Lecture 7: Thrombosis and Embolism

Thrombosis and Embolism

A thrombus is a blood clot that forms inside a vessel where it shouldn’t

A clot can block blood flow → tissue doesn’t get enough oxygen

An embolus is a piece of clot that breaks off and travels

Emboli can get stuck in another vessel and cause problems

In the lungs → pulmonary embolism

In the brain → stroke

In the heart → heart attack

Virchow’s Triad

Three main factors explain why clots form inside vessels

Endothelial injury: Damage to vessel lining makes it “sticky” for platelets

Abnormal blood flow: Stasis or turbulence slows blood and promotes clotting

Hypercoagulability: Blood is more likely to clot due to genetic or acquired conditions

Most cases of thrombosis involve more than one of these factors

Endothelial Injury

Normal endothelium prevents clotting

Releases prostacyclin and nitric oxide → stop platelets from sticking

Has anticoagulant properties (thrombomodulin, TF pathway inhibitor)

When injured, endothelium promotes clotting

Exposes collagen and tissue factor → platelets stick and clotting begins

Causes include atherosclerosis, high blood pressure, toxins, infection, inflammation

Even without rupture, “activated” endothelium can tip balance

↑ Tissue factor and plasminogen activator inhibitor (PAI-1)

↓ Thrombomodulin → less anticoagulant activity

Abnormal Blood- Stasis

Normal flow is laminar

Platelets and cells flow in the center

Plasma separates them from endothelium

Abnormal flow promotes clotting

Stasis slows washout of clotting factors and brings platelets in contact with vessel wall

Turbulence disrupts laminar flow and injures endothelium

Common causes:

Atrial fibrillation → stasis in atrial appendage

Aneurysms → turbulence and local stasis

Bed rest/immobility → venous stasis in legs

Varicose veins → stasis and superficial thrombosis

Hypercoagulability

An abnormal tendency of blood to clot due to change in the balance of pro and anti clotting mechanisms

Factor V Leiden mutation → most common inherited thrombophilia

Prothrombin G20210A mutation → ↑ prothrombin levels

Protein C, Protein S, or Antithrombin III deficiency

Pregnancy or oral contraceptives → estrogen increases clotting factors

Cancer → tumors release pro-coagulant substances

Heparin-induced thrombocytopenia (HIT) → antibody-mediated platelet activation

Antiphospholipid antibody syndrome (APS) → autoantibodies promote thrombosis

Often contributes to venous thrombosis (DVT, pulmonary embolism)

Venous clots are more likely than arterial clots

Suspect in young patients with unexplained or recurrent clots

Factor V Leiden mutation

Most common inherited form

Mutation leads to resistance to Protein C inactivation

Prothrombin G20210A mutation

Mutation in noncoding region → ↑ mRNA processing

Increased prothrombin levels → ↑ thrombin generation

Protein C deficiency

Autosomal dominant, impaired inactivation of Va, VIIIa

Protein S deficiency

Co-factor for Protein C, deficiency → hypercoagulability

Antithrombin deficiency

Impaired inhibition of thrombin and Xa

Homocystinuria

Can’t break down Methionine

High plasma homocysteine damages endothelial cells

High plasma homocysteine activates platelets

Acquired Thrombophilia

Increased tendency to clot due to medical or environmental conditions

Pregnancy and oral contraceptives → estrogen increases clotting factors, decreases anticoagulants

Malignancy → tumor cells release tissue factor and procoagulant cytokines

Prolonged immobility or bed rest → venous stasis + risk of DVT

Obesity and aging → associated with inflammation and higher PAI-1 levels

Heparin-induced thrombocytopenia (HIT) → antibodies to PF4-heparin activate platelets

Antiphospholipid antibody syndrome (APS) → autoantibodies promote arterial and venous thrombosis, pregnancy loss

Usually manifests as venous clots (DVT, pulmonary embolism)

Heparin-induced thrombocytopenia (HIT)

Immune reaction to heparin that paradoxically causes clotting

Antibodies form against heparin bound to platelet factor 4 (PF4)

Antibody-PF4-heparin complexes activate platelets

Platelet activation → thrombosis, even though platelet count drops

Onset usually 5–10 days after starting heparin

Platelet count falls by >50% from baseline

Complications include DVT, pulmonary embolism, stroke, limb ischemia, skin necrosis

Antiphospholipid antibody syndrome (APS)

Clinical syndrome caused by antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, β2-glycoprotein I)

Characterized by clotting in arteries and veins, pregnancy complications, and abnormal lab findings

Recurrent venous thrombosis (DVT, pulmonary embolism)

Arterial thrombosis (stroke, MI, limb ischemia)

Recurrent pregnancy loss, stillbirth, or severe preeclampsia

Thrombocytopenia may occur

Prolonged PTT that does not correct with mixing study

Anticardiolipin antibody → false-positive syphilis (VDRL/RPR)

Primary APS (no underlying disease)

Secondary APS (commonly associated with systemic lupus erythematosus)

Deep Vein Thrombosis

Thrombus formation in the deep veins, most often legs (popliteal, femoral, iliac)

Pathogenesis (Virchow’s Triad): Stasis; Bed rest, immobility, long flights; Post-surgical or post-trauma states; Hypercoagulability

Cancer, pregnancy, oral contraceptives/estrogen therapy

Genetic thrombophilias (e.g., Factor V Leiden, prothrombin mutation)

Endothelial injury

Trauma, surgery, venous catheters

May be asymptomatic

Classic symptoms: calf/thigh swelling, pain, warmth, erythema

Unilateral edema

Pulmonary embolism (95% of pulmonary emboli arise from leg DVTs above the knee)

Chronic venous insufficiency → stasis dermatitis, varicose ulcers

Post-thrombotic syndrome → chronic pain, swelling, skin thickening

Labs: D-dimer elevate

Morphology of Thrombus

Lines of Zahn:

Alternating pale layers (platelets + fibrin) and darker layers (red cells)

Indicate thrombus formed in flowing blood (antemortem)

Arterial thrombi:

Platelet-rich, pale in color

Often form over ruptured atherosclerotic plaques

Usually occlusive

Venous thrombi:

Rich in red cells (“red thrombi”)

Almost always occlusive

Propagate in the direction of blood flow (toward the heart)

Valve vegetations:

Thrombi on heart valves

Seen in infective endocarditis, nonbacterial thrombotic endocarditis, or Libman–Sacks endocarditis in SLE

Mural Thrombus

A thrombus that forms inside a heart chamber or large artery

Adheres to the wall rather than filling the entire lumen

After myocardial infarction → damaged endocardium, akinetic wall

Atrial fibrillation → stasis in left atrial appendage

Dilated cardiomyopathy or myocarditis → poor contractility

Aortic aneurysm → turbulence and endothelial injury

Major source of systemic (arterial) emboli: Stroke, Limb ischemia, Renal or splenic infarcts

Fate of a Thrombus

Propagation:

Thrombus enlarges along vessel

May further obstruct blood flow

↑ Risk of embolization

Embolization:

Part or all of thrombus breaks off

Travels downstream as an embolus

Can lodge in lungs (PE) or systemic arteries (stroke, infarct)

Dissolution:

Fresh thrombi may be removed by fibrinolysis (plasmin)

Most effective in early stages before clot becomes organized

Organization and Recanalization:

Fibroblasts and endothelial cells grow into thrombus

Thrombus incorporated into vessel wall (scar)

New capillary channels may form → partial restoration of blood flow

Outcome depends on size, location, and balance of coagulation vs fibrinolysis

Embolism

Detached solid, liquid, or gas mass carried in the blood

Travels to a site distant from its origin

Thromboembolism:

Most common type of embolus

Arises from a thrombus (blood clot) that breaks free

Infarction: Area of ischemic necrosis caused by arterial or venous occlusion

Pulmonary embolism (PE): Embolus that lodges in pulmonary arteries; Systemic venous thrombi are the usual source

Systemic (arterial) embolism:

Embolus from the heart or large arteries

Travels to brain, limbs, kidneys, spleen, bowel

Fat/marrow embolism, air embolism, amniotic fluid embolism, tumor emboli

Always distinguish venous (→ lungs) from arterial (→ systemic organs) emboli

Thromboembolism

Most common type

Fragments of a thrombus

Venous → pulmonary embolism

Arterial → systemic infarction (brain, limb, viscera)

Paradoxical thromboembolism: A venous thrombus crosses into the arterial circulation through a right-to-left shunt (most often a patent foramen ovale), allowing a clot to bypass the lungs and cause systemic embolism such as stroke or limb ischemia

Fat and Marrow Embolism

Follows long bone fractures or trauma

Fat globules enter bloodstream

Can cause respiratory distress and petechial rash

Venous/Pulmonary Embolism

An embolus that lodges in the pulmonary arteries

>95% of PEs arise from large leg veins above the knee (popliteal, femoral, iliac)

Thrombus fragment travels → right heart → pulmonary arteries

Small PEs may be silent

Larger emboli cause sudden shortness of breath, chest pain, tachypnea, hypoxia

Massive “saddle embolus” at pulmonary artery bifurcation → sudden death

Recurrent small emboli → pulmonary hypertension and right heart failure (cor pulmonale)

Pulmonary hemorrhage or infarction (if dual blood supply is compromised)

Sudden death from acute right heart strain

Chronic thromboembolic pulmonary hypertension

Pulmonary Embolism Clinical Features

Presentation is highly variable

Small emboli → often asymptomatic

Moderate emboli → pleuritic chest pain, dyspnea, tachypnea, cough, hemoptysis

Large emboli → sudden shortness of breath, syncope, hypotension, shock, sudden death

Dyspnea (most common)

Tachypnea, tachycardia

Pleuritic chest pain, hemoptysis if pulmonary infarct

Syncope or collapse in massive PE

May show cyanosis, signs of right heart strain

Leg swelling or tenderness may suggest DVT source

Systemic Arterial Emboli

Emboli that travel in the arterial circulation and block systemic vessels

Intracardiac mural thrombi (most common, especially after left ventricular MI)

Atrial fibrillation → left atrial appendage thrombus

Valvular vegetations (infective or nonbacterial endocarditis)

Aortic aneurysms or ulcerated atherosclerotic plaques

Paradoxical emboli crossing through a PFO or septal defect

Lower extremities (≈75%) → sudden pain, pallor, pulselessness, possible gangrene

Brain (≈10%) → ischemic stroke

Other sites: intestine (mesenteric infarction), kidney, spleen, retina

Almost always cause tissue infarction

Urgent recognition and revascularization are critical to limit damage

Fat and Marrow Embolism

Usually follows long bone fractures, orthopedic surgery, or severe trauma

Fat globules and marrow elements enter venous circulation

Pathogenesis: mechanical obstruction + toxic injury from free fatty acids

Clinical: 1–3 days post-injury

Respiratory distress / hypoxemia (ARDS)

Neurologic symptoms (confusion, coma, seizures)

Petechial rash (skin, conjunctiva) from thrombocytopenia

Air Embolism

Air bubbles in circulation obstruct flow

Causes: trauma, surgery, central venous lines, obstetric procedures

Decompression sickness (divers, caisson workers)

Amniotic Fluid Embolism

Rare but catastrophic complication of labor or delivery

Amniotic fluid (fetal cells, hair, vernix) enters maternal circulation via uterine veins

Sudden dyspnea, cyanosis, shock

Followed by seizures, coma, and disseminated intravascular coagulation (DIC)

Maternal mortality 40–60%; survivors often with permanent neurologic injury

Infant also at high risk if event occurs before delivery

Infarction

Area of ischemic necrosis caused by obstruction of blood supply or venous drainage

Arterial thrombosis or arterial embolism

Occasionally venous outflow obstruction (e.g., torsion of ovary/testis)

Myocardial infarction (heart attack)

Cerebral infarction (ischemic stroke)

Pulmonary infarction

Bowel infarction (ischemia → necrosis → perforation)

Factors influencing infarction:

Nature of vascular supply (dual vs end-arterial)

Rate of occlusion (sudden vs gradual)

Tissue vulnerability to hypoxia (neurons vs skeletal muscle)

Oxygen content of blood (anemia, hypoxemia)

Red Hemorrhagic Infarct

Pulmonary embolism

Red Hemorrhagic Infarct

Embolism with reperfusion

Red Hemorrhagic Infarct

Loose tissues with dual blood supply (lung, intestine)

Reperfusion of an occluded artery (blood flows back into damaged area)

Venous occlusion in organs with single outflow vein (testis, ovary)

Tissue appears dark red, hemorrhagic

Blood leaks into necrotic tissue

Often associated with pulmonary embolism

Reperfusion injury can worsen damage by free radicals and inflammation

Renal infarct

White anemic infarct

Splenic infarct

White anemic infarct

Myocardial infarct

White anemic infarct

Cerebral infarct

Disseminated Intravascular Coagulation (DIC)

Systemic activation of coagulation cascade

Widespread microthrombi form in small vessels → tissue ischemia and organ dysfunction

Consumption of platelets and clotting factors → paradoxical bleeding

Excessive tissue factor release or widespread endothelial activation

Thrombin generation → fibrin deposition

Activation of fibrinolysis adds to bleeding risk

Bleeding from multiple sites (IV lines, mucosa, skin, GI tract)

Purpura, petechiae, ecchymoses

Signs of organ ischemia (renal failure, neurologic changes, respiratory distress)

Possible shock and multiorgan failure

Thrombocytopenia (platelets consumed)

Prolonged PT and PTT (clotting factors depleted)

Low fibrinogen (used up in clotting)

Elevated D-dimer and fibrin degradation products (due to fibrinolysis)

Microangiopathic hemolytic anemia (schistocytes on blood smear)

DIC Complications

Bleeding complications:

Intracranial hemorrhage

Gastrointestinal bleeding

Mucosal bleeding and hematuria

Severe postpartum hemorrhage

Thrombotic complications:

Microvascular thrombosis → tissue ischemia

Renal cortical necrosis → acute kidney injury

Liver necrosis (“shock liver”)

Adrenal hemorrhage / necrosis → Waterhouse-Friderichsen syndrome (esp. meningococcemia)

Limb ischemia and gangrene

Respiratory complications:

Pulmonary microthrombi and hemorrhage

May progress to acute respiratory distress syndrome (ARDS)

Long-term outcomes:

Neurologic sequelae after ischemia or hemorrhage

High mortality if not treated promptly

Shock

A state of systemic hypoperfusion due to reduced cardiac output or reduced effective circulating blood volume

Results in Inadequate oxygen and nutrient delivery to tissues, Cellular hypoxia → switch to anaerobic metabolism → lactic acidosis; Cell injury and death if not corrected

Hypotension (MAP <65 mmHg is typical threshold)

Tachycardia, weak rapid pulse

Tachypnea (compensatory)

Altered mental status (confusion, agitation, coma if severe)

Skin changes

Cool, clammy, cyanotic skin in most types

Exception: septic shock may begin with warm, flushed skin

Shock is a final common pathway of many lethal conditions

Initially reversible, but prolonged shock leads to irreversible multi-organ failure

Cardiogenic Shock

Failure of the heart as a pump → ↓ cardiac output

Causes: massive MI, severe arrhythmia, myocarditis, dilated cardiomyopathy

Hypotension, weak pulse, pulmonary edema, high mortality

Obstructive Shock

Blockage of blood flow despite normal heart function

Causes: massive pulmonary embolism, cardiac tamponade, tension pneumothorax

Sudden collapse, jugular venous distension, pulseless electrical activity

Hypovolemic Shock

Loss of circulating blood or plasma volume

Causes: trauma with hemorrhage, GI bleeding, severe burns, dehydration

Hypotension, tachycardia, cold clammy skin, oliguria

Distributive Shock

Peripheral vasodilation → pooling of blood, ↓ effective circulating volume

Septic shock: cytokine-driven vasodilation + endothelial injury; most common cause in hospitals

Anaphylactic shock: IgE-mediated mast cell degranulation → histamine release → vasodilation, edema

Neurogenic shock: loss of sympathetic tone after spinal cord or brain injury

Phases of Shock

Septic Shock

Organ Dysfunction in Shcok

Kidneys: Acute tubular necrosis → acute kidney injury (oliguria, anuria, ↑ creatinine)

Liver: Centrilobular necrosis → “shock liver” with elevated AST/ALT

Lungs: Acute respiratory distress syndrome (ARDS) from diffuse alveolar damage

Heart: Ischemia, arrhythmias, loss of contractility

Brain: Confusion, delirium, ischemic injury, coma in severe cases

Adrenals: Hemorrhage and necrosis in severe septic shock (Waterhouse–Friderichsen syndrome)