Deep vein thrombosis and pulmonary embolism: Pathology review

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Case Study 0:00–0:42

Hannah is a 42 year old woman who came to the emergency department due to pain in her right calf. She reports flying from Japan back to the United States 2 days ago.
She denies fever, chills, or history of trauma to the leg. She reports a 25 pack year smoking history for 20 years, and she takes oral contraceptive pills.
On physical examination, she is stable, and her BMI is 32. Her right leg is shown in this image.
On laboratory investigation, her D-dimer levels are elevated. Deep vein thrombosis, or DVT and pulmonary embolism, or PE are a spectrum of clinical manifestations that result from venous thromboembolism.

Pathophysiology of DVT 0:42–3:01

The pathogenesis and risk factors of both DVT and PE centers around Virchow’s triad, that is; stasis of blood flow, hypercoagulability, and endothelial injury.
Board exams like to test your ability to identify a PE by using scenarios that promote venous stasis such as paralysis after a stroke, the postoperative period, as well as long drives or flights.
People with varicose veins are also at risk of DVT, because incompetent venous valves prevent proper venous outflow, causing stasis.
An interesting risk factor is pregnancy, where the enlarged uterus may compress the iliac veins, causing stasis of venous outflow.
Another similar cause is May-Thurner syndrome where the left iliac vein gets sandwiched between the right iliac artery anteriorly and the lumbar vertebrae posteriorly, which also leads to venous stasis.
Now, the coagulation system is normally balancing clot formation and clot lysis. Hypercoagulability occurs is when the scale is tipped towards clot formation.
This may be genetic, such as factor V Leiden, or antithrombin III deficiency. Or it may be acquired, like when there’s high estrogen during pregnancy or when using estrogen-containing oral contraceptive pills.
Also, nephrotic syndrome causes loss of antithrombin III in the urine, resulting in hypercoagulability. This is especially prominent in membranous glomerulonephropathy.
Other acquired causes of hypercoagulability include malignancies, sepsis, and autoimmune diseases like lupus or antiphospholipid syndrome.
Finally, endothelial damage, like when there’s truma, can expose the underlying collagen, which initiates the coagulation cascade.
Alright, now DVTs typically affect the deep veins of the lower extremity, such as the popliteal, iliac and femoral veins.

Clinical Presentation3:01–4:21

The popliteal veins of the calf are most commonly affected, however, it’s important to remember that the more proximal iliofemoral DVTs that commonly embolize and cause PE.
DVTs present with unilateral, painful swelling and redness of the affected extremity. However, it’s important to know that there are other differential diagnoses, like cellulitis or a popliteal Baker cyst that can present similarly.
So, when it comes to diagnosis, the best choice on an exam is a compression ultrasound with Doppler. Normally, veins are easily compressible using the ultrasound probe, but when there’s a clot, the affected vein becomes incompressible.
Doppler is beneficial because they can also look at blood flow. Next, D-dimer is a fibrinogen degradation product that may be measured if DVT is suspected.
A negative test may be helpful to rule out DVT, but a positive test does not necessarily mean there is DVT, so D-dimer has a high sensitivity but a low specificity for DVT.
Now, PE most commonly occurs when a DVT breaks off and travels to the pulmonary artery or one of its branches. When the pulmonary artery is obstructed, perfusion to the supplied segment of the lung is limited.

Pathophysiology of PE4:21–6:10

However, there’s nothing wrong with ventilation. So now we have a ventilation-perfusion mismatch, or a V/Q mismatch where there’s plenty of oxygen in the alveoli, but there’s not enough RBCs to pick it up.
This decreases the oxygen saturation in the blood, or hypoxemia. In response to hypoxemia, the pulmonary blood vessels vasoconstrict, which shunts blood from the poorly perfused segments to the well-perfused segments.
This process is called intrapulmonary shunting. Additionally, peripheral chemoreceptors pick up on hypoxemia, and send signals to the brain to increase ventilation in an attempt to compensate.
hyperventilation causes the individual to blow off lots of carbon dioxide, resulting in respiratory alkalosis. Now, most of the time, when a clot occludes a blood vessel, the distal organ tissue dies becomes infarcted.
The lung is an exception, because it receives a dual blood supply from both the pulmonary artery and bronchial arteries, which are branches of the aorta.
Okay, so large emboli that occlude the pulmonary trunk place tremendous amounts of sudden pressure on the right heart, so it’s important for you to remember that this can result in acute right heart failure and a form of shock called obstructive shock.
Obstruction of the right ventricular outflow tract means the left heart isn’t getting enough blood, which decreases left ventricular filling and ultimately, stroke volume.
Okay, now let’s tie the pathophysiology to the clinical presentation. Hypoxemia and hyperventilation means individuals with PE present with sudden-onset shortness of breath and tachypnea.

Clinical Presentation6:10–8:19

Additionally, because PEs limits left ventricular stroke volume, the heart tries to compensate by increasing the heart rate, so tachycardia.
PE can also present with pleuritic chest pain that is worse on inspiration. Additionally, hemorrhagic infarction may cause the individual to develop hemoptysis.
A combination of hypotension, a distended jugular vein and clear lung sounds often clue towards obstructive shock. Now approximately 20 percent of the population have a patent foramen ovale.
This means that the clot can travel from the right atrium to the left atrium to the left ventricle and into the arterial circulation.
So a possible presentation to consider is actually an embolic stroke. The ECG in PE most commonly shows sinus tachycardia, but sometimes a unique pattern called the S1Q3T3 pattern may appear.
This means an S-wave in lead one, a Q-wave in lead III and an inverted T-wave, also in lead III. This pattern is not specific for PE, rather it’s essentially a distress signal from the right heart, signifying right heart strain.
The best diagnostic test is a CT pulmonary angiogram, which shows a filling defect in the pulmonary artery or its branches.
For your exams, it’s also important to remember that microscopic examination of the thrombus will show the characteristic lines of Zahn.
These are alternating layers of pink platelets and fibrin and layers of red RBCs. These lines are only found in thrombi formed before death, so they help distinguish a premortem from a postmortem thrombus.
Okay, when using the term “PE”, this usually refers to pulmonary “thromboembolism”. However, there are some rare causes of PE that might also show up on a test.

Fat Emboli8:19–9:19

Fat emboli occur when there’s long-bone fractures, orthopedic procedures and liposuction. In these scenarios, fat globules are released into the circulation, they are exposed to lipoprotein lipase, which degrades them into free fatty acids like oleic acid.
These free fatty acids damage the endothelium of various organs. When it’s the endothelium of the lungs, acute respiratory distress syndrome, a form of pulmonary edema, occurs.
When it’s the endothelium of the skin, a petechial rash appears. And when it’s the endothelium of the brain capillaries, neurological deficit occurs.
This culminates into a triad of ARDS, petechiae, and diffuse neurological impairment. On microscopy, fat can be seen intravascularly and stains black with osmium tetroxide.
Then, there’s amniotic fluid emboli. Risk factors include being in the peripartum period, maternal age above 30, and uterine trauma.

Amniotic Fluid Emb.9:19–10:09

These all increase the risk of amniotic membrane rupture. Amniotic fluid contains amino acid metabolites that are considered foreign to mom’s body.
So this triggers an immune reaction that looks like anaphylaxis, or an anaphylactoid reaction. This causes vasospasm in the pulmonary arteries, leading to pulmonary hypertension and left heart failure.
Amniotic fluid also contains tissue factor, which triggers the coagulation cascade, resulting in disseminated intravascular coagulation, or DIC.
On microscopy, fetal squamous cells and mucin are seen in mom’s pulmonary arteries. Air emboli are up next, and for these to happen, there must be direct communication between the atmosphere and a blood vessel lumen, as well as a pressure gradient favoring air entry.

Air Emboli10:09–11:07

Risk factors include neurosurgical procedures, laparoscopic surgery, and any blunt or penetrating trauma that exposes blood vessels to air.
Once air enters smaller vessels, it could form bubbles that end up blocking blood flow. A specific form of air embolism that occurs in divers is decompression sickness, or Caisson disease.
To put it simply, when a diver descends, nitrogen begins to accumulate in lipid rich tissues. If they ascend rapidly, large amounts of nitrogen quickly transform into its gas form, forming bubbles that obstruct the circulation.
This is why it’s advised to ascend slowly, to allow nitrogen to slowly get out of the circulation and to the lungs. Finally, septic emboli can occur in people with endocarditis.

Septic emboli11:07–11:28

These are little clumps of pathogens that detach from the surface of the tricuspid valve and travel through the pulmonary arteries and into the lungs.
For your exams, remember that the major risk factor for tricuspid valve endocarditis is IV drug use. All right, as a quick recap, the two main forms of venous thromboembolism are DVT and PE.

Review11:28–12:35

The pathogenesis and risk factors for both revolve around Virchow’s triad, which includes stasis, hypercoagulability and endothelial injury.
DVT most commonly affects the calf, but it’s the proximal venous DVTs that usually embolize to cause PE. DVT presents with unilateral limb swelling and erythema, and diagnosis is confirmed with a compression ultrasound.
PE causes a V/Q mismatch, resulting in hypoxemia and hyperventilation, which causes a respiratory alkalosis. Individuals present with acute, sudden-onset shortness of breath, pleuritic chest pain, hemoptysis and sometimes obstructive shock.
Diagnosis is confirmed with a CT pulmonary angiogram. It’s also important to consider rarer causes of PE, such as fat, air, septic, and amniotic fluid emboli.
Okay, back to our case. Hannah is presenting with DVT.

Summary12:35–13:03

Her risk factors include a prolonged period of immobilization from her long flight, obesity, smoking, and use of oral contraceptive pills which all increase coagulability.
Her D-dimer was elevated, suggesting the possibility of DVT. A compression ultrasound was performed and confirmed DVT.
She is now doing well on anticoagulation therapy. And that’s DVT and PE pathology in a nutshell…