Sage Journals: Discover world-class research

Abstract

Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Factors such as the presence of transient risk factors for VTE, risk of bleeding, and location of deep vein thrombosis (DVT) determine the duration of anticoagulation. Extended anticoagulation is offered to patients with unprovoked pulmonary embolism (PE) or proximal DVT and a low risk of bleeding. Anticoagulation for 3 months is advised in patients with provoked DVT or PE, high risk of bleeding, and isolated distal or upper extremity DVT. In patients with unprovoked PE or proximal DVT and a low risk of bleeding, who want to stop anticoagulation after 3 months, further risk stratification is necessary. Clinical scoring system, and thrombophilia testing otherwise not routinely performed, may be considered to measure risk of annual recurrence in such cases. Short-term anticoagulation may be considered in subsegmental PE and superficial vein thrombosis, particularly if patients are at low risk of bleeding and have persistent risk factors for recurrent VTE. In cases of catheter-associated thrombosis, the catheter need not be removed routinely, and the patient may be anticoagulated for 3 months or longer if the catheter is maintained in patients with cancer. Extensive screening for occult cancer in cases of unprovoked VTE is not beneficial. New oral anticoagulants such as apixaban, rivaroxaban, or dabigatran may be preferred to vitamin K antagonists in patients without cancer or renal failure, more so after the development of reversal agents such as idarucizumab and andexanet alfa.

Keywords

venous thromboembolism deep venous thrombosis pulmonary embolism new oral anticoagulants low-molecular-weight heparin reversal agents

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) of the extremities or pelvis and pulmonary embolism (PE), is a public health problem associated with significant morbidity and mortality.¹ Approximately 900 000 annual cases of VTE result in 300 000 deaths annually in the United States.² Venous thromboembolism results in substantial health-care cost, with approximately 2.5-fold increase in cost compared to inpatients without VTE.³ Thrombophilia testing alone costs more than USD 500 to 1300 per test and is frequently performed in many cases of VTE, despite recommendations by the American Society of Hematology against the routine testing. Understanding the duration of anticoagulation and the role of thrombophilia testing can be difficult for a busy practitioner. Here, we present a focused review on this topic and provide an algorithm for management of VTE. A detailed discussion of literature is available in the most recent American College of Chest Physicians (ACCP) guidelines.⁴

Management of Proximal DVT and Symptomatic PE

The major factors that determine the duration of anticoagulation include the presence of any risk factor for VTE (provoked or unprovoked VTE), degree of risk of bleeding, presence of cancer, and location of DVT (distal or proximal⁴; Figure 1).

Figure 1.

Simplified schema of the management of venous thromboembolism. DASH indicates elevated D-dimer post anticoagulation, age <50 years at initial VTE, male sex, and hormone use in women at initial VTE; DVT, deep vein thrombosis; HERDOO-2, hyperpigmentation, edema or redness of affected leg, elevated d-dimer while on anticoagulation, obesity with body mass index >30, and age ≥65 years; PE, Pulmonary embolism; USG, ultrasonography; VTE, venous thromboembolism. *Superficial femoral and popliteal veins are proximal veins.

Patients with unprovoked PE or proximal DVT with low risk of bleeding should be offered an extended anticoagulation. Anticoagulation for 3 months is advised in provoked DVT or PE, unprovoked PE or DVT in a patient with high risk of bleeding, and in isolated distal or upper extremity DVT.⁴ In these patients, routine thrombophilia testing is not necessary and does not change management.^5,6

Further risk stratification is necessary in patients with unprovoked PE or proximal DVT and a low risk of bleeding who want to stop anticoagulation after 3 months. High-risk thrombophilia testing as discussed subsequently may be helpful in such situation; the presence of high-risk thrombophilia may indicate a higher risk of recurrence. Scoring systems such as DASH or HERDOO-2 may be used to measure risk of annual recurrence and guide duration of anticoagulation. DASH stands for elevated d-dimer post anticoagulation, age <50 years at initial VTE, male sex, and hormone use in women at initial VTE.⁷ DASH score of ≤1 predicts a low annual risk of recurrence of 3.1% per year in more than half of the patients with unprovoked VTE. HERDOO-2 stands for hyperpigmentation, edema or redness of affected leg, elevated d-dimer while on anticoagulation, obesity with body mass index >30, and age ≥65 years.⁸ Women with ≤1 risk factors have an annual risk of recurrence of 1.3% and may be able to safely stop anticoagulation. However, in men, the annual risk of recurrence is 9.9% or higher. Normal d-dimer level during or after anticoagulation and resolution of clot on repeat ultrasonography of affected extremity may be associated with a lower risk of VTE recurrence.^9
–11 In a recent cohort study, however, the annual risk of VTE recurrence in men with a first episode of unprovoked VTE and negative d-dimer result was high (9.7%) to safely stop anticoagulation. The risk was considered low in women (5.4%), particularly those women with estrogen therapy-associated VTE (0%).¹²

One alternative to extended use of therapeutic anticoagulation may be the use of new oral anticoagulants (eg, apixaban) at a prophylactic dose after 3 months of anticoagulation. In Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment (AMPLIFY-EXT) study, extended anticoagulation with apixaban led to reduced risk of recurrent VTE without increasing the rate of major bleeding at both treatment and thromboprophylactic doses. A prophylactic dose of apixaban (2.5 mg twice daily) was associated with similar risk of VTE recurrence (1.7%) and major bleeding (0.2% vs 0.1%) but slightly lower risk of clinically relevant nonmajor bleeding (3% vs 4.2%), compared to the treatment dose (5 mg twice daily).¹³ Hence, we offer a prophylactic dose apixaban as an option to our patients.

In patients with unprovoked VTE, who decide to stop anticoagulation, low-dose aspirin should be used in the absence of any contraindication because of a reduction in the risk of recurrent VTE or the rate of major cardiovascular events.^14
–16 In women or younger men without a family history of prostate cancer, vitamin E 600 IU every other day may be an alternative, particularly in patients with factor V Leiden or the prothrombin mutation.¹⁷ However, it is not recommended to check for factor V Leiden or the prothrombin mutation.

Thrombolysis and newer surgical and interventional measures are available to be used in addition to the medical therapy. A study described pharmacomechanical thrombolysis with a rotator thrombolysis device in iliofemoral deep venous thrombosis in 67 patients.¹⁸ Immediate total recanalization was conducted in all patients, the leg diameters returned to normal ranges in the early postoperative period, and hospital mortality or severe complications were not detected. In general, the ACCP guidelines recommend anticoagulant alone over thrombolysis or catheter-assisted thrombus removal including in patients with acute DVT and PE. Thrombolysis is recommended only in select patients such as those with low risk of bleeding and PE associated with hypotension.⁴

Management of Other VTE

Any VTE including subsegmental PE, isolated distal DVT, and superficial vein thrombosis may require anticoagulation, particularly if there are persistent risk factors and low risk of bleeding.¹⁹ The 2016 ACCP guideline does not differentiate isolated subsegmental PE from a more proximal PE; however, 2014 European Society of Cardiology recommends that an individualized decision about anticoagulation be made after careful assessment of the risk–benefit ratio.²⁰ Clinical surveillance may be chosen over anticoagulation in select patients in the absence of symptoms and risk factors for extension. However, a recent study by den Exter et al concluded that patients with subsegmental PE have a high risk of VTE and clinical outcomes similar to that of more proximally located PE.²¹ Patients with cancer having subsegmental PE are frequently treated with anticoagulation due to the underlying heightened risk of recurrent VTE.^19,22

The optimal duration of anticoagulation is not clear in patients with subsegmental PE. Based on the ACCP guidelines, the duration of anticoagulation depends on the presence of transient risk factors, presence of cancer, number of VTE, and risk of bleeding. Although there is a possibility that small or asymptomatic PE may resolve without anticoagulation in certain patient population, based on the current guidelines and the lack of studies to justify withholding anticoagulation, the patients are usually treated with anticoagulation for at least 3 months.¹⁹ A careful evaluation of the risks and indications of indefinite anticoagulation must be conducted in all cases.¹⁹

Cancer-related thromboses have a high risk of recurrence and are expected to derive substantial benefit from extended anticoagulant therapy.²³ Anticoagulation may be stopped after 3 months of treatment in provoked VTE if the cancer is thought to have been cured (eg, following surgical resection) or after 6 months of therapy if there is uncertainty about cancer status.²⁴

In cases of isolated distal DVT, the risk of recurrence is about half that of proximal DVT or PE, thus, anticoagulation is advised for a total of 3 months.²⁴ Given the lack of extensive studies in such cases, clinical surveillance and serial ultrasound over 2 weeks may be chosen over anticoagulation in select patients with isolated distal DVT in the absence of symptoms and risk factors for extension.

Superficial vein thrombosis may increase the risk of VTE 4- to 6-fold, and when combined with acquired strong thrombotic risk factors, the risk of VTE is 10- to 100-fold.²⁵ In superficial vein thromboses, 5 cm or more in size, close to deep veins, or associated with underlying diseases such as cancer, fondaparinux 2.5 mg for 6 weeks is approved by the Food and Drug Administration (FDA) for treatment.²⁶ Fondaparinux consistently decreases the risk of symptomatic extensions of the superficial thrombus from the saphenofemoral junction and subsequent VTE complications.²⁷

In cases of catheter-associated thrombosis (such as peripherally inserted central catheters, central venous catheters, cardiac pacemakers, and defibrillators), the catheter need not be removed routinely if it is functional and needed, and the patient can be anticoagulated.²⁸ The ACCP guidelines recommend anticoagulation for 3 months, which may be extended if the catheter is maintained, particularly in patients with cancer.²³

Role of Thrombophilia Testing

High-risk thrombophilia testing may be considered in select patients who are young, have unprovoked VTE, have thrombosis in unusual sites, have a family history of thrombophilia,^29,30 and who are interested in stopping anticoagulation. Thrombophilia evaluation may include testing for antithrombin deficiency (antithrombin activity), protein C deficiency (protein C activity), protein S deficiency (free protein S antigen and activity), and antiphospholipid syndrome. Thrombophilia evaluation should generally be performed by a hematologist with a plan to guide duration of anticoagulation based on the results. Testing may be avoided at the time of diagnosis of VTE or when the patient is on any anticoagulant. Methylenetetrahydrofolate reductase mutation and heterozygous mutation of prothrombin gene mutation or factor V Leiden do not alter management, hence should not be tested routinely.^31,32

The role of thrombophilia testing in pregnant patients with a personal or family history of VTE is controversial. Pregnant patients with prior VTE should receive postpartum VTE prophylaxis in the absence of high risk of bleeding; those with moderate-to-high risk of recurrence should also receive antepartum VTE prophylaxis. Select pregnant patients without a personal history of VTE but with a family history of VTE may benefit from limited thrombophilia testing, where the presence of homozygous factor V Leiden or prothrombin 20210A mutation requires both antepartum and postpartum VTE prophylaxis. However, homozygous factor V Leiden or prothrombin 20210A mutation is rare. Additionally, all other thrombophilias require antepartum vigilance and postpartum prophylaxis, thus may not necessarily alter management.²³

The diagnosis of antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, and myelodysplastic syndrome can significantly impact management. Hence, antiphospholipid antibody syndrome testing should be considered in unprovoked VTE in young patients or those with a history of unexplained recurrent abortion. Testing includes lupus anticoagulant, anti-β2-glycoprotein antibody, and anticardiolipin antibody. The diagnosis is made based on the Sapporo criteria.³³ In addition to paroxysmal nocturnal hemoglobinuria and myelodysplastic syndrome, trauma, surgery, intra-abdominal infections, inflammatory bowel disease, pancreatic disease, and cirrhosis are associated with and can cause splanchnic vein thrombosis. Paroxysmal nocturnal hemoglobinuria may be considered in patients with unexplained VTE of sites other than extremity, for example, hepatic vein thrombosis or those with unexplained cytopenia, hemolysis, or iron deficiency.³⁴ JAK-2V617F mutation, which occurs in patients with myeloproliferative neoplasms disorder, may be tested for patients with unexplained portal vein or mesenteric vein thrombosis and those with elevated blood count.³⁵

In appropriate setting (eg, critically ill patients), diagnosis such as heparin-induced thrombocytopenia,³⁶ disseminated intravascular coagulation,³⁷ thrombotic microangiopathy,³⁸ catastrophic antiphospholipid antibody syndrome,³⁹ or thrombotic storm⁴⁰ may be considered.

Role of Cancer Screening

Reported incidence of cancer varies widely; older studies had estimated a risk of as high as 20% to 30% in patients with first episode of unprovoked VTE.^41

–47 In a study, the prevalence of an occult cancer in patients with unprovoked VTE was 6% at the time of diagnosis of VTE and increased to 10% after 12 months of diagnosis.⁴⁸ More recent studies, however, show a much lower risk, with a cumulative incidence as low as 3.2% over a follow-up of 2.5 years.⁴⁹ Although unprovoked VTE may be the first sign of an occult cancer, extensive screening with imaging and tumor markers is not of benefit.

Carrier et al demonstrated that use of imaging studies such as computed tomography (CT) of chest, abdomen, and pelvis did not confer any advantage over the use of limited cancer screening in patients with unprovoked VTE.⁵⁰ In another study, screening with ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) combined with low-dose CT, used routinely for the diagnosis and staging of various malignant diseases, was not associated with significantly higher rate of cancer diagnosis compared to limited screening. However, the risk of subsequent cancer diagnosis after initial negative screening with ¹⁸F-FDG PET/CT was lower than that in patients who had negative initial limited screening.⁵¹ Thus, only age- and sex-appropriate cancer screening should be performed. For example, colonoscopy should be offered to patients older than 50 years. A mammography should be performed in women older than 40 to 50 years of age, and a Papanicolaou smear should be performed in women aged 21 to 65 years.⁵⁰ The role of prostate-specific antigen test in men is unclear, given the recommendations of US Preventive Services Task Force against prostate cancer screening.⁵²

Anticoagulants and Reversal Agents

Commonly utilized anticoagulants for long-term management of VTE include oral anticoagulants such as factor Xa inhibitors (rivaroxaban, apixaban, or edoxaban), direct thrombin inhibitors (dabigatran), vitamin K antagonist (warfarin), low-molecular-weight heparin (LMWH), and fondaparinux. In patients with cancer, pregnant patients, and those with liver disease, LMWH is the preferred agent. Vitamin K antagonist (warfarin) is the preferred agent in patients who require reversal agent and those with chronic kidney disease with creatinine clearance <30 mL/min. Dabigatran and rivaroxaban, but not apixaban, may be associated with an increased risk of gastrointestinal bleeding, thus are less preferred in at-risk patients. In most other patients, new oral anticoagulants such as apixaban, rivaroxaban, or dabigatran may be preferred over vitamin K antagonist.⁴ The 4 oral anticoagulants (apixaban, dabigatran, edoxaban, and rivaroxaban) have been shown to be noninferior to standard therapy (warfarin or LMWH).⁵³ Additionally, oral anticoagulants have exhibited at least similar safety profile compared to standard therapy, with a lower risk of major bleeding with apixaban and rivaroxaban in some studies.^54,55

Reversal agents are discussed in Table 1.⁵⁶ In a bleeding patient, platelet and cryoprecipitate transfusion may be required to achieve a platelet count >50 000 to 100 000/µL and fibrinogen level >100 to 150 mg/dL depending on the severity and site of bleeding. The dose of fresh frozen plasma is 10 to 15 mL/kg intravenously (IV; approximately 3-5 units) in most adults; this should increase plasma coagulation factors by ∼15% to 25%. If hemostasis is not achieved, use higher doses and adjust dose based on desired clinical response.⁵⁹ Urgent infusion of prothrombin complex concentrate (PCC) may be preferred in major bleeding such as intracranial bleed.⁶⁰ Dose of PCC is based on the international normalized ratio (INR) values and ranges from 25 U/kg (maximum dose of 2500 units) for INR of 2 to 4, 35 U/kg (maximum dose 3500 units) for INR of 4 to 6, and 50 U/kg (maximum dose 5000 units) for INR of >6.^61,62 Approximately 1 mg of protamine neutralizes about 100 units of heparin. Maximum dose of protamine is 50 mg. In cases of continuous heparin infusion, consider only the heparin given in the preceding several hours and adjust the protamine dosage depending upon the duration of time since heparin administration.⁶³ For every 100 units of heparin, 1 to 1.5 mg, 0.5 to 0.75 g, or 0.25 to 0.375 g of protamine is given if the last dose of heparin was given <30 minutes, 30 to 60 minutes or >2 hours, respectively, prior to protamine administration. For subcutaneous heparin, about 1 to 1.5 mg protamine per 100 units of heparin is required. A portion of the dose (eg, 25-50 mg) is given slowly IV followed by the remaining portion as a continuous infusion over 8 to 16 hours (the expected absorption time of the subcutaneous heparin dose). Protamine sulfate only partially reverses enoxaparin.^64,65 For enoxaparin administered <8 hours ago, administer 1 mg protamine for 1 mg enoxaparin. For enoxaparin administered >8 hours ago, administer 0.5 mg protamine for 1 mg enoxaparin.⁶³ Andexanet alfa is shown to be effective at rapidly reversing anticoagulant activity of therapeutic doses of apixaban and rivaroxaban.⁶⁶ Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and its acylglucuronide metabolites and neutralizes the anticoagulant effect within minutes.^67,68 A dose of 5-gm IV (administered as 2 separate 2.5 g doses no more than 15 minutes apart) is FDA approved in cases of life-threatening bleeding or need for emergency surgery in patients on dabigatran.⁶⁹

Table 1.

Common Anticoagulants in Clinical Practice and Reversal Agents.

Agent	Route of Administration	Time Interval to Stop Agent Before Procedure^a	Monitoring	Reversal Agent in Patients With Bleeding
Warfarin	Oral	5-7 days, recheck INR before procedure	INR	Vitamin K, FFP, PCC
LMWH	SubQ	24-48 hours	Anti-Xa level	Protamine sulfate
UFH	IV, SubQ	IV: 4-6 hours; SubQ: 12-24 hours	PTT	Protamine sulfate
Fondaparinux	SubQ	36-48 hours	Anti-Xa level	None
Rivaroxaban or apixaban	Oral	24-48 hours	Anti-Xa level	PCC; andexanet alfa
Dabigatran	Oral	24-48 hours	ECT, HTI, PTT, TT^b	Idarucizumab

Abbreviations: ECT, Ecarin clotting time; FFP, fresh frozen plasma; HTI, Hemoclot Thrombin Inhibitor assay; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; PCC, prothrombin complex concentrates; PTT, partial thromboplastin time; SubQ, subcutaneous; TT, thrombin time; UFH, unfractionated heparin.

^aThis time period is valid in patients without renal or liver dysfunction.⁵⁶

^bHemoclot thrombin inhibitor assay and ECT may quantify the effects of dabigatran, however, limitations include the lack of exact reference values, widespread commercial availability, and validation in bleeding patients.^57,58 In emergency situations, the TT and PTT are the most accessible qualitative methods.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Vijaya Bhatt is supported by the 2015-2016 Physician-Scientist Training Program Grant from the College of Medicine, University of Nebraska Medical Center.

References

Heit

. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12(8):464–474.

Heit

Cohen

Anderson

. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106(11):910–910.

Cohoon

Leibson

Ransom

. Costs of venous thromboembolism associated with hospitalization for medical illness. Am J Manag Care. 2015;21(4):e255–e263.

Kearon

Akl

Ornelas

. Antithrombotic therapy for VTE disease: CHEST guideline and Expert Panel Report. Chest. 2016;149(2):315–352.

Baglin

Gray

Greaves

; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209–220.

Chong

Fenu

Stansby

Hodgkinson

; Guideline Development Group. Management of venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE guidance. BMJ. 2012;344:e3979.

Tosetto

Iorio

Marcucci

. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost. 2012;10(6):1019–1025.

Rodger

Kahn

Wells

. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417–426.

Eichinger

Minar

Bialonczyk

. D-dimer levels and risk of recurrent venous thromboembolism. JAMA. 2003;290(8):1071–1074.

10.

Palareti

Cosmi

Legnani

; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196–203.

11.

Napolitano

Saccullo

Malato

. Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis: the Cancer-DACUS Study. J Clin Oncol. 2014;32(32):3607–3612.

12.

Kearon

Spencer

O’Keeffe

; D-dimer Optimal Duration Study Investigators. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med. 2015;162(1):27–34.

13.

Agnelli

Buller

Cohen

; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708.

14.

Brighton

Eikelboom

Mann

; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979–1987.

15.

Becattini

Agnelli

Schenone

; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959–1967.

16.

Douketis

Schulman

Ghirarduzzi

Pengo

Prandoni

. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766–774.

17.

Glynn

Ridker

Goldhaber

Zee

Buring

. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women’s Health Study. Circulation. 2007;116(13):1497–1503.

18.

Karahan

Kutas

Gurbuz

. Pharmacomechanical thrombolysis with a rotator thrombolysis device in iliofemoral deep venous thrombosis. [published online October 20, 2015.] Vascular. 2015.

19.

O’Connell

. How I treat incidental pulmonary embolism. Blood. 2015;125(12):1877–1882.

20.

Konstantinides

Torbicki

Agnelli

; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033–3069, 3069a–3069k.

21.

den Exter

van Es

Klok

. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood. 2013;122(7):1144–1149; quiz 1329.

22.

Ikesaka

Carrier

. Clinical significance and management of subsegmental pulmonary embolism. J Thromb Thrombolysis. 2015;39(3):311–314.

23.

Kearon

Akl

Comerota

; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S–e494S.

24.

Kearon

Akl

. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood. 2014;123(12):1794–1801.

25.

Roach

Lijfering

van Hylckama Vlieg

Helmerhorst

Rosendaal

Cannegieter

. The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood. 2013;122(26):4264–4269.

26.

Decousus

Prandoni

Mismetti

; CALISTO Study Group. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222–1232.

27.

Leizorovicz

Becker

Buchmüller

Quéré

Prandoni

Decousus

. Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study. Blood. 2013;122(10):1724–1729.

28.

Kucher

. Deep-vein thrombosis of the upper extremities. N Engl J Med. 2011;364(9):861–869.

29.

Middeldorp

. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis. 2011;31(3):275–281.

30.

Lijfering

Brouwer

Veeger

. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009;113(21):5314–5322.

31.

Coppens

van de Poel

Bank

. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood. 2006;108(8):2604–2607.

32.

Hickey

Curry

Toriello

. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153–156.

33.

Cervera

Piette

Font

. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019–1027.

34.

Hill

Kelly

Hillmen

. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985–4996.

35.

Colaizzo

Amitrano

Tiscia

. The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost. 2007;5(1):55–61.

36.

Warkentin

Kelton

. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101(5):502–507.

37.

Levi

Toh

Thachil

Watson

. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145(1):24–33.

38.

George

Nester

. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654–666.

39.

Erkan

Espinosa

Cervera

. Catastrophic antiphospholipid syndrome: updated diagnostic algorithms. Autoimmun Rev. 2010;10(2):74–79.

40.

Kitchens

Erkan

Brandao

. Thrombotic storm revisited: preliminary diagnostic criteria suggested by the thrombotic storm study group. Am J Med. 2011;124(4):290–296.

41.

Brækkan

Borch

Mathiesen

Njølstad

Wilsgaard

Hansen

. Body height and risk of venous thromboembolism: the Tromsø Study. Am J Epidemiol. 2010;171(10):1109–1115.

42.

Gussoni

Frasson

La Regina

Di Micco

Monreal

; RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res. 2013;131(1):24–30.

43.

Heit

O’Fallon

Petterson

. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162(11):1245–1248.

44.

Imberti

Agnelli

Ageno

; MASTER Investigators. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry. Haematologica. 2008;93(2):273–278.

45.

Naess

Christiansen

Romundstad

Cannegieter

Rosendaal

Hammerstrom

. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5(4):692–699.

46.

Spencer

Lessard

Emery

Reed

Goldberg

. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167(14):1471–1475.

47.

White

Zhou

Murin

Harvey

. Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Haemost. 2005;93(2):298–305.

48.

Carrier

Le Gal

Wells

Fergusson

Ramsay

Rodger

. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med. 2008;149(5):323–333.

49.

Prandoni

Casiglia

Piccioli

. The risk of cancer in patients with venous thromboembolism does not exceed that expected in the general population after the first 6 months. J Thromb Haemost. 2010;8(5):1126–1127.

50.

Carrier

Lazo-Langner

Shivakumar

; SOME Investigators. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697–704.

51.

Robin

Le Roux

Planquette

; MVTEP study group. Limited screening with versus without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial. Lancet Oncol. 2016;17(2):193–199.

52.

Chou

Croswell

Dana

. Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(11):762–771.

53.

Granziera

Hasan

Cohen

. Direct oral anticoagulants and their use in treatment and secondary prevention of acute symptomatic venous thromboembolism. Clin Appl Thromb Hemost. 2016;22(3):209–221.

54.

Prins

Lensing

Bauersachs

; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.

55.

Agnelli

Buller

Cohen

; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.

56.

Baron

Kamath

McBane

. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med. 2013;368(22):2113–2124.

57.

van Ryn

Stangier

Haertter

. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–1127.

58.

Samos

Stanciakova

Ivankova

. Monitoring of dabigatran therapy using Hemoclot(Ò) Thrombin Inhibitor assay in patients with atrial fibrillation. J Thromb Thrombolysis. 2015;39(1):95–100.

59.

Ansell

Hirsh

Hylek

Jacobson

Crowther

Palareti

; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6):160s–198s.

60.

Huttner

Schellinger

Hartmann

. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006;37(6):1465–1470.

61.

Tran

Collecutt

Whitehead

Salem

. Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation. Intern Med J. 2011;41(4):337–343.

62.

Pabinger

Brenner

Kalina

. Prothrombin complex concentrate (Beriplex^® P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemostasis. 2008;6(4):622–631.

63.

Garcia

Baglin

Weitz

Samama

; American College of Chest Physicians. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e24S–e43S.

64.

Massonnet-Castel

Pelissier

Bara

. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis. 1986;16(2):139–146.

65.

van Veen

Maclean

Hampton

. Protamine reversal of low molecular weight heparin: clinically effective? Blood Coagul Fibrinolysis. 2011;22(7):565–570.

66.

Siegal

Curnutte

Connolly

. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–2424.

67.

Das

Liu

. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol. 2015;4:25.

68.

Schiele

van Ryn

Canada

. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554–3562.

69.

Pollack

Jr Reilly

Eikelboom

. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520.

An Algorithmic Approach to Management of Venous Thromboembolism

Abstract

Keywords

Introduction

Management of Proximal DVT and Symptomatic PE

Management of Other VTE

Role of Thrombophilia Testing

Role of Cancer Screening

Anticoagulants and Reversal Agents

Footnotes

Declaration of Conflicting Interests

Funding

References