = fresh clot is broken down.
• Organization/recanalization = old clot becomes incorporated into tissue and develops new channels for blood flow.
• Fresh thrombi respond better to fibrinolysis; older thrombi become resistant.

CONCEPTUAL EXAMPLES

• More fibrin and platelets collect → thrombus enlarges → propagation.
• Piece of thrombus breaks off → travels elsewhere → embolization.
• Fresh coronary thrombus + early t-PA → clot may dissolve → dissolution.
• Old thrombus → cells grow into it → small channels form through it → organization + recanalization.

Clinical Features

• Thrombi are dangerous mainly because they:
  • obstruct arteries or veins
  • may break off and form emboli
• Clinical effect depends mainly on the site of thrombosis.
• Venous thrombi:
  • obstruct venous return → congestion + edema
  • greatest danger → embolize to the lungs → potentially fatal pulmonary embolism
• Arterial thrombi:
  • may embolize, but more importantly they block local blood flow
  • obstruction of coronary or cerebral arteries → infarction
• Most venous thrombi occur in superficial or deep veins of the legs.
• Superficial venous thrombosis:
  • commonly occurs in the saphenous veins, especially with varicose veins
  • rarely embolizes
  • may cause pain + local congestion + swelling
  • impaired venous drainage may predispose to skin infection and varicose ulcers
• Deep venous thrombosis (DVT):
  • commonly involves large veins at or above the knee:
    • popliteal
    • femoral
    • iliac veins
  • more serious because it can embolize to the lungs
  • may cause pain and edema, but collateral veins can bypass the obstruction
  • therefore, about 50% of DVTs may be asymptomatic until pulmonary embolization occurs
• Lower-limb DVT is strongly associated with stasis + hypercoagulability (Table 3.2).
• Common predisposing factors:
  • Congestive heart failure → venous stasis
  • Bed rest/immobilization → ↓ leg-muscle pumping → ↓ venous return
  • Trauma, surgery, burns → immobilization + vascular injury + increased procoagulant activity + ↓ t-PA
  • Pregnancy → enlarged uterus/fetus compresses leg veins → stasis; late pregnancy and postpartum hormonal changes → hypercoagulability
  • Disseminated cancer → tumor procoagulants → increased thrombosis
• Cancer-associated recurrent thrombosis in different venous sites is called migratory thrombophlebitis or Trousseau syndrome.
• DVT risk increases after 50 years of age and is greater in males than females.
• Atherosclerosis promotes arterial thrombosis through endothelial injury and abnormal blood flow (Fig. 3.13B).
• Myocardial infarction may cause abnormal ventricular contraction + endocardial injury → mural thrombus (Fig. 3.13A).
• Rheumatic heart disease may cause atrial dilation + atrial fibrillation → stasis → mural thrombus.
• Cardiac and aortic mural thrombi may embolize, especially to organs with rich blood flow:
  • brain
  • kidneys
  • spleen

Disseminated Intravascular Coagulation (DIC)

• DIC = widespread formation of thrombi throughout the microcirculation.
• It may develop suddenly or gradually.
• It can occur in conditions ranging from obstetric complications to advanced malignancy.
• Widespread clotting consumes:
  • platelets
  • coagulation factors
• Therefore, DIC is also called consumptive coagulopathy.
• At the same time, fibrinolysis is activated.
• Final result:
  widespread clotting + consumption of clotting components + fibrinolysis → thrombosis and bleeding can occur together.

KEY CONCEPT

• Venous thrombus → major danger = pulmonary embolism.
• Arterial thrombus → major danger = local obstruction → infarction.
• DVT may be silent in about 50% of patients.
• DVT is promoted mainly by stasis + hypercoagulability.
• Cancer-associated migratory thrombosis = Trousseau syndrome.
• DIC = widespread microthrombi + consumption of platelets/coagulation factors → simultaneous clotting and bleeding.

CONCEPTUAL EXAMPLES

• Bed rest → leg muscles stop pumping effectively → venous stasis → DVT.
• DVT breaks off → travels to lungs → pulmonary embolism.
• Coronary arterial thrombus → blocks blood flow → myocardial infarction.
• Cancer releases procoagulants → repeated thrombosis in different veins → Trousseau syndrome.
• DIC → many tiny clots use up platelets and clotting factors → patient can clot and bleed at the same time.