Thrombosis

Etiology

As noted, thrombosis occurs when there is an imbalance in endogenous anticoagulation and hemostasis. Historically, three common factors predispose to thrombosis: 1) damage to the endothelial lining of a vessel wall 2) hypercoagulable state 3) arterial or venous blood stasis. These three factors are known by the eponym "Virchow's triad," described by Rudolf Virchow in 1856. Endothelial wall damage is caused by different factors. Direct causes include disruption of the vessel via catheter placement, trauma, or surgery. Indirect causes include inflammatory factors, disruption of intracellular junctions, and tissue factor expression.[2] 

Hypercoagulability is a general hematologic concept that means an increased risk of thrombosis via enhanced levels of prothrombotic components in the bloodstream. This hypercoagulability is due to a variety of alterations in the hemostatic system, which can result from inflammatory factors, increased viscosity of blood and blood components, cytokine release, prothrombotic proteins in circulation, and deficiencies of endogenous anticoagulant factors.

Hypercoagulable states can be acquired or inherited. The most common inherited forms include loss of function mutations (antithrombin III deficiency, protein C and S deficiencies) and gain of function mutations (factor V Leiden and prothrombin gene mutations.) Acquired hypercoagulability is far more common and can result from medications (eg, oral contraceptives, estrogen, or other hormonal replacement); acute inflammatory conditions such as pregnancy, surgery, trauma, or infection; and chronic inflammatory conditions, such as morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking. Two specific types of acquired hypercoagulable states that can lead to both venous and arterial thrombus include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT). Malignancy is also a well-known risk factor for hypercoagulability, as tumor cells can express a variety of procoagulant proteins, including increased expression tissue factor.  Some malignancies, such as pancreatic cancer, are known to increase the risk of thrombosis significantly. Another risk factor for thrombosis is increased cellular blood components such in polycythemia vera or essential thrombocytosis. Please see our companion article, "Myeloproliferative Neoplasms" for further information.[3][4]

The third aspect of Virchow's triad includes arterial or venous stasis of the blood, which can be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis (eg, residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis). Long plane or car trips with limited mobility can also become a relative risk factor for thrombosis, especially if additional predisposing factors are present.  

Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis. However, some studies have proven that there is a link between these two types of thrombosis through activated coagulation and inflammatory pathways.[5] Both kinds of thrombosis have similar risk factors, including age, obesity, smoking, chronic inflammation, and metabolic syndrome. It is paramount to determine whether the thrombosis was likely provoked or unprovoked, as each has management implications. Knowledge of the location (proximal or distal) and extent of the thrombosis can also guide further workup and may alter the treatment approach.

Vemous thromboemolisms (VTEs) usually manifest as deep venous thromboses (DVTs) or pulmonary embolisms (PE). When considering VTE, an appreciation of the anatomy of the deep veins of the extremities and the pulmonary system is helpful. For example, the deep veins of the lower extremity include the femoral, iliac, and popliteal veins. Thrombosis can also occur in the veins of the upper extremity, such as the subclavian, axillary, and brachial veins. Other thrombosis sites include the superior vena cava, jugular vein, cerebral venous sinus, cavernous sinus, and retinal vein. The latter sites are less common, and with the identification of an isolated thrombus in one of these sites, one must consider the potential for other explanatory diagnoses or predisposing conditions (eg, hepatic thrombus due to cirrhosis). Thrombosis of superficial veins is also possible, especially with provoking factors such as intravenous catheterization or localized cellulitis; treatment of superficial vein thrombosis does not typically require any anticoagulation.[6]  

As noted, arterial thrombosis can present as an acute stroke, myocardial infarction, or both acute and chronic peripheral arterial disease. Other less common sites include renal arteries, mesenteric arteries, and retinal arteries.  In addition to acute management, secondary prevention focuses on reducing cardiovascular risk factors such as obesity, high cholesterol, diabetes, and high blood pressure and encouraging lifestyle modification such as smoking cessation.[7] Other risk factors include underlying connective tissue or rheumatologic conditions, such as systemic lupus erythematous or vasculitis. as well as the aforementioned rare HITT, antiphospholipid syndrome, myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria (all of these can predispose to both venous and arterial thrombosis.)  

Age also contributes to the development of thrombosis. For instance, studies have shown that older patients have increased production of prothrombotic coagulation factors such as von Willebrand factor and thrombin, as well as more physiologic activation of platelets compared to younger patients.[8]   

Epidemiology

The epidemiology of thrombosis varies depending on whether venous or arterial, provoked or unprovoked, and the first or subsequent episode. For venous thromboembolism (VTE), the annual incidence is 1 per 100000 in children, 1 per 10000 in reproductive age, 1 per 1000 in later middle age, and 1 per 100 in older patients.[9] Reports also indicate that the incidence of PE is 29 to 48 per 100,000 person-years, and DVT incidence is 45 to 117 per 100,000 person-years.[10] Studies demonstrate that there is an increased incidence of venous thrombosis in people of European descent compared with non-Europeans.[11][12]   

Patients with cancer have a 4-fold to 7-fold risk of VTE compared to those without cancer, and these usually occur in the first few months after diagnosis.[13] A scoring system was designed to predict recurrent VTE risk in the first 6 months of anticoagulation therapy in patients with malignancy called the Ottawa score. Stratification criteria include sex, cancer type and stage, and prior VTE.[14]

Pregnancy is a period of particularly high risk for thrombosis, causing a relative risk increase of 5 to 10 times baseline due to a combination of increased coagulation factors, increased venous compliance resulting in stasis, and complications such as hypertension.[15] The presence of a thrombophilic defect further amplifies this risk several-fold, and venous strokes are especially prevalent in this population.[16][15] Another condition affecting primarily women is APS with an estimated incidence at 50 per 100,000 people, with a female-to-male ratio of approximately 5:1.[17]

Pathophysiology

As noted, Virchow's triad (ie, endothelial damage, hypercoagulability, and venous or arterial blood stasis) plays a significant role in the pathophysiology of thrombosis. Damage to the vessel wall leads to the production of pro-inflammatory cytokines, increased expression of tissue factor, proliferation of adhesion molecules, and enhanced platelet activation.[18] Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection and endothelial damage, whether acute (eg, trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease). The activation of the leucocytes and endothelial cells causes the formation of adhesion molecules, which will eventually initiate clot formation.[18] The body's endogenous anticoagulants, such as proteins C and S and antithrombin III, prevent the formation of thrombosis. When an imbalance exists in the formation and lysis of clots, thrombosis occurs; this explains why patients with thrombophilias such as protein C, protein S, and antithrombin III deficiencies are prone to acquiring blood clots.  

In recent times, COVID-19 has appeared as a deadly disease due to a hypercoagulable state, with the widespread presence of venous and arterial thrombi.[19][20] One belief is that the development of a cytokine storm and endothelial dysfunction leads to significant VTE. Elevated levels of D-dimer and fibrin degradation products (FDP) are associated with significant morbidity and mortality.[21] COVID patients were also found to have high rates of lupus anticoagulant development. The macrophage activation syndrome, the complement cascade, and the renin-angiotensin system are also implicated. The American Society of Chest Physicians recommends that patients who experience VTE in the setting of COVID-19 should be anticoagulated for 3 to 6 months.[22] The risk of arterial thromboembolism in the form of acute coronary syndrome and stroke is also increased in patients hospitalized with COVID-19. Recommendations are to continue antiplatelet therapy in patients already prescribed this for CAD, PAD, or a history of stroke. Dual antiplatelet therapy is recommended if a patient already on an antiplatelet agent has acute coronary syndrome but not if the patient has elevated cardiac enzymes without acute coronary syndrome. It is also recommended that hospitalized patients who develop atrial fibrillation should be started on anticoagulation, to be continued indefinitely depending on risk factors.[23] The vaccines used to combat COVID can themselves have the propensity for VTE. This very rare condition has been found in both mRNA and adenovector vaccines (available outside the US) and is thought to be mediated by a reaction similar to HITT.[24][25]

Thrombosis occurs throughout the arterial system and is responsible for mortality from CVAs and MIs. In the heart, microthrombi can develop as a result of blood stasis in the ventricles or atria due to underlying valvular heart disease, cardiomyopathies, or arrhythmias such as atrial fibrillation predisposing to ischemic emboli and CVA. Arterial thrombosis is typically initiated by the accumulation of lipid plaques in the arterial wall, provoking chronic inflammatory cells and platelet activation.[26] Platelets play a significant role in the development of arterial thrombosis compared to venous thrombosis, and this explains why antiplatelet agents form a cornerstone of the prevention and treatment of arterial thrombosis. The initial lipid plaques evolve into fibrous plaques. Fibrous plaques can rupture, and the erosion of the surfaces of some of these plaques can lead to the release of additional pro-coagulating factors.[26] This process is called atherosclerosis. The activation of platelets causes adhesion and aggregation, which leads to the formation of a clot. The occlusion of vessels due to atherosclerosis and thrombin formation in the coronary arteries of the heart leads to ischemic heart disease and myocardial infarction. A similar process can occur with ischemic stroke in the cerebral vessels, and ischemic strokes can result from both thrombosis of the cerebral arteries and emboli from the heart.[27]

Histopathology

Histopathology of arterial vessels that contain thrombosis shows an area of fibrin with numerous platelets and leukocytes. Older layers tend to have fewer leucocytes compared to newer areas. Red blood cells can also be present, and these lines are called lines of Zahn. In arterial histopathology, there is usually a fibrous cap atheroma, which can contain a lipid-rich necrotic core.[26] In the venous system following acute thrombosis formation, an extensive remodeling process occurs. Neutrophils and macrophages infiltrate the fibrin clot from within the lumen of the vessel over weeks leading to cytokine release and, eventually, fibroblast and collagen replacement of fibrin. This remodeling and fibrosis can result in diminished blood flow long after the acute thrombosis resolves. 

History and Physical

The signs and symptoms of thrombosis vary depending on the presumed location and acuity. Patients with a DVT often present with isolated extremity swelling, pain, warmth, and erythema at the site of the blockage. The patient typically describes the pain associated with a DVT as “crampy” located in the affected extremity. There may be a decreased range of motion of the extremity, inability to ambulate, or radiation of pain (eg, into the groin for LE DVT extending to the femoral vein). Patients with acute PE may present with pleuritic chest pain, shortness of breath, fatigue, back pain, syncope, or even death in severe cases.[28] Signs include tachycardia, tachypnea, and fever, and may include oxygen desaturation.

Most commonly, arterial thrombosis results in cardiac or cerebrovascular compromise. Those with acute thrombosis in the coronary arteries of the heart will often report “crushing” left-sided chest pain or heaviness with radiation to the left arm or jaw. If thrombosis occurs in one of the cerebral arteries, symptoms may include acute onset of unilateral weakness, headache, confusion, vision changes, dysarthria, dysphagia, paresthesias, difficulty ambulating, or frank paralysis of one or more extremities. 

Evaluation

The evaluation of patients with venous thrombosis differs from that of suspected arterial thrombosis. This section will focus briefly on the workup for suspected venous and arterial thrombosis.

When patients present to the emergency department with signs and symptoms suggestive of possible venous thrombosis, a well-validated scale known as the modified Wells' criteria is applied to help guide further diagnostic studies. For patients with a high Wells score, a serum D-dimer should be checked. The D-dimer is a fibrin degradation product that is present in the blood after fibrinolysis. Its elevation is very sensitive (though less specific) to detect venous thrombosis. It is important to note that D-dimer is also elevated in other conditions such as pregnancy, malignancy, post-surgery, and infection. A negative D-dimer result helps to rule out a clot and avoid unnecessary imaging studies or anticoagulation initiation.[29]

When there is a high pretest probability for pulmonary embolism (PE) or DVT, imaging studies should be completed immediately without regard to D-dimer levels. For PE, the recommended imaging studies are CT angiography or ventilation/perfusion imaging (V/Q scan).  The V/Q scan is sometimes preferred over CT angiography to avoid intravenous contrast in those with underlying renal impairment.[30] However, not all facilities have V/Q scanning capabilities or expertise in interpreting the results, so CT angiography is often used. Often, pulmonary emboli result from fragmentation of preexisting DVT. Hence, ultrasound of the lower and/or upper extremities is also often performed to evaluate for concurrent DVT. This is especially important if a provoking catheter-related thrombosis is suspected, as the catheter may require eventual removal.  

Determining whether a blood clot classifies as provoked or unprovoked and whether it is the first or subsequent episode are critical aspects of the initial evaluation that can guide further workup and treatment. Clinicians should take a careful personal and family history to document any thrombosis history or pregnancy morbidity. A family history of VTE in a first-degree relative correlates more with hypercoagulability than does a known thrombophilia.[16] In general, hypercoagulability testing is only recommended if it would change treatment. For example, in the case of a provoked VTE, treatment is the same regardless of the presence or absence of a thrombophilia, so testing is not recommended. Patients with an unprovoked VTE have a 5-year risk of recurrence without treatment, so long-term anticoagulation is recommended barring contraindications—also regardless of thrombophilia status. In terms of assessing risks, patients without a history of VTE do not need testing when evaluating pregnancy risk or use of estrogen (such as in oral contraceptives or hormone replacement therapy). The exception to this is in women with a first-degree relative who have a history of VTE and are found to have thrombophilia. This situation may warrant VTE prophylaxis or the avoidance of exogenous estrogen.[16]

Hypercoaguability testing may include checking the amount of proteins C and S, antithrombin III, or mutational testing for factor V Leiden or prothrombin gene mutation. Acquired thrombophilia testing may also be indicated, such as antiphospholipid antibody testing, which includes lupus anticoagulant, IgG/IgM anticardiolipin, and anti-beta-2-glycoprotein I.

Acute thrombotic events can make testing for thrombophilia inaccurate due to consumption of coagulation factors, and anticoagulation therapy can also interfere with the interpretation of test results in the acute setting. It is recommended that hypercoagulability workup be postponed until 3 months after anticoagulation for the thrombotic event is discontinued. For antiphospholipid antibody testing, many medications (including several anticoagulants), as well as underlying connective tissue diseases such as SLE, can affect the testing results. When antiphospholipid antibody testing is indicated, the recommendation is that the tests be repeated 12 weeks apart. This testing is often performed in the outpatient setting after the acute phase of the thrombosis has resolved and under the guidance of a hematologist.[16]  

Malignancy can be an underlying provoking factor for both venous and arterial thrombosis. In general, it is not recommended for patients to have an extensive malignancy workup aside from age-appropriate cancer screening (including a chest CT for patients who smoke) unless clinical symptoms suggest additional workup. In carefully selected patients, especially those over the age of 50 with seemingly unprovoked thrombosis, further evaluation to search for occult malignancy may be indicated.[31] 

Arterial thrombosis is most commonly caused by atherosclerosis. Diagnostic imaging includes CT angiography or magnetic resonance angiography to image the vasculature of the affected organ. This will also reveal vascular abnormalities such as aneurysms, dissections, fibromuscular dysplasia, or other anatomic abnormalities. If an MI occurs, cardiac catheterization is usually performed. Uncommon causes of MI are illicit drug use or vasospastic angina (ie, Prinzmetal's angina).[32]  

To image for cardioembolic sources (a common cause of CVA and the leading differential diagnosis cause of thromobosis), a detailed echocardiogram with a bubble study to evaluate for a patent foramen ovale is warranted. Telemetry to look for paroxysmal atrial fibrillation is often used. Medications and illicit drug use can also precipitate arterial thrombosis, so a detailed medication history and drug screen are useful.[31][32] 

Treatment of arterial thromboses is specific to the location of thrombus and underlying medical conditions. As previously noted, antiplatelet medications are generally indicated. Depending on other risk factors and prior use of antiplatelet therapy, treatment with an additional antiplatelet agent (such as a P2Y12 inhibitor) or with very low-dose anticoagulation may be warranted. DOACs are also being studied for use in arterial thrombi, however, with a known cardioembolic source, vitamin K antagonist therapy is still the recommended treatment.[31][33] 

Treatment / Management

The treatment of both arterial and venous thrombosis differs. Venous thromboembolism management encompasses the use of various anticoagulant agents that target procoagulant factors, while arterial thrombosis management is predominantly with antiplatelet agents as monotherapy or dual-antiplatelet therapy. There are many variations and combinations of these treatment options.

As noted, many of the specific scenarios on anticoagulation and antiplatelet therapy indications are beyond the scope of this review article. Subspecialty consultation with pulmonology, cardiology, neurology, and/or hematology may be necessary in special cases. Please refer to societal guidelines (ie, American Society of Chest Physicians, American Heart Association, and American Society of Hematology) for case- and disease-specific recommendations.

Regarding VTE, the American Society of Hematology established a 2018 update to their guidelines for managing venous thrombosis, including prophylaxis use in hospitalized patients. In general, venous thrombosis is categorized into provoked or unprovoked etiologies. Furthermore, one must determine if the thrombosis is a first episode or recurrent episode. A thorough personal and family history of VTE with careful assessment of provoking risk factors and comorbidities is essential. A  provoked VTE results from reversible, modifiable, or acquired risk factors (eg, recent surgery, trauma, infection, pregnancy, morbid obesity, oral contraceptive usage, prolonged immobility, heavy smoking, or underlying malignancy). Unprovoked thrombosis, on the other hand, occurs in the absence of any apparent provoking factor. The treatment of venous thrombosis entails three stages, the initial, chronic, and extended stages.[34] Treatment may vary depending on whether it is a first episode or recurrent episode, the extent of the thrombosis burden, whether provoking risk factors are transient or persistent, and whether symptoms resolve or remain chronic such as in post-thromobitic syndrome.[35]

Guidelines now suggest the use of direct oral anticoagulants (DOACs) over vitamin K antagonists (ie, warfarin) for most VTE conditions. The DOACs most commonly used are dabigatran, apixaban, edoxaban and rivaroxaban. Dabigatran is a direct thrombin inhibitor, while the other 3 medications are Factor Xa inhibitors. Previously, these medications were less commonly used due to an unknown safety profile and lack of reversal; but currently their safety profile is recognized, and reversal agents are available.[36][37] Current recommendations strongly favor the use of DOACs in VTE based on increased efficacy, ease of monitoring, and fewer bleeding events.[38][39][40] DOACs are generally preferred for anticoagulation in cases of atrial fibrillation as well. The only strong indications for Vitamin K antagonists over DOACs are in valvular heart disease (including mechanical valves, mitral stenosis, or rheumatic heart disease) and anti-phospholipid syndrome where DOACs show worsened outcomes.[17][41] The main barriers to increased DOAC are availability, cost, and renal clearance.[36](B3)

Management of acute DVT and PE in hospitalized patients typically includes anticoagulation with IV unfractionated heparin (UFH) or low molecular weight heparin with an eventual transition to oral anticoagulation.[42] After initiating heparin-based anticoagulants, warfarin or DOACs can then be added for chronic and extended management. For an initial provoked thrombosis, such as a simple distal DVT, the recommended duration is typically 3 months.  For the first episode of provoked thrombosis with extensive clot burden, massive PE associated with hemodynamic compromise, or in patients with multiple persistent provoking risk factors, a 3 to 6 month duration is warranted. In patients with recurrent DVT or PE, the duration of therapy becomes more complex, and the determination of significant provoking or transient risk factors is important for guiding treatment. Patients with active malignancy as a provoking risk factor for thrombosis should typically continue anticoagulation therapy for 6 months or longer. LMWH is preferred in those with malignancy-associated thrombosis for initial treatment, followed by the use of DOACs in patients without a significant bleeding risk and GFR>30. Caution must also be used in those with gastrointestinal malignancies.[43]  (A1)

Unfractionated heparin requires monitoring the partial thromboplastin time (PTT). LMWH does not require monitoring, although occasionally patients who are morbidly obese can be monitored by checking anti-Factor Xa levels. For vitamin K antagonists (eg, warfarin), the PT/INR should be monitored and maintained in the therapeutic range. With the DOACs, no routine blood monitoring is necessary; however, medication compliance/adherence remains paramount to assuring the efficacy of these medications. For patients with confirmed acute heparin-induced thrombocytopenia & thrombosis (HITT), a non-heparin anticoagulant—such as argatroban, bivalirudin, danaparoid, or fondaparinux—should be utilized, and expert consultation with hematology is the recommendation. Warfarin should be avoided acutely as there is a risk of skin necrosis in the setting of HITT. DOACs in this setting have not been extensively studied but may become a viable alternative.[44]

For inpatients, the American Society of Hematology (ASH) recommends that prophylactic-dose unfractionated heparin (UFH) or low molecular heparin (LMWH) should be used (with adjustment for renal impairment as indicated). If there is any contraindication to anticoagulation or high bleeding risk, mechanical prophylaxis of the lower extremities should be employed. Mechanical methods of prophylaxis include intermittent compression devices and graduated elastic compression stockings.[45] (B3)

Apart from pharmacological management, endovascular treatment is also used in some facilities to manage thrombosis. It is reported to be more successful if the thrombus is truly acute (ie formation two weeks before the presentation). Different endovascular methods include catheter-directed thrombolysis, percutaneous aspiration thrombectomy, venous balloon dilatation, and pharmacomechanical catheter-directed thrombolysis.[46] The use of inferior vena cava (IVC) filters remains controversial and should only be considered in select cases. IVC filters carry their own risk of potential complications and can serve as a nidus for thrombus formation. In general, for acute DVT, the use of IVC filters should be avoided unless there is an absolute contraindication to anticoagulation or severe active bleeding. When used, a retrievable type of IVC filter is preferred, and anticoagulation should be offered as soon as safely feasible. A risk-benefit analysis of various options and informed patient decision-making is the key to the selection of these specialized intervention modalities, and subspecialty consultation is strongly advised. (B3)

Differential Diagnosis

An embolism is the leading contender in the differential diagnosis of thrombosis. In the latter, a clot is formed in the affected location, causing the narrowing of vessels. In embolism, the clot travels from a primary site to a different location. For instance, in patients with DVT, the clot can get dislocated to the lungs ending up forming PE. Septic emboli should be considered in patients with a risk of systemic infection, IV drug abuse history, or those with suspected or confirmed bacterial endocarditis. Chronic peripheral vascular disease can lead to similar symptoms in the extremities, and patients should have vascular surgery evaluation if suspected. 

Prognosis

The prognosis of thrombosis varies depending on the type of thrombosis (venous or arterial), the location of the thrombosis, the severity of thrombosis, the persistence of provoking risk factors and comorbidities, and whether it is the first or subsequent episode of thrombosis.  Patients with VTE are at a higher risk than the general population for recurrence, especially if they have underlying provoking risk factors. Up to 25% of patients who have experienced VTE may encounter recurrent VTE within 10 years.[47]  The risk of recurrence is higher among patients with multiple cumulative provoking risk factors or underlying confirmed hereditary or acquired thrombophilia. An estimated 300000 deaths occur per year due to venous thromboembolism in the European Union.[48] Cardiovascular disease remains the leading cause of mortality in the U.S., and in patients with cerebrovascular disease, mortality is as high as 20% within the first 30 days of sustaining an ischemic CVA; as many as 30% of survivors will be permanently disabled following a stroke.[46] Prevention of venous and arterial thrombosis is critical, and an understanding of lifestyle characteristics and modifiable risk factors should be conveyed to patients. 

Complications

Thrombosis can give rise to complications if improperly managed during an initial presentation. One significant, well-studied complication is post-thrombotic syndrome, which is a complication of DVT. Reports are that about 20 to 50% of DVT patients will develop this condition within 1 to 2 years after presentation.[49] The risk factors for developing post-thrombotic syndrome are recurrent DVT at the same site, obesity, and poor compliance with anticoagulation. Patients usually present with chronic pain, heaviness, cramps, and swelling exacerbated during exercise and relieved with rest.[42] Studies have shown that the use of elastic compression stockings may help prevent this condition.[50] 

Pulmonary hypertension is also another complication seen as a result of chronic thromboembolism in the pulmonary vasculature. Estimates are that 0.1 to 9% of patients with a history of PE develop pulmonary vascular disease. Unlike other types of pulmonary hypertension, chronic thromboembolic disease is curable by the removal of the clot in the vasculature.[42] This is called pulmonary endarterectomy.

Another major complication associated with thrombosis is spontaneous hemorrhage (both intracranial and extracranial) that can result from therapy with full-dose anticoagulation or antiplatelet agents.  Intracranial hemorrhage can have especially damaging long-term effects. There are reports that the mortality of intracranial hemorrhage could be as high as 50% in patients using vitamin K antagonists (ie, warfarin).[51] Patients treated with anticoagulation due to VTE have a risk of major bleeding of 7.2 events per 100 person-years, a risk of fatal bleeding of 1.31 per 100 person-years, and a case fatality rate of 13.4% due to major bleed.[51] Assessing the risk of bleeding from anticoagulant or antiplatelet agents is an essential clinical objective, and patients should receive counsel on this risk and avoidance of situations that could predispose to bleeding (such as contact sports). Patients at particularly high risk of bleeding complications include the elderly, those with uncontrolled hypertension, those taking antiplatelet agents alongside anticoagulation, and those on warfarin.