Thoracic outlet syndrome

Risk for UEDVT increases in thoracic outlet syndrome. The subclavian vein is compressed by one of the following: first rib, a cervical rib, clavicle, subclavian muscle, or anterior scalene muscle. This is typically seen in athletes with hypertrophied muscles who perform heavy lifting and overhead movements.

Paget-Schroetter syndrome

Paget-Schroetter syndrome (often referred to as effort-related thrombosis) is typically caused by microtrauma to the subclavian vein from repetitive arm movements. This subcategory of thoracic outlet syndrome leads to primary thrombosis of the subclavian vein at the costoclavicular junction. Typical cases include sporting activities such as pitching, swimming, or rowing, and occupations such as painting or automotive mechanics. If Paget-Schroetter syndrome is suspected, consult vascular surgery for consideration of thrombolytic therapy in addition to surgical intervention.²

Idiopathic (unprovoked)

The specific etiology is unknown; consider an underlying hypercoagulable state.

Background

The need for treatment of calf-level DVT remains controversial, with clinical recommendations both for and against anticoagulant treatment.^12-14 Outpatient studies report that the proportion of all DVTs that are “distal” is as high as 60% to 70%, demonstrating the magnitude of the problem.^14,15 Calf DVT is more commonly associated with transient risk factors, and has lower mortality than proximal DVT (4.4% vs. 8.0%, p < 0.01).¹⁶ The important clinical consequences of calf DVT include proximal extension, VTE recurrence, pulmonary embolism (PE), and post-thrombotic syndrome (PTS). The limited available evidence for the natural history of calf level DVT suggests that complications, including PE and PTS, are significantly decreased with distal versus proximal DVT, although these rates still remain somewhat high.¹⁷ The studies are highly heterogeneous, and rates vary widely between earlier and more recent cohorts.

Diagnosis

Compression ultrasonography is the first-line imaging modality for the diagnosis of distal DVT. The performance of the D-dimer to evaluate symptomatic distal DVT is controversial, with not all assays found to be reliable for this purpose.¹⁸ Therefore, we do not recommend the routine use of the D-dimer for diagnosis.

Treatment

Two recommended options for the management of distal (calf) DVT:

• weekly serial compression ultrasound for 2 weeks to assess for clot propagation, or
• anticoagulation therapy using the same strategy as for patients with acute proximal DVT.

Although both of these options are acceptable, Table 2 provides information to help individualize the treatment decision. Calf DVTs such as the gastrocnemius and soleus vein, although technically distal deep veins, are usually considered superficial veins for treatment purposes and, as such, do not require anticoagulation therapy (Table 3), but should still undergo serial compression ultrasound surveillance. There may be circumstances where they should be considered deep veins (see discussion below).

Extension of distal blood clots to proximal veins is a known risk of proximal DVT. In a review of the literature, the rate of proximal extension was highly variable, ranging from 0% to 23% in patients without anticoagulation, and 0% to 44% in patients with anticoagulation.¹⁹ The studies are too heterogeneous for meaningful comparisons between untreated and treated patients, but in studies following untreated patients with serial ultrasound, the rate of proximal extension ranges from 0.9% to 5.7%.¹⁹

The CALTHRO study²⁰ assessed the clinical consequence of untreated calf DVT in 431 symptomatic outpatients with initial negative ultrasound for proximal vein DVT and an abnormal D-dimer. At the 3-month follow-up, adverse outcomes occurred in three patients: 1 with proximal vein extension, 1 with PE, and 1 with worsening symptoms.²⁰ In contrast, limited randomized studies have shown recurrent thrombotic events in up to 29% of patients with inadequately treated calf vein thrombosis.²¹ In prospective cohorts of patients with isolated calf-level DVT largely treated with anticoagulation, VTE recurrence rates at 3 months are 2% to 2.2%, which includes 0.7% to 1.1% rates of PE.^16,22

Thus, there is clinical equipoise to the treatment of calf vein DVT. Widely accepted management studies suggest that withholding anticoagulation is safe in outpatients with suspected DVT if serial compression ultrasound is negative for proximal DVT at baseline and at 1 week.^23-28 Withholding anticoagulation in outpatients with suspected calf vein DVT, if serial compression ultrasound is negative for proximal DVT at baseline, and negative 1 week later results in 3 month pooled estimate for thromboembolic risk of 0.6% (95% CI 0.4%-0.9%).²⁹ Given these findings, the Compression Alone Versus Anticoagulation for Symptomatic Calf Vein Thrombosis Diagnosed by Ultrasonography (CACTUS) trial was performed to determine the safety of withholding anticoagulation in patients with isolated symptomatic calf vein DVT at low risk for proximal extension/VTE, as defined by no personal VTE history or active malignancy.⁵ LMWH treatment resulted in increased bleeding complications without reducing proximal extension. This study was underpowered for its endpoints, as only 259 patients were enrolled (the power calculation for this study was 572 patients). Avoiding anticoagulation may be safer and more cost effective for low-risk patients than placing the patients on anticoagulation. Data from smaller studies evaluating low-risk patients with calf vein DVT suggests that a shorter duration period and lower intensity anticoagulation (full dose LMWH ×1 week and half dose for 3 weeks) was associated with a low recurrence and VTE complication rate. This of course raises the provocative question – should patients at high-risk be treated in the same manner as those patients with proximal DVT.⁶

Regarding post-thrombotic syndrome, Meissner and colleagues followed a prospective cohort of patients with acute DVT and noted that, at 12 months, symptoms of post-thrombotic syndrome occurred in 23% of limbs with calf DVT (3/13) and 54% of limbs with proximal DVT (51/95).³⁰ In various studies the proportion of patients treated with anticoagulation has varied from 51% to 72%, and varied in the length of time of anticoagulation.^31-33

The 2021 American College of Chest Physicians (ACCP) guidelines for venous thromboembolism⁷ recommend that patients with isolated distal DVT of the leg without severe symptoms or risk factors for extension receive weekly serial imaging of the deep veins for 2 weeks over anticoagulation. Conversely, if significant calf pain or risk factors for extension are present (Table 2), anticoagulation for 3 months is recommended over serial imaging.

In patients with acute isolated distal DVT who are managed with anticoagulation, recommended treatment is the same as for patients with acute proximal DVT. Anticoagulation options include a DOAC (e.g., rivaroxaban, apixaban, edoxaban, or dabigatran) or warfarin. Initial treatment with LMWH is required if transitioning to edoxaban, dabigatran, or warfarin, while rivaroxaban and apixaban do not require initial treatment with heparin. Finally, in patients with an acute isolated distal DVT who are managed with serial imaging, switching to anticoagulation is recommended when the thrombus extends but remains confined to the distal veins, or extends into a proximal vein.

For patients with distal DVT, the patient’s bleeding risk may influence the decision to prescribe anticoagulation or prescribe serial compression ultrasonography. Furthermore, patient preferences with respect to proximal DVT or PE risk versus bleeding risk need to be taken into consideration. The most recent Cochrane review identified eight RCTs reporting on 1239 participants. This review suggests a benefit for distal DVT treated with anticoagulation therapy using VKA with little or no difference in major bleeding. There was an increase in clinically relevant non-major bleeding when compared with no intervention or placebo.⁸

Background

Proximal DVT is usually manifested by unilateral calf swelling, pitting edema, and pain of the affected leg. Proximal DVT includes thrombosis of the iliac, femoral, and popliteal segments (Table 3). Severe obstructive iliofemoral DVT sometimes manifests with severe swelling and pain. In all cases, the mainstay of therapy involves compression, elevation, and prompt initiation of anticoagulation. If an absolute contraindication to anticoagulation exists, consider inferior vena cava filter placement to prevent pulmonary emboli.

Diagnosis

The gold standard for imaging is duplex ultrasonography. If iliofemoral venous thrombosis is suspected, but not confirmed using standard diagnostic modalities such as venous duplex ultrasound imaging, use adjunctive imaging modalities such as computerized tomography venography (CTV) or magnetic resonance venography (MRV) to characterize the most proximal extent.^34,35

CTV and MRV evaluate the inferior vena cava and veins of the pelvis better than ultrasound or contrast venography. Pooled analysis of studies comparing CTV to ultrasound or venography demonstrate a sensitivity and specificity of >95%.³⁶ MRV has also been found to be accurate in the diagnosis of DVT. In a large meta-analysis, compared to venography or ultrasound imaging, sensitivity and specificity of 92% (94% for proximal DVT) and 95% was found,³⁷ and MRV is accurate in the diagnosis of pelvic vein thrombosis.³⁸

Treatment Overview (Figure 1)

For proximal DVT treatment, the goals are three-fold:

• To prevent extension or recurrence of DVT
• To prevent pulmonary embolism
• To minimize the late sequelae of thrombosis, including chronic venous insufficiency and post-thrombotic syndrome

Standard anticoagulants typically accomplish the first two goals but do not always accomplish the third goal. Post-thrombotic syndrome occurs in up to 30% of patients after DVT, and that number is even higher in patients with iliofemoral-level DVT.³⁹ In select ambulatory patients who have a reasonable life expectancy and a favorable risk profile, more aggressive therapies for extensive thrombosis are indicated. For DVT limited to the femoropopliteal region, and without extension into the iliac system, anticoagulation alone is recommended. Phlegmasia is an exceedingly rare condition associated with massive iliofemoral DVT.

Anticoagulation (Figure 2, Table 4)

The standard treatment of VTE is systemic anticoagulation, which reduces extension of thrombosis, thrombus recurrence, and the risk of PE. Immediate anticoagulation should be undertaken as the recurrence rate for VTE is higher if anticoagulation is not therapeutic in the first 24 hours. Treatment at home is preferred over inpatient therapy for most patients.⁴⁰

Today, DOACs are recommended as first line treatment of acute VTE over VKAs in non-pregnant patients due to evidence demonstrating their effectiveness and safety.⁴¹ They are recommended over LMWH and warfarin in most circumstances, allowing much easier treatment of VTE.^42,43 Currently four DOACs are approved by the US Food and Drug Administration (FDA) for the treatment of DVT. These include rivaroxaban (Xarelto) and apixaban (Eliquis) as oral monotherapy (both require a high-dose initiation period followed by standard therapeutic dose), and dabigatran (Pradaxa) and edoxaban (Savaysa) which require a LMWH bridge. The DOACs are all administered orally, have fixed doses, and do not need monitoring (in most circumstances). One of the appealing aspects of heparin and VKAs is the ability to be quickly reversed by readily available agents (protamine for heparin and to a lesser degree LMWH and fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) for VKAs). Until recently, DOAC reversal was limited to supportive measures, PCC, or selective dialysis. The FDA approved idarucizumab (Praxbind™), a monoclonal antibody, that binds to dabigatran and can reverse its anticoagulant effects within minutes⁴⁴ and andexanet alfa (Andexxa™), a recombinant factor Xa decoy, for all factor Xa inhibitors, including DOACs, LMWHs and fondaparinux.⁴⁵ The final reversal agent progressing in development with FDA fast track designation for hemorrhage is ciraparantag, a water soluble, catatonic molecule available as an intravenous infusion. This agent non-covalently binds to and reverses the anticoagulant effects of all anticoagulation agents (LMWH, UFH, factor Xa inhibitors, dabigatran) in animal models and healthy volunteers.⁴⁶ DOACs may not be appropriate in some patients with impaired renal function, and are not appropriate for patients with mechanical heart valves. VKAs are the best option in these cases. Also, for some patients, DOACs may be cost prohibitive. When a parenteral agent is selected for acute treatment, LMWH is the treatment of choice, with unfractionated IV heparin as an alternative.

Cancer and VTE (Figure 2)

DOACs are now recommended over LMWH for the initiation and treatment phases of cancer-associated VTE. LMWH has traditionally been considered definitive first line treatment for these patients; however, a meta-analysis of cancer patients enrolled in phase 3 DOAC trials demonstrate the feasibility and safety in cancer, although this analysis was hampered by lack of comparison to LMWHs as standard of care. The DOACs rivaroxaban, edoxaban, and apixaban have all been studied in patients with active malignancy. Although DOACS have been felt to be equivalent to LMWH in efficacy in cancer patients, they have been associated with higher rates of bleeding (particularly GI bleeding) until a recent study demonstrated that apixaban was superior to the LMWH daltaparin, for VTE recurrence with a similar major bleeding rate.⁴⁷ Apixaban or LMWH is preferred in patients with luminal GI cancer.⁴³

Duration of Therapy (Figure 2, Tables 6 and 7)

The recommended duration of anticoagulation for the treatment of provoked proximal and symptomatic distal VTE is 3 months.^42,43 Extended therapy is considered under the following circumstances: Unprovoked VTE or provoked by persistent risk factor(s), previous VTE event, and/or diagnosed thrombophilia. For patients with a diagnosed hereditary thrombophilia, those that are associated with a higher risk of VTE recurrence are protein C/S deficiency (especially with a family history), antithrombin deficiency, homozygous factor V Leiden, and homozygous prothrombin 20210 gene mutation, as well as multiple thrombophilias (i.e., more than one diagnosed thrombophilia in the same patient). For these situations, prolonged anticoagulation is recommended. Although Factor V Leiden heterozygous mutation alone does not confer an increased risk of recurrence, when combined with prothrombin 20210 gene mutation recurrence is increased and prolonged anticoagulation is recommended. Amongst acquired thrombophilias, antiphospholipid antibodies and active cancer mandate extended therapy.⁴⁸ In patients with confirmed antiphospholipid syndrome being treated with anticoagulants, the use of adjusted dose VKA (with a targeted INR 2.5) is recommended over DOACs.⁷

Unprovoked first-time VTE remains a difficult clinical decision, balancing the competing risks and implications of recurrent VTE and major bleeding. D-dimer elevation measured approximately 1 month after stopping anticoagulation and repeat duplex testing with persistent scar tissue in the veins have both been advocated as potential reasons to recommend extension of anticoagulation. The rate of recurrence with an elevated D-dimer is higher (15% compared to 6.2% with a normal D-dimer). This risk can be mitigated with resumption of anticoagulation, reducing the VTE rate down to 2.9%.⁴⁹ A new advance is the validation of the HERDOO2 score, which was developed and prospectively validated to identify women at low risk of recurrence following unprovoked VTE.⁵⁰ In this score, women receive a point for (a) hyperpigmentation, edema, or redness in either leg, (b) VIDAS D-dimer ≥ 250 μg/L, (c) Obesity (BMI ≥ 30), and (d) Older age (≥ 65 years). Patients with 0 or 1 point are at low risk for recurrent VTE and may discontinue long-term anticoagulation therapy. Women who were defined as low risk and discontinued therapy had a 3.0% risk of recurrent VTE per patient year, compared to an 8.1% risk in women at high-risk. Unfortunately, a similar score does not exist for men.

The advent of the DOACs has reinvigorated the use of low dose anticoagulation to improve the risk-benefit profile of extended therapy with decreased bleeding risk. Historically, low-dose VKAs resulted in similar bleeding profiles to standard therapy. Both treatment and prophylaxis doses of rivaroxaban and apixaban have been shown to be more effective in prevention of VTE recurrence with no increased risk of bleeding compared to placebo or ASA.^51,52 The WARFASA and ASPIRE trials have also demonstrated a reduced risk of VTE recurrence in patients treated with aspirin compared to placebo, but less than that seen with DOACs.^53,54 The current recommendation is to use reduced dose DOAC over aspirin or no therapy, and specifically rivaroxaban over aspirin based on direct trial data.⁵⁵ In patients who qualify for prolonged therapy and who cannot receive a DOAC, the current recommendation is to use VKA.⁷ Another indication for prolonged therapy is in active cancer patients. DOACs or LMWHs should be considered instead of VKAs. Although DOACs may reduce recurrence rates more than LMWH, they also appear to increase the risk of major bleeding.⁵⁶ However, based on recent trial data, the most updated guidelines suggest an oral Xa inhibitor (apixaban, edoxaban, rivaroxaban) over LMWH in patients with acute VTE in the setting of cancer.⁷

Post-Thrombotic Syndrome

Anticoagulation is indicated for all patients with proximal LEDVT. However, standard anticoagulants do not prevent the development of pain and swelling after DVT, which can occur in up to 30-50% of cases of proximal DVT and in up to 80% of patients with iliofemoral DVT, the so-called post-thrombotic syndrome (PTS).^57-59 The 2016 ACCP guidelines emphasize anticoagulant therapy over catheter directed thrombolysis in most cases. The exception is in patients who attach a high value to the prevention of post thrombotic syndrome for quality of life considerations, and a lower value to the initial complexity, cost, and risk for bleeding of aggressive therapies as compared to anticoagulation alone.⁴¹ This is mostly for patients with iliofemoral DVT and significant symptoms (see Table 5).

Anticoagulation alone is recommended over early thrombus removal for isolated femoropopliteal DVT. Evidence is insufficient to recommend early thrombus removal instead of a thrombolytic agent.^34,60 Patients with femoropopliteal DVT show a lower risk of thrombosis recurrence (11.8% iliofemoral vs. 5.3% femoropopliteal),⁶¹ a lower risk of the development of post-thrombotic syndrome,⁶² fewer symptoms on presentation, and inferior outcomes with thrombolysis. Most patients with femoropopliteal DVT do not need aggressive thrombus removal.

Thrombus removal

In some cases of iliofemoral DVT, thrombus removal (usually involving a catheter-based procedure) is recommended over anticoagulation alone. These procedures should be performed urgently in cases of limb-threatening disease, characterized by massive painful limb swelling, with or without cyanosis, skin blisters or necrosis, or loss of or diminished arterial pulses. In addition, thrombus removal may also be appropriate for other patients as a method to prevent long term limb complications, as summarized in Table 5. Consultation for venous thrombectomy may occur on an outpatient basis, or on an emergency/inpatient basis (if the patient requires admission or has evidence of limb threat). Please follow the consultation guidelines below for optimal patient care:

• Patients with evidence of immediate limb threat, including phlegmasia, venous gangrene, and/or arterial insufficiency: emergent consultation of vascular surgery and IR.
• Patients with mild to severely symptomatic iliofemoral DVT, who require inpatient admission: routine consultation to IR only.
• Patients with mild to severely symptomatic iliofemoral DVT, who are stable for discharge to home: referral to Venous Health Program (as urgent DVT referral) and DOAC prescription. The VHP program will coordinate further anticoagulation, compression therapy and thrombectomy (if indicated). This is the preferred clinical pathway for most patients.

Catheter directed thrombolysis (CDT)

While not currently endorsed by major society guidelines, CDT has been shown to decrease symptoms of pain and swelling at 30 days and may decrease development of post thrombotic syndrome in highly select groups of patients (acute iliofemoral DVT, Villalta score ≥ 10 after a trial of anticoagulation) (Table 5).

CDT has been employed in many non-randomized studies. In small, randomized trials, CDT was more effective than standard therapy in patients with acute proximal lower extremity DVT. Quality of life was improved with thrombolysis. Results are optimized by combining CDT with mechanical devices, known as pharmacomechanical thrombolysis (PMT).^63,64 These devices hasten thrombolysis, decrease the amount of thrombolytic agent needed, and thus decrease bleeding potential. Unfortunately, a large randomized study to address the question of when PMT might be indicated did not find that the overall incidence of PTS was decreased using PMT for DVT, although there was a signal that in the most highly affected patients with iliofemoral DVT, improvements may occur with PMT.⁶⁵ The most recent Cochrane review with 1943 patients looking at systemic, loco-regional and CDT including PMT concluded that complete clot lysis occurred more frequently after thrombolysis (with or without additional clot removal strategies), PTS was slightly reduced (50% compared to 53%), and bleeding complications increased with thrombolysis. Additionally, systemic thrombolysis and CDT have similar effectiveness. There was no benefit seen depending on the level of DVT, and evidence to date is of moderate certainty.⁶⁶ At Michigan Medicine, outpatients may be seen in the Venous Health Program clinic for consideration of CDT or PMT, or if hospitalized, in consultation by the vascular surgery service and interventional radiology for a discussion of risks and benefits of such a procedure.

Phlegmasia and venous gangrene

This is rare clinical phenomena that places the affected limb at risk of ischemia. Phlegmasia cerulea dolens (PCD) is an uncommon form of DVT characterized by severe pain, swelling, cyanosis, and edema. This is preceded by phlegmasia alba dolens, which is characterized by the same clinical signs except the limb is pale and white due to early ischemia, and not yet cyanotic. Venous gangrene is defined as skin necrosis, discoloration, and documented VTE.

Initial treatment for PCD or venous gangrene is the same as for proximal DVT with an emphasis on immediate anticoagulation and vascular surgical consultation. Early thrombus removal is the treatment of choice in patients with limb-threatening venous ischemia due to iliofemoral venous thrombosis, with or without associated femoropopliteal venous thrombosis. ^34,67,68 These patients require thrombolysis when characterized by any the following:

• Massive painful limb swelling, with or without cyanosis
• Skin blisters or necrosis
• Loss of or diminished arterial pulses

Aggressive therapies for phlegmasia include both venous thrombectomy and thrombolysis. If the patient does not respond to initial extremity elevation, fluid resuscitation, and aggressive systemic anticoagulation (usually within the first 6 hours), then CDT with pharmacomechanical assist should be first-line therapy. Surgical venous thrombectomy is reserved for patients who have contraindications to thrombolysis.⁶⁹

Background

Extensive lower extremity acute DVT frequently occurs in the setting of chronic thrombosis of large central veins, such as the inferior vena cava or common iliac veins.

Treatment

Treat the acute thrombus to restore the patient to baseline status. Then address the chronic occlusion at a later date after the inflammatory state has abated. Occasionally, restoring flow also requires treatment of the chronic occlusion. In these cases, the chronically occluded segment can be recanalized with stenting.⁷⁰ At Michigan Medicine, patients needing to be recanalized with stenting should be referred to the outpatient Venous Health Program within 72 hours of discharge.

Consideration for alternate imaging

CT pulmonary angiography is the preferred diagnostic imaging modality given its high sensitivity and specificity (particularly when used with diagnostic algorithms as outlined above) and widespread availability. In cases when CT angiography is contraindicated, ventilation perfusion (V/Q) scanning is recommended.

V/Q scan results are reported as high-, intermediate-, or low-probability for PE, or normal. Interpretation can be challenging as only a high-probability V/Q scan (with a high clinical pretest probability) is sufficient to confirm PE. And while a normal scan or a low-probability scan (with a low clinical pretest probability) can be used to rule out PE, all other V/Q results with associated pretest probabilities are nondiagnostic. Other limitations of V/Q scanning include: 1) a normal chest x-ray is typically required prior to V/Q scanning; 2) the potential for delays in obtaining this study during evenings and weekends; and 3) the requirement for patients to lie still for 30-60 minutes.

In cases where CT pulmonary angiography and V/Q scanning are not possible, obtaining a lower extremity ultrasound with Doppler should be considered. If results are positive for DVT, initiating systemic anticoagulation is justified. If results are negative for DVT, and the patient was determined to be of low- or intermediate-risk for PE, anticoagulation can likely be withheld. However, if results are negative for DVT but the patient was determined to be at high-risk for PE, it is reasonable to initiate systemic anticoagulation while reconsidering if CT pulmonary angiography or V/Q scanning can be obtained.

Catheter-based pulmonary angiography, once considered the gold standard, is now rarely performed as CT pulmonary angiography has shown to be more accurate in diagnosing PE.⁷⁸

Diagnosis

Incidentally discovered asymptomatic PE includes PEs that are found as a result of testing not intended to diagnose PE.

Treatment

Incidentally discovered asymptomatic PEs are clinically relevant based on observational data. Treatment with systemic anticoagulation should be considered just as for patients with symptomatic PE. In patients with contraindications to anticoagulation, deciding not to treat PE with systemic anticoagulation is reasonable.

Most incidentally discovered asymptomatic PEs are found during CT imaging performed for oncologic staging in patients with active cancer.⁷⁹ Decisions on treating these findings are clinically challenging. Among patients with asymptomatic PE, no randomized trials have compared outcomes for treatment with anticoagulation versus surveillance without anticoagulation. Evidence is limited to small observational and retrospective cohort studies. Most of these studies included patients with a malignancy diagnosis.

Evidence is mixed as to whether patients with asymptomatic PE have increased mortality. A retrospective cohort study of lung cancer patients who were incidentally found to have a PE, but were not treated with anticoagulation, showed increased mortality.⁸⁰ Another retrospective cohort study found no statistical difference in mortality, recurrent pulmonary embolism, or bleeding complications among patients treated with anticoagulation for both symptomatic and asymptomatic PE.⁸¹

Diagnosis/Classification

Massive (or high-risk) PE is an acute PE with resultant sustained hypotension despite adequate fluid resuscitation, with either a systolic blood pressure (SBP) < 90 mmHg for more than 15 minutes, a drop in systolic blood pressure of at least 40 mm Hg for at least 15 minutes or hypotension requiring vasopressor support. The cause of hypotension should not be due to other causes (i.e. septic shock, hypovolemia, known left ventricular systolic dysfunction, or bradycardia). Radiographic findings such as a “saddle embolism” are not part of criteria to classify massive PE and thus, should not be used.

While no definition of massive PE is universally accepted, two large international registries of acute pulmonary embolism report excess attributable mortality with PE-associated sustained systemic hypotension. The registries are the International Cooperative Pulmonary Embolism Registry (ICOPER) and the Management Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET). The ICOPER registry demonstrated a 52.4% 90-day mortality in patients presenting with an SBP < 90 mm Hg vs. 14.7% in those with a SBP > 90 mm Hg.⁸⁵ The MAPPET registry showed an 8.1% in-hospital mortality for hemodynamically stable patients with acute PE vs. 25% in-hospital mortality in those with cardiogenic shock, and 65% in those presenting with cardiac arrest.⁸⁶

Treatment

All patients with massive PE should be systemically anticoagulated with either LMWH or unfractionated heparin depending on their renal function. Patients with massive PE should receive systemic thrombolytic therapy unless a contraindication exists (Table 6). If a contraindication for thrombolytic therapy exists, consultation with the PE Response Team (PERT) can be obtained. At Michigan Medicine, the PERT team provides expert opinion in the management of acute PE. PERT can be activated by the paging system and is available 24 hours a day, 7 days a week.

National guidelines^11,41,87 endorse administering systemic thrombolytics for patients with hemodynamic decompensation, shock, or cardiac arrest unless a contraindication exists (Table 8). Although few trials have evaluated systemic thrombolytics in patients with massive PE, a meta-analysis that included a subgroup of these patients demonstrated a decrease in the composite endpoint of death and recurrent thromboembolism compared to heparin alone.⁸⁸ If there are contraindications to systemic thrombolysis (i.e. patients with a high bleeding risk), mechanical and catheter-directed thrombolysis (CDT) may be considered but only upon consultation with a multidisciplinary team of subspecialists (At Michigan Medicine, this is the Pulmonary Embolism Response Team [PERT]). It should be emphasized that the data on catheter-directed thrombolytic therapy at the present time is evolving but limited. Temporary placement of an inferior vena cava (IVC) filter is reasonable in patients who are not candidates for systemic anticoagulation, particularly in those with concomitant proximal DVT.

If hemodynamic collapse is imminent or thrombolytic therapies (systemic and catheter-directed therapy) are contraindicated, cardiac/thoracic surgery should be urgently consulted for consideration of an open pulmonary artery embolectomy or extracorporeal membrane oxygenation (ECMO).

For blood pressure support, an initial IV crystalloid fluid bolus of no more than 500 mL can be administered. Excessive IV fluids may result in right ventricular (RV) overload and worsening RV failure. For persistent hypotension, initiate IV vasopressor therapy; norepinephrine is the drug of choice and is preferred over both dopamine and dobutamine.

IV unfractionated heparin (UFH) is the anticoagulant of choice for massive PE. Heated High Flow Nasal Cannula is the oxygen delivery modality of choice in patients with acute hypoxic respiratory failure. Avoid intubation and positive pressure ventilation whenever possible.

Systemic thrombolysis with alteplase (tPA): dosing, preparation, administration and monitoring

Prior to systemic thrombolytic therapy, obtain a baseline CBC, fibrinogen, PT/INR and activated partial thromboplastin time (aPTT). For massive PE patients who are already receiving systemic anticoagulation, systemic anticoagulation should be discontinued prior to administration of thrombolytic therapy. At Michigan Medicine, alteplase is the thrombolytic therapy of choice. Administer alteplase at 100 mg IV infused over 2 hours (10mg bolus followed by a 90mg infusion over 2 hours). Alternatively, alteplase can be given more quickly with the first 50 mg given over 15 minutes in patients exhibiting rapid deterioration.⁷ There are no head-to-head studies comparing these two alteplase dosing regimens.

After the alteplase infusion has been completed, check the aPTT and fibrinogen level every 1-hour post-infusion. When the aPTT decreases to twice the upper normal level or less (<80 seconds) with normalization of fibrinogen level, resume IV heparin infusion at the previous dose.

Before, during, and after the alteplase infusion, obtain blood pressure measurements frequently and monitor the patient for signs of bleeding. Post-infusion blood pressures and neuro checks should be performed every 15 minutes for 2 hours, every 30 minutes for the next 6 hours, and hourly for the next 16 hours. Monitoring should take place in an ICU or moderate care area but the alteplase infusion may be initiated on a general care floor or the emergency department prior to patient transfer.

Diagnosis/Classification

Although no high-quality studies definitively define submassive PE, this guideline defines it as an acute PE without hypotension, but with evidence of right ventricular (RV) dysfunction and/or myocardial necrosis.

While registries and clinical scoring tools for PE support the concept that patients with advanced age and comorbidities are at increased risk of poor outcomes, these do not predict adverse outcomes independent of imaging findings (i.e., from chest CT or transthoracic echocardiogram) or biomarker results (i.e. elevated troponin or BNP). While submassive PE is not consistently defined, cohort studies reliably show an increased risk of adverse outcomes in certain subgroups of patients with acute PE, including patients with abnormal biomarkers or abnormal imaging (chest CT and echocardiography) that suggest RV strain. Such criteria have recently been accepted by other society guidelines including the American Heart Association (AHA) and the American College of Chest Physicians (ACCP).

Clinicians need to rely on clinical judgement as to whether a patient may have a submassive PE. Concerning findings may include transient hypotension unexplained by other findings, arrhythmia, patient appearance (i.e., altered mental status, syncope, cool extremities, diaphoresis), elevated lactate, and poor urine output. In these settings, the clinician should obtain additional data. Any of the following findings are consistent with a diagnosis of submassive PE:

• Elevated BNP (either above the laboratory reference range or higher than a patient’s baseline, if known)
• Elevated troponin
• CT imaging evidence of RV strain (CT findings of an RV:LV ratio of ≥ 0.9). If this information is not present in the radiology report, it can be obtained by conferring with the radiologist.
• Transthoracic echocardiogram evidence of RV strain (RV size > LV size; RV pressure overload with flattening of the interventricular septum in both systole and diastole; reduced tricuspid annular plane systolic excursion (TAPSE) of < 16 mm). Of note, the RV systolic pressure (RVSP) may only be modestly elevated in submassive PE.

Michigan Medicine’s PERT service uses the European Society of Cardiology’s⁸⁹ definition of intermediate-risk (or submassive) PE as follows:

• Intermediate-low risk PE: acute PE with RV strain as demonstrated by either laboratory biomarker abnormalities OR imaging findings
• Intermediate-high risk PE: acute PE with RV strain as demonstrated by both laboratory biomarker abnormalities AND imaging findings

Treatment

As with massive PE, patients with submassive PE require urgent systemic anticoagulation. LMWH is the treatment of choice, and unfractionated IV heparin is an alternative (i.e., patients with poor renal function or who are anticipated to undergo a procedure should be treated with UFH).

Urgent consultation from medical and interventional experts in PE is advised for all patients with suspected submassive PE. At Michigan Medicine, this can be achieved at any time by activating the PE Response Team (PERT) by page.

IV crystalloid fluids may be administered but should generally be limited to a fluid bolus of no more than 500 mL. If persistent hypotension develops, initiate IV vasopressor therapy; norepinephrine is the drug of choice (preferred over both dopamine and dobutamine). Persistent hypotension despite above strategies should prompt consideration of the diagnosis of massive PE. Due to right ventricular dysfunction commonly seen in massive and submassive PE, careful consideration should be employed in patients who may require intubation and mechanical ventilation.

The effectiveness of systemic thrombolytic therapy for patients with submassive PE is not clear. The PEITHO trial is the largest randomized controlled trial to assess the role of thrombolytic therapy in patients with submassive PE (n=1006).⁹⁰ The primary endpoint of death or hemodynamic decompensation occurred in significantly fewer patients randomized to tenecteplase (2.6% vs 5.6%) while major bleeding (including hemorrhagic stroke) was more common (11.5% vs 2.4%). The TOPCOAT trial was a randomized trial of 83 patients with submassive PE that demonstrated a favorable composite outcome including improved quality of life, RV function, exercise capacity, and perception of physical wellness in patients randomized to LMWH and tenecteplase versus LMWH alone.⁹¹ A meta-analysis showed thrombolysis was associated with lower mortality in submassive PE vs anticoagulation alone (NNT=65) but with significantly more major bleeding (NNH=18).⁹² Importantly, this analysis also found that major bleeding was not significantly increased in patients 65 years of age and younger.

In higher risk patients (eg. age > 65 years or medical frailty) or those with a higher predicted risk of bleeding complications with systemic thrombolytic therapy, half-dose thrombolytic therapy or catheter-directed thrombolysis are potential treatment options. Although published data are limited, half-dose thrombolytics have shown favorable results in specific outcomes (i.e., less clot burden and pulmonary hypertension)⁹³ in addition to demonstrating a lower bleeding risk when compared to full-dose thrombolytic.⁹⁴ At Michigan Medicine, activation of the PERT pager will provide expert multidisciplinary consultation recommendations regarding these potential therapeutic options.

In patients with submassive PE who have signs of clinical deterioration despite systemic anticoagulation should consider activating PERT for further discussion of advanced PE management and therapy. These deteriorations include: decrease in systolic BP, increase in heart rate, worsening gas exchange, signs of inadequate perfusion, worsening RV function.

Indications for systemic thrombolytic therapy are outlined in Table 8. Systemic thrombolytic therapy (i.e., IV alteplase) is not recommended for patients with either non-sustained hypotension or minor RV dysfunction (i.e., mildly elevated BNP or troponin and insignificant RV strain by either chest CT or transthoracic echocardiogram). However, if clinical evidence indicates progression from submassive to massive PE, systemic thrombolytic therapy can be considered.

Temporary placement of IVC filters can be deployed in patients with PE who have a contraindication to systemic anticoagulation, particularly if they have a concomitant acute DVT of the lower extremity.

Registries have been the largest source of data on adverse outcomes in submassive PE. In addition to the ICOPER⁸⁵ and MAPPET⁸⁶ registries, the EMPEROR registry reported a 30-day attributable mortality rate due to PE of 0.9%.⁹⁵ The subset of these patients considered to have submassive PE treated with heparin alone was estimated to be < 3%. As a result, it is very unlikely that thrombolytic therapy would show a statistically significant reduction in mortality. However, several cohort studies have reported improved outcomes for secondary end-points such as RV dysfunction, chronic thromboembolic pulmonary hypertension (CTEPH), and exertional dyspnea.^96-98

Outpatient treatment of pulmonary embolism

Patients diagnosed with PE in the emergency department or as outpatients who meet select criteria may be safely treated entirely in the outpatient setting. Although high quality evidence is lacking, a randomized controlled trial used the Pulmonary Embolism Severity Index (PESI) (Table 9) to risk stratify patients and determine if discharge from the ED was safe.⁹⁹ This multi-center international trial randomized to inpatient vs. outpatient treatment 344 patients who presented to the emergency department with acute, symptomatic PE and a PESI score of less than 86. Results demonstrated no difference in recurrent VTE events or major bleeding at 90 days. Numerous cohort studies and retrospective studies show that the risk of treating acute PE as an outpatient can be relatively low when patients are appropriately selected. Most studies use one of several existing risk stratification tools, but none of the currently available scoring systems is reliable enough to supplant clinical judgment.

Even when employing one of the many risk stratification tools, some low-risk patients may still have features that make inpatient treatment preferable (Table 10). A meta-analysis¹⁰⁰ included 40 studies reporting 11 clinical prediction rules. PESI, sPESI (simplified PESI) and the European Society of Cardiology (ESC) score were the most sensitive tools. The sPESI is the easiest to use, but it may be too restrictive, leading to unnecessary admissions. PESI has received the most attention and has the most evidence supporting its use. The PESI score has multiple data points (Table 9) and yields a score that relates to a risk category of I-IV. Patients with PESI scores > 105 (category III), or > 125 (category IV) should probably be admitted to the hospital for initiation of anticoagulation, but there may still be some in this group (based on some idiosyncrasies of the scoring) who are safe for discharge (i.e., a 60-year-old patient with a history of malignancy will be a PESI category III).

Patients with low-risk PESI scores (categories I and II, which include scores ≤ 85) may be considered for treatment as an outpatient if none of the exclusion criteria are met. Multiple retrospective studies corroborate the safety of outpatient treatment in this group. However, a single smaller retrospective analysis showed an unacceptably high percentage of patients (14%) that had significant in-hospital complications even though the patients were in PESI categories of I or II.¹⁰¹

Biomarkers (troponin or BNP) might be used to help better risk stratify such patients. An elevated troponin¹⁰² or an elevated BNP (or N-terminal-pro-BNP)¹⁰³ is associated with higher risk of adverse outcomes, but it is unclear how these factors should be incorporated into risk stratification.

Patients with structural evidence of RV dysfunction on chest CT scan or echocardiogram should be admitted. Patients should also be admitted if they have an acute PE and a proximal lower extremity DVT by Doppler ultrasound, as this is an independent predictor of death. The risk of death was two times higher and risk from PE-specific death was four times higher in patients with this finding.¹⁰⁴

When is it safe to discharge a hospitalized patient with an acute PE?

The recommended length of time to monitor and treat hospitalized patients with an acute PE has not been extensively studied. Thus, a safe timeframe from diagnosis to discharge is not clear. A strategy including reassessment of the PESI score (Table 9) in addition to observing clinical improvement of the patient is recommended.

Patients at low risk (PESI ≤ 85) and demonstrated clinical improvement (i.e., significantly improved or resolved symptoms, stable vital signs, no hypoxia), can be safely discharged from the hospital. A post-hoc analysis on data from a multi-centre prospective cohort study performed in 12 hospitals in the Netherlands showed that in low-risk PE patients, the risk of recurrent VTE, major bleeding, and death, were comparable between those admitted to the hospital for treatment versus those treated at home.¹⁰⁵

If a patient’s PESI score has increased to the intermediate-risk category (≥ 86) after reassessment, then continued monitoring in the hospital for another 24-48 hours is reasonable. However, given the lack of published data on this issue, the decision to discharge should largely be determined on clinical grounds and at the discretion of the primary service.

In patients admitted with an initial PESI score ≥ 86, a repeat assessment of the PESI score at 24-48 hours after admission can be helpful. If the repeat score is ≤ 85, and the patient has demonstrated clinical improvement, hospital discharge is reasonable. If the patient’s PESI score continues to remain ≥ 86 but the patient is clinically stable (i.e., improved symptoms, stable vital signs, no hypoxia), discharge should be at the discretion of the primary service.

A retrospective cohort study of 304 patients analyzed changes in the PESI score to predict 30-day mortality in intermediate-risk patients.¹⁰⁶ Patients classified at the time of admission into PESI class III (PESI score 86 – 105) were reclassified 48 hours after admission. Eighty-three patients (27%) were reclassified from intermediate-risk (PESI Class III) on admission to low-risk (Classes I and II, PESI score ≤ 85). Thirty-day mortality in these patients was 1.2% as opposed to 11.3% in those patients remaining at higher risk. Reclassifying patients using a second PESI score at 48 hours from admission increased correctly identifying low-risk patients that survived, as well as correctly identifying high-risk non-survivors. Thus, reclassifying patients by PESI risk score is a useful method to determine when patients are safe to discharge after an acute PE diagnosis.

Background

The risk of developing a portal vein thrombosis (PVT) increases with more advanced cirrhosis and portal hypertension. One study of 849 liver transplant candidates demonstrated a 10% incidence of partial or complete occlusion of main portal vein at transplant.¹⁰⁷ PVT can also be associated with non-cirrhotic and non-hepatocellular cancer patients such as those with intra-abdominal infection, trauma, other malignancies, and myeloproliferative disorders. PVT is often incidentally diagnosed on imaging performed for other clinical indications, although patients with PVT can present symptomatically with acute colicky abdominal pain, ileus, and even upper gastrointestinal bleeding secondary to varices and portal hypertensive gastropathy. A partially obstructing PVT is less likely to be symptomatic. Extension of a portal vein thrombosis into the superior mesenteric vein can lead to bowel ischemia, with increased morbidity and mortality.

PVT is classified as either acute or chronic, and as either related to a diagnosis of liver cirrhosis or not.

Acute PVT in a patient with cirrhosis (Figure 6)

Screen patients for gastroesophageal varices with upper endoscopy prior to initiating anticoagulation.

If no large varices are present, start patients on anticoagulation immediately if no contraindications exist. Possible contraindications include limited life expectancy due to advanced liver failure (Child-Turcotte-Pugh part C (CTP C) or MELD > 30), unresectable/metastatic hepatocellular carcinoma (HCC) and excessive risk of bleeding due to frailty, encephalopathy, refractory ascites, and medical co-morbidities. These recommendations are based on systematic reviews of observational studies.¹⁰⁸

If varices are present, the risk of bleeding is higher. The hepatology service should be consulted to consider the optimal treatment strategy, including the role of anticoagulation. The decision to initiate anticoagulation for acute PVT in a patient with cirrhosis is on a case-by-case basis and should take into account the severity of underlying liver disease, risk of anti-coagulation, liver transplant candidacy and presence of underlying thrombophilia. Up to 45% of patients with cirrhosis and non-malignant partial PVT will have spontaneous recanalization without anticoagulation^109-111 and natural history studies have demonstrated conflicting results on the impact of spontaneous PVT on liver disease progression and survival. However, due to increased morbidity and mortality in liver transplant candidates with PVT undergoing transplantation, the threshold to start anticoagulation is lower.¹¹² After endoscopic band ligation of varices, anticoagulation should be held for 48 hours to prevent post ligation ulcerative bleeding.¹⁰⁸

Management of PVT is important to prevent thrombosis-related complications, including portal hypertension, gastrointestinal bleeding secondary to gastroesophageal varices, ischemic hepatitis, and intestinal ischemia from extension of clot to the superior mesenteric vein. The goal of anticoagulation is to allow recanalization of the portal vein.

No consensus exists for the optimal choice of anticoagulant for PVT.¹¹³ Warfarin and LMWH have been the mainstays of therapy. In patients with a baseline INR > 2 (as is common in advanced liver disease), LMWH is preferred.¹⁰⁸ In addition, LMWH is preferred in patients with refractory ascites requiring frequent paracentesis and patients with moderate to severe liver insufficiency with jaundice or those receiving antibiotics at risk for vitamin K deficiency. For hospitalized patients, heparin or LMWH are preferred given their shorter half-lives and ease of reversibility. There are also evolving data on the use of direct acting oral anticoagulants (DOACs) in highly selected patients, but further studies are needed.^114-116 Two recent clinical trials demonstrated similar efficacy and safety of DOAC’s to either warfarin or LMWH in patients with cirrhosis with PVT^117,118 Transition to a DOAC as an outpatient will be at the discretion of the hepatologist. Six months of anticoagulation therapy has a higher rate of recanalization, but no specific duration has been established.

Chronic PVT in a patient with cirrhosis (Figure 6)

Systemic anticoagulation is not recommended for patients with cirrhosis found to have a chronic PVT, because little data exists for any benefit of anticoagulation in this patient population.¹¹⁹ A non-urgent upper endoscopy should be performed to assess for esophageal varices or gastrointestinal bleeding, along with standard primary and secondary treatments of varices with esophageal banding and nonselective beta-blockers. If beta-blockers and endoscopic therapy are unsuccessful for management of bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) should be considered.

Acute PVT in a patient without cirrhosis (Figures 7 and 8)

Evaluation for a thrombophilia disorder should be considered with hematology consultation. If no active gastrointestinal bleeding is present, it is advised to initiate anticoagulation as early as possible. If active bleeding is present, an upper endoscopy is indicated to evaluate for variceal bleeding.

Continue anticoagulation for at least 6 months, followed by re-imaging. If the portal vein is recanalized, anticoagulation can be discontinued if no thrombophilia is present. If the portal vein is not recanalized, continue anticoagulation for another 6 months. If the patient has an irreversible hypercoagulable state (Table 6), continue anticoagulation indefinitely (Figure 8). There are increasing data demonstrating similar safety and possibly increased efficacy of DOAC’s compared to warfarin and LMWH. ^120,121 Although prospective studies are needed, DOAC use will likely continue to expand in this population.

Chronic PVT in a patient without cirrhosis (Figures 7 and 8)

For patients without cirrhosis found to have a chronic portal vein thrombosis, screening for gastroesophageal varices with upper endoscopy is advised, followed by treatment if present. Systemic anticoagulation in patients without cirrhosis should only be considered if they have a permanent risk factor for venous thrombosis or if the thrombus has extended (or has risk of extension) into the superior mesenteric vein.¹⁰⁸

Mesenteric Vein Thrombosis (MVT)

Note: The recommendations in this section are based on evidence focusing on the superior mesenteric vein. Isolated inferior mesenteric vein thrombosis (or isolated branch vein thrombosis) should receive individualized treatment, depending on the perceived risks and benefits of anticoagulaton.

Acute Mesenteric Vein Thrombosis (MVT)

MVT is the cause of mesenteric ischemia in approximately 5-15% of cases.^122-124 It can be associated with hypercoagulable states, malignancy, inflammatory bowel disease, intra-abdominal infections, and surgery. Presenting symptoms for acute MVT can include abdominal pain, nausea, vomiting, and even hematemesis, hematochezia, and melena. The imaging modality of choice to diagnose this condition is contrast-enhanced CT of the abdomen and pelvis. Chronic MVT is usually detected incidentally on imaging and is differentiated from an acute MVT by the presence of extensive collateral circulation.

Management of acute MVT

For acute MVT without evidence of bowel ischemia or peritonitis and a reversible condition, provide a minimum of 3-6 months of anticoagulation (Figure 9). Repeat CT after 3-6 months to ensure resolution. Patients with a known thrombophilia or unexplained acute MVT may need to continue anticoagulation indefinitely.

Anticoagulation

The goals of therapy in acute symptomatic MVT include preventing extension of thrombus and preventing intestinal infarction by recanalizing thrombosed mesenteric veins.

• For patients with reversible or transient conditions associated with acute MVT (i.e., pancreatitis, infection, or trauma) and without evidence of bowel ischemia, peritonitis, or perforation, early anticoagulation should be initiated and continued for at least 3-6 months (Figure 9).
• For patients with a chronic hypercoagulable state or an unknown etiology for their acute MVT, indefinite anticoagulation is indicated and DOAC’s may be preferred due to ease of administration.¹²⁵
• Incidentally discovered asymptomatic acute MVT can be treated with anticoagulation in a patient at low risk of bleeding, with the understanding that no studies have been performed to assess the role of anticoagulation versus watchful waiting in this setting.

Warfarin (with a goal INR of 2-3) or LMWH have been the mainstays of therapy, but a recent systematic review suggests that DOACs may be another option.¹²⁶ However, DOACs have not been specifically studied in patients with acute MVT.

Surveillance imaging should be obtained at 3-6 months to ensure it is appropriate to discontinue anticoagulation in patients with transient risk factors.

Surgical evaluation

For patients with evidence of bowel ischemia, infarction, or peritonitis, an urgent evaluation by general surgery in addition to anticoagulation is recommended.

Even if a potential surgical abdomen is a concern, anticoagulation treatment should begin with IV unfractionated heparin. For patients with evidence of bowel infarction, development of peritonitis, or other systemic signs of intra-abdominal sepsis, obtain a general surgical evaluation for laparotomy and possible bowel resection. Anticoagulation should be continued post-operatively as soon as adequate hemostasis has been achieved (as determined by the surgeon).

Operative thrombectomy is not recommended for acute MVT.

Management of chronic MVT

Chronic MVT is usually detected incidentally on imaging and is differentiated from acute MVT by the presence of extensive collateral circulation. Management of chronic MVT requires a multidisciplinary approach that may include, but is not limited to, surgery, gastroenterology, and interventional radiology.

Anticoagulation

Consider anticoagulation for patients with chronic MVT only after evaluation and treatment of esophageal and gastric varices. Anticoagulation may be of particular benefit in patients with a thrombophilia. Additionally, it is important to weigh the risks of bleeding against the benefits of anticoagulation.¹²⁵

Esophageal band ligation

Patients with chronic MVT should undergo non-urgent evaluation with an upper endoscopy. If esophageal varices are present, they should undergo esophageal band ligation to decrease the risk of variceal bleeding.¹²⁵

Beta blockers

For patients with chronic MVT and evidence of portal hypertension (including varices), initiating non-selective beta-blockers is advised when feasible to decrease the risk of variceal bleeding.

TIPS

A transjugular intrahepatic portosystemic shunt (TIPS) should be considered for patients with variceal bleeding complications that are not amenable to endoscopic or pharmacologic therapies.¹²⁵