Nonthrombotic Embolism

An embolus is an intravascular solid, liquid, or gaseous material that is carried by the blood to a site distant from its point of origin. Emboli of all types warrant immediate medical attention. The majority of emboli dislodge from a thrombus, forming a thromboembolus. Other less common nonthrombotic types of emboli are cholesterol, fat, air, amniotic fluid, and tumor emboli. The cause of the embolus depends on the type, as does the clinical presentation, diagnosis, and management of each embolic condition. Due to their effects on circulation, all emboli have the potential to result in end-organ failure and death.

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Cholesterol Embolism

Overview

  • Also known as atheroembolism or cholesterol crystal embolism
  • Occurs when cholesterol crystals within an atherosclerotic plaque dislodge and embolize
  • Cholesterol crystals tend to:
    • Dislodge from proximal, large-caliber arteries 
    • Move to many more distal, small-to-medium arteries → simultaneous damage to multiple end-organs

Epidemiology and etiology

  • Incidence: unknown (many unrecognized cases)
  • Typical patient characteristics:
    • Age: > 50 years
    • Gender: higher prevalence in men than in women
    • Medical history: atherosclerotic disease
  • Etiology:
    • Iatrogenic following an invasive vascular procedure (75%):
      • Angiography
      • Cardiac catheterization
      • Endovascular grafting
    • Spontaneous (25%)
  • Risk factors (similar to those associated with atherosclerosis):
    • Hypercholesterolemia
    • Hypertension
    • Diabetes mellitus 
    • Obesity 
    • Smoking
    • Abdominal aortic aneurysms
  • Worse atherosclerotic disease → higher risk for cholesterol embolization

Pathophysiology

  • Cholesterol crystals within a ruptured atherosclerotic plaque embolize → “showering” of debris into the circulation → multiple emboli → lodge in arterioles
  • Results in multiple occlusions that affect multiple organs

Clinical presentation

The classic presentation includes skin findings, abdominal pain, and progressive renal failure following a vascular procedure. Neurological and ocular symptoms are also common if the emboli travel superiorly.

  • Symptoms vary and depend on several factors:
    • Location of the embolic source:
      • The aortic arch may embolize to the brain, eye, or upper extremity.
      • Thoracic aorta or abdominal aorta may embolize to the GI tract or lower extremities.
    • Extent of embolization
    • Partial versus complete occlusion of the affected vessels 
    • Presence or absence of pre-existing vascular disease in the affected area
  • Common dermatological presentations:
    • Cyanosis 
    • Ulcers 
    • Purpura 
    • Petechiae
    • Firm, painful erythematous nodules
    • Livedo reticularis: lace-like purplish discoloration of the skin that blanches with pressure
    • Blue-toe syndrome: a retiform purpura, blue discoloration of the toes 
  • Renal presentations:
    • AKI:
      • Most commonly causes distal parenchymal ischemia
      • Irregularly shaped emboli produce incomplete occlusion → secondary ischemic atrophy 
      • Progressive renal dysfunction
      • Occurs weeks after a possible inciting event
      • Bland sediment
      • Flank pain and hematuria are uncommon with cholesterol emboli (but common with thromboemboli that cause acute renal infarction)
    • Rhabdomyolysis:
      • Red-brown urine (due to myoglobinuria)
      • Electrolyte abnormalities
      • ↑ CK
  • GI presentations:
    • General symptoms:
      • Abdominal pain
      • Diarrhea
      • GI bleeding
    • GI ischemia
    • Acute pancreatitis
    • Hepatic cell necrosis
    • Necrotizing cholecystitis
  • Neurological presentations:
    • General symptoms:
      • Headache
      • Dizziness
      • Paralysis
      • Confusion
    • Transient ischemic attack 
    • Stroke 
  • Ocular presentations:
    • Amaurosis fugax: temporary acute loss of vision due to a lack of blood flow to the eye
    • Hollenhorst plaque on ophthalmoscopy: bright, refractile lesions in the retina indicative of cholesterol crystal embolization from a proximal source (e.g., carotid artery)
    • Eye pain
    • Blurred vision

Diagnosis

The diagnosis is usually clinical. Definitive diagnosis requires a biopsy.

  • Laboratory testing: generally nonspecific
    • CBC: ↑ eosinophils, ↓ RBCs, ↓ platelets 
    • Inflammatory markers: ↑ CRP, ↑ ESR
    • Organ-specific tests may be abnormal if the organ is affected: 
      • ↑ Creatinine/BUN (kidneys)
      • ↑ Amylase (pancreas)
      • ↑ Transaminases (liver)
  • Imaging:
    • Useful in assessing the extent of atherosclerotic disease
    • Rarely useful in identifying the index plaque
    • Identification of multiple complex plaques or multiple ischemic strokes assists in presumptive diagnosis.
    • Modalities:
      • Transesophageal echocardiography (TEE): 1st-line approach for thoracic aortic sources
      • Chest CT
      • Chest MRI
      • Brain imaging (may reveal multiple small ischemic lesions)
  • Histopathology:
    • Biopsy sample can be obtained from any affected organs (e.g., skin, kidney, muscle).
    • Cholesterol clefts (“ghosts”) within the arterioles: 
      • Cholesterol crystals are dissolved during tissue fixation leaving behind clefts.
      • Crescent-shaped clefts with pointed ends
      • Elongated ovoid spaces
Nontrhombotic embolism contrast induced nephropathy

Kidney biopsies showing cholesterol clefts:

A: Low-power view showing an interlobular artery with luminal occlusion and needle-like crystals in the lumina. Two glomeruli are seen in the vicinity with minor changes on light microscopy. Mild patchy tubular atrophy is seen (Masson’s trichrome stain, ×100).
B: Medium-power view showing a small artery with luminal cholesterol clefts causing luminal occlusion (Periodic acid-Schiff stain, ×200).
C: High-power view showing typical empty-looking and needle-like cholesterol clefts in the lumina (Jones methenamine silver stain, ×400).
D: High-power view showing luminal cholesterol clefts and intimal fibrosis. Media appears red on this stain (Masson’s trichrome stain, ×400).

Image: “” by Department of Nephrology, Division of Nephropathology, Isfahan University of Medical Sciences, Isfahan, Iran. License: CC BY 4.0

Management

  • Supportive management for presenting symptoms:
    • Pain management
    • Avoid further vascular instrumentation if possible.
    • Anti-thrombotic therapy is controversial and generally not recommended.
  • Prevention of kidney injury:
    • Aggressive saline hydration
    • Bicarbonate
    • Mannitol
    • Dialysis may be needed if the injury is significant.
  • Surgical plaque removal or exclusion (if the embolic source is clearly identified)
  • Risk-factor reduction to prevent recurrent disease:
    • Aspirin
    • Statins
    • BP control
    • Smoking cessation
    • Glycemic control

Fat Embolism

Overview

  • Occurs when fat globules enter the pulmonary or systemic circulation 
  • Most common in patients with orthopedic trauma, especially:
    • Multiple fractures
    • Open (instead of closed) fractures
  • Incidence:
    • 20%–30% in patients after trauma
    • 1%–11% in long-bone fractures
    •  Occurs in 90% of individuals with severe skeletal injuries, but < 10% show any clinical findings
  • Gender bias: men > women
  • Age: most common in individuals between 10 and 40 years of age

Etiology

  • Traumatic causes:
    • Orthopedic causes (vast majority of cases):
      • Long-bone fractures
      • Pelvic fractures
      • Fractures of other marrow-containing bones (e.g., ribs)
    • Non-orthopedic causes (rare): 
      • Cardiopulmonary resuscitation
      • Severe burns
      • Crush injuries
      • Liposuction 
      • Bone marrow transplant
  • Nontraumatic causes (very rare):
    • Acute pancreatitis 
    • Sickle-cell hemoglobinopathies
    • Lipid infusion
    • Bone marrow necrosis

Pathogenesis

Pathogenesis may be by 1 or both of the following mechanisms:

  • Fat globules cause mechanical obstruction in the vasculature.
  • Embolized fat may degrade into toxic intermediaries → leads to inflammation and endothelial injury

Clinical presentation

Signs and symptoms typically develop 24–72 hours after the inciting event.

  • Classic triad of symptoms after trauma:
    • Hypoxemia
    • Neurological abnormalities
    • Petechial rash
  • Cardiopulmonary symptoms:
    • Sudden onset tachypnea
    • Dyspnea
    • Hypoxemia 
    • Tachycardia
  • Neurological symptoms:
    • Changes in mental status
    • Seizures
  • Dermatological symptoms: diffuse petechial rash
  • Hematological signs:
    • Anemia
    • Thrombocytopenia

Diagnosis and management

Fat embolism is usually a clinical diagnosis after excluding other possibilities.

  • Imaging: 
    • Chest X-ray and/or CT in patients with respiratory symptoms
    • Brain CT or MRI in patients with neurological symptoms
  • Management: 
    • No definitive treatment
    • Supportive care during natural resolution:
      • Ensure hemodynamic stability
      • Oxygenation and ventilation as needed
      • Adequate nutrition and hydration
      • Prophylaxis for deep vein thrombosis (DVT)
    • Early reduction and fixation of long-bone fractures

Air Embolism

Overview

An air embolism occurs when gas bubbles enter the circulation and block blood flow.

  • 2 types:
    • Venous air embolism
    • Arterial air embolism
  • Incidence: unknown

Pathophysiology and etiology

  • Air embolisms occur when:
    • There is direct communication between air and the vasculature, AND pressure gradient favors air movement into the vessel (instead of bleeding, which would result in blood moving out of the vessel) 
    • Example: Procedures involving surgical incision above the heart create negative venous pressure with respect to the atmospheric pressure.
  • Venous air embolism: 
    • Obstruction occurs when the volume of air in a vessel exceeds the ability of the lungs to remove gas (approximately 50 mL).
    • Large bubbles obstruct the pulmonary arteries → ↓ blood flow to lungs:
      • ↑ Central venous pressure
      • ↓ Pulmonary arterial pressure
      • ↓ Systemic arterial pressure
    • Small bubbles obstruct the pulmonary arterioles and microcirculation:
      • ↑ Pulmonary vascular resistance
      • ↑ Pulmonary arterial pressure
      • ↑ Right ventricular pressure
      • Local inflammation and endothelial damage → noncardiogenic pulmonary edema, bronchoconstriction, and hypoxia
    • Very small bubbles may pass through the capillaries into arterial circulation.
    • Fatal volume: estimated range between 50 and 500 mL in venous circulation at a rate of 100 mL/sec
  • Arterial air embolism:
    • Air occludes microcirculation → end-organ ischemia
    • Ischemia induces inflammation → endothelial damage
    • Fatal volumes:
      • 2 mL in cerebral arteries
      • 0.5–1 mL in coronary arteries
Table: Etiologies of air embolisms
Etiology Examples
Surgical procedures
  • Head and neck surgery:
    • Most common
    • Affects up to 80% of patients who have undergone neurosurgery, especially when surgery is performed on patients sitting upright
  • Cardiopulmonary bypass
  • Lung resection or biopsy
  • Cardiac catheter ablations
  • Pacemaker placement
  • Endoscopies when gas is used as a distension media:
    • Arthroscopy
    • Laparoscopy
    • Colonoscopy
    • Hysteroscopy
IV catheterization
  • Highest risk IV catheters:
    • Central lines
    • Hemodialysis catheters
    • IV contrast injection
  • Can occur during catheter insertion, removal, or while in place
Trauma
  • Head and neck injuries
  • Penetrating and blunt chest/abdominal trauma
Pulmonary barotrauma
  • Positive pressure ventilation
  • Decompression sickness in scuba divers

Clinical presentation

Presentation depends on the site and size of the embolism.

Venous air embolism → air travels to the right ventricle → pulmonary circulation:

  • Mimics a thrombotic pulmonary embolism (PE)
  • Symptoms:
    • Sudden-onset dyspnea
    • Tachycardia 
    • Decreased oxygen saturation
    • Lightheaded/dizziness

Arterial air embolism → air travels to end organs → ischemia:

  • Most commonly affected organs:
    • Brain → stroke
    • Heart → MI
  • Symptoms: 
    • Sudden onset of focal neurological deficits (e.g., hemiparesis)
    • Changes in mental status
    • Seizures
    • Chest pain/dyspnea

Diagnosis

Diagnosis is made by determining air in the intravascular space or organs of a patient with known risk factors. However, air is often rapidly reabsorbed and no longer present by the time the patient undergoes diagnostic testing; thus, the diagnosis is often made clinically.

  • Imaging:
    • CT:
      • Head (most helpful): intraparenchymal gas, diffuse edema, areas of infarction
      • Chest: may demonstrate air in the cardiac chambers or large vessels
    • Transthoracic echocardiography: may reveal air in the cardiac chambers or large veins
  • ECG: 
    • Venous embolism: right heart strain (peaked T waves, right bundle branch block, right axis deviation)
    • Arterial embolism: ST depression or elevation
  • Arterial blood gas:
    • Hypoxemia
    • Hypercarbia
    • Metabolic acidosis
Gas in bilateral cerebral arteries

CT scan of head: axial and sagittal cuts showing foci of gas in bilateral cerebral arteries (blue arrows)

Image: “Case 2 CT scan of head” by Rashmi Mishra et al. License: CC BY 4.0

Management

Stabilize the patient:

  • Airway: Secure the airway (intubate), if needed.
  • Breathing 
    • High flow of oxygen
    • Mechanical ventilation if needed
  • Circulation 
    • IV access 
    • Volume resuscitation
    • Vasopressors
    • Advanced cardiac life support if needed

Repositioning:

  • Venous embolism: 
    • Left lateral decubitus position with head down
    • Keeps air in the right ventricle and away from the pulmonary outflow tract
  • Arterial embolism: 
    • Supine position
    • Arteries are strong enough to overcome positioning; the supine position attempts to minimize cerebral edema caused by a cerebral air embolism.

Definitive therapies:

  • Hyperbaric oxygen: 
    • ↑↑ Levels of blood oxygen create a large gradient for nitrogen to move from the air bubbles into the blood → ↓ the size of the bubbles 
    • ↑ Oxygen helps treat tissue ischemia (secondary benefit)
  • Removal of embolized air (e.g., aspiration through a catheter)
  • Chest compression: 
    • Forces air into smaller vessels
    • Used as a last resort in unstable patients
Hyperbaric oxygen therapy

Hyperbaric oxygen therapy chamber

Image: “Hyperbaric oxygen therapy chamber” by Mark Murphy. License: Public Domain

Amniotic Fluid Embolism

Overview

Amniotic fluid embolism (AFE) is a complication during labor and the immediate postpartum period.

  • Caused by the entry of the amniotic fluid into the maternal circulation by:
    • Placental tears
    • Uterine vein rupture
  • Incidence: 1:40,000 deliveries
  • Mortality:
    •  80% mortality rate due to AFE 
    • AFE causes 10% of maternal deaths in developed countries.

Risk factors

  • Cesarean delivery
  • Instrumented vaginal delivery (e.g., forceps or vacuum-assisted deliveries)
  • Placental abnormalities (e.g., placenta previa)
  • Preeclampsia/eclampsia

Pathogenesis

  • Unclear
  • Amniotic fluid enters maternal circulation and triggers:
    • Intense pulmonary vasoconstriction:
      • ↑ Pulmonary pressure → right ventricular failure → systemic hypotension
      • Hypoxemic respiratory failure
      • Pulmonary edema
    • Abnormal immune responses are activated:
      • Intense inflammatory response (similar to SIRS)
      • Inflammatory mediators activate the coagulation cascade systemically → disseminated intravascular coagulation (DIC) 
  • DIC leads to:
    • Hemorrhage → further hemodynamic instability
    • Ischemic multi-organ failure
  • Mechanical obstruction from the amniotic-fluid debris likely does not play a significant role.

Clinical presentation

AFE typically presents dramatically, as sudden-onset cardiopulmonary collapse occurring during labor or within 30 minutes after delivery.

  • Signs: 
    • Cardiopulmonary collapse: loss of breathing and pulse
    • Hypoxemia/cyanosis
    • Dyspnea
    • Hypotension
    • Tachycardia 
  • Other symptoms: 
    • Nausea and vomiting
    • Changes in mental status
    • Seizure 
  • DIC:
    • Usually develops shortly after an AFE
    • Leads to obstetric hemorrhage
  • Fetal heart-rate abnormalities indicating distress (e.g., late decelerations, terminal bradycardia) if still pregnant

Diagnosis

AFE is a clinical diagnosis based on presentation. 

  • Laboratory evaluation (primarily to help with resuscitation):
    • Coagulation profile:
      • ↑ Prothrombin time
      • ↓ Fibrinogen
      • ↑ D-dimer
    • CBC:
      • Anemia 
      • Leukocytosis
      • Thrombocytopenia 
    • Arterial blood gas:
      • Hypoxemia
      • Acidosis (both respiratory and metabolic)
  • Imaging (once the patient is stable): 
    • Chest radiography: bilateral diffuse infiltrates
    • Echocardiography to assess cardiac function
Amniotic fluid embolism x-ray

Chest X-ray of a patient with amniotic fluid embolism:
Diffuse infiltration is observed throughout the lungs.

Image: “X-ray” by Department of Emergency and Critical Care, The University of Tokushima Graduate School, Kuramoto Tokushima, 770-8503, Japan. License: CC BY 2.0

Management

Survival depends on prompt diagnosis and effective resuscitation.

  • Airway: Secure the airway.
  • Breathing: mechanical ventilation
  • Circulation:
    • High-quality CPR
    • 2 large-bore IVs → fluid resuscitation
    • Transfuse to combat DIC; typically a 1:1:1 ratio of:
      • Packed RBCs
      • Fresh frozen plasma
      • Cryoprecipitate
    • Vasopressors
  • Immediate delivery if the patient is still pregnant

Complications

  • Hematological: DIC
  • Cardiovascular: hemorrhage and cardiac arrest
  • Pulmonary complications: pulmonary edema and ARDS
  • Permanent neurological deficits due to cerebral hypoxia (85% of survivors)

Tumor and Foreign-body Embolism

Tumor embolism

  • Embolization of tumor within the pulmonary vessels
  • Rare, end-stage manifestation of malignancy
  • Can occur with any malignancy, though most commonly associated with:
    • Renal-cell carcinoma
    • Hepatocellular carcinoma
    • Adenocarcinomas:
      • Breast
      • Stomach
      • Colon
      • Lung
  • Clinical presentation: 
    • Subacute progressive dyspnea
    • Cough, with or without hemoptysis
    • May present with signs of venous thromboembolism (dyspnea, hypoxia, right heart strain)
  • Diagnosis is often made on autopsy:
    • Imaging studies are insensitive.
    • Lab studies are nonspecific.
  • Poor prognosis

Foreign-body embolism

  • Most commonly involves silicone and occurs after cosmetic or therapeutic injection
  • Clinical presentation:
    • Hypoxemia
    • Fever
    • Petechial rash
    • Neurological symptoms
  • Management is supportive.

Summary

Table: Summary of nonthrombotic embolisms
Type of embolism Most common clinical presentations Management
Cholesterol embolism From thoracic sources:
  • Skin: livedo reticularis, blue toe
  • Renal: AKI
  • GI symptoms
From aortic-arch sources:
  • Brain: TIA, stroke
  • Eyes symptoms
Focus on risk reduction in atherosclerotic disease:
  • Aspirin
  • Statins
  • Smoking cessation
  • BP and glycemic control
Fat embolism From orthopedic trauma:
  • Hypoxemia
  • Neurological abnormalities
  • Petechial rash
Supportive care
Air embolism From:
  • Head and neck surgeries
  • Endoscopies
  • IV catheterization
Symptoms:
  • Venous: mimics PE
  • Arterial: stroke or MI
  • Stabilization
  • Resuscitation
  • Positioning
  • Remove or exclude air
Amniotic fluid embolism During labor or within 30 minutes of delivery:
  • Acute cardiopulmonary collapse
  • DIC
  • Stabilization
  • Resuscitation
  • Transfusion
  • Deliver infant (if still pregnant)
Tumor embolism From any end-stage malignancy:
  • Progressive dyspnea
  • May mimic PE
  • Poor prognosis
  • Supportive care
PE: thrombotic pulmonary embolism
DIC: disseminated intravascular coagulation
TIA: transient ischemic attack

References

  1. Shah. N., Nagalli, S. (2020) Cholesterol Emboli. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK556091/ 
  2. Kronzon, I., Saric, M. (2010). Cholesterol Embolization Syndrome. Circulation 122:631–641. https://doi.org/10.1161/CIRCULATIONAHA.109.886465
  3. Agrawal, A., et al. (2017). Cholesterol embolization syndrome: An under‐recognized entity in cardiovascular interventions. https://doi.org/10.1111/joic.12483
  4. Saric, M. (2020). Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism). UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism
  5. Thompson, T., Kabrhel, C. (2020). Overview of acute pulmonary embolism in adults. UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/overview-of-acute-pulmonary-embolism-in-adults
  6. O’Dowd, C., Kelley, M. (2020). Air embolism. UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/air-embolism
  7. Kerrigan, M. (2020). Venous gas embolism. In Cooper, J. (Ed.), StatPearls. Retrieved March 16, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/31056/ 
  8. Alexander, A. (2021). Arterial gas embolism. In Martin, N. (Ed.), StatPearls. Retrieved March 16, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/32891/ 
  9. Winehouse, G. (2019). Fat embolism syndrome. In Finlay, G. (Ed.), UpToDate. Retrieved March 17, 2021, from https://www.uptodate.com/contents/fat-embolism-syndrome 
  10. Adeyinka, A. (2020). Fat embolism. In Pierre, L. (Ed.), StatPearls. Retrieved March 16, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21632/ 
  11. Weinhouse, G. (2020). Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management. In Finlay, G. (Ed.), UpToDate. Retrieved March 17, 2021, from https://www.uptodate.com/contents/pulmonary-tumor-embolism-and-lymphangitic-carcinomatosis-in-adults-diagnostic-evaluation-and-managemen

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