The signs and symptoms of thrombosis vary depending on the presumed location and acuity. Patients with deep vein thrombosis (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 calf or thigh of the affected lower extremity (though can occur in any extremity). They may exhibit a decreased range of motion of the extremity, inability to ambulate, or radiation of pain (e.g., into the groin for LE DVT extending to femoral vein). Patients with acute pulmonary embolism (PE) may present with pleuritic chest pain, shortness of breath, fatigue, back pain, syncope, or even death if severe (e.g., PE associated with hemodynamic instability or right heart strain).[11] Signs include tachycardia, tachypnea, 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 (classic presentation; though atypical presentations occur frequently). If thrombosis occurs in one of the cerebral arteries (e.g., ischemic stroke), symptoms may include acute onset of unilateral or bilateral weakness, headache, confusion, vision changes, dysarthria, dysphagia, paresthesias, difficulty ambulating, or frank paralysis of one or more extremities.

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 thromboembolism (VTE).

When patients present to the emergency department with signs and symptoms suggestive of possible venous thrombosis (see previous section H&P findings), a well-validated scale known as the modified Wells' criteria is applied to help guide further diagnostic studies. For patients with 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 a D-dimer could also be elevated in other patients such as pregnant and post-surgical patients, or those with underlying malignancy. However, it aids clinicians in deciding whether to pursue further diagnostic imaging. A negative D-dimer result helps to rule out a clot and avoid unnecessary imaging studies or anticoagulation initiation. The pulmonary embolism rule-out criteria (PERC) is also occasionally applied to help decide whether the patient has developed an acute pulmonary embolism (PE), though not applicable for DVT. The modified Wells score can also be used if physicians suspect an acute DVT. When there is a high pretest probability for PE or DVT, imaging studies should be completed immediately without regard to D-dimer levels. For pulmonary embolism, the recommended imaging studies are CT angiography and ventilation/perfusion imaging (V/Q scan).  The V/Q scan is sometimes preferred over CTPA to avoid radiation exposure or intravenous contrast in those with underlying renal impairment.[12] However, not all facilities have V/Q scanning capabilities or expertise at interpreting the results, so CTPA is often used. Often, pulmonary emboli result from fragmentation of preexisting thrombosis in an extremity (i.e., DVT). Hence, compression sonography (Duplex US) of 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 (most common) vs. unprovoked, and whether it is the first episode vs. subsequent 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. In carefully selected patients suspected of having an underlying hereditary thrombophilia, a targeted hypercoagulable workup may be indicated.  Such testing may include checking the amount of protein 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. In general, a full hypercoagulable workup is rarely necessary and strongly discouraged on initial presentation in the absence of subspecialty evaluation with a hematologist; this is especially true in the acute setting, as many factors can affect the accuracy of test results (e.g., acute inflammation or consumption of coagulation factors due to acute thrombosis can lead to falsely low levels of some coagulation factors). Anticoagulation therapy can also interfere with the interpretation of test results in the acute setting (e.g., heparin can affect the interpretation of Antithrombin III). For antiphospholipid antibody testing, many medications (including several anticoagulants), as well as underlying connective tissue diseases such as SLE, can affect the testing result and interpretation of the lupus anticoagulant. When antiphospholipid antibody testing is indicated, the recommendation is that the tests be repeated 12 weeks apart. As such, clinicians should reserve such hypercoagulable testing to carefully selected patients (e.g., young patients with unprovoked thrombosis or in those with confirmed or strong family history thrombophilia). 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 consultant.  

Malignancy can be an underlying provoking factor for thrombosis (both venous and arterial). In general, it is not recommended for patients to have an extensive malignancy workup in the absence of any clinical factors to suggest underlying malignancy as the provoking cause. Age-appropriate cancer screening is recommended for all patients. In carefully selected patients, especially in those over the age of 50 with seemingly unprovoked thrombosis, in whom malignancy is a possibility, further evaluation to search for occult malignancy as the culprit may be indicated.

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 (i.e., American Society of Chest Physicians, American Heart Association, & American Society of Hematology) for case- and disease-specific recommendations.

Regarding venous thromboembolism (VTE), the American Society of Hematology (ASH) established a 2018 update to their guidelines for managing venous thrombosis, including prophylaxis use in hospitalized patients. In general, venous thrombosis divides into provoked or unprovoked etiologies; this is incredibly important as it helps to guide management and consideration of any further hypercoagulable workup that may be necessary for select patients. Furthermore, one must determine if the thrombosis is a first episode or recurrent episode, as this may change the duration of anticoagulation or antiplatelet therapy. A thorough personal and family history of VTE with careful assessment of provoking risk factors and comorbidities is essential. As noted, a provoked venous thrombosis results from reversible, modifiable, or acquired risk factors (e.g., recent surgery, trauma, infection, pregnancy, morbid obesity, OCP usage, long voyage, or immobility, heavy smoking, underlying malignancy, among others). Unprovoked thrombosis, on the other hand, occurs in the absence of any apparent or strong provoking factor. The treatment of venous thrombosis entails three stages, the initial, chronic, and extended stages,s according to Becattini C. et al. (2016).[13]  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-thrombotic syndrome.  

Management of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients typically includes anticoagulation with IV unfractionated heparin (UFH) or low molecular weight heparin with an eventual transition to oral anticoagulation as below. Anticoagulation promptly with heparin or LMWH provides a quick therapeutic range to avoid the progression of thrombosis and reduce associated mortality.[14] After initiating these intravenous anticoagulants, vitamin K antagonists (e.g., warfarin) can then be added for chronic and extended management once patients achieve a therapeutic INR. For an initial, provoked thrombosis (especially simple distal DVT), the recommended duration is typically 3 months.  For the first episode of provoked thrombosis with extensive clot burden, massive pulmonary embolism associated with hemodynamic compromise, or in patients with multiple persistent provoking risk factors, one should consider at least 3-6 months duration (or longer in select cases). Discontinuing therapy, before established guidelines on duration, can increase the risk of recurrent thrombosis. Medication compliance/adherence is very important to decrease the risk of recurrence. In patients with recurrent DVT or PE, the duration of therapy becomes more complex, and the determination of strong 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. Historically, LMWH has been preferred in those with thrombosis and malignancy. However, exceptions exist, and newer guidelines are now incorporating the use of certain direct oral anticoagulants (e.g., edoxaban) for management in patients with malignancy. Anticoagulation with thrombosis in pregnancy, perioperatively in those with thrombosis (especially orthopedic surgery), thrombosis in those with hereditary or acquired thrombophilia, and management of patients with recurrent or "breakthrough" thrombosis (despite therapeutic anticoagulation) becomes significantly more complicated. These cases are best managed under the guidance of a hematologist consultant.  

In those with true unprovoked thrombosis, the duration of therapy is typically longterm and can be lifelong. With the advent of newer direct oral anticoagulants (DOACs), many of which are non-inferior to older agents such as warfarin (with certain clinical exceptions, notably antiphospholipid syndrome or valvular A. Fib), the options for anticoagulation in acute thrombosis continues to expand. As of this writing, DOAC agents include dabigatran, edoxaban, rivaroxaban, and apixaban. Dabigatran is a direct thrombin inhibitor, while the other three are direct factor Xa inhibitors. The American Society of Hematology (ASH) has recommended in 2018 that the direct oral anticoagulants (DOACs) can be used in certain circumstances for the management of acute VTE while taking into consideration the risk of bleeding, renal impairment, and comorbidities that may reduce their efficacy (e.g., morbid obesity).[15]  When using unfractionated heparin, the partial thromboplastin time requires close monitoring, and the dose should be adjusted each time based on the value.  LMWH does not require monitoring, though occasionally for patients who are morbidly obese can be monitored by checking anti-Factor Xa levels. For vitamin K antagonists (i.e., warfarin), the PT/INR should be monitored and maintained in therapeutic range (INR typically between 2 and 3). With the DOACs, no routine blood monitoring is necessary; however, medication compliance/adherence remains paramount to assuring the efficacy of these medications. As of this writing, for patients with confirmed acute heparin-induced thrombocytopenia & thrombosis (HITT), a non-heparin anticoagulant such as argatroban should be utilized, and expert consultation with hematology is the recommendation.  In patients with confirmed antiphospholipid syndrome and acute thrombosis, vitamin k antagonism with warfarin is preferred, and consultation with hematology may be helpful. The use of DOACs in these settings is still under investigation.  

For patients who are admitted to the hospital, the American Society of Hematology (ASH), consistent with other subspecialty society guidelines have recommended 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 lower extremities should be employed.[16] Mechanical methods of prophylaxis include intermittent compression devices and graduated elastic compression stockings. With certain exceptions, it is not generally recommended to extend pharmacologic prophylaxis following hospitalization.[16] Prophylaxis should be strongly considered in acutely and critically ill patients who are hospitalized.[16]

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 (i.e., formation two weeks before the presentation). Different endovascular methods include catheter-directed thrombolysis, percutaneous aspiration thrombectomy, venous balloon dilatation, pharmacomechanical catheter-directed thrombolysis.[17] The use of inferior vena cava (IVC) filters remains controversial in the acute setting and should only be considered in select cases. IVC filters carry their own risk of potential complications, and they can serve as a nidus for thrombus formation. In general, for acute venous thrombosis, 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.

An embolism is a differential diagnosis of thrombosis. In the later, the clot is formed in a location, causing the narrowing of vessels. In embolism, the clot travels from a primary site to a different location. For instance, in patients with deep venous thrombosis, the clot can get dislocated to the lungs ending up forming pulmonary embolism. Septic emboli should be considered in patients with 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 of thrombosis varies depending on which type of thrombosis (venous or arterial), the location of the thrombosis, severity/extent of thrombosis, the persistence of provoking risk factors and comorbidities, and whether the first or subsequent/recurrent episode of thrombosis.  Patients with venous thromboembolism are at a higher risk than the general population for recurrent VTE, especially if they have underlying provoking risk factors. Up to 25% of patients who have experienced VTE may encounter a recurrent venous thrombosis within 10 years.[18]  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.[19] 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% survivors will be permanently disabled following a stroke.[17] Prevention of venous and arterial thrombosis is critical, and an understanding of lifestyle characteristics and modifiable risk factors should be conveyed to patients.

Thrombosis can give rise to complications if improperly managed an initial presentation. One significant, well-studied complication is a post-thrombotic syndrome, which is a complication of deep venous thrombosis. Reports are that about 20 to 50% of deep vein thrombosis patients will develop this condition within 1 to 2 years after presentation.[20] 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.[14] Studies have shown that the use of elastic compression stockings may help prevent this condition. Brandjes et al. observed a reported 50% reduction of post-thrombotic syndrome.[21] 

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 pulmonary embolism develop the pulmonary vascular disease.[14] Unlike the other types of pulmonary hypertension, chronic thromboembolic induced is curable by the removal of the clot in the vasculature.[14] This is called pulmonary endarterectomy.

Arterial thrombosis can result in many complications, particularly concerning cardiac and cerebrovascular disease resulting in significant morbidity and disability and the risk of recurrent events in the absence of lifestyle modifications and medical management.  

Another major complication associated with thrombosis is spontaneous hemorrhage (both intracranial and extracranial) that can result due to therapy with full-dose anticoagulation or antiplatelet agents.  Intracranial hemorrhage, when it occurs, is more devastating than extracranial. There are reports that the mortality of intracranial hemorrhage could be as high as 50% in patients using vitamin K antagonists (i.e., warfarin).[22] Patients treated with anticoagulation due to venous thromboembolism have a risk of major bleeding of 7.2 events per 100 person-years, the risk of fatal bleeding of 1.31 per 100 person-years, and a case fatality rate of 13.4% due to major bleed.[22] 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 (e.g., contact sports). Patients at particularly high risk of bleeding complications include the elderly, those with uncontrolled hypertension, those taking antiplatelet agents alongside anticoagulation, or those on warfarin, and multiple other medications that may interfere with warfarin metabolism.

As noted, the causes of venous and arterial thrombosis are multifactorial and context matters. Many acquired or modifiable risk factors can increase the likelihood of developing thrombosis. Patients should receive counseling regarding these risk factors and what they can do to ameliorate their risk. Patients who are known to have an underlying hypercoagulable state (e.g., those taking estrogen, pregnant women, or morbidly obese patients) should be informed of their risk of thrombosis. Patients should be counseled to avoid long periods of immobility (long trips) and to stretch often. The use of elastic compression stockings may be helpful. Smoking cessation should be reinforced.

For patients on anticoagulant or antiplatelet therapy, it is prudent to conduct a review of the risks of major bleeding.  Patients should be counseled on fall precautions while on these agents.

Primary physicians and other health professionals should help patients reduce their risk of thrombosis by providing accurate information on prevention and treatment. Both venous and arterial thrombosis share similar risk factors, and efforts should be made to educate and encourage patients to make healthy lifestyle choices. For example, chronic smokers should be encouraged to quit smoking. Those who are morbidly obese should be encouraged to change their diet and lifestyle accordingly.  Patients with metabolic syndrome or uncontrolled blood pressure should receive education on the importance of lifestyle modification and, when indicated, secondary prevention with medical management. 

Patients admitted to the hospital are also at higher risk of thrombosis. The American Society of Hematology (ASH) in 2018 recommended prophylaxis in patients admitted to hospital settings. Patients who do not get prophylaxis like unfractionated heparin (UFH), low molecular weight heparin (LMWH), or mechanical prophylaxis are at high risk of developing thrombosis. Therefore, care is necessary when managing patients admitted to the hospital, and daily reassessment of the risk of thrombosis is recommended in these settings.