Deep Venous Thrombosis 2022. ANNALS

Annals of Internal MedicineT
In the ClinicT
Deep Venous
Thrombosis
Prevention
V
enous thromboembolism (VTE) is the third
most common cardiovascular disorder,
affecting up to 5% of the population. VTE
commonly manifests as lower-extremity deep ve- Diagnosis
nous thrombosis (DVT) or pulmonary embolism.
Half of these events are associated with a transient
risk factor and may be preventable with prophy-
laxis. Direct oral anticoagulants are effective and Treatment
safe and carry a lower risk for bleeding than vita-
min K antagonists. Many patients with VTE will
have a chronic disease requiring long-term antico- Practice Improvement
agulation. Postthrombotic syndrome affects 25% to
40% of patients with DVT and significantly impacts
function and quality of life.
CME/MOC activity available at Annals.org.
Physician Writer doi:10.7326/AITC202209200

Lisa Duffett, MD
The Ottawa Hospital, Ottawa, This article was published at Annals.org on 13 September 2022.
Ontario, Canada CME Objective: To review current evidence for prevention, diagnosis, treatment,
and practice improvement of deep venous thrombosis.
Funding Source: American College of Physicians.
Acknowledgment: The author thanks John Spandorfer, MD, and Taki Galanis,
MD, authors of the previous version of this In the Clinic.
Disclosures: All relevant financial relationships have been mitigated. Disclosures
can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.
do?msNum=M22-1364.
With the assistance of additional physician writers, the editors of Annals of

Internal Medicine develop In the Clinic using MKSAP and other resources of
the American College of Physicians. The patient information page was written by
Julia Thayer from the Center for Quality at the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP
clinical guidelines, please go to https://www.acponline.org/clinical_information/
guidelines/.
© 2022 American College of Physicians
Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

Venous thromboembolism (VTE) is a systematic review of 5 randomized trials
1. Heit JA. The epidemiology
of venous thromboembo- relatively common and potentially life- and 24 507 patients with acute VTE, the
lism in the community.
Arterioscler Thromb Vasc threatening condition. The annual inci- pooled rate of recurrent fatal VTE dur-
Biol. 2008;28:370-2. dence is estimated at 1 per 1000 per- ing the initial 3-month treatment period
[PMID: 18296591]
2. Stevens SM, Woller SC, sons (1). About one third of patients was 0.14% (95% CI, 0.05% to 0.27%) for
Kreuziger LB, et al.
Antithrombotic therapy for with VTE present with pulmonary em- VKAs and 0.16% (CI, 0.05% to 0.27%)
VTE disease: second update bolism (PE), and two thirds present for DOACs. Rates of fatal major bleed-
of the CHEST guideline and
expert panel report. Chest. with deep venous thrombosis (DVT). ing events with these treatments were
2021;160:e545-e608.
[PMID: 34352278] Fifty to sixty percent of VTE events are 0.33% (CI, 0.21% to 0.48%) and 0.14%
3. Ortel TL, Neumann I, provoked by recent surgery or hospi- (CI, 0.07% to 0.24%), respectively (4).
Ageno W, et al. American
Society of Hematology talization, 20% are associated with
2020 guidelines for man- Select patients should be considered
agement of venous throm- active cancer, and the remaining 20%
for extended-duration anticoagulation
boembolism: treatment of to 30% are considered unprovoked (1).
deep vein thrombosis and for secondary prevention of recurrent
pulmonary embolism. Diagnosis of DVT combines an assess-
Blood Adv. 2020;4:4693- VTE. The most common complications
4738. [PMID: 33007077] ment of pretest probability, D-dimer
of VTE are postthrombotic syndrome
4. Wu C, Alotaibi GS, Alsaleh testing, and compression ultrasonogra-
K, et al. Case fatality of and venous ulcer, with overall inci-
bleeding and recurrent ve- phy (CUS). The mainstay of DVT treat-
nous thromboembolism dence of 76.1 and 18.0 per 100 000
during, initial therapy with ment is anticoagulation, with direct oral
person-years, respectively (1). This
direct oral anticoagulants: a anticoagulants (DOACs) being the pre-
systematic review. Thromb review focuses on the diagnosis and
Res. 2014;134:627-32. ferred choice in most patients (2, 3).
[PMID: 25047174] management of patients presenting
5. Konstantinides SV, Meyer
G, Becattini C, et al; ESC
Anticoagulation with low-molecular- with DVT; however, discussion of risk
Scientific Document Group. weight heparin (LMWH) followed by a factors, prevention, and some aspects
2019 ESC Guidelines for
the diagnosis and manage- vitamin K antagonist (VKA) or a DOAC of treatment applies to patients with
ment of acute pulmonary
embolism developed in
is an effective treatment for VTE. In a DVT and PE.
collaboration with the
European Respiratory
Society (ERS). Eur Heart J.
2020;41:543-603. [PMID:
31504429]
6. Timp JF, Braekkan SK,
Prevention
Versteeg HH, et al. What factors increase risk for VTE? include non-O blood type and heterozy-
Epidemiology of cancer-
associated venous throm- Surgery and hospitalization for acute ill- gous gene mutations for factor V Leiden
bosis. Blood.
2013;122:1712-23. [PMID: ness account for half of VTE events. and prothrombin (Appendix Table 1,
23908465]
Although epidemiologic studies have available at Annals.org) (8, 9). Despite
7. Key NS, Khorana AA,
Kuderer NM, et al. Venous identified many associated risk factors the availability of genetic thrombophilia
thromboembolism prophy-
laxis and treatment in for VTE, it is essential to consider the testing, identifying a family history of
patients with cancer: ASCO
strength of this association when decid- VTE is more valuable, as only 30% of
clinical practice guideline
update. J Clin Oncol. ing on prophylactic treatment (Table 1) persons with a first-degree relative with
2020;38:496-520. [PMID:
31381464] (5). Frequently, VTE results from multi- VTE have a positive result on genetic
8. Middeldorp S, van
ple risk factors that, when combined, thrombophilia screening (10). For this
Hylckama Vlieg A. Does
thrombophilia testing help exceed the “thrombosis threshold.” reason, genetic thrombophilia testing of
in the clinical management
of patients. Br J Haematol. Cancer is one of the most substantial patients and family members is not
2008;143:321-35. [PMID:
18710381] risk factors, with a 7-fold increased risk recommended.
9. Connors JM.
Thrombophilia testing and
and a 5% to 20% absolute risk for VTE
venous thrombosis. N Engl within the first year after a cancer diag- Antiphospholipid syndrome (APS) is an
J Med. 2017;377:1177-87.
nosis (6). Furthermore, 4% to 10% of autoimmune disorder and a type of
[PMID: 28930509]
10. Bezemer ID, van der Meer
patients presenting with a first unpro- acquired thrombophilia. Patients with
FJ, Eikenboom JC, et al.
The value of family history voked VTE will ultimately have cancer APS are at significantly increased risk for
as a risk indicator for ve-
diagnosed within 1 year, making VTE arterial and venous thromboembolic
nous thrombosis. Arch
Intern Med.
an important first sign of cancer (7). complications and pregnancy-related
2009;169:610-5. [PMID:
19307525]
complications. Antiphospholipid anti-
11. Tektonidou MG, Andreoli A family history of VTE, especially a first- bodies include anticardiolipin antibod-
L, Limper M, et al. EULAR
recommendations for the degree relative with an unprovoked ies, b2-glycoprotein antibodies, and the
management of antiphos-
pholipid syndrome in VTE before age 50 years, is a significant lupus anticoagulant. APS requires clini-
adults. Ann Rheum Dis.
2019;78:1296-1304.
risk factor for VTE. The most common cal and laboratory criteria as well as
[PMID: 31092409] genetic risk factors (thrombophilia) demonstration of persistent antibodies
© 2022 American College of Physicians ITC2 In the Clinic Annals of Internal Medicine

Table 1. Transient Risk Factors for Venous Thrombosis
Strong risk factor (odds ratio >10)

Hip or leg fracture
Hip or leg joint replacement
Major general surgery
Major trauma
Spinal cord injury 12. Kearon C, Akl EA,
Moderate risk factor (odds ratio of 2 to 9) Comerota AJ, et al.
Antithrombotic therapy
Arthroscopic knee surgery for VTE disease:
Cancer Antithrombotic Therapy
and Prevention of
Central venous lines Thrombosis, 9th Ed:
American College of
Congestive heart or respiratory failure Chest Physicians evi-
Hormone replacement therapy dence-based clinical prac-
tice guidelines. Chest.
Oral contraceptive therapy 2012;141:e419S-e496S.
Paralytic stroke [PMID: 22315268]
13. Quinlan DJ, Eikelboom
Postpartum JW, Dahl OE, et al.
Association between
Previous venous thromboembolism asymptomatic deep vein
Thrombophilia thrombosis detected by
venography and sympto-
Weak risk factor (odds ratio <2) matic venous throm-
Bed rest >3 d boembolism in patients
undergoing elective hip
Immobility due to sitting (e.g., prolonged road or air travel) or knee surgery. J
Thromb Haemost.
Increasing age 2007;5:1438-43. [PMID:
Laparoscopic surgery (e.g., cholecystectomy) 17425687]
14. Sch€unemann HJ,
Obesity Cushman M, Burnett AE,
Pregnancy (antepartum) et al. American Society of
Hematology 2018 guide-
Varicose veins lines for management of
venous thromboembo-
lism: prophylaxis for hos-
pitalized and
nonhospitalized medical
patients. Blood Adv.
over a span of 12 weeks (because of the What factors should be considered 2018;2:3198-3225.
[PMID: 30482763]
possibility of clinically insignificant tran- when deciding on prophylaxis? 15. Barbar S, Noventa F,
sient antibodies). Unlike hereditary Rossetto V, et al. A risk
VTE prophylaxis may be given phar- assessment model for the
thrombophilia, testing for APS is recom- identification of hospital-
macologically (for example, anticoa- ized medical patients at
mended because most patients should risk for venous throm-
gulation) or via mechanical means
remain on extended-duration anticoa- boembolism: the Padua
(for example, graduated compression Prediction Score. J Thromb
gulation for secondary prophylaxis if the Haemost. 2010;8:2450-7.
stockings and intermittent pneumatic [PMID: 20738765]
result is positive (11). 16. Spyropoulos AC,
compression devices). Decisions on Anderson FA Jr ,
Should clinicians screen specific which patients should receive pro- FitzGerald G, et al;
IMPROVE Investigators.
patients for DVT? phylaxis should include an assess- Predictive and associative
models to identify hospi-
Primary prophylaxis with anticoagula- ment of the risk for VTE, the benefit of talized medical patients at
tion is preferred over withholding pharmacologic prophylaxis, and the risk for VTE. Chest.
2011;140:706-14.
prophylaxis and screening high-risk risk for bleeding. The goal of prophy- [PMID: 21436241]
17. Greene MT, Spyropoulos
patients for asymptomatic DVT (12). laxis should be to reduce fatal PE and AC, Chopra V, et al.
Although asymptomatic DVT detected symptomatic VTE without increasing Validation of risk assess-
ment models of venous
by screening venography or CUS is a major bleeding. thromboembolism in hos-
pitalized medical patients.
common efficacy outcome in thrombo- Am J Med.
Which patients should receive
prophylaxis trials, there is no evidence 2016;129:1001.e9-1001.
to support screening of patients for prophylaxis, and what agents should e18. [PMID: 27107925]
18. Zayed Y, Kheiri B,
asymptomatic DVT as a strategy to pre- be used? Barbarawi M, et al.
Extended duration of
Hospitalized medical patients
vent symptomatic VTE. Asymptomatic thromboprophylaxis for
medically ill patients: a
DVT detected by routine screening Universal prophylaxis strategies in hos- systematic review and
meta-analysis of rando-
protocols is 5 to 21 times more com- pitalized medical patients have minimal mised controlled trials.
mon than symptomatic DVT, and its effect on VTE incidence because of the Intern Med J.
2020;50:192-9. [PMID:
clinical significance is unclear (13). heterogeneity of risk in this population 31276276]
Annals of Internal Medicine In the Clinic ITC3 © 2022 American College of Physicians

(14). However, predicting which medi- reduces symptomatic VTE by up to 70%
19. Collins R, Scrimgeour A,
Yusuf S, et al. Reduction cal patients would benefit from prophy- (19). In recent years, improved surgical
in fatal pulmonary embo-
lism and venous thrombo- laxis is challenging. Clinical prediction techniques, early ambulation, and wide-
sis by perioperative rules, such as the IMPROVE score and spread use of pharmacologic prophy-
administration of subcuta-
neous heparin. Overview the Padua Prediction Score (Table 2), laxis have substantially decreased post-
of results of randomized
can be used to identify medical operative VTE (20). The Caprini Risk
trials in general, orthope-
dic, and urologic surgery. patients at increased risk, but fewer Assessment Model is the most widely
N Engl J Med.
1988;318:1162-73. than 20% of hospitalized medical used tool to assess thromboembolic
[PMID: 3283548]
patients will be identified as being at risk (Table 2) (21). The American
20. Chan NC, Siegal D, Lauw
MN, et al. A systematic College of Chest Physicians (ACCP) sug-
increased risk, and their impact on clini-
review of contemporary gests using the Caprini score to assess a
trials of anticoagulants in cal outcomes requires additional exter-
orthopaedic thrombopro- patient's VTE risk and adopting a
phylaxis: suggestions for nal validation (14–17). Clinical practice graded approach: no prophylaxis or
a radical reappraisal. J
Thromb Thrombolysis.
guidelines recommend that pharmaco- early ambulation for very low risk, me-
2015;40:231-9. [PMID: logic prophylaxis be considered in chanical prophylaxis for low risk (Caprini
25403952]
21. Pannucci CJ, Laird S, hospitalized patients without increased score of 1 to 2), pharmacologic or me-
Dimick JB, et al. A vali-
dated risk model to pre-
risk for bleeding, and LMWH is recom- chanical prophylaxis for moderate risk
dict 90-day VTE events in mended over DOACs (14). In patients (Caprini score of 3 to 4), and combined
postsurgical patients.
Chest. 2014;145:567-73. who cannot receive pharmacologic pro- pharmacologic and mechanical prophy-
[PMID: 24091567]
22. Gould MK, Garcia DA, phylaxis because of high bleeding risk, laxis for high risk (Caprini score ≥5) (22).
Wren SM, et al. mechanical prophylaxis is suggested The American Society of Hematology
Prevention of VTE in non-
orthopedic surgical (14). Evidence for routine extended anti- (ASH) clinical practice guidelines offer a
patients: Antithrombotic
Therapy and Prevention of coagulation (30 to 45 days) with DOACs more general suggestion of pharmaco-
Thrombosis, 9th Ed: or LMWH to reduce VTE events after hos- logic prophylaxis in patients having
American College of Chest
Physicians evidence-based pitalization has been mixed and suggests major general surgery (such as nonor-
clinical practice guide-
increased risk for major bleeding (18). thopedic general, abdominal, and pel-
lines. Chest. 2012;141:
e227S-e277S. [PMID: Extended-duration prophylaxis (beyond vic surgery) (23). Unlike for hospitalized
22315263]
23. Anderson DR, Morgano hospital discharge) and prophylaxis in medical patients, extended anticoagula-
GP, Bennett C, et al.
the long-term care setting are not recom- tion for 3 to 4 weeks after discharge is
American Society of
Hematology 2019 guide- suggested for hospitalized surgical
mended (14).
lines for management of patients (22, 23). Further refinement of
venous thromboembo-
lism: prevention of ve- Surgical patients which subtype of surgical patients
nous thromboembolism
would benefit most from extended anti-
in surgical hospitalized The risk for VTE after surgery depends
patients. Blood Adv. coagulation is needed.
2019;3:3898-3944. on the type of surgery and patient fac-
[PMID: 31794602]
24. Anderson DR, Dunbar M, tors. Use of unfractionated heparin In orthopedic surgery, DOACs have
Murnaghan J, et al. (UFH) for postoperative VTE prophylaxis largely replaced LMWH for postoperative
Aspirin or rivaroxaban for
VTE prophylaxis after hip
or knee arthroplasty. N
Engl J Med. Table 2. Risk Scores for VTE Prophylaxis
2018;378:699-707.
[PMID: 29466159] Risk Scores, by Patient Population Risk Predicted Interpretation
25. Lyman GH, Carrier M, Ay
C, et al. American Society Hospitalized medical patients
of Hematology 2021
guidelines for manage-
Padua Prediction Score Risk for VTE at 3 mo Low risk (<4 points): 1.1%
ment of venous throm- High risk (≥4 points): 3.5%
boembolism: prevention IMPROVE score Risk for VTE at 3 mo Low risk (0 points): 0.4%
and treatment in patients
with cancer. Blood Adv.
High risk (≥4 points): 5.7%
2021;5:927-74. [PMID: Geneva score Risk for VTE at 3 mo Low risk (<3 points): 0.6%
33570602] High risk (≥3 points): 3.2%
26. Khorana AA, Kuderer NM,
Culakova E, et al. Surgical patients
Development and valida-
tion of a predictive model
Caprini Risk Assessment Model Risk for VTE at 3 mo Low risk (0 points): <0.7%
for chemotherapy-associ- High risk (≥9 points): 10.7%
ated thrombosis. Blood. Ambulatory patients with cancer
2008;111:4902-7. [PMID:
18216292] Khorana score Risk for VTE at 2.5 mo Low risk (0 points): 0.8%
27. Carrier M, Abou-Nassar K, High risk (≥3 points): 7.1%
Mallick R, et al; AVERT
Investigators. Apixaban to Postpartum patients
prevent venous throm- RCOG score Not studied Low risk (<2 risk factors)
boembolism in patients
with cancer. N Engl J
Intermediate/high risk (≥2 risk factors)
Med. 2019;380:711-9.
[PMID: 30511879] RCOG = Royal College of Obstetricians and Gynaecologists; VTE = venous thromboembolism.

VTE prophylaxis, and aspirin is an emerg- anticoagulation outside of pregnancy,
28. Khorana AA, Soff GA,
ing alternative. A large randomized con- antepartum and postpartum anticoa- Kakkar AK, et al; CASSINI
Investigators. Rivaroxaban
trolled trial (RCT) compared extended gulation are recommended (30). For for thromboprophylaxis in
prophylaxis with a DOAC (rivaroxaban) other at-risk persons (Appendix Table high-risk ambulatory
patients with cancer. N
versus a DOAC for 5 days followed by as- 2, available at Annals.org), prophylaxis Engl J Med.
pirin after hip and knee arthroplasty and is targeted at the first 6 weeks post- 2019;380:720-8. [PMID:
30786186]
found no difference in symptomatic VTE partum, as VTE risk is 15- to 35-fold 29. Kotaska A. Postpartum ve-
nous thromboembolism
or bleeding (24). The ASH guidelines higher during this period versus the prophylaxis may cause
more harm than benefit:
suggest pharmacologic prophylaxis with nonpregnant state (31). LMWH is safe a critical analysis of inter-
either a DOAC or aspirin (23). during pregnancy and breastfeeding national guidelines
through an evidence-
and is the anticoagulant of choice based lens. BJOG.
Ambulatory patients with cancer 2018;125:1109-16.
in the antepartum and postpartum [PMID: 29512316]
The incidence of VTE in ambulatory 30. Bates SM, Rajasekhar A,
patients with cancer ranges from 5% periods. Risk factors for pregnancy- Middeldorp S, et al.
to 20%, with considerable variability associated VTE include varicose veins, American Society of
according to such factors as cancer emergency cesarean section, stillbirth, lines for management of
venous thromboembo-
type, prothrombotic anticancer treat- comorbidities (heart, kidney, inflamma- lism: venous throm-
ments, and patient-specific risk factors tory bowel disease), smoking, inherited boembolism in the
context of pregnancy.
(25). Ambulatory patients who have thrombophilia, preeclampsia, postpar- Blood Adv. 2018;2:3317-
59. [PMID: 30482767]
cancer-associated thrombosis (CAT) tum infection, and postpartum hemor- 31. Heit JA, Kobbervig CE,
have increased risk for bleeding, recur- rhage (32). How these risk factors James AH, et al. Trends in
the incidence of venous
rent VTE, and early death (25). The should be used to select patients who thromboembolism during
pregnancy or postpartum:
Khorana score (Table 2) can be used to would benefit from thromboprophy- a 30-year population-
estimate VTE risk and identify which laxis is unclear. Clinical trials have based study. Ann Intern
Med. 2005;143:697-706.
patients with cancer might benefit from focused on post–cesarean section pa- [PMID: 16287790]
32. Sultan AA, West J,
primary prophylaxis (26). DOACs are tients but are limited by low event rates Grainge MJ, et al.
the preferred anticoagulant for pre- and poor recruitment. Recommen- Development and valida-
tion of risk prediction
venting CAT because of their oral route dations for postpartum prophylaxis model for venous throm-
boembolism in postpar-
and established safety profile (25). Two from several professional societies are tum women:
summarized in Appendix Table 2 (30, multinational cohort
RCTs have compared DOACs versus no study. BMJ. 2016;355:
prophylaxis in ambulatory patients with 33–37). i6253. [PMID:
27919934]
cancer with high-risk Khorana scores Should patients with thrombophilia 33. ACOG practice bulletin
no. 196 summary:
(≥2) (27, 28). The CASSINI trial showed a routinely receive pharmacologic thromboembolism in
pregnancy. Obstet
trend toward reduced VTE events but prophylaxis? Gynecol. 2018;132:243-
did not reach statistical significance (28). Patients may be identified as carriers
8. [PMID: 29939933]
34. American College of
In contrast, the AVERT trial showed a sta- of inherited thrombophilia because of Obstetricians and
Gynecologists' Committee
tistical reduction in VTE events (27). Both a prior VTE event or family screening. on Practice Bulletins—
trials showed a slight increase in major Prophylaxis for VTE in patients with
Obstetrics. ACOG practice
bulletin no. 197:
bleeding of about 1%. Major practice thrombophilia without a history of
inherited thrombophilias
in pregnancy. Obstet
guideline recommendations are consist- VTE is not recommended. Because Gynecol. 2018;132:e18-
ent, however, and suggest the use of e34. [PMID: 29939939]
the incidence of VTE in the general 35. Chan WS, Rey E, Kent NE,
pharmacologic prophylaxis in high-risk population is low, even if some
et al; VTE in Pregnancy
Guideline Working
patients (Khorana score ≥2) while con- thrombophilia is associated with in- Group. Venous throm-
sidering bleeding risk, treatment cost, boembolism and antith-
creased risk for VTE, the absolute risk rombotic therapy in
and patient preference (7, 25). pregnancy. J Obstet
remains small (Appendix Table 1). Gynaecol Can.
2014;36:527-53. [PMID:
Pregnant patients Similarly, the presence of thrombo- 24927193]
Although peripartum VTE occurs in 1 philia should not influence the dura- 36. Bates SM, Greer IA,
Middeldorp S, et al. VTE,
in 1000 deliveries and is the causal fac- tion of therapy after an initial VTE thrombophilia, antithrom-
botic therapy, and preg-
tor in 15% (1 to 5 maternal deaths per event. However, during transient nancy: Antithrombotic
100 000 live births), consensus on who high-risk periods, such as hospitaliza- Therapy and Prevention
of Thrombosis, 9th Ed:
should receive prophylaxis is elusive tion or postpartum, the presence of American College of
Chest Physicians evi-
(29). For those with a history of unpro- thrombophilia may warrant consider- dence-based clinical prac-
voked VTE or estrogen-associated ation, especially if other high-risk con- tice guidelines. Chest.
2012;141:e691S-e736S.
VTE or those receiving long-term ditions are present. [PMID: 22315276]

How should physicians counsel aspirin, or a single dose of LMWH 2 to 4
37. Nelson-Piercy C,
MacCallum P, Mackillop patients about prevention of VTE hours before a flight (39). The trial
L; Royal College of
Obstetricians and during travel? showed a reduction in DVT in LMWH-
Gynaecologists. Reducing
the Risk of Venous Air travel is a weak risk factor for VTE, treated patients compared with pla-
Thromboembolism during with a 2- to 4-fold increased risk for cebo or aspirin; however, 60% of events
Pregnancy and the
Puerperium. Green-top symptomatic DVT after a flight lasting 4 were asymptomatic DVT and thus of
Guideline No. 37a. April
2015. hours or longer and an absolute risk uncertain clinical importance.
38. Chandra D, Parisini E, increase of 1 in 4600 flights for sympto-
Mozaffarian D. Meta-anal- Although data are limited, expert guide-
ysis: travel and risk for ve- matic events (14, 38).
nous thromboembolism. lines state that patients at high risk may
Ann Intern Med.
2009;151:180-90. [PMID:
In the LONFLIT3 RCT, patients at high benefit from graduated compression
19581633] risk for DVT (previous DVT, coagulation stockings (below the knee, pressure of
39. Cesarone MR, Belcaro G,
Nicolaides AN, et al. disorder, obesity, limited mobility, can- 15 to 30 mm Hg) or pharmacologic pro-
Venous thrombosis from phylaxis, with consideration of patient
air travel: the LONFLIT3
cer, or varicose veins) were randomly
study—prevention with as- assigned to no prophylaxis, 400 mg of values and preferences (14, 40).
pirin vs low-molecular-
weight heparin (LMWH)
in high-risk subjects: a
randomized trial.
Angiology. 2002;53:1-6. Prevention... DVT has many risk factors, and risk scores are helpful for clinicians to
[PMID: 11863301] select which patients might benefit from prophylaxis. Determining the clinical benefit of
40. Kahn SR, Lim W, Dunn prophylaxis should include assessment of risk for fatal PE and symptomatic VTE versus
AS, et al. Prevention of
VTE in nonsurgical risk for major bleeding. DOACs are the agents of choice for prophylaxis in orthopedic
patients: Antithrombotic patients and patients with cancer, whereas LMWH is the treatment of choice in pregnant
Therapy and Prevention of
Thrombosis, 9th Ed: patients and hospitalized medical patients.
American College of Chest
Physicians evidence-based
clinical practice guide-
lines. Chest. 2012;141: CLINICAL BOTTOM LINE
e195S-e226S. [PMID:
22315261]
41. Goodacre S, Sutton AJ,
Sampson FC. Meta-analy-
sis: The value of clinical
assessment in the diagno-
sis of deep venous throm-
bosis. Ann Intern Med. Diagnosis
2005;143:129-39. [PMID:
16027455] When should clinicians suspect DVT? What is the role of D-dimer testing?
42. Siccama RN, Janssen KJ,
Verheijden NA, et al.
Clinical features, such as pain, warmth, D-dimer, a degradation product of
Systematic review: diag- and erythema, have limited value in the cross-linked fibrin, is typically elevated
nostic accuracy of clinical
decision rules for venous diagnosis of DVT. The differential diag- in patients with acute VTE and some
thromboembolism in el-
derly. Ageing Res Rev. nosis for suspected DVT is extensive nonthrombotic disorders. D-dimer lev-
2011;10:304-13. [PMID: (Table 3). Therefore, when DVT is clini- els have good sensitivity but poor spec-
21130902]
43. Oudega R, Moons KG, cally suspected, a pretest probability of ificity for diagnosis of VTE; therefore,
Hoes AW. Ruling out
deep venous thrombosis DVT should be determined using vali- their utility is in a negative result. In
in primary care. A simple dated clinical prediction rules (Table patients with a low or “unlikely” pretest
diagnostic algorithm
including D-dimer testing. 4). Although the Wells score is the probability of DVT (<10%), a negative
Thromb Haemost.
2005;94:200-5. [PMID: most extensively evaluated tool (41), it D-dimer result can safely rule out DVT
16113804] has not been validated in pregnant or and obviate the need for additional
44. Geersing GJ, Zuithoff NP,
Kearon C, et al. Exclusion hospitalized patients and may have investigation. In fact, when a clinical
of deep vein thrombosis
using the Wells rule in lower specificity in elderly patients (42). prediction rule and D-dimer testing are
clinically important sub- An alternative prediction rule, the pri- used together, DVT can be excluded in
groups: individual patient
data meta-analysis. BMJ. mary care rule, was derived and vali- 29% of patients with suspected DVT
2014;348:g1340. [PMID:
24615063] dated in ambulatory patients presen- without the need for additional diag-
45. Freund Y, Chauvin A, ting with symptoms of DVT and may be nostic imaging (44). The sensitivity of
Jimenez S, et al. Effect of
a diagnostic strategy more appropriate in this context (43). D-dimer testing for PE can be improved
using an elevated and
age-adjusted D-dimer No matter which tool is used, a clinical when clinical probability and age are
threshold on thromboem-
bolic events in emergency
prediction rule should not be the sole included (45). There is an ongoing clini-
department patients with criterion for diagnosis; rather, it should cal trial of age-adjusted D-dimer in DVT
suspected pulmonary em-
bolism: a randomized be used in conjunction with D-dimer diagnosis (NCT02384135). D-dimer
clinical trial. JAMA.
2021;326:2141-9. [PMID:
testing to determine whether diagnos- should not be used as a screening test
34874418] tic imaging is necessary. when DVT is not clinically suspected.

46. Kraaijpoel N, Carrier M,
Table 3. Differential Diagnosis of DVT Le Gal G, et al. Diagnostic
accuracy of three ultraso-
Disease Characteristics Notes nography strategies for
deep vein thrombosis of
Venous insufficiency (venous Usually due to venous hyperten- Obtain ultrasonography of venous the lower extremity: a sys-
reflux) sion from such causes as venous reflux tematic review and meta-
analysis. PLoS One.
reflux or obesity 2020;15:e0228788.
Superficial thrombophlebitis Firm, tender, varicose vein Superficial thrombosis is rarely [PMID: 32045437]
associated with DVT 47. Ageno W, Squizzato A,
Wells PS, et al. The diag-
Muscle strain, tear, or trauma Pain occurring with a range of Perform appropriate orthopedic nosis of symptomatic
motion more characteristic of evaluation recurrent pulmonary em-
orthopedic problem due to bolism and deep vein
thrombosis: guidance
trauma; usually a history of leg
from the SSC of the ISTH.
injury J Thromb Haemost.
Swelling in a paralyzed leg History of paraplegia Patients with paralyzed limb may 2013;11:1597-602.
[PMID: 23682905]
develop edema without DVT
48. van Es N, Le Gal G, Otten
Baker cyst Pain localized to popliteal region Seen on ultrasonography HM, et al. Screening for
of leg occult cancer in patients
with unprovoked venous
Cellulitis Skin erythema and warmth Consider antibiotic treatment thromboembolism: a sys-
tematic review and meta-
Lymphedema Toe edema is more characteristic Lymphedema can occur in 1 or
analysis of individual
of lymphedema than of venous both legs patient data. Ann Intern
edema Med. 2017;167:410-7.
[PMID: 28828492]
49. Aujesky D, Obrosky DS,
DVT = deep venous thrombosis. Stone RA, et al. Derivation
and validation of a prog-
nostic model for pulmo-
What is the role of CUS? vein DVT, which is of uncertain clinical nary embolism. Am J
Respir Crit Care Med.
Owing to safety, ease of application, significance. 2005;172:1041-6.
[PMID: 16020800]
and absence of contrast and ionizing How should pregnant patients be 50. Kahn SR, Shapiro S, Wells
PS, et al; SOX trial investi-
radiation, CUS is the preferred diag- evaluated for suspected DVT? gators. Compression
nostic imaging modality for DVT. CUS Clinical prediction rules have not been
stockings to prevent post-
thrombotic syndrome: a
can be performed according to 3 pro- formally validated in pregnant patients. randomised placebo-con-
trolled trial. Lancet.
tocols: 1) continuous visualization with Furthermore, D-dimer assays are asso- 2014;383:880-8. [PMID:
compression of proximal leg deep ciated with poor specificity in preg-
24315521]
51. Franco L, Giustozzi M,
veins only, stopping at the calf trifurca- nancy, as levels naturally increase Agnelli G, et al.
Anticoagulation in
tion; 2) 2-point visualization with com- during the third trimester. CUS is thus patients with isolated dis-
pression limited to the common recommended as the initial test when
tal deep vein thrombosis:
a meta-analysis. J Thromb
femoral vein and popliteal trifurcation; DVT is suspected, and follow-up ultra- Haemost. 2017;15:1142-
54. [PMID: 28316124]
or 3) continuous visualization with com- sonography is suggested in pregnant 52. Ageno W, Bertuª L,
pression from common femoral veins patients with an initial normal ultra-
Bucherini E, et al; RIDTS
study group. Rivaroxaban
to calf veins. For protocols that limit sound. Patients with symptoms sugges-
for the treatment of
symptomatic isolated distal
imaging to the proximal leg vein, serial tive of iliac venous thrombosis (whole- deep vein thrombosis –
RIDTS study [abstract]. Res
CUS is needed in patients with a high leg edema or discomfort in the flank, Pract Thromb Haemost.
or “likely” clinical probability and a pos- back, or buttock) should have the pel-
2021;5 (Suppl 2).
53. Mulder FI, Bosch FTM,
itive D-dimer result (Appendix Figure, vic vessels evaluated with ultrasonogra- Young AM, et al. Direct
oral anticoagulants for
available at Annals.org). phy or magnetic resonance imaging cancer-associated venous
thromboembolism: a sys-
A meta-analysis comparing serial lim- (30, 36). tematic review and meta-
analysis. Blood.
ited proximal CUS and whole-leg CUS 2020;136:1433-41.
When should clinicians consider [PMID: 32396939]
showed similar failure rates (VTE diag- 54. Carrier M, Blais N,
recurrent DVT?
nosed within 45 days of follow-up) of Crowther M, et al.
Treatment algorithm in
1.4% and 1.0%, respectively. The pro- After acute treatment of DVT, approxi- cancer-associated throm-
portion of isolated distal DVT identified mately half of patients have residual bosis: Canadian expert
consensus. Curr Oncol.
by whole-leg CUS ranged from 23% to vein occlusion on follow-up imaging, 2018;25:329-37. [PMID:
30464682]
62% (46). and 25% to 40% have persistent pain, 55. Bates SM, Middeldorp S,
skin discoloration, and swelling, known Rodger M, et al. Guidance
for the treatment and pre-
Although a potential advantage of as postthrombotic syndrome (PTS) vention of obstetric-associ-
ated venous
whole-leg CUS may be that it precludes (47). The presence of PTS makes distin- thromboembolism. J
the need for repeated testing, it may guishing the symptoms and the imag- Thromb Thrombolysis.
2016;41:92-128. [PMID:
identify more patients with isolated calf ing findings of DVT challenging when 26780741]

Table 4. Clinical Prediction Rules for DVT
56. Pengo V, Denas G,
Zoppellaro G, et al. Clinical Prediction Rule Score
Rivaroxaban vs warfarin in
high-risk patients with Wells score*
antiphospholipid syn-
drome. Blood. Active cancer (treatment ongoing, within 6 mo, or palliative) 1
2018;132:1365-71.
[PMID: 30002145] Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
57. Ordi-Ros J, Sáez-Comet L, Recently bedridden for >3 d or major surgery within 12 wk requiring general or regional 1
Perez-Conesa M, et al. anesthesia
Rivaroxaban versus vita-
min K antagonist in anti- Localized tenderness along the distribution of the deep venous system 1
phospholipid syndrome: a
randomized noninferiority Entire leg swollen 1
trial. Ann Intern Med. Calf swelling 3 cm larger than the asymptomatic side (measured 10 cm below the tibial 1
2019;171:685-94. [PMID: tuberosity)
31610549]
58. Cohen H, Cuadrado MJ, Pitting edema confined to the symptomatic leg 1
Erkan D, et al. 16th
International Congress on Collateral superficial veins (nonvaricose) 1
Antiphospholipid Previously documented DVT 1
Antibodies Task Force
report on antiphospholi- Alternative diagnosis at least as likely as DVT –2
pid syndrome treatment Primary care rule†
trends. Lupus.
2020;29:1571-93. [PMID: Male sex 1
33100166]
59. Douxfils J, Adcock DM, Use of hormonal contraceptives 1
Bates SM, et al. 2021 Active cancer in past 6 mo 1
update of the
International Council for Surgery in previous month 1
Standardization in Absence of leg trauma 1
Haematology recommen-
dations for laboratory Distention of collateral leg veins 1
measurement of direct
oral anticoagulants. Difference in calf circumference ≥3 cm 2
Thromb Haemost. Abnormal D-dimer assay result 6
2021;121:1008-20.
[PMID: 33742436]
60. Poller L, Keown M, DVT = deep venous thrombosis.
Ibrahim S, et al. An inter- * Using the original score, <0 points indicates low probability, 0–2 points indicates intermediate proba-
national multicenter bility, and >2 points indicates high probability. Using the dichotomized score, ≤1 point indicates that
randomized study of com- DVT is unlikely and ≥2 points indicates that DVT is likely. From Wells PS, Anderson DR, Rodger M, et al.
puter-assisted oral antico- Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med.
agulant dosage vs.
medical staff dosage. J 2003;349:1227-35.
Thromb Haemost. † Very low risk (score ≤3) or increased risk (score ≥4). From Toll DB, Oudega R, Vergouwe Y, et al. A
2008;6:935-43. [PMID: new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups.
18489430] Fam Pract. 2008;25:3-8.
61. Stergiopoulos K, Brown
DL. Genotype-guided vs
clinical dosing of warfarin
and its analogues: meta- considering DVT recurrence. The most month prevalence of cancer after VTE
analysis of randomized
clinical trials. JAMA Intern reliable way to diagnose recurrent DVT diagnosis of 5.2% (CI, 4.1% to 6.5%).
Med. 2014;174:1330-8.
[PMID: 24935087] is to compare repeated imaging with a Overall, this was higher in patients with
62. Rodger MA, Miranda S, extensive screening than in those with
Delluc A, et al.
posttreatment image. For this reason,
Management of sus- CUS is suggested in all patients at the limited screening (odds ratio, 2.0 [CI,
pected and confirmed
recurrent venous throm- time of withdrawal of anticoagulation 1.2 to 3.4]) (48). Patients aged 50 years
bosis while on anticoagu-
lant therapy. What next.
(baseline). The finding of a new non- or older were 7 times more likely to be
Thromb Res. compressible venous segment or an diagnosed with cancer (odds ratio, 7.1
2019;180:105-9. [PMID:
31279158] increase of 4 mm in clot diameter from [CI, 3.1 to 16]).
63. Khan F, Rahman A, Carrier
M, et al; MARVELOUS baseline imaging suggests recurrent Although there is insufficient evidence
Collaborators. Long term DVT (47). to inform a specific routine screening
risk of symptomatic recur-
rent venous thromboemb-
olism after discontinuation What other underlying conditions strategy, clinicians should keep in mind
of anticoagulant treatment
and clinical manifestations should that 1 in 20 patients with unprovoked
for first unprovoked ve-
nous thromboembolism clinicians look for? VTE may have cancer diagnosed within
event: systematic review
and meta-analysis. BMJ. Within 12 months of an unprovoked the following 12 months and the high-
2019;366:l4363. [PMID:
VTE diagnosis, 4% to 10% of patients est risk is in patients aged 50 years or
31340984]
64. Douketis J, Tosetto A,
are diagnosed with cancer. older. Existing age- and sex-appropri-
Marcucci M, et al. Risk of
recurrence after venous ate cancer screening guidelines should
thromboembolism in A systematic review and patient-level be followed, and clinicians should have
men and women: patient
level meta-analysis. BMJ. meta-analysis of 10 studies evaluating a low index to investigate cancer in
2011;342:d813. [PMID:
21349898] cancer screening strategies found a 12- older patients.

Diagnosis... Clinical features have little predictive value in diagnosing DVT. Clinicians
should use a clinical prediction rule that incorporates D-dimer to stratify risk for throm-
bosis. Various clinical prediction rules exist, of which the Wells score is the most studied.
Whole-leg ultrasonography may limit the need for repeated testing but identifies more
patients with isolated distal DVT. The use of an extensive cancer screening and thrombo-
philia testing strategy is controversial and is not routinely recommended. Clinicians
should consider consulting a specialist if DVT recurrence or breakthrough is suspected.
CLINICAL BOTTOM LINE 65. Rodger MA, Le Gal G,

Anderson DR, et al;
REVERSE II Study
Investigators. Validating
the HERDOO2 rule to
guide treatment duration
Treatment for women with unpro-

voked venous thrombosis:
multinational prospective
As shown in the Figure, DVT treat- How should clinicians decide whether cohort management study.
BMJ. 2017;356:j1065.
ment is divided into 3 phases. For to treat patients on an outpatient or [PMID: 28314711]
66. Broderick C, Watson L,
most patients, a DOAC is the pre- inpatient basis? Armon MP. Thrombolytic
strategies versus standard
ferred treatment (see the discussion Most patients with DVT can be safely anticoagulation for acute
of choice of anticoagulant later in this treated with either a DOAC or LMWH
deep vein thrombosis of
the lower limb. Cochrane
section). Some DOACs (rivaroxaban as outpatients. Patients with associated Database Syst Rev.
2021;1:CD002783.
and apixaban) can be used immedi- PE at the time of diagnosis of DVT [PMID: 33464575]
67. Rabinovich A, Kahn SR.
ately during the initial phase of treat- should be assessed for risk for short- How I treat the post-
thrombotic syndrome.
ment, whereas others (dabigatran term PE-related mortality, such as with Blood. 2018;131:2215-
and edoxaban) require 5 to 10 days the Pulmonary Embolism Severity 22. [PMID: 29545327]
68. Kearon C, Akl EA, Ornelas
of LMWH before starting. Table 5 Index (49). Those with hemodynamic J, et al. Antithrombotic
therapy for VTE disease:
summarizes the various anticoagu- instability, defined as systolic blood CHEST guideline and
expert panel report.
lants used for DVT treatment, includ- pressure below 90 mm Hg for 15 Chest. 2016;149:315-52.
ing mechanisms of action, pharma- minutes or more, should be consid- [PMID: 26867832]
69. Witt DM, Nieuwlaat R,
cokinetics, prescribing information, ered for thrombolysis. Those with high- Clark NP, et al. American
Society of Hematology
and availability of reversal agents. risk features, based on either a risk 2018 guidelines for man-
agement of venous
thromboembolism: opti-
mal management of anti-
coagulation therapy.
Blood Adv. 2018;2:3257-
Figure. Phases of anticoagulation. 91. [PMID: 30482765]
70. Lim W, Le Gal G, Bates SM,
et al. American Society of
lines for management of
venous thromboembolism:
Initial Long-term Extended diagnosis of venous throm-
boembolism. Blood Adv.
2018;2:3226-56. [PMID:
30482764]
71. Qaseem A, Chou R,
Apixaban, 10 mg BID for 7 d Apixaban, 5 mg BID Apixaban, 5 mg BID or Humphrey LL, et al;
Rivaroxaban, 15 mg BID for Dabigatran, 150 mg BID 2.5 mg BID‡ Clinical Guidelines
21 d Edoxaban, 60 mg OD† Aspirin, 81–100 mg OD, if Committee of the
Rivaroxaban, 20 mg OD anticoagulation not possible American College of
LMWH/fondaparinux* for
Physicians. Venous throm-
≥5 d and INR ≥2 for 2 d VKA (warfarin), INR 2–3 Dabigatran, 150 mg BID boembolism prophylaxis in
Edoxaban, 60 mg OD† hospitalized patients: a clin-
Rivaroxaban, 20 mg OD or ical practice guideline from
10 mg OD‡ the American College of
VKA (warfarin), INR 2–3 Physicians. Ann Intern
Med. 2011;155:625-32.
[PMID: 22041951]
72. American College of
0 to 7 d 8 d to 3 mo 3 mo to indefinitely Obstetricians and
Gynecologists' Committee
on Practice Bulletins—
BID = twice daily; INR = international normalized ratio; LMWH = low-molecular-weight heparin; OD = Obstetrics. ACOG practice
once daily; VKA = vitamin K antagonist. bulletin no. 196:
thromboembolism in
* LMWH is needed for 5 to 10 days before starting dabigatran or edoxaban. pregnancy. Obstet
† 30 mg/d if creatinine clearance is 30 to 50 mL/min or weight is <60 kg. Gynecol. 2018;132:e1-
‡ Dose reduction may be considered after 6 months of therapy. e17. [PMID: 29939938]

Table 5. Characteristics of Common Anticoagulants
Drug Target Peak Effect Half-Life Renal Protein Use in Renal Laboratory Reversal/
Elimination Clearance, % Binding, % Failure Measurement Bypassing Agent
Warfarin Vitamin K– 5–7 d 20–60 h* None 99 Safe INR Vitamin K and/or

(vitamin K dependent PCC, or frozen
antagonist) factors II, VII, IX, X; plasma
protein C and S
Unfractionated Antithrombin/ Immediate 30–90 min Minimal Very high Safe Anti-Xa† or aPTT Protamine
heparin indirect factor (intravenous)
IIa, factor Xa
(other factors to
lesser extent)
Low-molecular- Factor Xa 3–5 h 2–7 h 40 None Avoid if GFR Not routinely Partial reversal
weight heparin <30 mL/min required; anti-Xa† with protamine
when needed
Apixaban Factor Xa 3h 8–14 h 25 85 Avoid if GFR Not routinely Andexanet alfa;
<25 mL/min required; anti-Xa† PCC may be
when needed effective if not
available
Dabigatran Factor IIa 1.5 h 14–17 h >80 35 Avoid if GFR dTT, anti-IIa Idarucizumab
<30 mL/min
Rivaroxaban‡ Factor Xa 2–3 h 7–11 h 33 90 Avoid if GFR Not routinely Andexanet alfa;
available
Edoxaban Factor Xa 4h 8–11 h 33 55 Avoid if GFR Not routinely Andexanet alfa;
available
aPTT = activated partial thromboplastin time; dTT = diluted thrombin time; GFR = glomerular filtration rate; INR = international nor-
malized ratio; PCC = prothrombin complex concentrate.
* Duration of clinical effect is 2 to 5 days.
† Requires drug-specific calibration.
‡ 15- and 20-mg tablets should be taken with food for maximum absorption and efficacy.
prediction rule or concerning clinical Should clinicians treat isolated

presentations, such as severe dyspnea distal DVT?
or syncope, should be admitted in a
Isolated distal (calf) DVT carries a signif-
closely monitored setting. Patients with
icantly lower risk for PE and recurrence.
uncomplicated isolated DVT who do
When a whole-leg CUS is performed to
not need admission for parenteral anti-
investigate DVT, half of all DVTs will be
coagulation (for example, UFH in renal
isolated to the calf veins (peroneal,
failure) or pain management can be
posterior tibial, anterior tibial) (12). A
treated as outpatients (3). Patients
diagnostic strategy of imaging only
with clinical signs suggestive of risk
the proximal leg veins is therefore
for limb ischemia (phlegmasia ceru-
lea dolens), severe pain, or a high risk one way to reduce overdiagnosis and
for bleeding should be admitted for treatment of isolated distal DVT. If an
initial management. isolated distal DVT is diagnosed,
treatment options include either no
73. Kahn SR, Comerota AJ,
Cushman M, et al; What local measures should clinicians anticoagulation and close serial CUS
American Heart
Association Council on recommend? or therapeutic anticoagulation.
Peripheral Vascular
Disease, Council on
Data on the efficacy of compression
Clinical Cardiology, and therapy in reducing risk for PTS are A meta-analysis of randomized and non-
Council on Cardiovascular
and Stroke Nursing. The conflicting. For example, elastic com- randomized studies suggested that anti-
postthrombotic syndrome:
evidence-based preven- pression stockings did not prevent PTS coagulation (both prophylactic and
tion, diagnosis, and treat-
ment strategies: a in an RCT (50). However, clinicians therapeutic dose) for distal DVT may
scientific statement from
the American Heart
should consider early ambulation, leg reduce recurrent VTE without increasing
Association. Circulation. elevation, and compression therapy for bleeding risk (51). A recent cohort study
2014;130:1636-61.
[PMID: 25246013] symptom relief. showed that stopping anticoagulation

(therapeutic LMWH or rivaroxa- Which anticoagulants should more effective than VKAs at
ban) in patients with resolution clinicians use? reducing recurrent VTE in CAT.
of symptoms and no extension Anticoagulation for confirmed Similarly, RCTs in patients with
on repeated CUS at 2 weeks was DVT is divided into 3 phases: the CAT have shown that DOACs
associated with a low rate of initial 7 days, 8 days to 3 months, have similar or increased efficacy
recurrent VTE at 3 months (1.3% and extended therapy beyond 3 compared with LMWH but may
[CI, 0.05% to 4.85%]). Further months (Figure). Cancer- and be associated with increased
data on DOAC therapy and du- pregnancy-associated DVT are bleeding (7, 25, 53). CAT DOAC
ration for treatment of distal DVT considered separately. Table 5 trials have studied the oral direct
are expected soon (52). summarizes the standard antico- Xa inhibitors (rivaroxaban, apixa-
agulation options for treatment. ban, edoxaban) only; there have
ACCP clinical practice guidelines been no trials of oral direct
Historically, VKAs (such as warfa-
suggest anticoagulation only in thrombin inhibitors (such as dabi-
rin) were the only oral treatment;
patients with severe symptoms gatran) for treatment of CAT. An
warfarin remains the preferred
or risk factors for progression (D- agent in patients with advanced increase in the overall trend of
dimer, extensive disease, proxim- renal failure, those with APS, or bleeding during CAT treatment is
ity to proximal veins, unprovoked those for whom medication cost observed for patients with gastro-
event, active cancer, history of is important. For VKAs, concur- intestinal or genitourinary cancer.
VTE, or hospitalization) (2, 12). rent parenteral anticoagulation DOACs are safe and affordable
When therapeutic anticoagula- is required for at least 5 days, and have an oral administration
tion is chosen, ACCP suggests 3 and 2 consecutive international route, making them the preferred
months' duration; however, pub- normalized ratios (INRs) must be choice for many patients with
lished data on the duration for between 2 and 3 before paren- CAT (7, 25, 54). There is insuffi-
distal DVT vary from 6 weeks to 3 teral therapy is withdrawn. UFH cient evidence to guide the choice
months (51). In low-risk patients, is used for this initial period in between DOACs for CAT, and
withholding anticoagulation and patients with advanced renal individualized decisions should be
performing serial CUS weekly for made with patients. Based on ana-
impairment, and LMWH is used
lysis of current trials, caution with
2 weeks is a reasonable clinical in most others. Except for the
DOACs is suggested in patients
approach. special populations discussed in
with an unresected gastrointestinal
the following sections, DOACs
lesion, thrombocytopenia (platelet
When should clinicians start are the preferred treatment for
count <50 109/L), recent life-
anticoagulants? acute DVT (2, 3). DOACs are
threatening bleeding, high-risk in-
given at fixed doses, do not
There are no randomized studies tracranial lesions, hepatic impair-
require laboratory monitoring,
investigating the timing of anti- ment (Child–Pugh B or C), and
and are noninferior to VKAs in
coagulant therapy initiation in concomitant use of antiplatelets. In
phase 3 RCTs for the acute treat-
patients with suspected DVT. In such patients, LMWH is the pre-
ment of DVT to prevent sympto-
patients with a high pretest prob- ferred therapy (54).
matic recurrent VTE.
ability and low risk for bleeding, Pregnant patients
clinicians should initiate a short- Several patient populations require
UFH and LMWH do not cross the
acting anticoagulant while await- attention for treatment decisions:
placenta. They are safe during
ing the results of the diagnostic patients with VTE associated with
pregnancy, with LMWH being the
work-up. In patients diagnosed active cancer, pregnant patients,
mainstay of treatment because it
with acute proximal DVT, clini- and patients with APS.
can be given as a self-adminis-
cians should initiate anticoagula- Patients with CAT tered subcutaneous injection.
tion with a parenteral antico- Treatment of CAT is distinct from DOACs, VKAs, and fondaparinux
agulant, apixaban, or rivaroxaban other causes of VTE because of cross the placenta and should be
immediately unless they are con- the high risk for recurrent VTE, avoided in pregnancy. Duration
traindicated (Figure). If a VKA is drug interactions, and increased of therapy should be 6 months or
chosen for the long-term phase of bleeding complications. CAT 6 weeks postpartum, whichever is
therapy, it should be started on treatment differs from noncancer longer (30, 36). Patients on antico-
the same day as the parenteral VTE in several ways. For example, agulation during pregnancy may
anticoagulant. clinical trials show that LMWH is benefit from scheduled induction

of labor, as this would enable anti- adjust the UFH dose. LMWH and and even less often in the exten-
coagulation to be held before DOACs do not require routine ded treatment phase (62). When
delivery, allowing for neuroaxial laboratory monitoring; however, confronted with this, clinicians
anesthesia while reducing peri- in exceptional circumstances, should examine drug adherence
partum hemorrhage. If the preg- such as major bleeding or the and risk factors for therapeutic
nancy-associated VTE event occu- failure, such as underlying can-
need for urgent, life-threatening
rred 4 weeks or more before cer, APS, and heparin-induced
surgery, laboratory testing to
delivery, the last dose of LMWH thrombocytopenia (if there was
can be administered 24 hours estimate drug levels may be
necessary (Table 5). It is impor- recent heparin exposure). There
before labor induction, and it can
tant to note that the correlation are no high-quality studies to
be restarted 6 hours after delivery
between these laboratory assays support one management strat-
in the absence of any ongoing
egy for therapeutic failures;
postpartum hemorrhage. If the and anticoagulation effects or
therefore, referral to a consultant
VTE event is within 4 weeks of bleeding risk has not been firmly
delivery, UFH at a therapeutic is recommended. Patients using
established. At best, these tests
dose should be started at induc- VKAs are generally switched to
can be used for determination
tion of labor and held once active LMWH for 4 weeks before
of the presence or absence of resuming their prior therapy or
labor begins. An inferior vena
anticoagulant effects rather than
cava (IVC) filter should be consid- switching to a DOAC. Failures
ered if a VTE event occurs within precise quantification (59). The with LMWH can be managed by
2 weeks of delivery (55). IVC filters INR, a calculated adjustment of increasing the LMWH weight-
should be removed as soon as the prothrombin time, can help based dose to 120% to 125% for
anticoagulation can be resumed monitor VKA therapy. For treat- 4 weeks and then resuming prior
postpartum. ment of VTE, the target thera- treatment. There is no evidence
peutic range of the INR should to guide treatment decisions af-
Patients with APS
be between 2 and 3. The mecha- ter DOAC failure. Switching to
Patients with VTE and APS are at
high risk for recurrent VTE, and nism of action of VKAs involves VKAs, switching to LMWH for 4
APS is an indication to remain on reducing the synthesis of new weeks, or reinitiating a higher “ini-
extended-duration or lifelong vitamin K–dependent clotting tial” treatment phase of DOAC
anticoagulation. TRAPS, an RCT factors only; therefore, VKA dose dosing are reasonable (Table 5).
of warfarin compared with rivarox- changes take approximately 3
When should clinicians stop
aban in triple-positive patients days to affect INR measurement.
anticoagulation?
with APS, was terminated early A systematic and coordinated
INR monitoring process is recom- Acute DVT should be treated
when an interim analysis showed
significantly more thrombotic ev- mended, and software may also for a minimum of 3 months,
ents in the rivaroxaban-treated assist in dose adjustments (60). A regardless of the cause (3, 12).
patients (19%) compared with patient's time in the therapeutic Extension of therapy beyond this
those receiving VKAs (3%) (56). range (TTR) should be reviewed period should be based on the
A second RCT, in which 60% periodically, with the goal of an risk for recurrence. The Inter-
of patients were triple-positive, average TTR greater than 60% to national Society on Thrombosis
found a higher annualized recur- 80%. Compared with standard and Haemostasis Scientific and
rent thrombosis rate in the rivar- dosing protocols, a genotype- Standardization Subcommittee
oxaban-treated patients (3.9%) guided dosing strategy does not suggests that patients with an
compared with those receiving estimated recurrence risk less
increase TTR or reduce bleeding
VKAs (2.1%), with stroke more than 5% at 1 year or 15% at
or thromboembolic complica-
common in rivaroxaban-treated 5 years should stop anticoagulation
tions with VKAs (61).
patients (57). Given these data, after 3 months. All others should
VKAs are the preferred anticoagu- How should clinicians manage be considered for extended-dura-
lant for patients with APS (2, 58). recurrent DVT during tion (indefinite) therapy. VTE pro-
How should clinicians monitor anticoagulant therapy? voked by major transient risk
anticoagulation? Recurrent VTE during anticoagu- factors, such as major surgery, car-
Clinicians should use a cali- lant therapy is uncommon, occur- ries a less than 1% risk for recur-
brated anti-Xa assay or activated ring in about 2% of patients rence at 1 year, and antico-
partial thromboplastin time to during the acute treatment phase agulation can be stopped after 3

months as long as the transient What options are available for studies have suggested a possi-
risk factor is resolved. However, patients who cannot tolerate ble benefit of reduced incidence
patients with minor transient risk anticoagulants? of PTS in patients treated with
factors, such as hormonal treat- An IVC filter may be used in thrombolytic therapy, the ATTRACT
ments, have a 15% risk at 5 years patients with an acute proximal trial found that the incidence of
and may still benefit from extended DVT or PE who cannot receive PTS at 24 months was the same
therapy. full-dose anticoagulation because between patients treated with
of uncontrollable active bleeding, local thrombolytic therapy com-
A systematic review and meta- a high risk for life-threatening bined with clot aspiration versus
analysis of 18 studies and 7515
bleeding, or urgent surgery anticoagulation alone. ATTRACT
patients with unprovoked VTE
showed that after anticoagula- requiring interruption of anti- also confirmed no benefit in
tion was stopped, VTE recurred coagulation. Anticoagulation mortality or VTE recurrence out-
in 10% of patients after 1 year should be started as soon as it is comes between the strategies.
and 36% after 5 years (63). safe to do so. Once full-dose An updated Cochrane review of
anticoagulation is resumed with- 19 RCTs showed that thromboly-
Guidelines recommend that pa- out recurrence of major bleed-
tients with unprovoked VTE who sis improved imaging assess-
ing, the IVC filter should be ment of complete clot lysis at
are not at high bleeding risk removed to reduce the risk for
continue anticoagulation indefi- early and intermediate follow-up
filter-related complications, which but not late follow-up (reported
nitely. The risk for recurrent VTE increases over time.
is 2.2-fold higher for men than in only 2 studies). There was a
for women (64), and the “Men When should clinicians use significant increase in bleeding
continue, and HERDOO-2” clinical thrombolysis? (6.7% vs. 2.2%; risk ratio, 2.45
prediction rule is one strategy Thrombolytic therapy for iso- [CI, 1.58 to 3.78]) and a modest
to safely identify a subset of lated DVT is generally reserved reduction in PTS (50% vs. 53%;
women with a low risk for recur- for patients with threatened limb risk ratio, 0.78 [CI, 0.66 to 0.93])
rent VTE who can stop anticoa- ischemia (phlegmasia cerulea among those who received
gulation (65). dolens) (12). Although some thrombolysis (66).
Table 6. The Villalta Scale for Diagnosis and Grading of PTS

Variable Score*
Symptoms†
Pain 0, 1, 2, 3
Cramps 0, 1, 2, 3
Heaviness 0, 1, 2, 3
Paresthesia 0, 1, 2, 3
Pruritus 0, 1, 2, 3
Clinical signs‡
Pretibial edema 0, 1, 2, 3
Skin induration 0, 1, 2, 3
Hyperpigmentation 0, 1, 2, 3
Redness 0, 1, 2, 3
Venous ectasia 0, 1, 2, 3
Pain on calf compression 0, 1, 2, 3
Venous ulcer Absent or present
Score
No PTS 0–4
Mild PTS 5–9
Moderate PTS 10–14
Severe PTS 15 or presence of venous ulcer
PTS = postthrombotic syndrome.

* For symptoms and clinical signs: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe.
† Self-rated by the patient.
‡ Rated by the clinician.

How should clinicians treat stockings for symptom control breakthrough DVT during anticoa-
PTS? are typically prescribed at 20 to gulation. A referral should also be
Approximately 25% to 40% of 40 mm Hg, and below-the-knee considered if imaging is nondiag-
patients with symptomatic DVT stockings are better tolerated nostic but suspicion for recurrence
develop PTS. Symptoms of PTS than those that cover the leg remains high, complications nece-
include pain in the affected limb, higher. Contraindications to com- ssitating alternatives to anticoagu-
heaviness, swelling, stasis der- pression stockings include severe lation emerge, or VTE in the set-
matitis, and ulceration and can peripheral artery disease and ting of pregnancy is encountered.
affect quality of life and lead to allergies to the material. Life-threatening bleeding and the
disability. The Villalta score need for urgent reversal of antico-
should be used to diagnose and When should clinicians agulation also benefit from consul-
grade the severity of PTS (Table consider consulting a specialist tation. Management of severe
6) (67). Treatment includes leg for DVT? PTS associated with venous ulcers
exercises, avoiding dependent Clinicians should consider consult- should involve a multidisciplinary
positions for lengthy periods, ing a specialist with expertise in team that includes internists, der-
and using elastic compression thrombosis when considering a matologists, vascular surgeons, and
stockings. Elastic compression diagnosis of recurrent DVT or wound care nurses.
Treatment... Most patients with DVT can be safely treated with DOACs as outpatients. In patients with renal
impairment or APS or those for whom medication cost is a concern, VKAs are more appropriate. Patients with a
transient reversible risk factor for VTE should be treated for 3 months. Extended treatment should be considered
when the patient has a low risk for bleeding and has had unprovoked VTE, has active cancer, or has had recurrent
VTE. IVC filters should be used only when full-dose anticoagulation is contraindicated. Thrombolytic therapy may
be considered for patients with a massive iliofemoral DVT and impending limb ischemia who are at low risk for
bleeding.
CLINICAL BOTTOM LINE
Practice Improvement
What measures do stakeholders hospital admission or surgery,” in complete form in 2012, with
use to evaluate the quality of 2) “patients who got treatment updated recommendations pub-
care for patients with VTE? to prevent blood clots on the lished in shorter expert panel
day of or the day after being reports since then (2, 12, 68).
The Centers for Medicare & admitted to the intensive care
Medicaid Services has devel- ASH also offers guidance on
unit,” 3) “patients who developed
oped 11 categories of hospital- anticoagulation, diagnosis, can-
a blood clot while in the hospital
acquired conditions, some of cer, pregnancy, and VTE preven-
who did not get the treatment
which are preventable by apply- that could have prevented it,” tion in surgical and medical
ing evidence-based guidelines. and 4) whether “patients with patients (14, 23, 25, 30, 69, 70).
One of these is prevention of VTE blood clots were discharged on Specific guidelines for prophy-
after total knee and hip replace- a blood thinner medicine and laxis (71), cancer (7), pregnancy
ment. Hospital Compare (http:// received written instructions ab- (72), recurrent VTE (47), and PTS
medicare.gov/hospitalcompare) out that medicine.” (73) are also available. A sum-
compiles information about the
What do professional mary of the recommendations
quality of VTE care at more than
organizations recommend from major professional organi-
4000 Medicare-certified hospi-
tals, including on the following regarding the care of patients zations for the most common
measures: 1) “patients who got with DVT? clinical questions is provided in
treatment to prevent blood ACCP offers a series of compre- Appendix Table 3 (available at
clots on the day of or day after hensive guidelines, last published Annals.org).

In the Clinic Patient Information
Tool Kit
https://medlineplus.gov/
deepveinthrombosis.html
https://medlineplus.gov/languages/
deepveinthrombosis.html
Information and handouts on deep venous
thrombosis in English and other languages
Deep Venous Thrombosis from the National Institutes of Health's
MedlinePlus.
www.nhlbi.nih.gov/health/venous-
thromboembolism
www.nhlbi.nih.gov/es/salud/
tromboembolia-venosa
Information on venous thromboembolism
in English and Spanish from the National
Heart, Lung, and Blood Institute.
www.heart.org/en/health-topics/venous-
thromboembolism
from the American Heart Association.
www.cdc.gov/ncbddd/dvt/index.html
In the Clinic
www.cdc.gov/NCBDDD/Spanish/dvt/
index.html
in English and Spanish from the Centers
for Disease Control and Prevention.
Information for Health Professionals
https://journal.chestnet.org/article/S0012-
3692(15)00335-9/fulltext
CHEST guideline and expert panel report on
antithrombotic therapy for venous
thromboembolism.
https://ashpublications.org/bloodadvances/
article/5/4/927/475194/American-Society-
of-Hematology-2021-guidelines-for
American Society of Hematology 2021
guidelines for prevention and treatment of
venous thromboembolism in patients with
cancer.
https://ashpublications.org/bloodadvances/
article/2/22/3317/16094/American-Society-
of-Hematology-2018-guidelines-for
American Society of Hematology 2018
guidelines for management of venous
thromboembolism in the context of
pregnancy.

In the Clinic
WHAT YOU SHOULD Annals of Internal Medicine
KNOW ABOUT VENOUS
THROMBOEMBOLISM
What Is Venous Thromboembolism?
Venous thromboembolism (VTE) is a common and
potentially life-threatening condition that causes
blood clots to form inside veins. VTE most com-
monly causes blood clots in the lower legs,
known as deep venous thrombosis (DVT), and it
can also cause blood clots in the lungs, known as
pulmonary embolism (PE). More than half of all
VTE disease results from transient risk factors
and may be preventable.
Risk factors for VTE include:
• Recent injury
• Recent surgery
• Recent bed rest, including prolonged How Is It Treated?
hospitalization Blood thinners are the most effective treatment for
• Active cancer VTE and may be given by injection and by
• Family history of VTE mouth. Most people can be successfully treated
• Autoimmune disorders as outpatients. Patients with VTE who are clini-
cally unstable or those who are at high risk for
How Can It Be Prevented? complications from DVT or PE may be treated in
• Blood thinners can prevent VTE in patients who the hospital. People with VTE may need to take
are at high risk. blood thinners for at least 3 months. Many
• Compression stockings may be applied to the patients with VTE may require lifelong treatment
legs to prevent VTE. with blood thinners. Moving the legs, elevating
• The risk for clots must be balanced with the risk the legs, and using compression stockings can
for bleeding. help keep the legs from swelling while the clot is
• Early mobilization also decreases VTE risk. being treated.
What Are the Warning Signs? Questions for My Doctor

• What are my risk factors for VTE?
Patient Information
In many cases of VTE, there may be no symptoms.
When symptoms do occur, they include: • What can I do to prevent blood clots in the
• Chest pain future?
• Shortness of breath • What are the risks and benefits of blood
• Swelling in the leg, including the calf, ankle, and thinners?
foot • What symptoms require emergency care?
• Pain in the leg • How long will I need to stay on blood thinners?
• Skin that feels warm to the touch • Are there any activities I should avoid?
• Changes in skin color (redness) • Can I take blood thinners if I am pregnant?
How Is It Diagnosed?
Your doctor will check your vital signs, including
your oxygen level, and examine your heart,
lungs, and legs for any swelling or tenderness.
Your doctor will also evaluate your risk factors
and may do blood tests to see if further testing is
needed. Additional tests may include an ultra-
sound of the legs or more advanced imaging of
the chest, such as computed tomography.
For More Information

Centers for Disease Control and Prevention
www.cdc.gov/ncbddd/dvt/facts.html
Mayo Clinic
www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/
symptoms-causes/syc-20352557

Appendix Table 1. Inherited and Acquired Thrombophilia
Thrombophilia Description Increased Risk Laboratory Prevalence
for First VTE Measurement
Factor V Leiden Point mutation (1691G!A Heterozygous: APCR, PCR Heterozygous:

substitution) resulting in 4- to 8-fold White: 5%
factor V resistance to cleavage Homozygous: Hispanic: 2.2%
by activated protein C 12-fold Black: 1.2%
Indigenous American: 1.2%
Homozygous: <1%
Prothrombin gene mutation Point mutation (20210G!A Heterozygous: PCR Heterozygous:
substitution) resulting in 2- to 4-fold White: 2%
increased production of factor II Homozygous: Black: 0.5%
7-fold Indigenous American: 1.2%
Homozygous: <1%
Protein C deficiency Various mutations leading to loss 4- to 6-fold Activity assay <0.5%
of function of protein C, a
natural anticoagulant that
degrades activated factors V
and VIII
Associated with warfarin-induced
skin necrosis
Protein S deficiency Various mutations leading to loss 1- to 10-fold Activity assay <0.5%
of function of protein S, a co-fac-
tor for protein C
Clinical features similar to protein
C deficiency
Antithrombin deficiency Various mutations leading to loss 14-fold Activity assay 0.02%
of function of antithrombin, a
natural anticoagulant that inhib-
its thrombin and activated fac-
tors IX and X
Associated with heparin
resistance
Antiphospholipid syndrome Autoimmune disorder associated 1- to 10-fold Lupus anticoagulant† 0%–5%
with arterial and venous throm- (PTT-LA, dRVVT)
bosis as well as obstetric ELISA: Anticardiolipin antibodies
complications (IgG and/or IgM) in medium or
Criteria*: high titer (>40 GPL/MPL or
Clinical criteria: >99th percentile)
1. Vascular thrombosis ELISA: Anti–b2-glycoprotein
(≥1 arterial, venous, or 1 antibody (IgG and/or IgM)
small-vessel thrombosis in >99th percentile
any tissue or organ)
2. Pregnancy morbidity
(≥1 unexplained loss at or
beyond 10 wk, or prema-
ture birth before the 34th
week of gestation because
of eclampsia, severe pree-
clampsia, or placental insuf-
ficiency, or 3 consecutive
unexplained spontaneous
abortions before 10 wk)
Laboratory criteria: ≥1 laboratory
criterion, present on ≥2
occasions ≥12 wk apart
APCR = activated protein C resistance; dRVVT = dilute Russell’s viper venom time; ELISA = enzyme-linked immunosorbent assay;
GPL/MPL = IgG/IgM phospholipid units; PCR = polymerase chain reaction; PTT-LA = lupus anticoagulant–sensitive partial thrombo-
plastin time; VTE = venous thromboembolism.
* Revised Sapporo/Sydney classification.
† Lupus anticoagulant detected according to guidelines of the International Society on Thrombosis and Haemostasis.
Annals of Internal Medicine In the Clinic © 2022 American College of Physicians

Appendix Table 2. Summary of Guideline Recommendations for Postpartum Prophylaxis
Indication ACOG SOGC RCOG ACCP ASH
Thrombophilia
Heterozygous Clinical surveillance or Clinical surveillance or Consider prophylaxis for Clinical surveillance if no No prophylaxis regard-
FVL/PGM prophylaxis if risk factors 6-wk prophylaxis if any ≥10 d if 1 other risk factor; family history; 6-wk less of family history
additional risk factors consider extending to 6 prophylaxis if family
wk if family history of VTE history
Protein C or S Clinical surveillance or Clinical surveillance or 6-wk prophylaxis Clinical surveillance if no Prophylaxis if family
deficiency prophylaxis if risk factors 6-wk prophylaxis if any family history; 6-wk history of VTE
additional risk factors prophylaxis if family
history
Homozygous Prophylaxis 6-wk prophylaxis 6-wk prophylaxis Clinical surveillance if no Prophylaxis
or compound family history; 6-wk
heterozygous prophylaxis if family
FVL/PGM history or homozygous
Antithrombin Prophylaxis 6-wk prophylaxis 6-wk prophylaxis Clinical surveillance if no Prophylaxis if family
deficiency family history; 6-wk history of VTE
prophylaxis if family
history
APS 6-wk prophylaxis 6-wk prophylaxis 6-wk prophylaxis No recommendation No recommendation
Cesarean section Emergency and elective Emergency cesarean sec- Emergency cesarean Emergency cesarean No recommendation
cesarean section: pneu- tion: if ≥1 risk factor, section: 10-d prophylaxis section: prophylaxis if ≥1
matic compression devi- consider prophylaxis Elective cesarean section: risk factor
ces before delivery if not Elective cesarean section: consider 10-d thrombo- Elective cesarean section:
already receiving if ≥2 risk factors, consider prophylaxis if additional prophylaxis if ≥1 major
thromboprophylaxis prophylaxis risk factors or ≥2 minor risk factors
6-wk prophylaxis if risk
persistent; up to 2-wk
prophylaxis if risk
transient
Vaginal delivery Prophylaxis if multiple risk Prophylaxis if risk factors Prophylaxis for 10 d if ≥2 No recommendation No prophylaxis if
factors (6-wk prophylaxis if risk risk factors ≤1 risk factor
factor ongoing; 2-wk No recommendation
prophylaxis if transient) for >1 risk factor
ACCP = American College of Chest Physicians; ACOG = American College of Obstetricians and Gynecologists; APS = antiphospholi-
pid syndrome; ASH = American Society of Hematology; FVL = factor V Leiden; PGM = prothrombin gene mutation; RCOG = Royal
College of Obstetricians and Gynaecologists; SOGC = Society of Obstetricians and Gynaecologists of Canada; VTE = venous
thromboembolism.
© 2022 American College of Physicians In the Clinic Annals of Internal Medicine

Appendix Table 3. Comparison of Major Society Guidelines for Diagnosis and Treatment of DVT
Clinical Question ACCP Recommendation ASH Recommendation
How should PTP and D-dimer be used Recommends that in patients with a low Suggests that in patients with a low PTP
for investigation of suspected DVT? or intermediate PTP and a negative and a negative D-dimer result, DVT
D-dimer result, DVT can be excluded can be excluded without CUS
without CUS (intermediate PTP must In patients with an intermediate or high
use a highly sensitive D-dimer) PTP, suggests CUS as the initial test
Recommends that patients with high (for intermediate PTP, a potentially
PTP undergo CUS as the initial test acceptable alternative strategy is to
No recommendation about age- exclude DVT if highly sensitive D-
adjusted D-dimer dimer result is negative and the preva-
lence of DVT is low)
Suggests that patients with high PTP
undergo CUS as the initial test
Suggestions for age-adjusted D-dimer
are made only for patients with sus-
pected PE, not DVT
How should PTP and D-dimer be Recommends an initial evaluation with Gives no recommendation for use of
adapted for use in pregnant patients proximal CUS followed by serial CUS PTP or D-dimer in pregnant patients
investigated for suspected DVT? (days 3 and 7) if negative with suspected DVT
Serial CUS can be omitted if D-dimer Suggests that all patients with sus-
result is negative pected DVT undergo a CUS with iliac
Suggests that if symptoms are sugges- vein imaging and, if negative, also
tive of isolated iliac vein thrombosis undergo either a serial CUS or MRI
and initial CUS is negative, the patient
should have imaging with Doppler of
iliac vein, venography, or MRI rather
than serial CUS
What anticoagulant should be used Recommends a DOAC over a VKA Suggests a DOAC over a VKA
for treatment of DVT (excluding
cancer and pregnancy)?
How should isolated distal DVT be Suggests anticoagulation if severe Does not offer suggestions
managed? symptoms or risk factors for extension;
otherwise, no treatment and serial
imaging for 2 wk
How should pregnancy-associated Recommends therapeutic, weight- Suggests therapeutic LMWH, either
DVT be managed? adjusted LMWH, with no recommen- once- or twice-daily dosing, and no
dation for dosing schedules or anti-Xa routine anti-Xa monitoring
monitoring
How should cancer-associated VTE be Recommends an anti-Xa inhibitor Suggests a DOAC (apixaban, edoxa-
managed? DOAC (apixaban, edoxaban, rivaroxaban, rivaroxaban) over LMWH
ban) over LMWH, and recommends Suggests that a DOAC should be used
that apixaban or LMWH may be pre- with caution in patients with GI cancer
ferred if luminal GI cancer is present
When should thrombolysis be used Suggests that DVT should not be Suggests that most patients with proxi-
for patients with DVT? treated with interventions such as mal DVT should not be treated with
thrombolytic, mechanical, or thrombolytic therapy
pharmacomechanical Suggests thrombolytic therapy be re-
served for patients with limb-threatening
DVT and select young patients at low
risk for bleeding with symptomatic DVT
involving the iliac and common femoral
veins; for these select patients, suggests
catheter-directed thrombolysis over
systemic therapy
How long should patients be treated Recommends 3-mo treatment duration Suggests 3 to 6 mo of treatment after a
after a first DVT event? after a first DVT that is provoked by a first DVT that is provoked by a tran-
major transient/reversible risk factor sient risk factor
Suggests extended treatment of indefi- Suggests extended treatment of indefi-
nite duration after a first DVT with no nite duration after a first DVT with a
identifiable risk factors if the patient is chronic risk factor or no identifiable
not at high risk for bleeding risk factor if the patient is not at high
risk for bleeding
ACCP = American College of Chest Physicians; ASH = American Society of Hematology; CUS = compression ultrasonography;
DOAC = direct oral anticoagulant; DVT = deep venous thrombosis; GI = gastrointestinal; LMWH = low-molecular-weight heparin;
MRI = magnetic resonance imaging; PE = pulmonary embolism; PTP = pretest probability; VKA = vitamin K antagonist.
Annals of Internal Medicine In the Clinic © 2022 American College of Physicians

Appendix Figure. Diagnostic management of outpatients with suspected DVT.
Suspected DVT
Calculate clinical probability score Whole-leg ultrasonography Limited ultrasonography

(from groin veins to calf trifurcation)
Likely clinical probability Normal Abnormal Normal Abnormal
Limited ultrasonography No anticoagulant Treat D-dimer testing Treat

therapy
Normal Abnormal
Negative Positive
D-dimer testing Treat
No anticoagulant Repeat ultrasonography

therapy in 7 d
Negative Positive
No anticoagulant Repeat ultrasonography

therapy in 7 d
Unlikely clinical probability
D-dimer testing
Negative Positive
No therapy Limited
ultrasonography
Normal Abnormal
No therapy Treat
DVT = deep venous thrombosis.
© 2022 American College of Physicians In the Clinic Annals of Internal Medicine

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Physician Writer doi:10.7326/AITC202209200

With the assistance of additional physician writers, the editors of Annals of

© 2022 American College of Physicians

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Strong risk factor (odds ratio >10)

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CLINICAL BOTTOM LINE 65. Rodger MA, Le Gal G,

Treatment for women with unpro-

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Warfarin Vitamin K– 5–7 d 20–60 h* None 99 Safe INR Vitamin K and/or

prediction rule or concerning clinical Should clinicians treat isolated

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Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

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Table 6. The Villalta Scale for Diagnosis and Grading of PTS

PTS = postthrombotic syndrome.

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CLINICAL BOTTOM LINE

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What Are the Warning Signs? Questions for My Doctor

For More Information

Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

Factor V Leiden Point mutation (1691G!A Heterozygous: APCR, PCR Heterozygous:

Annals of Internal Medicine In the Clinic © 2022 American College of Physicians

Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

© 2022 American College of Physicians In the Clinic Annals of Internal Medicine

Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

Annals of Internal Medicine In the Clinic © 2022 American College of Physicians

Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

Calculate clinical probability score Whole-leg ultrasonography Limited ultrasonography

Likely clinical probability Normal Abnormal Normal Abnormal

Limited ultrasonography No anticoagulant Treat D-dimer testing Treat

No anticoagulant Repeat ultrasonography

No anticoagulant Repeat ultrasonography

Unlikely clinical probability

DVT = deep venous thrombosis.

© 2022 American College of Physicians In the Clinic Annals of Internal Medicine

Downloaded from https://annals.org by Jose Alvarez Payares on 09/12/2022.

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