Blood clots form when three conditions converge: damage to a blood vessel wall, slowed blood flow, and blood that’s more prone to clotting than normal. You don’t need all three at once, but the more factors present, the higher the risk. Up to 900,000 people in the United States develop a blood clot in their veins each year, and an estimated 60,000 to 100,000 die from one.
The Three Conditions That Trigger Clotting
Your blood is designed to clot. It’s a survival mechanism that stops you from bleeding out when you cut yourself. Problems arise when that same system activates inside a blood vessel where there’s no wound to heal. Three overlapping factors drive this process.
The first is damage to the vessel wall. Healthy blood vessels have a lining that actively repels clots, releasing molecules that keep platelets from sticking and prevent the clotting cascade from firing. When that lining gets damaged, whether from high blood pressure, high cholesterol, smoking, or infection, it loses those protective molecules. The surface shifts from anti-clotting to pro-clotting, and platelets begin to gather at the injury site.
The second factor is sluggish blood flow. Moving blood keeps clotting proteins diluted and swept away before they can accumulate. When flow slows down or pools, those proteins concentrate in one spot and begin building a clot. This is why sitting still for hours on a long flight, being bedridden after surgery, or having an irregular heart rhythm like atrial fibrillation all raise clot risk. The blood simply sits too long in one place.
The third is a hypercoagulable state, meaning the blood itself is primed to clot more easily than normal. This can come from genetics, medications, cancer, pregnancy, or chronic inflammation. Even subtle shifts in the balance of clotting proteins and anti-clotting proteins can tip the scales toward a clot forming when it shouldn’t.
Arterial Clots vs. Venous Clots
Not all blood clots are the same. Where they form changes what they’re made of, what causes them, and how dangerous they are.
Arterial clots form in arteries, usually at the site of a ruptured cholesterol plaque. They’re packed with platelets and tend to block blood flow to the heart (causing a heart attack) or the brain (causing a stroke). The underlying problem is almost always atherosclerosis, the slow buildup of fatty deposits in artery walls over years or decades.
Venous clots form in veins, most commonly in the deep veins of the legs. These clots contain more fibrin, the stringy protein that acts like a net to trap blood cells. The classic venous clot is a deep vein thrombosis (DVT), which becomes life-threatening if a piece breaks off and travels to the lungs, blocking blood flow there. That’s called a pulmonary embolism (PE). Because arterial and venous clots differ in composition, they’re treated with different types of blood thinners: antiplatelet drugs for arterial clots and anticoagulants for venous clots.
Genetic Factors That Increase Risk
Some people are born with blood that clots more easily. The most common inherited clotting disorder involves a mutation called Factor V Leiden, which makes one of the body’s natural clot-braking systems less effective. About 3% to 8% of people of European descent carry one copy of this mutation. Prevalence varies widely: 10% to 15% in parts of Sweden and Greece, but only 2% to 3% in Italy and Spain. The mutation is extremely rare in people of Asian, African, and Indigenous Australian descent.
Carrying one copy of Factor V Leiden modestly increases your clot risk. Carrying two copies (about 1 in 5,000 people) raises it significantly more. Another common inherited mutation affects prothrombin, a key clotting protein. People who carry both the Factor V Leiden and prothrombin mutations together face three to nine times the risk of recurrent clots compared to people with neither.
Having an inherited clotting tendency doesn’t mean you’ll definitely develop a clot. Many carriers go their entire lives without one. But it does mean that when other risk factors pile on, like surgery, pregnancy, or a long period of immobility, the threshold for clot formation is lower.
Surgery and Immobility
Surgery is one of the strongest short-term triggers for blood clots. The combination of tissue damage, inflammation, and hours of lying still on an operating table creates near-perfect conditions for clotting. Orthopedic procedures carry the highest risk. In a large nationwide study, total knee replacement had the highest rate of clot-related events at nearly 13%, followed by hip replacement at about 11% and spine surgery at roughly 6%. Cardiac surgery, including coronary artery bypass, also carries significant risk.
Non-orthopedic surgeries aren’t exempt. Hysterectomy, liver resection, and stomach surgery all show elevated venous clot rates. This is why hospitals routinely use compression devices on your legs during surgery and often prescribe blood thinners afterward, especially after joint replacement.
You don’t need surgery to trigger immobility-related clots. Long hospital stays, extended bed rest after illness, leg casts, and even long-haul travel can slow blood flow enough to allow clots to form in the deep leg veins.
Cancer and Blood Clots
Cancer significantly increases clotting risk because tumor cells directly hijack the coagulation system. Malignant cells produce substances that activate clotting proteins, essentially forcing the blood into a pro-clotting state. They also release inflammatory signals that damage blood vessel linings and reduce the body’s natural anticoagulant defenses.
The risk isn’t equal across all cancers. Pancreatic cancer has the highest estimated clot prevalence at about 28%, followed by lung cancer at 27% and stomach cancer at 13%. Mucin-producing cancers of the gastrointestinal tract and ovarian cancer are also notably high-risk. By comparison, colon cancer carries about a 3% clot rate, and premenopausal breast cancer only 1% to 2%. For some patients, an unexpected blood clot is actually the first sign that leads to a cancer diagnosis.
Hormones, Smoking, and Obesity
Estrogen-containing medications, including combination birth control pills and hormone replacement therapy, raise clot risk by increasing the liver’s production of clotting proteins. The absolute risk is still low for most women. Among users of standard hormonal contraceptives, roughly 6 in 10,000 women per year develop a clot. Newer formulations containing drospirenone raise that to about 10 in 10,000, roughly a 1.5-fold increase.
Smoking compounds this risk substantially. It damages blood vessel walls, thickens the blood, and promotes inflammation, hitting multiple clotting triggers simultaneously. The combination of smoking and estrogen-containing birth control is particularly dangerous, which is why prescribers screen for tobacco use before writing these prescriptions. Obesity is another independent risk factor. Excess body weight promotes chronic low-grade inflammation and alters the balance of clotting proteins in the blood.
Warning Signs of a Dangerous Clot
A deep vein thrombosis in the leg typically causes pain or tenderness (often in the calf), swelling, warmth, and redness or discoloration of the skin over the clot. Sometimes only one or two of these signs are present. The affected leg may look noticeably larger than the other.
A pulmonary embolism, which happens when a clot travels to the lungs, causes sudden unexplained shortness of breath, sharp chest pain that worsens with breathing, coughing (sometimes with blood), and in severe cases, fainting. PE can escalate quickly from mild breathlessness to a medical emergency, so these symptoms warrant immediate attention, especially if you have any of the risk factors described above.
How Blood Clots Are Detected
When doctors suspect a clot, they typically start with a blood test that measures a substance called D-dimer, a fragment released when a clot breaks down. The test is extremely sensitive: it correctly identifies about 96% of people who have a DVT and about 95% of those with a PE. A normal D-dimer result is very reliable for ruling out a clot. An elevated result, however, doesn’t confirm one, since D-dimer rises with infection, inflammation, surgery, pregnancy, and other conditions. If D-dimer is elevated, imaging follows: usually an ultrasound for a suspected leg clot or a CT scan of the chest for a suspected pulmonary embolism.