Thrombosis & Embolism: Pathologic Features

Thrombus formation and morphology

Virchow's triad. Thrombosis follows endothelial injury, abnormal blood flow (turbulence in arteries and heart chambers, stasis in veins), hypercoagulability, or a combination. Endothelial injury dominates in the heart and arteries; stasis and hypercoagulability dominate in veins. A thrombus, by definition, forms inside the vessels of a living person, whereas a clot can form anywhere, including a test tube or the vessels after death.

Lines of Zahn. Thrombi that form in flowing blood are laminated: pale layers of platelets and fibrin alternate with darker layers rich in red cells. These lines of Zahn, visible grossly and microscopically, prove that the thrombus formed during life. Antemortem thrombi are firmly attached to the vessel or heart wall at their point of origin and become dry and friable as they age.

Postmortem clots. After death, blood clots without flow, so red cells settle by gravity. The result is a dark red, gelatinous dependent portion (currant jelly) beneath a yellow, fibrin-rich upper layer (chicken fat). Postmortem clots lack lines of Zahn and are not attached, so they lift out of the vessel easily.

Arterial versus venous thrombi

Arterial and cardiac thrombi. In high-flow vessels, thrombi are pale and platelet-rich and grow backward (retrograde) from their attachment. They usually form on ruptured atherosclerotic plaques in coronary, cerebral, and femoral arteries and are often occlusive. Mural thrombi line the heart chambers or aorta: over an akinetic ventricular wall after MI, in dilated cardiomyopathy, in the left atrial appendage in atrial fibrillation or mitral stenosis, and within aortic aneurysms.

Venous thrombi. Phlebothrombosis occurs in sluggish flow and traps many red cells in fibrin, giving red, usually occlusive thrombi that extend toward the heart as long casts of the vein. More than 90% arise in the deep veins of the legs; proximal (popliteal, femoral, iliac) thrombi are the main source of pulmonary emboli.

At autopsy a venous thrombus can mimic a postmortem clot, but it is firmer, anchored at its origin, and shows at least faint lines of Zahn.

Fates of a thrombus

• Propagation: added platelets and fibrin enlarge it toward complete obstruction.
• Embolization: all or part breaks off and travels.
• Dissolution: plasmin-mediated fibrinolysis removes it, mainly while it is fresh.
• Organization and recanalization: endothelial cells, smooth muscle cells, and fibroblasts grow in, and new capillary channels partly restore flow; the remnant may merge into a thickened vessel wall.

Fibrin cross-links as a thrombus ages, so older thrombi resist lysis; thrombolytic therapy works only in the first hours.

Thromboembolism: pulmonary, systemic, and paradoxical

Pulmonary emboli. Most come from deep leg-vein thrombi. Many are clinically silent; a large saddle embolus at the pulmonary artery bifurcation can cause sudden death or acute right heart failure, and because the lung has a dual (bronchial) blood supply, only a minority of emboli cause infarction.

Systemic emboli. About 80% arise from intracardiac mural thrombi, mostly over post-MI left ventricular walls and in dilated, fibrillating left atria; the rest come from aortic aneurysms, ulcerated plaques, and valve vegetations. They lodge mainly in the lower extremities (about 75%) and brain (about 10%), and also in the intestines, kidneys, and spleen. The kidney and spleen have end-arterial supply, so their infarcts are pale and wedge-shaped.

Paradoxical emboli. A venous thrombus reaches the systemic arteries only through a right-to-left shunt: usually a patent foramen ovale, present in about a quarter of adults, or an atrial septal defect. The shunt opens when right atrial pressure rises with Valsalva, coughing, pulmonary embolism, or pulmonary hypertension. The classic scenario is a stroke in a young patient with a DVT.

Nonthrombotic emboli

Fat embolism. After long-bone (especially femoral) or pelvic fractures, marrow fat enters torn venules. Microscopic fat emboli are common, but only a minority of patients develop fat embolism syndrome, typically 24–72 hours after injury: hypoxemia and respiratory distress, neurologic change from confusion to coma, and petechiae on the chest, axillae, and conjunctivae, often with thrombocytopenia. Damage is obstructive and chemical, because free fatty acids released from the globules injure endothelium.

Air embolism. Air entering veins during central line insertion or removal, chest trauma, laparoscopy, or obstetric procedures coalesces into frothy masses that obstruct the right ventricular outflow or pulmonary vessels; usually more than 100 mL is needed to cause symptoms. A churning mill-wheel murmur may be heard. An upright position lowers central venous pressure and draws air in, so head-down positioning and occluding the site during line manipulation prevent it; for suspected air embolism the patient is placed left side down and head down (Durant maneuver).

Decompression sickness. Breathing gas at high pressure during diving dissolves extra nitrogen in blood and tissues; rapid ascent releases N₂ bubbles. Acute effects are the bends (joint and muscle pain), the chokes (dyspnea, pulmonary edema), and neurologic deficits; treatment is hyperbaric recompression. The chronic form, caisson disease, produces ischemic (avascular) necrosis of the femoral heads, tibiae, and humeri.

Amniotic fluid embolism. During labor or just after delivery, fluid enters torn uterine or endocervical veins. Abrupt dyspnea, cyanosis, hypotensive shock, and seizures are followed by DIC, driven by the fluid's procoagulant (tissue factor) activity. The maternal pulmonary microvessels contain fetal squamous cells, lanugo hair, vernix fat, and mucin.

Cholesterol (atheroembolic) emboli. Arterial catheterization, aortic surgery, or anticoagulation and thrombolysis can dislodge cholesterol crystals from ulcerated aortic plaques. Days to weeks later: blue toes with intact pedal pulses, livedo reticularis, subacute kidney injury, eosinophilia and eosinophiluria, low complement, and bright retinal Hollenhorst plaques. Biopsies show biconvex, needle-shaped clefts where the crystals dissolved during processing; contrast nephropathy, by contrast, appears within 1–3 days without livedo or eosinophilia.

Septic and tumor emboli. Left-sided endocarditis seeds the brain, spleen, and kidneys with infarcts and abscesses and can create mycotic aneurysms (infected, weakened arterial walls, usually bacterial despite the name). Tricuspid endocarditis in people who inject drugs sends septic emboli to the lungs, producing peripheral nodules that cavitate. Tumor emboli come from cancers that invade veins, such as renal cell carcinoma growing into the renal vein and IVC and hepatocellular carcinoma into hepatic and portal veins, or from fragments of an atrial myxoma.