21
Pulmonary Embolism and Deep Vein Thrombosis

1. PULMONARY EMBOLISM

I. Presentation of pulmonary embolism (PE) and risk factors

A. Signs and symptoms

Dyspnea and tachypnea are the most common findings; however, they may not be seen at rest and may be purely exertional.
Tachycardia is common and is occasionally an isolated finding. Frequently, however, tachycardia is either transient or relative
(80–90 bpm).
Chest pain is usually a pleuritic pain in patients with distal emboli; angina-like pain may be seen in patients with large central emboli and secondary RV ischemia. Hemoptysis is seen with pulmonary infarction, often resulting from small distal emboli.
Hypotension, syncope, and RV failure with increased JVP/RV heave/right-sided S₃ are seen with large PE and imply reduced hemodynamic reserve.
Lower extremity edema or tenderness on palpation is seen in 50% of DVTs.

B. Risk factors (see Table 21.1)

Table 21.1 Risk factors for PE/DVT.

Active cancer within the last 6 months, or active therapy for cancer
Transient major risk factors within the last 4 weeks: acute medical illness with hospitalization, surgery, trauma with fractures
Transient minor risk factors: pregnancy, oral contraceptive therapy, travel >8 hours, leg injury without fracture, immobility at home
History of PE/DVT
Hypercoagulability
- Genetic: factor V Leiden, prothrombin gene mutation, protein C or S deficiency, antithrombin III deficiency
- Acquired: antiphospholipid syndrome, active cancer, myeloproliferative disorders, nephrotic syndrome
Idiopathic: ~10% of patients with idiopathic PE/DVT will end up being diagnosed with cancer within the next year
Other risk factors: age, smoking, obesity

II. Probability of PE

The clinical probability of PE is assessed using the Wells criteria, which essentially give weight to three features:¹

No alternative diagnosis for the patient’s presentation, whether it is dyspnea, hypoxia <95%, chest pain, or tachycardia
Major risk factors for DVT/PE
Clinical signs of DVT or hemoptysis

The probability is high when two or three features are present, intermediate when only one feature is present, and low when none is present.

III. Initial workup

ECG, chest X-ray, and arterial blood gas (ABG) are initially performed to look for alternative explanations and for suggestive PE signs.

A. ECG

ECG findings in PE:

Sinus tachycardia or “relative” tachycardia (80–100 bpm) is common.
Right axis deviation, RVH/RBBB, P pulmonale.
T-wave inversion in the anterior precordial leads, corresponding to RV strain.²
Deep S in lead I, Q and T-wave inversion in the inferior lead III and sometimes aVF (S₁Q₃T₃). The deep S wave in lead I actually represents depolarization of an RV that has expanded down and to the right, and corresponds to right-axis deviation.^3,4

These findings are not specific for PE and may be seen in any RV volume or pressure overload state, whether acute or chronic. In the right context, however, they are specific for PE. Sinus tachycardia is sensitive (~50–70%); each one of the other criteria is ~10–20% sensitive, and the combination of several of them is ~50% sensitive for the diagnosis of PE. When PE is large enough to produce marked hypoxemia or shock, several of those changes are almost always present, especially T inversion in V₁–V₃, which is present in 85% of massive or submassive PEs. A heart rate that is consistently ≤60 bpm in a patient who is not receiving rate-slowing drugs makes PE highly unlikely. It is important to look at the admission ECG, as tachycardia may be transient.

B. Arterial blood gas

Arterial blood gas usually shows hypoxia, hypocapnia, and a high A–a gradient (>10 mmHg at ambient air, >50 mmHg on high-dose O₂). O₂ saturation and A–a gradient are, however, normal in up to 20% of the patients.⁵ An abnormal A–a gradient is non-specific and is seen in most pulmonary illnesses as a result of ventilation/perfusion mismatch. Hypercapnia is rare and frequently suggests a different diagnosis

or an associated illness (e.g., COPD). Only a massive PE with massive increase in dead space can cause hypercapnia, per se.

C. Chest X-ray

Chest X-ray is grossly normal. It often shows some subtle abnormalities (linear atelectasis, pleural effusion, pulmonary artery cutoff sign).

D. D-dimer

D-dimer is a fibrin degradation product that results from the intrinsic, albeit ineffective, lysis of a clot. If the PE pre-test probability is not high, a negative D-dimer rules out PE. A positive D-dimer, on the other hand, is non-specific and may be seen with any inflammation, pregnancy, or active clotting for any reason, e.g., cancer, bleed, trauma, medical procedure, or even venipuncture. D-dimer should not be used in the high pre-test probability population, especially the cancer population (in whom falsely negative and positive results may be seen). Also, D-dimer cutoff should be adjusted for age: at age <50, D-dimer cutoff is 0.5 mg/l, and at age >50, the cutoff is age divided by 100 (e.g., 0.75 for a 75 year-old patient) (ADAPT-PE trial).⁶

IV. Specific PE workup

A diagnostic strategy is provided in Figure 21.1 (ESC).^1,5 If PE is highly probable and the bleeding risk is low, start IV unfractionated heparin (UFH) therapy, then establish a definitive diagnosis:

Spiral CT PE protocol is very sensitive but may miss subsegmental, small PEs (Figure 21.2). Meta-analyses of long-term follow-ups of CT results have shown that CT is almost as accurate as pulmonary angiogram for ruling out PE. The negative predictive value is 95–99%, and in patients with a negative study the rate of PE diagnosis or mortality on 3-month follow-up is very low (<1%).^7,8 Moreover, spiral CT can establish other diagnoses (pneumonia, pulmonary edema) and establish the severity of PE by looking at RV enlargement and interventricular septal bulge.

Figure 21.1 Algorithm for the diagnosis of pulmonary embolism

*Most hospitalized patients have an elevated D-dimer because of comorbidities, inflammation, or blood draws. Hospitalized patients should undergo initial testing with an imaging study

Figure 21.2 (a) Massive bilateral PEs in the proximal right and left pulmonary arteries, as evidenced by the filling defects (arrows). (b) RV (arrow) and RA (line) enlargement. RV and RA are the anterior structures; see how the RV is more than three times the size of the LV (dot). RA is also much larger than LA.

Caveat: an isolated subsegmental defect is commonly a false positive finding, hence it may not warrant anticoagulation once DVT is ruled out (ACCP guidelines, observational data).

While the thrombus often lyses within weeks of anticoagulant therapy, defects may persist on CT for over 6 months in up to 50% of patients, albeit becoming eccentric and non-occlusive (recanalized). Thus, on a repeat study, defects in the same territory do not necessarily imply recurrent PE.¹⁰

V/Q scan is useful when its result is normal or “low probability,” which either means there are no perfusion defects or there are perfusion defects that are matched with ventilation defects. V/Q scan is also useful when the result is “high probability,” as noted by multiple unmatched perfusion defects. However, ~30–40% of the studies have intermediate probability results. Overall, V/Q scan is valuable if the chest X-ray is normal and the patient does not have any severe cardiopulmonary abnormality that would interfere with the result. It is also valuable in renal failure, when CT may be risky.
Pulmonary angiogram is rarely used and does not have a higher yield than current-generation chest CT. It may be considered if the CT or V/Q scan is indeterminate yet the PE clinical probability is high.
Lower extremity venous ultrasound is positive in ~70% of DVTs. It is useful as an additional test if V/Q scan or CT is indeterminate or negative but the PE clinical probability is high.⁹ In addition, it may be performed before CT if renal failure is present and one is trying to avoid the performance of CT. The results are only reliable if positive, ruling in DVT (and PE in the right setting). Negative results do not lessen the PE probability.
In pregnancy: When PE is suspected in pregnancy, start with lower extremity venous study. If it is negative, perform CT or V/Q scan, both of which are associated with a reasonably low fetal radiation.⁵

Transthoracic echo may show signs of RV strain in ~30–60% of PEs, and in almost all cases of submassive or massive PE.¹¹ RV strain manifests as: (i) RV dilatation (RV >30 mm on long-axis view, or RV >LV on four-chamber view); (ii) systolic PA pressure >35 mmHg; or (iii) D-shaped septum in systole (pressure overload). Systolic PA pressure >50 mmHg cannot be generated by an acutely failing RV, and thus PA pressure over 50 mmHg suggests some degree of chronicity. Without a proper TR jet, pulmonary hypertension is suggested by a notched RV ejection envelope across the pulmonic valve (W shaped, midsystolic ejection slowing). Rarely, a thrombus in transit is seen in the right-sided chambers (~4%); this is associated with a high mortality.

In a patient with shock and suspected PE, these echo features can make a presumptive diagnosis of PE and may be enough to justify thrombolytic therapy in this unstable context, even without further definitive diagnostic studies.^12,13 In those unstable patients, emergent TTE may also help rule out other causes of shock, such as MI or tamponade. TEE may show a saddle embolus in the proximal PA branches but is rarely needed.

The McConnell sign signifies hypokinesis of the RV free wall with normal RV apical motion. In hospitalized patients with RV dysfunction, this sign was initially described as highly specific for PE, but later data suggest limited sensitivity and specificity (both <70%).^14,15 This sign may be seen in RV infarct and chronic PH.

BNP and troponin I as prognostic markers. Troponin increases in 50% of patients with moderate-to-large PE associated with RV strain. Also, BNP often increases in large PE (the degree of increase in PE is less marked than in HF).

V. Submassive or intermediate-high risk PE, pulmonary hypertension, and thrombolysis

Acute pulmonary hypertension occurs when emboli obstruct >30% of the pulmonary vascular bed, or less so in a patient with prior cardio-pulmonary disease. The thin RV is poorly tolerant of the acute rise in afterload and, as a result, fails and dilates; the dilatation further increases RV afterload and leads to a vicious circle of RV failure. RV dilatation compresses the LV and further reduces cardiac output. Hypotension may ensue and worsen RV ischemia, as the RV is more dependent on systolic blood pressure than the LV. Peripheral vasocon-striction and tachycardia acutely preserve the systemic pressure.

Thrombolytics achieve quick lysis of the PE (a few hours) and a quick, almost immediate improvement in pulmonary pressure and RV function in 92% of patients.^5,16 However, intrinsic thrombolysis is also potent and often dissolves a large part of the thrombus burden in patients receiving anticoagulation only, in a way that the hemodynamic superiority of thrombolysis over anticoagulation may be limited to a few days only. In addition, while acute pulmonary hypertension mainly results from the embolic obstruction per se, pulmonary vasoconstriction is a secondary contributor that improves over the course of therapy (vasoconstriction results from hypoxemia and from platelet-released serotonin and thromboxane).¹⁷ Several studies suggest that 1 week after therapy, the degree of vascular obstruction on perfusion imaging and the degree of RV dysfunction are similar between thrombolysis-treated and anticoagulation-treated patients. PA pressure dramatically improves within a week of therapy, and heparin-treated patients often catch up with thrombolysis-treated patients.^1218–21 Thus, thrombolysis is mostly useful in patients who are in shock, since those patients are unlikely to survive the first few days and catch up with thrombolysis- treated patients.

Massive PE or high-risk PE is defined as shock, i.e., sustained hypotension (SBP <90 mmHg or 40 mmHg lower than baseline for over 15 minutes). This must be distinguished from the transient hypotension of syncope, which may imply reduced cardiac output reserve (submassive PE), but not massive PE.

Submassive PE or intermediate-high risk PE is defined as PE without shock but with the triple combination of the following (ESC):^5,12

Clinical features (any): hypoxemia with O2 saturation <90% on ambient air, SBP <100 mmHg, pulse >110 bpm, or shock index (pulse/SBP ratio) >1. Baseline cancer or chronic cardiopulmonary disease also confers increased risk.
Imaging evidence of pulmonary hypertension or RV dysfunction: (i) systolic PA pressure >35 mmHg, often implying significant pulmonary hypertension as the RV cannot generate pressures >50 mmHg acutely; or (ii) RV hypokinesis or dilatation (RV/LV diameter >0.9 on echo or CT four-chamber view).
Biochemical evidence of RV injury (troponin beyond the “gray zone,” e.g., >0.1 ng/ml) or RV dysfunction (NT-proBNP ≥ 600).

Intermediate-low risk PE is characterized by only 1 or 2 of the above features, while low-risk PE has none.⁵

Massive and submassive PE are clinical terms that correlate with the size of PE but also with the patient’s underlying cardiopulmonary reserve. Whereas most stable, anticoagulated patients catch up with thrombolysis-treated patients, data suggest that a subgroup of patients with submassive PE are at risk of acute clinical deterioration and of persistent pulmonary hypertension and RV failure.^12,22,23 In two studies, thrombolysis of stable patients with evidence of RV dysfunction or pulmonary hypertension more effectively reduced PA pressure than standard anticoagulation, not only acutely but over the long term.^22,23 In the landmark PEITHO trial of submassive PE, defined by a combination of both RV imaging features and troponin>0.06 ng/ml, systematic thrombolysis was compared with standalone anticoagulation; systematic thrombolysis reduced acute deterioration but did not affect the overall acute mortality and was associated with increased bleeding events, including a 2% rate of intracranial bleeding, mostly occurring in patients older than 75.²⁴ Hemodynamic deterioration requiring rescue thrombolysis occurred in only 5% of the control patients. Also, after 3 years of follow-up, thrombolysis was not associated with improved functional capacity, which was mildly impaired in ~1/3 of patients, nor a reduction of chronic pulmonary hypertension (~infrequent, 3%).²⁵ Thus, the widespread use of thrombolysis in submassive PE is not clearly superior to its selective use. As such, standalone anticoagulant is an appropriate initial strategy, as many patients improve their PA and RV parameters quickly; thrombolysis is reserved for patients who do not improve their PA pressure within few days, or those with persistent or deteriorating pre-shock state, even before hypotension occurs (persistent tachycardia, borderline BP, persistent severe hypoxia) (rescue thrombolysis: class I in ESC and grade 2 in ACCP guidelines).⁵ When used selectively in submassive PE patients younger than 65, thrombolysis slightly reduced mortality in a meta-analysis.²⁶

While mostly effective in the first 2 days after the onset of PE symptoms, thrombolysis remains effective in patients who have had symptoms for 6–14 days, with 70% of the latter patients demonstrating improvement with thrombolysis on lung scan.²⁷ In practice, it is often difficult to define the onset of PE, especially in patients who have subacute symptoms of several weeks and who may have multiple emboli of various ages, some of which are acute;²⁷ thrombolysis may be attempted in patients with recent symptoms and persistent

pulmonary hypertension. The benefit of thrombolysis is less time-dependent in PE than in MI or stroke for the following reasons: (i) thrombolysis is more effective in lysing a PA clot than a coronary or cerebral clot; 100% of the cardiac output goes through the pulmonary circulation, while only 5% and 15% of the cardiac output goes to the coronary and cerebral circulations, respectively; (ii) as opposed to a coronary occlusion, which quickly leads to MI and makes late thrombolysis futile, pulmonary arterial occlusion rarely leads to a large pulmonary infarction, as the pulmonary parenchyma receives most of its supply from the bronchial arterial circulation. Only small infarctions may be seen with distal emboli.

Catheter-directed therapy of the main and lobar PA branches may be performed in patients who have a high bleeding risk with a full thrombolytic dose. Typically, catheter therapy consists of thrombus fragmentation and aspiration, often followed by a low-dose direct catheter infusion of alteplase over 12–24 hours. This relatively low dose of alteplase is assumed to be safer.⁵

Considering the high mortality of patients with submassive PE and free-floating right heart thrombus (>20%), those patients are best treated with systemic thrombolysis or surgical thromboembolectomy in an experienced center. Catheter thrombectomy is risky in those patients, as it may dislodge emboli into the right circulation, but also the left circulation if PFO is present.

VI. PE and chronic pulmonary hypertension

A first episode of PE leads to a significant risk of symptomatic chronic thromboembolic pulmonary hypertension (CTPH) of about 4% at 2 years, even without recurrence of PE.²⁸ This risk may be higher in patients whose initial presentation is submassive PE, according to older data suggesting a 25% risk of persistent pulmonary hypertension, reduced by acute thrombolysis;^22,23 this was not the case in the large PEITHO trial (3% risk, not reduced by acute thrombolysis).²⁵ CTPH is treatable with surgical pulmonary thromboendarterectomy when the pulmonary obstruction is central (~70% of the cases), but not when it is distal and microvascular.

VII. Acute treatment of PE

A. Initial anticoagulation

One of the following two strategies may be initiated:

Parenteral anticoagulation:
- IV UFH, 80 units/kg bolus then 18 units/kg IV drip, with PTT monitoring Q6h. The PTT goal is 1.5–2.5 times normal.
- Enoxaparin 1 mg/kg SQ Q12h, reduced to 1 mg/kg Q24h if GFR <30 ml/min (avoid in ESRD). Or Fondaparinux 5–10 mg SQ Q24h.
Acute therapy with oral apixaban or rivaroxaban

Apixaban or rivaroxaban may be used as upfront therapy in low- or intermediate-low risk patients, who have a low likelihood of requiring bailout thrombolysis.⁵ Otherwise, parenteral anticoagulation is used the first 2–3 days, then switched to apixaban or rivaroxaban. In the absence of renal failure (GFR <30 ml/min) or high bleeding risk, LMWH or fondaparinux is preferred to UFH. They have been shown to be at least as efficacious as UFH in PE, with a trend towards superiority and a similar bleeding risk.^29,30 In patients with a high bleeding risk, UFH is preferred because of its shorter half-life.

Rarely, when chosen as the oral anticoagulant, warfarin is started on the first day, usually at a dose of 5 mg per day. A dose of 10 mg for 2 days allows faster achievement of INR goal and is recommended in young healthy patients, whereas a 5 mg dose is recommended in elderly patients or those with heart or liver failure (ACCP guidelines).^31,32 Anticoagulation reaches steady state in ~7 days. INR is checked at 3–4 days, when it is expected to be 1.5–1.9, and warfarin is titrated accordingly. UFH or LMWH should be continued until INR is therapeutic for 2 consecutive days.

B. Initial outpatient treatment of acute PE

For a PE with no high-risk clinical features (PE score index of 0) and no RV dilatation on CT, treatment may be initiated in the outpatient setting (ESC and ACCP guidelines).^5,32 Simplified PE score index (PESI) consists of 1 point for each of the following: age >80, history of cancer, history of cardiopulmonary disease, O2 saturation <90%, SBP<100, pulse>110. In one randomized trial of outpatient PE treatment, enoxaparin was initially used and followed by warfarin;³³ in a later trial of early discharge<48 hours, initial rivaroxaban was used.³⁴ Either anticoagulant strategy is acceptable (ACCP).

C. Indications for thrombolysis and thrombectomy

Thrombolysis results in a quick, almost immediate improvement of PA pressure and RV hemodynamics. However, by 1 week, pulmonary perfusion and RV function improve in most anticoagulated patients almost similarly to thrombolysis-treated patients, albeit more slowly (they often catch up with thrombolysis-treated patients). Thus, thrombolysis is indicated in the following patients (ACCP, ESC):^5,12,32

Massive PE where immediate improvement of hemodynamics is necessary (SBP <90 mmHg for over 15 minutes) (class I).
Few select cases of intermediate–high-risk PE. Thrombolysis is not routinely recommended in intermediate-high risk PE with both imaging and biomarker evidence of RV involvement (class III, ESC and ACCP). It is only indicated for patients who do not quickly improve their PA pressure within few days of therapy or show signs of cardiopulmonary deterioration even if hypotension has not developed yet (class I ESC).

Alteplase is administered as a 100 mg intravenous dose over 2 hours. Heparin is restarted at the end of the alteplase infusion. Alternatively, a weight-based bolus of tenecteplase has been used (30–50 mg, dose similar to STEMI).²⁴

As an alternative to systemic thrombolysis, catheter thrombectomy and a low-dose local infusion of alteplase may be used (~0.5–1 mg/h, for a total of ~10–20 mg) (class IIa ESC). In massive PE that fails thrombolysis, catheter or surgical embolectomy +/- ECMO is used. Some devices (e.g., Flowtriever) allow effective standalone thrombectomy without any thrombolysis.

D. IVC filter

According to the modern PREPIC-2 trial, which recruited high risk PE (e.g., age >75, underlying cardiopulmonary disease, submassive PE), IVC filter does not provide any additional reduction of PE recurrence in patients receiving anticoagulation.³⁵ Furthermore, it doubles the DVT risk and may lead to IVC thrombosis (~25%) or adjacent organ penetration (~4%) over the long term.^5,36

An IVC filter is therefore only indicated in one instance:

Contraindication to anticoagulation, such as a recent major bleed, trauma, surgery (<3 weeks), or a history of intracranial hemorrhage. If the contraindication is likely to be transient, placement of a retrievable IVC filter is preferred. The retrievable filter has a hook that allows later removal, generally within a few weeks (up to 3–12 months with some devices).

Recurrent PE/DVT despite therapeutic anticoagulation is a relative indication for IVC filter. This situation is usually due to off-and-on periods of subtherapeutic anticoagulation, rather than a truly ineffective anticoagulation. Anticoagulation should be continued along with IVC filter placement, as the IVC filter will only increase the DVT risk. Massive PE is not, per se, an indication for IVC filter, even massive PE that required thrombolysis.

VIII. Duration of anticoagulation

In the absence of anticoagulation, the risk of recurrence of PE/DVT is highest in the first 3 months, and may be as high as 20%.⁵ Beyond the first 3 months, in the absence of anticoagulation, the yearly risk of recurrence of provoked PE/DVT is ≤3% (major risk factor 1%, tran- sient minor risk factor 3%), while the yearly risk of recurrence of unprovoked PE/DVT is 3–10%.³² A similar risk of recurrence is expected after anticoagulation is stopped, whether it is stopped at 3 months or 6–12 months.^5,37 A meta-analysis has shown that 3 months of anticoagulation vs. ≥6 months was associated with a similar risk of DVT/PE during the 2 years following cessation of anticoagulation.^38,39 Anticoagulation is associated with a 2–3% yearly risk of major bleeding, reduced by 40% with NOACs.

In unprovoked PE/DVT, certain risk factors are associated with a doubling of the risk of recurrence, making it close to 10%, whereas the lack of those risk factors reduces the recurrence risk to 3%. The risk factors for recurrence are:

Recurrent DVT/PE.
High-risk thrombophilias: antiphospholipid syndrome (highest risk factor, >8% per year), protein C or S deficiency, antithrombin III deficiency, homozygote factor V Leiden, or homozygote prothrombin gene mutation.
Elevated D-dimer 1 month after stopping anticoagulation, which implies active subclinical clotting and increased thrombotic events.⁴⁰
Residual thrombus or defect on venous ultrasound, which increases the risk of a new DVT. The residual thrombus, even if old and organized, may serve as a nidus for further thrombus deposition or impair venous flow in a way that favors recurrent DVT.⁴¹
Male sex (1.75-fold higher risk).

For unprovoked PE/DVT, extended anticoagulation beyond 3 months (possibly lifelong) is warranted, as long as the bleeding risk is low or moderate (Table 21.2).^5,32 This also applies to the PE/DVT provoked by minor transient risk factors (per ESC, but not per ACCP). Cancer patients have the highest risk of recurrence, ~20–30% within a year, and require extended therapy even if the bleeding risk is high (as long as cancer is active). LMWH is twice as effective as warfarin in reducing PE/DVT recurrence in cancer patients;^32,42 vomiting, fluctuant nutritional status, and liver dysfunction are common in these patients and alter the efficacy and safety of warfarin. Initial treatment with NOACs has compared favorably to LMWH in 3 cancer trials. Edoxaban and rivaroxaban more effectively reduced PE/DVT recurrences than LMWH, at the cost of a higher GI bleed; conversely, apixaban was at least as effective as LMWH, with no increased bleeding (CARAVAGGIO trial).^43,44 Thus, either LMWH or the above NOACs may be used in cancer patients.

Table 21.2 Duration of long-term anticoagulation.

1. Provoked PE or DVT (major transient risk factor)	3 months
2. Unprovoked idiopathic PE or DVT +/- provoked by a minor risk factor	>3 months (extended therapy) if the bleeding risk is low or moderate^a 3 months if the bleeding risk is high Consider D-dimer testing, venous ultrasound, and testing for thrombophilias to decide about pursuing therapy beyond 3 months
3. Recurrent PE or DVT	>3 months if the bleeding risk is low or moderate^a
4. High-risk thrombophilias	>3 months if the bleeding risk is low or moderate^a
5. Active cancer within the last 6 months	Extended LMWH or NOAC: apixaban, edoxaban, or rivaroxaban

^a Even with recurrent PE or thrombophilias, limiting anticoagulant therapy to 3 months is appropriate in high-bleeding-risk patients. Cancer patients have the highest risk of recurrence (20–30% within a year) and qualify for extended therapy even if bleeding risk is high. Extended therapy implies routine reassessment of bleeding risk and reconsideration of the duration of anticoagulation, and does not necessarily equate with indefinite therapy.

When extended therapy is chosen in non-cancer patients, a reduced-dose apixaban (2.5 mg bid) or rivaroxaban (10 mg daily) is favored after the first 6 months. In 2 trials, these lower doses were as effective as standard doses and did not increase major or even nonmajor bleeding in comparison with placebo or aspirin (AMPLIFY-ext and EINSTEIN-CHOICE trials).^45,46

Bleeding risk is high in the following patients: (i) age >75; (ii) previous GI bleed, especially when the cause is not reversible; (iii) chronic severe HTN; (iv) prior stroke; (v) requirement for dual antiplatelet therapy; (vi) baseline anemia Hb <10 g/dl; (vii) hepatic or renal disease.

While anticoagulation reduces the risk of PE/DVT recurrence by 90%, aspirin has been shown to reduce this risk by ~30%, and may be a reasonable alternative to anticoagulation in patients who have an intermediate, rather than high, risk of recurrence (ACCP).⁴⁷

IX. Thrombophilias

Thrombophilias are classified into high-risk and moderate-risk thrombophilias:⁴⁸

High-risk thrombophilias: antiphospholipid syndrome, protein C or S deficiency, antithrombin III deficiency, homozygote factor V Leiden or prothrombin gene mutation. Each one of the high-risk thrombophilias has a 1–3% prevalence among patients with a first PE/DVT and is associated with a 2.5× increase in the risk of recurrence.
Moderate-risk thrombophilias: Heterozygote factor V Leiden or prothrombin gene mutation. While highly prevalent among patients with PE/DVT (15% and 5%, respectively), they only modestly increase the risk of recurrence by ~30% and do not merit extended anticoagulation per se.^5,48 They are highly prevalent in the general white population (5% for factor V Leiden, and 2% for prothrombin mutation).

HIT is the highest-risk thrombophilia and should be considered in any hospitalized patient who develops DVT despite receiving heparin, along with a reduction in platelet count.

Thrombophilias do not modify the INR goal (2–3), and likely can be treated with NOACs, except for antiphospholipid syndrome (rivaroxaban was inferior to warfarin in one trial of antiphospholipid syndrome).⁴⁹ Indefinite warfarin anticoagulation is recommended in antiphospholipid syndrome (ESC class I), with an INR goal of 2–3; if thrombosis recurs while on warfarin, INR goal is best raised to 3–4, particularly as antiphospholipid antibodies may falsely raise INR.

After a DVT/PE, testing for thrombophilia is indicated in the following cases: (i) idiopathic DVT/PE; (ii) recurrent DVT/PE; (iii) DVT/PE at age <40; (iv) DVT at an unusual site, including upper extremity; (v) family history of DVT/PE. Yet, if extended anticoagulation is planned anyway, the value of thrombophilia testing is questionable. Antithrombin III and, occasionally, proteins C and S may decrease in acute thrombosis. In addition, antithrombin III is reduced with heparin and proteins C and S are reduced with warfarin. Thus, measurement may be done acutely before initiation of anticoagulation, but if the levels of antithrombin III or protein C or S are abnormal, they need to be confirmed in a stable phase, after anticoagulation is discontinued (e.g., beyond 3 months). The genetic testing of factor V Leiden and prothrombin mutation may be performed at any time. Cancer screening should also be performed.

Antiphospholipid syndrome is tested using two modalities: (i) antibody testing (anticardiolipin, β₂-microglobulin); (ii) demonstration of prolongation of a clotting time, not correctable with the addition of normal plasma (= lupus anticoagulant = prolongation of PTT or Russell viper venom time). Since the clotting time is also prolonged by heparin therapy, it has no diagnostic value during heparin therapy.

In asymptomatic patients, thrombophilias drastically increase the risk of DVT/PE in relative terms (up to 15 times), but the absolute yearly risk of spontaneous DVT/PE remains low, ≤1%, even for antiphospholipid syndrome.⁵⁰ Asymptomatic thrombophilias do not warrant anticoagulation, but warrant the avoidance of additional risk factors (e.g., oral contraception) and appropriate prophylaxis during high-risk situations.

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