- Risk Factors
- How to Prevent
- Doctor Specialists
Blood clot facts
- A blood clot is a gel-like mass formed by platelets and fibrin in the blood to stop bleeding.
- A blood clot forms to try to repair damage to a blood vessel, either an artery or vein.
- When blood clots form inappropriately inside an artery or vein, they may cause significant problems because blood flow past the clot is decreased.
- There are many risk factors and illnesses that can lead to blood clot formation.
- Risk factors of blood clots forming in a vein may include:
- Risk factors of blood clots forming in arteries include:
- Symptoms of blood clots depend on their location in the body. Some blood clots produce no symptoms until they rupture or become dislodged and travel through the circulatory system to other sites. Symptoms of blood clots in specific body locations include:
- Symptoms of blood clots in the legs (deep vein thrombosis, or DVT) are pain, redness, and swelling.
- Symptoms of an arterial blood clot in a limb (leg or arm) include pain, pale color, numbness, loss of feeling, and coolness to the touch.
- Symptoms of blood clots in the lung (pulmonary embolus, or PE) include chest pain, shortness of breath, fainting, and rapid pulse and breathing.
- Symptoms of a stroke (blood clot in an artery of the brain) include possible loss of speech, vision, profound dizziness, and weakness on one side of the body.
- Symptoms of a heart attack (blood clot in a coronary artery) are chest pain, shortness of breath, nausea, indigestion, and sweating. Women, people with diabetes, and the elderly may experience other non-specific symptoms.
- Symptoms of mesenteric ischemia (blood clot to an artery that supplies the intestine) include abdominal pain, nausea, bloating, and blood in the stool.
- The diagnosis of a blood clot is suggested by the history and physical examination and is often confirmed with an imaging test. Depending upon the location of the blood clot and its cause, treatment may require surgery, anti-coagulation medications, or a combination of the two.
- Prevention of blood clots involves attention to the risk factors for vascular disease and includes avoiding smoking and lifelong control of high blood pressure, high cholesterol, and diabetes.
- Serious and even life-threatening complications may arise from blood clots, and individuals should seek emergency medical care if they believe they may have a blood clot, especially if signs and symptoms of a heart attack or stroke occur.
What are blood clots?
Blood flows through blood vessels (arteries and veins), and is constantly in motion as the heart pumps blood through arteries to the different areas (organs, glands, cells etc.) of the body. Blood is then returned back to the heart by the veins. Blood returns to the heart by the motion of the body. Muscles squeeze blood through the veins back toward the heart. Without motion, blood has a tendency to stagnate by gravity, and stagnant blood has the tendency to clot.
Blood clotting is an important mechanism to help the body repair injured blood vessels. Blood consists of:
- Red blood cells containing hemoglobin that carry oxygen to cells and remove carbon dioxide (the waste product of metabolism),
- White blood cells that fight infection,
- Platelets that are part of the clotting process of the body, and
- Blood plasma, which contains fluid, chemicals, and proteins important for bodily functions.
Complex mechanisms exist in the bloodstream to form clots where they are needed. If the lining of the blood vessels becomes damaged, platelets are recruited to the injured area to form an initial plug. These activated platelets release chemicals that start a clotting cascade, using a series of clotting factors produced by the body. Ultimately, fibrin is formed, a protein that crosslinks with itself to form a mesh that makes up the final blood clot.
The medical term for a blood clot is a thrombus (plural = thrombi). When a thrombus is formed as part of a normal repair process of the body, there is little consequence. When a thrombus (blood clot) forms when it is not needed, it can have significant consequences.
What causes blood clots in the leg?
Blood clots form when there is damage to the lining of a blood vessel, either an artery or a vein. The damage may be obvious, such as a cut or laceration, or may not be visible to the naked eye. Blood also will begin to clot if it stops moving and becomes stagnant, or in diseases that cause the blood to clot abnormally.
Blood clots in a vein (venous thrombosis) occur when a person becomes immobilized and muscles are not contracting to push blood back to the heart. This stagnant blood begins to form small clots along the walls of the vein. This initial clot can gradually grow to partially or completely block (occlude) the vein and prevent blood from returning to the heart.
Blood clots in an artery (arterial thrombi) occur by a different mechanism. For those with atherosclerotic disease, plaque deposits form along the lining of the artery and grow, which causes the vessel to narrow. This disease process may cause:
If a plaque ruptures, a blood clot can form at the site of that rupture and can completely or partially block the blood flow at that point.
What are other causes blood clots?
Blood clots in the heart: In atrial fibrillation, the upper chamber (atrium) of the heart does not beat in an organized manner. Instead, it jiggles, and blood tends to become stagnant along the walls of the atrium. Over time this may cause small blood clots to form. Clots also can form in the ventricle after a heart attack when part of the heart muscle is injured and unable to contract normally. Since the damaged area doesn't contract with the rest of the heart, blood can start to pool or stagnate, leading to clot formation.
Blood leaking out of a blood vessel: Blood clots can form when blood leaks out of a blood vessel, and this process can be very beneficial because the clot helps stop further bleeding at the site of injury. A few examples of how bleeding is controlled by the body's clotting mechanism are
Blood clots causing other medical problems: Sometimes, normal blood clotting can cause medical problems because of its location. For example, blood in the urine may occur from any of a variety of reasons (such as infection, trauma, or tumor/cancer), and clots may form over the urethra, the tube that empties the bladder, preventing the bladder from emptying, causing urinary retention.
Clot formation in the uterus may cause pain when the clots are passed through the cervix and can lead to vaginal bleeding, either as part of menstruation or as abnormal vaginal bleeding (menorrhagia, dysmenorrhea).
What are the symptoms and signs of blood clots?
Signs and symptoms of blood clots in the veins
Blood clots in the veins do not allow blood to return to the heart, and symptoms occur because of this "damming effect." These clots often occur in the legs or the arms, symptoms include:
Most often, only one leg or arm is affected and the swelling occurs over the course of many hours. Because the leg or arm becomes red, warm, and swollen, it is sometimes difficult to decide whether the cause is a DVT (deep vein thrombosis) or an infection.
On occasion, the whole leg may become very swollen, painful, and turn bluish in color due to a blood clot located in the femoral vein in the upper leg or the iliac vein in the pelvis. This is called phlegmasia cerulean dolens. A similar situation may occur in the arm if the blood clot affects the subclavian vein located in the chest.
Signs and symptoms of blood clots in the arteries
Blood clots in the arteries do not allow blood to pump to an affected area. Body tissue that is deprived of blood and oxygen begins to die and becomes ischemic. Symptoms of blood clots in the arteries depend upon the location of the clot. Arterial blood clots cause diseases and illnesses that are medical emergencies or call 911.
Heart attack: Blood clots in the coronary arteries of the heart cause a heart attack. Symptoms of a heart attack may include:
- Chest pain or pressure
- Shortness of breath
- Loss of speech
- Loss of vision
- Profound dizziness
- Weakness and/or loss of sensation on one side of the body
FAST is the memory tool to remember regarding the symptoms for stroke:
- Facial drooping
- Arm weakness
- Speech difficulties
- Time (time is of the essence to try to reverse the stroke process. Call 911 and go to a hospital.)
What are the risk factors for forming blood clots?
The risk factors for arterial clots are those that are common to all diseases that cause narrowing of blood vessels, cholesterol plaque formation, and plaque rupture, including:
- High blood pressure
- High cholesterol levels
- Family history of early heart attack or stroke
Blood clots in the veins are formed due to one of two main reasons: 1) immobility, and 2) genetic errors in the clotting mechanism. There are other associated risk factors including smoking and the use of birth control pills.
- Immobility: Commonly, when the body stops moving, the risk of blood clots increases since muscle movement is required to pump blood toward the heart. Stagnant blood in a vein is prone to clot. Examples of how blood clots may occur from immobility include:
- Being hospitalized or bedridden after illness or surgery
- Taking long trips (such as in a car, train, or plane), when hours may pass without standing to move, walk, or stretch, and blood pools in the leg veins and may potentially clot
- Orthopedic injuries and/or has casts placed over broken bones or limbs
- Undergoing knee or hip replacement
- Pregnancy is a risk factor for forming blood clots in the legs and pelvis, due to insufficient blood flow back to the heart.
- Immobility due to paralysis from a stroke or spinal cord injury.
- Genetic errors in the clotting mechanism: There may be a genetic or inborn error in the clotting mechanism, making a person hypercoagulable (hyper=more + coagulation= clotting) and at greater risk for forming clots.
What happens when a blood clot forms in the leg and travels to the lung?
Blood clots may cause life-threatening medical conditions and may be considered in the diagnosis.
Deep venous thrombosis (DVT) and pulmonary embolism (PE)
Deep venous thrombosis (DVT) may lead to a pulmonary embolism. If there is a blood clot or thrombus in a deep vein of the leg or arm, it has the potential to break off (embolize) and flow through the veins toward the heart, and into the lung where it can become lodged in a pulmonary artery, which prevents the lung from functioning. Pulmonary embolism is a medical emergency and can cause serious illness or death.
- The lungs' blood supply is comprised and the affected area of lung tissue may infarct, or die.
- Because of the blockage, the ability of the lung to provide oxygen to the body is decreased and hypoxia (decreased levels of oxygen in the blood and throughout the body) may occur.
Even if venous blood clots do not embolize, they may cause significant local problems with swelling and pain. Since blood cannot return to the heart if a clot blocks a vein, the limbs may chronically swell and have decreased function in a condition called chronic thrombophlebitis.
What happens when blood clots form and travel to the heart?
An arterial thrombus stops the blood supply to the tissues beyond the blockage, depriving cells of oxygen and nutrients. This quickly leads to tissue death. Arterial thrombus is the mechanism that causes:
- Heart attack (when it occurs in the coronary arteries that supply blood to the heart)
- Stroke (when it occurs in arteries within the brain),
- Peripheral vascular disease (occurring in the arteries of the legs), or
- Ischemic bowel or mesenteric ischemia (when it occurs in the arteries that supply blood to the intestine)
Atrial fibrillation (AFib, AF)
In atrial fibrillation (AFib, AF), small clots may form along the walls of the atrium or the upper chambers of the heart. If one of these clots break off, it may embolize, or travel in the bloodstream to the brain, blocking an artery and causing a stroke. Other arteries also may be involved when blood clots caused by the presence of AFib dislodge to stop blood flow (embolize), including those that supply blood to the bowel. This can cause bowel ischemia and tissue death (potential necrosis) of the intestine. Clots also can affect blood supply to the extremities (arms, fingers, and toes).
Other types of blood clots
Blood should clot anytime it becomes stagnant. This also means clots will form when blood leaks out of blood vessels.
- With bleeding peptic ulcers, patients may vomit liquid blood mixed with clot.
- Patients with rectal bleeding may also have clot mixed with bloody stool if there has been time for the clot to form.
- Sometimes patients with urinary tract or bladder infections may develop associated bleeding in their urine, and small clots can form. On occasion, these clots may be so big that they cannot be passed and block the urethra (the tube that empties the bladder), preventing urination and causing urinary retention.
- Vaginal bleeding is a normal event for most women in the reproductive years and occasionally, blood can pool in the vagina and form clots before being expelled. If clots form in the uterus, they may cause significant pain and pressure as they pass through the cervix while being expelled.
How are blood clots found and diagnosed?
The first step in making the diagnosis of a blood clot is talking to the patient and family to understand the situation. The location of the blood clot and its effect on blood flow is what causes symptoms and signs. If a blood clot or thrombus is a consideration, the history may explore risk factors or situations that might put the patient at risk for forming a clot.
Venous blood clots often develop slowly with a gradual onset of swelling, pain, and discoloration. Symptoms of a venous thrombus will often progress over hours.
Arterial thrombi occur as an acute (sudden onset) event. Tissues need oxygen immediately, and the loss of blood supply creates a situation in which symptoms begin immediately.
Arterial thrombi occur as an acute event. Tissues need oxygen immediately, and the loss of blood supply creates a situation in which symptoms begin immediately.
There may be symptoms that precede the acute artery blockage that may be warning signs of the potential future complete occlusion of the blood vessel.
- Patients with an acute heart attack may experience angina or chest discomfort (pressure, pain, indigestion, fatigue) in the days and weeks prior to the heart attack. It is important to remember that women may experience atypical and non-specific symptoms as part of their angina equivalent, including fatigue and malaise.
- Patients with peripheral artery disease may have pain with walking (claudication)
- A TIA (transient ischemia attack, mini-stroke) in which the symptoms resolve without treatment may precede a stroke.
The physical examination can assist in providing additional information that may increase the suspicion of a blood clot.
- Vital signs may be helpful in deciding how stable the patient is. These include blood pressure, pulse rate, respiratory rate, body temperature, and oxygen saturation (what percentage of red blood cells have oxygen attached).
- Heart monitoring and an EKG may be ordered to assess heart rate and rhythm.
- Venous thrombi may cause swelling of an extremity (arm, leg). The limb may appear to be red, warm, and tender; sometimes the appearance is difficult to distinguish from cellulitis or an infection of the extremity. If there is concern about a pulmonary embolus, the doctor may examine the lungs to listen for abnormal sounds caused by an area of inflamed lung tissue.
- Arterial thrombus symptoms are much more dramatic. If a leg or arm is involved, the tissue may be white because of the lack of blood supply. In addition, it may be cool to touch and there may be loss of sensation and movement (paralysis). The patient may be writhing in pain.
Arterial thrombus is also the cause of heart attack and stroke (cerebrovascular accident) and their associated symptoms.
What procedures and test diagnose blood clots?
Testing for venous blood clots
- Ultrasound: Venous blood clots may be detected in a variety of ways, though ultrasound is most commonly used. Occasionally, the patient's size and shape limit the ability of the person performing the ultrasound to adequately see the veins.
- Venography: Venography is an alternative test to look for a clot. In this test, a radiologist injects a contrast dye into a small vein in the hand or foot and using fluoroscopy (video X-ray), watch the dye fill the veins in the extremity as it travels back to the heart. The area of clot or obstruction can thus be visualized.
- D-Dimer: Sometimes, a blood test is used to screen for blood clots. D-Dimer is a breakdown product of a blood clot, and its levels in the bloodstream may be measured. D-Dimer is not specific for a blood clot in a given area and cannot distinguish a "good" or needed blood clot (for example, a clot that forms after surgery or due to bruising from a fall) from one that is causing medical problems. It is used as a screening test in low-risk patients with the expectation that a negative result will conclude that there is no need to look further for blood clots. The healthcare professional usually counsel the patient that a positive blood test will likely require additional tests being considered. D-Dimer also may be elevated in women who are pregnant and patients with cancer.
- CT scan: Computerized tomography (CT scan) is often the test of choice when suspicion of pulmonary embolus is high. Contrast material is injected intravenously, and the radiologist can determine whether a clot is present in the pulmonary vessels. The contrast material injected into the body can be irritating to the kidney(s) and should not be used in patients who have impaired kidney function. In older patients, screening blood tests (serum creatinine) to check kidney function may be required before a dye study is considered. The radiologist may also be able to advise whether the heart is straining to pump because of the number of clots that might be present in the lung. The more clot there is, the harder the heart has to work to pump.
- Ventilation-perfusion (V/Q) scan: On occasion, a ventilation-perfusion (V/Q) scan is performed to look for pulmonary emboli. This test uses labeled chemicals to identify inhaled air into the lungs and match it with blood flow in the arteries. If a mismatch occurs, meaning that there is lung tissue that has good air entry but no blood flow, it may be indicative of a pulmonary embolus. It is less accurate and more subjective than a CT scan and requires the skill and experience of a radiologist to interpret. The VQ scan is often performed when a CT scan is contraindicated, for example, with a major dye allergy or in a patient with kidney compromise.
If a blood clot travels to the lung, this is a medical emergency. There are varieties of tests to look for pulmonary emboli. A plain chest X-ray will not show blood clots, but the X-ray may be done to look for other conditions that can cause chest pain and shortness of breath, which are the most common symptoms of a pulmonary embolus. An electrocardiogram (EKG) may show abnormalities suggestive of a pulmonary embolus and may reveal other causes of chest pain.
Testing for arterial blood clots
Arterial thrombosis is an emergency since tissue cannot survive long without blood supply delivering oxygen and nutrients and shortly causing irreversible damage. When this occurs in an arm or leg, often a surgeon is consulted on an emergency basis. Arteriography may be considered, a test in which contrast material is injected into the artery in question to look for blockage on imaging studies. Sometimes, if there is a large artery that is blocked (occluded) this test is done in the operating room with the presumption that a surgical procedure will be needed to open the vessel and restore blood flow. An interventional radiologist may be part of the treatment team to also try to remove the clot directly or dissolve the clot with medications.
Heart attack: The EKG may establish the diagnosis, although blood tests may be used to look for enzymes (troponin) that leak into the bloodstream from the irritated heart muscle. In an acute heart attack, the diagnostic and therapeutic procedure of choice is heart catheterization. A catheter is threaded into the coronary artery to the level of the blockage, and the clot and plaque are squashed in the artery wall (angioplasty), and a stent is placed to keep the artery open. If the hospital does not have a cardiologist or heart catheterization facility available, clot-busting drugs (TPA, TNK) may be used to try to restore blood supply to the affected part of the heart. A heart catheterization may be performed later.
Acute stroke: The test of choice is a computerized tomography (CT) scan of the head to look for bleeding or tumor as the cause of stroke symptoms instead of a blood clot blocking an artery.
Other studies: Other CT studies of the head may help guide treatment of a stroke and include CT perfusion to look at brain blood flow and CT angiography (CTA) to map the anatomy of the arteries and look for any acute clot that might need to be treated. An MRI may be considered but the test is not always readily available and also takes significantly more time to perform and interpret. If the symptoms of a stroke resolve quickly, the diagnosis becomes a transient ischemic attack (TIA, mini-stroke), and further tests may include carotid ultrasound to look for blockages in the major arteries of the neck and echocardiography to look for blood clots in the heart that may embolize to the brain and cause permanent stroke damage in the future.
What is the treatment for blood clots? Can it go away without treatment?
Depending upon their location, blood clots may be aggressively treated or may need nothing more than symptomatic care.
Blood clots in superficial veins (venous blood clots)
- Clots may develop in the superficial or deep veins of the leg.
- Treatment for a superficial blood clot is directed at managing pain and decreasing inflammation with medication (for example, acetaminophen [Tylenol and others] or ibuprofen [Advil, Motrin, etc.]).
- The risk of these clots lodging and obstructing (embolizing) in the vein is low because of the anatomy of the leg.
- Specialized veins (perforator veins) connect the superficial veins to the deep veins and have valves that act as strainers to prevent clots from traveling to the lung.
Clots in the deep vein system of the arm or leg may need to have the blood "thinned" with anticoagulation medications.
The American College of Chest Physicians' 2016 guidelines recommends that patients who have deep vein thrombosis (DVT) or pulmonary embolus (PE) be treated with different anticoagulation medications depending upon their situation.
- Patients with DVT or PE who have no active cancer should be treated with NOACs (novel oral anticoagulant) medications. These are also known as DOACs (direct oral anticoagulants).
- Patients with DVT or PE who have active cancer should be treated with low molecular weight heparin (enoxaparin [Lovenox])
NOACs work by blocking factors in the clotting cascade. These include:
Direct thrombin inhibitor
Enoxaparin (Lovenox) is low molecular weight heparin that may be injected under the skin to "thin" the blood and anticoagulant the patient. In addition to its indication to treat DVT and PE in cancer patients, it is often used as a bridge treatment should a patient be treated with edoxaban, dabigatran, or warfarin, since these medications take time to reach a therapeutic level in the body. Enoxaparin is often the medication of choice in pregnant patients who develops blood clots like deep vein thrombosis or pulmonary embolism.
Unfractionated heparin is used intravenously to anticoagulant a patient in the hospital, especially if the patient is unstable due to an underlying condition.
Warfarin (Coumadin, Jantoven) is one type of anticoagulation medication that has been used for many years to treat blood clots. It blocks clotting factors II, VII, IX, and X, those that depend upon Vitamin K, and historically was prescribed as soon as DVT (deep venous thrombosis) or blood clot is diagnosed. Because it takes a few days to effectively thin the blood, low molecular weight Heparin (enoxaparin) or regular heparin is used to immediately cause anticoagulation.
Pulmonary emboli are treated similarly to deep venous thrombosis, but depending on the severity of the symptoms, the amount of clot formation, and the underlying health of the patient, admission to the hospital for treatment and observation may be needed. Usually, unstable or potentially unstable patients are treated with intravenous unfractionated heparin.
Patients who are critically ill and display symptoms of heart strain or shock may be candidates for thrombolytic therapy using drugs known as tissue plasminogen activators (tPA). tPA may be injected into a peripheral vein in the arm to immediately thin the blood and act as a clot-busting drug, or it can be dripped directly into the clot through a catheter that an interventional radiologist places.
Arterial blood clot treatment
Arterial blood clots are often managed more aggressively. Surgery may be attempted to remove the clot, or medication may be administered directly into the clot to try to dissolve it. Alteplase (Activase, r-tPA) or tenecteplase (TNKase) are examples of tissue plasminogen activator (see above) medications that may be used in peripheral arteries to try to restore blood supply.
This same approach is used for heart attacks. If possible, cardiac catheterization is performed to locate the blocked blood vessel and a balloon is used to open the occluded area, restore blood flow, and place a stent to keep it open. This is a time-sensitive procedure, and if a hospital is not available to do the procedure emergently (within 60-90 minutes of the patient's symptoms), TPA or TNK may be used intravenously to try to dissolve the thrombus and minimize heart damage. Eventually, when stable, the patient will be transferred for a potential heart catheterization to evaluate the heart anatomy and decide whether stents may be needed to keep an artery open or whether bypass surgery might be needed to restore blood supply to the heart.
Stroke is also treated with tPA if the patient is an appropriate candidate for this therapy. As well, there are now opportunities in some hospitals to have an interventional radiologist or neurologist thread a catheter into the blocked artery in the brain, try to find the clot causing the stroke and remove it. This same strategy is used for heart attack and some patients with peripheral artery clots in an arm or leg.
What are the complications of blood clots?
- Blood clots prevent proper circulation of blood.
- Deep vein thrombosis of the leg or arm may cause permanent damage to the veins themselves and cause persistent swelling of the extremity (post-phlebitis syndrome). The life-threatening issue that may arise from deep vein clots in the arm or leg is that they may break off and embolize to the lungs (pulmonary embolus), causing problems with lung function and oxygenation of the blood.
- Arterial thrombus often is a life- or limb-threatening event, since organs and cells do not get enough oxygen when cut off from their oxygen supply.
How can you prevent blood clots?
Prevention is key in thrombosis or clot formation.
- For arterial thrombosis, the most likely precipitating event is a plaque rupture with clot formation in the artery.
- Minimizing the risk of vascular disease requires life-long attention to the risk factors that lead to plaque buildup and "hardening" of the arteries.
- Blood pressure and cholesterol control, diabetes management, and refraining from smoking all minimize the risk of arterial disease.
- Although family history is an important risk factor, one needs to be even more vigilant about the other risk factors if there is a family history of early heart attack or stroke.
Deep vein thrombosis
The main risk factor for deep vein thrombosis risks is immobilization. It is important to move around routinely so that blood can circulate in the venous system. On long trips, it is recommended to get out of the car every couple of hours, or in an airplane to routinely get up and stretch.
Physicians and nurses work hard at getting people moving after surgery or while in the hospital for medical conditions. The low molecular weight heparin known as enoxaparin (Lovenox) can also be used in low doses to prevent clot formation. Patients are often given tight stockings to promote blood return from the legs and prevent pooling of blood.
In patients who have had hip or knee replacement, anticoagulation with a NOAC may be appropriate.
In patients with atrial fibrillation, anticoagulation may be appropriate depending upon the patient's underlying condition, the clinical situation, and the risk factors for stroke. Using the CHA2DS2-VASc scoring system, the risk for stroke in atrial fibrillation may be calculated and discussed with the patient. This system considers various factors to determine the patient's risk:
- Age in years
- Congestive heart failure (CHF) history
- Hypertension (high blood pressure) history
- Stroke/TIA/ blood clot history
- Vascular disease history
Anticoagulation with a NOAC or warfarin may be appropriate.
Which type of doctor treat blood clots?
A variety of different specialists may be involved in the care of a patient with a blood clot, from diagnosis to treatment and prevention, depending upon the exact type and location of the clot. These may include internists, family medicine specialists, emergency physicians, interventional radiologists, surgeons, cardiologists, cardiothoracic surgeons, neurologists, and critical care specialists.
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Dzsheka, M.S., et al. "Stroke and bleeding risk in atrial fibrillation." Clin Cardiol 37.10 Oct. 2014.
Kasper, D.L., et al., eds. Harrison's Principles of Internal Medicine, 19th Ed. United States: McGraw-Hill Education, 2015.
Kearon, C., et al. "Antithrombotic Therapy for VTE Disease: Chest Guideline and Expert Panel Report." Chest. 149.2 (2016): 315-352.