Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Embolism and Deep Vein Thrombosis (JSC 2009) (1)

8/10/2019 Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Embolism and Deep Vein Thrombosis (JSC 2

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Circulation Journal Vol.75, May 2011

CirculationJournal

OfficialJournaloftheJapaneseCirculationSociety

http://www.j-circ.or.jp

AaDO2: alveolar-arterial oxygen differenceACE: angiotensin converting enzymeAPTT: activated partial thromboplastin timeBNP: brain natriuretic peptideCABG: coronary artery bypass graftingCDT: catheter-directed thrombolysisCT: computed tomographyCTEPH: chronic thromboembolic pulmonary hypertensionCTR: cardiothoracic ratioDBP: diastolic blood pressureDVT: deep vein thrombosisHIT: heparin-induced thrombocytopeniaHLA: human leukocyte antigenHOT: home oxygen therapyICU: intensive care unitINR: international normalized ratioIPC: intermittent pneumatic compressionIVC: inferior vena cavaMDCT: multi-detector CTMHLW: Ministry of Health, Labour and WelfareMRA: magnetic resonance angiography

MRV: magnetic resonance venographyMSCT: multi-slice CTNHI: National Health InsuranceNO: nitric oxideNYHA: New York Heart AssociationPaCO2: partial pressure of arterial carbon dioxidePaO2: partial pressure of arterial oxygenPCPS: percutaneous cardiopulmonary supportPE: pulmonary embolismPEA: pulmonary thromboendarterectomyPEEP: positive end-expiratory pressurePG: prostaglandinPH: pulmonary hypertensionPT: prothrombin timePTCA: percutaneous transluminal coronary angioplastyPTE: pulmonary thromboembolismSBP: systolic blood pressureSpO2: peripheral oxygen saturationUK: urokinaseVTE: venous thromboembolism

Abbreviations Used in the Guidelines

Released online March 25, 2011

Mailing address: Scientific Committee of the Japanese Circulation Society, 8th Floor CUBE OIKE Bldg., 599 Bano-cho, KarasumaAneyakoji, Nakagyo-ku, Kyoto 604-8172, Japan. E-mail: [email protected]

This English language document is a revised digest version of Guidelines for the Diagnosis, Treatment and Prevention of PulmonaryThromboembolism and Deep Vein Thrombosis reported at the Japanese Circulation Society Joint Working Groups performed in 2008.(website: http://www.j-circ.or.jp/guideline/pdf/JCS2009_andod_h.pdf)

Joint Working Groups: The Japanese Circulation Society, The Japan Radiological Society, The Japanese Association for Thoracic Surgery,The Japanese Society for Vascular Surgery, The Japanese Society on Thrombosis and Hemostasis, The Japanese Respiratory Society,The Japanese Society of Phlebology, The Japanese Society for Cardiovascular Surgery, The Japanese College of Cardiology

ISSN-1346-9843 doi: 10.1253/circj.CJ-88-0010

All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Guidelines for the Diagnosis, Treatment andPrevention of Pulmonary Thromboembolism and

Deep Vein Thrombosis (JCS 2009)

Digest Version JCS Joint Working Group

Table of Contents

Abbreviations Used in the Guidelines 1258

Introduction to the Revised Guidelines 1259

I General Descriptions 1259 1. Acute Pulmonary Thromboembolism 1259 2. Chronic Pulmonary Thromboembolism 1261 3. Deep Vein Thrombosis 1262

II Descriptions of Individual Diseases1263 1. Acute Pulmonary Thromboembolism 1263

2. Chronic Pulmonary Thromboembolism 1268 3. Deep Vein Thrombosis 1272 4. Prevention of Pulmonary Thromboembolism/

Deep Vein Thrombosis (VenousThromboembolism) 1275

References 1277

(Circ J 2011; 75:1258 1281)

JCS GUIDELINES


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JCS Guidelines for Pulmonary Thromboembolism and DVT

The Japanese Circulation Society (JCS) has already providedguidelines for the diagnosis and treatment of major cardio-vascular diseases. The JCS decided to revise the Guidelinesfor the Diagnosis, Treatment and Prevention of PulmonaryThromboembolism and Deep Vein Thrombosis, which werefirst completed in April 2004, to include new advanced tech-

niques of diagnosis and treatment of these conditions that havebeen developed since publication of the first guidelines. Aswas the case for the previous guidelines, the Working Groupsfor the present guidelines consisted of cardiologists and car-diovascular surgeons who have been involved in research onthe diagnosis, treatment and prevention of pulmonary throm-boembolism (PTE).

Although the etiology and pathology of PTE have yet to becompletely determined, it is known that deep vein thrombosis(DVT) plays an important role in the development of PTE.PTE may thus be considered a complication of DVT, and theseconditions are regarded as a single disease entity that shouldbe called venous thromboembolism (VTE). Treatment forPTE differs significantly depending on whether the conditionis acute or chronic. Although acute PTE is an emergent con-dition especially prevalent in Europe and the United States, itis becoming increasingly prevalent in Japan as well becauseof Westernization of Japanese lifestyle, the rapid increase inpopulation of the elderly, increased recognition of this dis-ease, and advancement of diagnostic techniques. Acute PTEhas received much media attention as an economy-class syn-drome and an unexpected secondary disaster following earth-quakes. It is also a postoperative complication that shouldbe careful monitored for in patients with prolonged bed restfollowing gastrointestinal surgery, gynecologic treatment, ororthopedic surgery. Patients with acute PTE require promptdiagnosis and appropriate treatment. Patients with acute PTEoften respond well to thrombolytic therapy and anticoagula-tion therapy, and new drugs have been approved and are avail-able for this patient population. Patients with large amountsof thrombus or circulatory collapse can be treated effectivelywith catheterization and surgery. Inferior vena cava (IVC)filters are used to prevent PTE, and the use of non-permanentfilters (also referred to as temporal filters and removable fil-ters) has become increasingly common. Chronic PTE associ-ated with pulmonary hypertension (PH) is a serious conditionthat causes right heart failure and respiratory failure and doesnot respond well to conventional medical treatment. However,

its prognosis has been improved by new drugs efficaciousin the treatment of PH. Pulmonary thromboendarterectomy(PEA) with cardiopulmonary bypass and deep hypothermicintermittent circulatory arrest is performed as radical treat-ment of PTE, and has significantly improved the outcome ofsurgery, clinical symptoms, and cardiopulmonary hemody-

namics as well as the QOL of patients with central type ofchronic PTE. Prevention of perioperative VTE by physicaltherapy is quite important, and new drugs have becomeavailable for this purpose.

The Working Groups revised the present guidelines, plac-ing emphasis on currently available evidence whenever possi-ble, but it should be noted that the present guidelines includeup-to-date information that may be utilized by cardiologists,cardiovascular surgeons, and other surgeons involved in sur-gical treatment of VTE in the clinical setting as guidance fordiagnosis and treatment of this disease. It should also be notedthat determination of treatment by attending physicians basedon the specific conditions and circumstances of their patientsshould take precedence over the guidelines, and that the pres-ent guidelines provide no grounds for argument in cases oflegal prosecution. The guidelines may be revised in the futureto include description of newer methods of diagnosis andtreatment of VTE.

We hope that the guidelines will aid physicians in thediagnosis, treatment, and prevention of VTE.

In the present guidelines, levels of recommendation arerated according to the following classification as used in otherguidelines for the Diagnosis and Treatment of CardiovascularDiseases.

Class I: Conditions for which there is evidence for and/orgeneral agreement that the procedure or treatmentis useful and effective.

Class II: Conditions for which there is conflicting evidenceand/or a divergence of opinion regarding the use-fulness/efficacy of a procedure or treatment.

Class IIa: The weight of evidence/opinion is in favor ofusefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established byevidence/opinion.

Class III: Conditions for which there is general agreementthat a procedure/treatment is neither useful norindicated and may be harmful.

I General Descriptions

1. Acute Pulmonary Thromboembolism

1 EpidemiologyPTE becoming prevalent in Japan, and should no longer beconsidered a rare condition. In 2006, PTE occurred in 7,864patients in Japan. The number of patients has increased 2.25-fold in the past decade,1and the incidence of this condition isestimated to be 62 cases/million population. Since the inci-dence of PTE in the United States is about 500 cases/millionpopulation, that in Japan in 2006 is about one-eighth that inthe United States.

The incidences of perioperative PTE in Japan were 4.41,

4.76, 3.62, and 2.79 cases/10,000 surgeries in 2002, 2003,2004, and 2005, respectively. The incidence began to decreasein 2004 when the guidelines for the prevention of PTE werepublished and healthcare costs for preventive treatment beganto be covered by the National Health Insurance (NHI) ofJapan.2

In Japan, acute PTE develops more frequently in femalesthan in males. The most common age of onset is in the sixthand seventh decades.3

2 Risk FactorsMajor risk factors for PTE are listed in Table 1. Virchowstriad, ie, the presence of (1) interrupted blood flow, (2) endo-

Introduction to the Revised Guidelines


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JCS Joint Working Group

thelial dysfunction, and (3) hypercoagulability, is a veryimportant set of factors that affect susceptibility to thrombusformation.

3 Conditions of OnsetAcute PTE often occurs when patients stand up or begin walk-ing or during micturition or defecation after resting.3,4Sincethe major source of emboli is thrombi in veins of the lowerlimbs or intrapelvic veins, it is believed that muscle contrac-tion in the lower limbs increases venous return, with themuscles acting in pump-like fashion to push blood, resultingin release of thrombi that cause PTE.

4 PathophysiologyAcute PTE is caused by abrupt blockage of pulmonary vesselsby thrombi that has formed in the veins or the heart and hastraveled through the blood stream. The source of emboli is theveins of the lower limbs or pelvis in more than 90% of cases.The main manifestations of acute PTE are sudden onset of PHand hypoxemia.5,6 Since the mean pulmonary arterial pres-

sure that can be generated by the right ventricle is 40 mmHgin individuals without cardiopulmonary disease,7when pul-monary arterial pressure exceeds 40 mmHg during the acutephase of PTE, physicians should suspect acute-on-chronicPTE, ie, acute exacerbation of chronic PTE due to the occur-rence of acute PTE, or chronic PTE. Pulmonary infarction,which occurs as a hemorrhagic infarction, develops in about10 to 15% of patients with acute PTE,8,9often as a result ofocclusion of a peripheral pulmonary artery.

5 Severity ClassificationSince the prognosis and rate of recurrence of acute PTE differsignificantly by the presence or absence of echocardiographicfindings of pressure overload in the right ventricle, the sever-ity of acute PTE is commonly classified according to clinicalsigns/symptoms and echocardiographic findings,10as outlinedin Table 2.

6 Prognosis and Clinical CourseAccording to available data in Japan, the mortality rate of

Table 1. Risk Factors for Pulmonary Thromboembolism

Acquired factors Congenital factors

Interrupted blood flow Prolonged bed restObesityPregnancyCardiopulmonary disease (eg, congestive heart

failure, chronic cor pulmonale)General anesthesiaAnesthesia of the lower limbs

Plaster bandage of the lower limbsVaricose veins in the lower limbs

Endothelial dysfunction SurgeriesTrauma, fracturesCentral venous catheterizationCatheter test/interventionVasculitisAntiphospholipid syndromeHyperhomocysteinemia

Hyperhomocysteinemia

Hypercoagulability Malignant tumorsPregnancySurgeries, trauma, fracturesBurnsDrugs (eg, oral contraceptives, estrogens)InfectionsNephrotic syndromeInflammatory bowel disease

Myeloproliferative disorders, polycythemiaParoxysmal nocturnal hemoglobinuriaAntiphospholipid syndromeDehydration

Antithrombin deficiencyProtein C deficiencyProtein S deficiencyAbnormal plasminogenAbnormal fibrinogenIncrease in tissue plasminogen activator inhibitorAbnormal thrombomodulinActivated protein C resistance (Factor V Leiden)*

Prothrombin gene mutation (G20210A)*

*Not observed in Japanese population.

Table 2. Classification of Clinical Severity of Acute Pulmonary Thromboembolism

HemodynamicsRight heart overload observed

on echocardiography

Cardiac arrestCollapse

Cardiac arrest or circulatory collapse Present

Massive UnstableShock or hypotension (defined as a systolic blood

pressure of 15 minutes or adecrease in blood pressure by >40 mmHg, regard-less of the presence/absence of new onset ofarrhythmia, dehydration or sepsis)

Present

Submassive Stable (absence of the above findings) Present

Non-massive Stable (absence of the above findings) Absent


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acute PTE is 14% overall, 30% among patients with cardio-genic shock (20% among those receiving thrombolytic ther-apy and 50% among those not receiving it), and 6% amongpatients without cardiogenic shock.3 According to data inEurope and the United States, the mortality rate of acute PTEis as high as 30% when it is not diagnosed and treated prompt-ly, but decreases to 2 to 8% when appropriate treatment isperformed.11,12It is known that early diagnosis and appro-priate treatment decrease the mortality rate substantially.

Independent determinants of mortality of acute PTE includeright ventricular dysfunction on echocardiography, advancedage (70 years), cancer, congestive heart failure, chronic ob-structive pulmonary disease, hypotension, and tachypnea.13

In a follow-up study in Japan, PH developed in 3.7% inpatients with acute PTE.14In the United States, it has beenestimated that PH secondary to chronic PTE develops in 0.1to 3.8% of patients with a history of acute PTE.1517

2. Chronic Pulmonary Thromboembolism

1 DefinitionChronic PTE develops as a result of chronic occlusion of pul-monary arteries by organized thrombi. In Japan, chronic PTEis defined as abnormal pulmonary blood flow distributionand pulmonary circulation hemodynamics that persist for6 months without substantial changes.18Some patients withchronic PTE exhibit clinical manifestations such as shortnessof breath during exercise (exertional dyspnea) due to throm-botic occlusion of several pulmonary arteries, which causesPH. This condition is referred to as chronic thromboembolicpulmonary hypertension (CTEPH). CTEPH is classified byclinical course into two types, ie, recurrent CTEPH with ahistory of signs/symptoms suggestive of acute PTE, and latentCTEPH with progression of PH but without clear clinicalfindings of acute PTE. Patients with mild CTEPH are treatedwith medical treatment mainly consisting of anticoagula-tion therapy to prevent progression of disease, while patientswith severe PH may also have right heart failure and a poorprognosis.19,20In 1998, the Ministry of Health, Labour andWelfare (MHLW; formery Ministry of Health and Welfare)of Japan termed CTEPH idiopathic chronic PTE with PHand designated it a specific disease for which healthcare costsare covered by public expenditure. In the present guidelines,however, the term CTEPH is used.

2 EpidemiologyThe incidence of PTE, including acute and chronic PTE, inJapan is believed to be lower than in Europe and the UnitedStates. According to data in annual reports on pathologicautopsy cases, the incidence of acute PTE in Japan is aboutone-tenth that in the United States,21although these data arerather old. In the United States, it is estimated that acute PTEoccurs in 0.5 to 0.6 million individuals each year, and thatCTEPH occurs in about 0.1 to 0.5% of patients surviving theacute phase of PTE.15,16However, a recent report noted thatCTEPH occurred in 3.8% of patients with a history of acutePTE.17Physicians should be aware of the risk of progressionto CTEPH when treating patients with acute PTE.

In Japan, the Specific Disease Respiratory Failure StudyGroup of the MHLWestablished criteria for the diagnosis ofCTEPH and conducted a nationwide survey in 1997.22Thenumber of patients with CTEPH was estimated to be 450(95% confidence interval: 360 to 530).23,24The MHLW thendesignated CTEPH a specific disease and has conducted an

annual epidemiological survey of it. In 2006, a total of 800 pa-tients with CTEPH were provided with medical care certifi-cates for the treatment of a specific disease. Assessment ofcase reports on 520 of the 800 patients with CTEPH revealedthat female patients were predominant, with a female to maleratio of 2.8:1, and that the mean age of patients was 6213 years. Female patients were predominant, especially amongthose over 40 years of age, with no gender difference observedin younger patients.25

3 EtiologyThe mechanisms of onset of CTEPH are still uncertain. InEurope and the United States, CTEPH is considered a chroniccondition occurring in patients with a history of acute PTEcaused by DVT. In a nationwide survey in Japan, only 28%of patients with CTEPH had DVT.24Although some patientswith CTEPH had known risk factors for DVT, such as coagu-lopathy (such as presence of antiphospholipid antibodies anddeficiency of antithrombin, protein C, or protein S), heart dis-ease, and malignant tumors, 43.9% of patients assessed hadno apparent underlying conditions. Frequencies of human leu-kocyte antigen (HLA)-B*5201 and HLA-DPB1*0202 werehigh among patients with a particular type of CTEPH, and inpatients carrying HLA-B*5201 and/or -DPB1*0202, the fre-quency of DVT was significantly lower than in other patients.26These findings suggest that there may be a different mecha-nism of onset of CTEPH in the Japanese population not sharedby Western populations. Some patients with CTEPH mayremain asymptomatic for several months to years followinga period with findings suggestive of acute PTE. This asymp-tomatic period is referred to as a honeymoon period.15Although the mechanism of latent progression of PH isunknown, several hypotheses, including repetition of latentthrombosis and progression of thrombosis in the pulmonaryarteries, have been suggested. Recently, the involvement ofsmall vessel disease in the pathogenesis of CTEPH has beenhypothesized.27

4 Clinical ManifestationsAlthough there are no symptoms specific to CTEPH, almostall patients experience exertional dyspnea. Abrupt dyspneaand chest pain develop repeatedly in patients with repetitiveCTEPH, while exertional dyspnea becomes severe over timein patients with latent CTEPH without apparent recurrence.Other symptoms such as chest pain, dry cough, and syn-cope, may develop as well, and bloody sputum and fever maydevelop in patients complicated by pulmonary bleeding andpulmonary infarction. Patients with right heart failure due toPH may exhibit abdominal distension, body weight gain, andedema of the lower legs.

5 DiagnosisThe diagnosis of CTEPH is made according to the criteriafor diagnosis of idiopathic chronic PTE with PH describedbelow. Contrast multi-slice computed tomography (termedmulti-slice CT [MSCT] or multi-detector CT [MDCT]) isuseful in the diagnosis and differential diagnosis of CTEPH.However, pulmonary angiography is required to determinewhether surgery is indicated.

6 PrognosisAccording to a report by Riedel et al and the results of asurvey of CTEPH in Japan, the prognosis of patients witha mean pulmonary arterial pressure during the stable periodof 30 mmHg is poor.19,20 The prognosis of patients under-


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going medical treatment has recently improved. However,since there are patients whose QOL and vital prognosis areimproved significantly following surgery (PEA), accuratediagnosis and severity classification are essential in consider-ing whether patients are indicated for surgery, including thedetermination whether lesions are surgically accessible andwhether significant disorder of major organs is present.

7 TreatmentSince the prognosis of patients receiving medical treatmentalone is poor, physicians should consider PEA when the or-ganized thrombi are surgically accessible and no significantdisorders are observed in other major organs.15,16,18,2834 Inpatients in whom the proximal ends of the organized thrombiare located in lobe arteries or main pulmonary arteries, sig-nificant improvement of pulmonary hemodynamics, QOL,and prognosis may be obtained after successful PEA.3034Ithas also been reported that surgery may improve the pulmo-nary hemodynamics and QOL of patients in whom thrombi arelocated in segmental arteries.32,34Recent reports have notedthat drugs for the treatment of pulmonary arterial hyperten-sion are effective in the treatment of patients with CTEPHnot indicated for surgery.3337

3. Deep Vein Thrombosis

1 DefinitionThe veins of the extremities are classified into superficialveins that lie above the fascia and deep veins that lie underthe fascia. Acute venous thrombosis is thus classified as DVTaffecting deep veins and thrombophlebitis affecting superfi-cial veins. The manifestations of DVT depend on the locationof affected veins. The present guidelines mainly describeDVT in the veins of the pelvis and lower limbs.38

2 EpidemiologyAt autopsy, DVT is observed in 24 to 60% of patients

who died in hospital in Europe and the United States and0.8% of those in Japan.3941In an epidemiological survey, theVenous Disease Survey Committee of the Japanese Societyof Phlebology in 1997 reported that DVT occurred in 506 pa-tients per year,42while the number of new patients with DVTwas estimated to be 14,674 patients/year,1 ie, 12/100,000population/year, in a questionnaire survey conducted by theJapanese Society of Pulmonary Embolism Research in 2006.These findings reflects the fact that the incidence of DVT

has increased about 30-fold during the last decade. On theother hand, the annual incidence of DVT in Europe and theUnited States were calculated as 50/100,000 population/yearon the basis of reports published between 1976 and 2000.43The incidence of DVT in Japan has increased rapidly to aboutone-fourth those in Europe and the United States.

3 Etiology and Risk FactorsThe major causes of venous thrombus are venous endo-thelial dysfunction, hypercoagulability, and interruption ofvenous blood flow.44 The development of DVT involvesthese major causes as well as various other risk factors ofvarious strengths38,45 (Table 3). Most cases of DVT in theveins in the neck and upper limbs are iatrogenic, and causedby the placement of an intravenous line, pacemaker catheter,or hemodialysis shunt, and cases of thoracic outlet syndromeare also observed. DVT in the superior vena cava developsin patients with superior vena cava syndrome in whom DVTis typically caused by mechanical compression of this vein bymediastinal tumor. DVT in the IVC often develops as a resultof extension of thrombus from veins in the pelvis or lowerlimb. Cases of IVC filter thrombosis and of Budd-Chiari syn-drome are also observed. In the veins in the pelvis and lowerlimb, DVT may develop as a result of venous compressiondue to congenital iliac bands and webs in the pelvis, iliaccompression by the iliac artery, insertion or placement of acatheter into the femoral vein, or bed rest with limited legmovement. Cases of DVT in the lower legs are predomi-nant.45,46DVT in the lower leg often develops in the veins ofthe soleus muscle,38,47which receive blood from the medial,central, and lateral parts of the lower leg,4851 and the veinrunning through the central portion of the soleus muscle islargest and the main location of DVT.48

4 PathophysiologyThrombus in a vein adheres to the venous wall over a periodof several days after thrombus formation as a result of in-flammatory changes, and then regresses due to organization.Although venous valves included within the lesion may bedamaged, some valves maintain function.38,45 Blood flowrecovers after lysis or regression of thrombi during the acutephase. During the chronic phase, recovery of blood flowoccurs after organization or recanalization of thrombi. Thrombiin the popliteal vein and the distal veins disappear almostcompletely in several days to several weeks, while thrombiin the proximal leg veins remain as fibrotic bands, althoughabout 50% of such thrombi regress within one year after for-mation.52The central edge of thrombus can become embolicor a source of emboli. While white thrombi and mixedthrombi tend to adhere to the venous wall, red thrombi donot adhere to the venous wall tightly and are easily detachedfrom the vascular wall and cause embolism.53Thrombus inveins in the pelvis and lower limbs are detached duringmovement of the hip and knee joints in the supine or sittingposition. During walking, thrombi are detached from the wallas a result of calf muscle pump function.49Embolism often

Table 3. Risk Factors for Deep Vein Thrombosis

Risk factors

Demographics/environment

ElderlyProlonged sitting: During trips and duringdisasters

Pathology Trauma: Leg fractures, leg palsy, spinal injuriesMalignant tumorsCongenital hypercoagulability: Coagulation in-

hibitor deficiencies

Acquired hypercoagulability: Following surgeryHeart failureInflammatory bowel disease, antiphospholipid

syndrome, vasculitisVaricose veins of lower limbsDehydration/polycythemiaObesity, pregnancy, postpartum statusCongenital iliac bands and webs, iliac compres-

sion by the iliac arteryHistory of venous thromboembolism: Vein

thrombosis, pulmonary thromboembolism

Treatment Surgeries: Orthopedic surgery, neurosurgery,abdominal surgery

Drugs: Female hormone, hemostatics, cortico-steroids

Catheter test/interventionProlonged bed rest: Management of severe

patients, postoperative patient management,patients with cerebrovascular disorders


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occurs within one week after formation or progression ofthrombus, but may recur depending on the amount of move-ment of the lower limbs and blood flow in the central edgeof thrombus.47,50The severity of PTE correlates with the sizeof emboli and frequency of formation of emboli. Severe PTEis often caused by thrombus in leg veins above the popli-teal vein, especially the femoral vein, but may be caused bythrombi in soleus veins.47,49,50Although the source of emboliis uncertain in 30 to 60% of patients with PTE,38,45autopsy

has frequently revealed the presence of new and old sourcesof emboli in the veins of lower limbs.50

5 Typing and Staging of DVTDVT in the pelvis and lower limb is classified into centraltype of DVT (iliac DVT and femoral DVT), which occurs inveins above the popliteal vein, and peripheral type of DVT(lower leg DVT), which occurs in popliteal vein and distalveins. In the present guidelines, DVT is also classified basedon clinical signs/symptoms and severity of anomalous venousdrainage into acute and chronic phases. Signs and symptomsof acute anomalous venous drainage include swelling, pain,and skin color change in patients with central type of DVT.In patients with iliac DVT with diffuse occlusion, venousnecrosis due to poor arterial perfusion develops in the acutephase. It is of practical use to classify the severity of clinicalsigns/symptoms according to the presence/absence of pain-ful swelling, painful swelling with discoloration (phlegmasiaalba dolens [milk leg], phlegmasia cerulea dolens [blue leg]),and venous necrosis.38,54 Although peripheral type of DVTtypically causes pain, many patients are asymptomatic. Impor-tant findings of physical examination include the presence of

thrombosed veins or tenderness on palpitation (direct find-ings) and hard lower leg muscles (indirect finding).38,54WhenDVT recurs during the chronic phase, the patient exhibitssigns and symptoms characteristic both the acute and chronicphases of DVT.

6 Prognosis and RecurrenceThe short-term prognosis of DVT in the pelvis and lowerlimb depends on the presence/absence and severity of acute

anomalous venous drainage, acute PTE, and arterial embo-lism. Acute anomalous venous drainage often subsides withinseveral months after onset. Acute PTE is the most serious con-dition,45,55and requires both primary and secondary preven-tion. In patients with arterial embolism, the presence/absenceof patent foramen ovale must be confirmed.56The long-termprognosis of DVT depends on the presence/absence and sever-ity of post-thrombotic syndrome, recurrent DVT, chronic PTE,and arterial embolism.38,45,54 Post-thrombotic syndrome de-velops in about 40% of patient with central type of DVT,57and is caused by abnormal valves in perforating arteries andsuperficial veins. When DVT recurs, acute manifestationsare observed, and the incidences of PTE and post-throm-botic syndrome are increased.58Early treatment improves theprognosis of patients with DVT. Patients with recurrent DVTfollowing anticoagulation therapy must be assessed for throm-bophilia.59,60To ensure prevention of recurrent DVT, patientsmust continue exercise and compression therapy as well asanticoagulation therapy for an appropriate length of time. Theduration of anticoagulation therapy should be determinedconsidering the reversibility of risk factors and whether thecondition is idiopathic and/or permanent.45,60

II Descriptions of Individual Diseases

1. Acute Pulmonary Thromboembolism

1 DiagnosisAccurate diagnosis of acute PTE is difficult, since no physical

or laboratory findings are specific to acute PTE. Physiciansshould suspect acute PTE when the following non-specificfindings are present. Acute PTE should be included in thedifferential diagnosis if patients have dyspnea that cannot beexplained by other causes.

Figure 1. Steps in the diagnosis of acute pulmonary thromboembolism. Start heparin therapy when pulmonary embolism issuspected. Examine for deep vein thrombosis at once. *1Screen the patient with chest X-ray, ECG, arterial blood gas analysis,transthoracic echocardiography, and blood chemistry. *2When PCPS is not available, maintain circulation with cardiac compres-sion and vasopressors. CT, computed tomography; PCPS, percutaneous cardiopulmonary support. Adapted from TherapeuticResearch2009; 30:744 747.


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(1) SymptomsThe absence of symptoms specific to acute PTE is a majorreason for delay or lack of diagnosis of this disease. Its com-mon and major symptoms are dyspnea and chest pain.3,6164Typically, such symptoms develop when patients begin walk-ing after bed rest, when they urinate or defecate, or whenthey change posture.

(2) Clinical FindingsTachypnea and tachycardia are frequently present.62,65Shockand hypotension may develop as well. DVT may cause swell-ing of the lower legs and Homans sign, etc.

(3) ExaminationsFigure 1 illustrates the recommended steps in diagnosis. Itshould be noted that the flow chart reflects currently avail-able techniques.66

[Levels of Recommendations]1. MSCT, pulmonary angiography, pulmonary scintigraphy,

arterial blood gas analysis, D-dimer: Class I2. Transthoracic echocardiography, magnetic resonance an-

giography (MRA): Class IIa3. Transesophageal echocardiography: Class IIb

2 Treatment(1) IntroductionIn the treatment of acute PTE, it should be noted that (1)prompt diagnosis and treatment are essential, since the prog-nosis after successful treatment during the acute phase isexcellent, and that (2) after achievement of stable hemody-namics patients should be carefully followed for recurrence ofPTE and should be treated promptly when DVT develop. Themain component of treatment of PTE is pharmacological anti-thrombotic therapy, and anticoagulants and thrombolyticsshould be used appropriately based on the severity of thepatients condition. Patients with a high risk of bleeding shouldadditionally be treated with non-permanent IVC filters andcatheter intervention to support drug treatment, and percuta-neous cardiopulmonary support (PCPS) and surgical throm-bectomy should be performed for patients with severe condi-tion. Physicians should also assess whether any DVT remainsas soon as possible to consider whether IVC filters are indi-cated. Figure 2shows an example of an algorithm of treat-ment during the acute phase of PTE. It should be noted thatthis algorithm involves basic concepts and should be modifiedappropriately according to the condition of individual patientsand hospital policies.

(2) Cardiopulmonary ManagementThe main pathological feature of acute PTE is acute cardio-

Figure 2. An example of a treatment algorithm for acute pulmonary thromboembolism. *1When risk of bleeding is high. *2Treatcomplications appropriately with available methods. *3Unstable hemodynamics consistent with shock or prolonged hypo-tension. *4Condition requiring cardiopulmonary resuscitation or prolonged severe shock. *5Consider PCPS according to hospitalequipments and patient condition. *6Select appropriate treatment according to hospital equipments and patient condition.*7Evaluate based on right ventricular enlargement on echocardiography and severity of pulmonary hypertension. * 8Presence/absence of DVT which may have serious effects if it releases emboli causing recurrent embolism. The above algorithm is an ex-ample. Each institution should select appropriate methods according to its healthcare resources. DVT, deep vein thrombosis;PCPS, percutaneous cardiopulmonary support; IVC, inferior vena cava.


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pulmonary failure. Since mortality is particularly high imme-diately after the onset of PTE,67appropriate cardiopulmonarymanagement is quite important.

1) Respiratory ManagementPatients with acute PTE typically exhibit hypoxemia andhypocapnia (type I respiratory failure).68 Oxygen therapyshould be initiated for patients with an partial pressure ofarterial oxygen (PaO2) of 60 Torr (mmHg) (or a peripheraloxygen saturation [SpO2] of 90%).

Nasal cannulas, an oxygen mask, or an oxygen mask withreservoir bag should be used as appropriate.

When oxygen therapy does not achieve a PaO2of 60 Torr(SpO290%), intubation and mechanical ventilation shouldbe initiated.69During mechanical intubation, the tidal volumeshould be set at a low level, 7 mL/kg, to avoid increase inintrathoracic pressure.10

2) Circulatory ManagementAlthough severity varies depending on the degree of occlu-sion in the pulmonary vascular bed, patients often exhibit PH,right heart overload, decreased right cardiac output, decreasedleft cardiac output, and/or shock. Theoretically, treatmentshould include drugs that have cardiotonic effects and widenthe pulmonary artery.

There is no evidence to recommend volume loading. It hasbeen pointed out that excessive volume loading in the rightventricle may compress the left ventricle and decrease leftcardiac output.70Drug treatment (the drugs of first choice aredopamine and dobutamine;71norepinephrine72is effective inpatients with hypotension; phosphodiesterase III inhibitorsrequire further evaluation to accumulate clinical data), nitricoxide (NO) inhalation, and other appropriate treatment shouldbe performed.

Patients with cardiopulmonary arrest and those not re-sponding well to drug treatment (patients with progressivehypotension) should be treated promptly with PCPS and beconsidered for surgical thrombectomy.73,74

[Levels of Recommendations]1. Respiratory management (oxygen therapy and low tidal

volume ventilation): Class I2. Circulatory management Volume loading: Class III Dopamine: Class IIa Dobutamine: Class IIa Norepinephrine: Class IIa Use of PCPS in severe patients: Class I

Table 4. Dose Adjustment Table for Unfractionated Heparin for Continuous Infusion*1

APTT(sec)

Bolus(units)

Hold(min)

Rate change(mL/hr)*2

Dose change(units/24 hr)

Repeat APTT

120 0 60 4 3,840 6 hrs later

Unfractionated heparin should be administered intravenously as an initial bolus dose at 5,000 units, followed bycontinuous infusion at 1,400 units/hr. Six hours after the initial administration of unfractionated heparin, APTT shouldbe determined for adjustment of the dose according to the above table.*1Use this table for APTT reagents with a therapeutic range of 1.9 to 2.7 times the control.*2

When unfractionated heparin is administered at a concentration 40 units/mL.APTT, activated partial thromboplastin time; Bolus, bolus dose for repeated administration; Hold, duration of suspen-sion of continuous infusion; Rate change, change in infusion rate during continuous infusion; Dose change, change indose during continuous infusion.Adapted from Cruickshank MK, et al. A standard heparin nomogram for the management of heparin therapy. Arch InternMed1991; 151:333 337, with permission from American Medical Association. Added Dose change to this table.

Table 5. Contraindications to Thrombolytic Therapy

Absolute contraindications

Active internal bleeding

Recent spontaneous intracranial bleeding

Relative contraindications

Major surgery, delivery, organ biopsy or puncture of non-compressible vessels within 10 days

Ischemic stroke within 2 months

Gastrointestinal bleeding within 10 days

Severe trauma within 15 days

Neurosurgery or ophthalmologic surgery within 1 month

Uncontrolled severe hypertension (SBP >180 mmHg,DBP >110 mmHg)

Recent cardiopulmonary resuscitation

Platelet count


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(3) Drug Treatment

1) Initial TreatmentThe major components of the treatment of acute PTE are anti-coagulation therapy and thrombolytic therapy. The treatmentof choice is anticoagulation therapy using unfractionatedheparin.75,76This should be performed in all patients unlessanticoagulation is contraindicated. When acute PTE is strong-ly suspected or a long period of time is required to confirm

the diagnosis, treatment may be initiated before confirmingthe diagnosis. Unfractionated heparin should be administeredas a single intravenous dose of 80 units/kg or 5,000 units,followed by continuous intravenous infusion at 18 units/kg/hror 1,300 units/hr. The dose should be adjusted to maintainan activated partial thromboplastin time (APTT) of 1.5 to2.5 times the control value (Table 4).77Infusion of unfrac-tionated heparin should be continued until control of anti-coagulation with warfarin is established.

Thrombolytic therapy is performed to promptly improvepulmonary circulation by dissolving thromboemboli, and isalso used for the treatment of patients with massive acute PTEwith unstable hemodynamics or echocardiography-provenenlargement of the right heart.78Monteplase, a recombinanttissue plasminogen activator, is the only drug officially indi-cated for the treatment of acute PTE in Japan.79The recom-mended regimen in adults is intravenous administration of13,750 to 27,500 units/kg over about 2 minutes. Table 5listscontraindications to thrombolytic therapy.10Although throm-bolytic therapy has been proven to be clearly superior to anti-coagulation therapy in ensuring prompt dissolution of thrombiand improvement of hemodynamics,7983 no difference inprognosis has been observed in randomized studies of throm-bolytic therapy and anticoagulation therapy.

The current criteria for drug treatment for acute PTE areas follows:(1) Anticoagulation therapy is the treatment of choice for

normotensive patients without right heart dysfunction.(2) Normotensive patients with right heart dysfunction should

be carefully assessed for expected benefits and risk ofbleeding in considering whether thrombolytic therapy isa treatment option.

(3) Thrombolytic therapy is the treatment of choice for pa-tients with persistent shock and hypotension unless it iscontraindicated.

2) Long-Term TreatmentFollowing treatment with unfractionated heparin, warfarintherapy is used. Warfarin therapy should be initiated duringthe early phase of treatment with unfractionated heparin, andthe dose of warfarin should be adjusted to achieve an optimalprothrombin time and international normalized ratio (PT-INR).The initial dose is 3 to 5 mg in many cases. Warfarin therapyshould be continued when the risk of recurrent PTE is higherthan the risk of bleeding, and the duration of warfarin therapywill vary depending on the presence and types of risk factors(Table 6). The optimal target range of warfarin therapy is 2.0to 3.0 PT-INR in foreign countries84,85but is 1.5 to 2.5 PT-INRin Japan because of the risk of bleeding.

[Levels of Recommendations]Class I

1. During the acute phase of acute PTE, unfractionatedheparin should be administered to achieve an APTT of1.5 to 2.5 times the control value for a period of timeuntil the effects of warfarin are stabilized.

2. Warfarin should be administered during the chronicphase of acute PTE. The duration of warfarin therapyshould be 3 months for patients with reversible risk fac-tors and at least 3 months for patients with congenitalcoagulopathy and those with idiopathic VTE. Warfarinshould be administered for a longer period of time topatients with cancer and those with recurrent PTE.

3. In patients with persistent shock, hypotension, and un-stable hemodynamics, thrombolytic therapy should be

performed during the acute phase of acute PTE.Class IIa

1. During the acute phase of acute PTE, thrombolytictherapy should be performed in normotensive patientswith right heart dysfunction.

Class IIb1. During the treatment of acute PTE, the dose of warfarin

should be adjusted to achieve a PT-INR of 1.5 to 2.5.

(4) Catheter InterventionCatheter intervention is indicated for patients with acute mas-sive PTE with unstable hemodynamics despite other appro-priate treatment.86,87Catheter interventions include catheter-directed thrombolysis (CDT) and catheter fragmentation/aspiration thrombectomy.

1) Catheter-Directed ThrombolysisUse of catheters to inject thrombolytics directly to thrombusin the pulmonary arteries is not currently supported.88Appro-priate methods of injection such as the pulse-spray techniqueshould be used to ensure the efficacy of treatment.

2) Catheter Fragmentation/Aspiration ThrombectomyCatheter interventions other than catheter-directed throm-bolytic therapy include aspiration thrombectomy, thrombusfragmentation, and rheolytic thrombectomy. These techniquesare followed by thrombolytic therapy in most cases. It hasbeen suggested that the clinical results of these techniquesare comparable to that of surgical thrombectomy.89Efficacyevaluation should be based on improvement of hemody-namics and oxygenation, and angiographic findings shouldnot be overemphasized.90 Physicians should be aware thatcomplications 91 such as injury of vascular walls, peripheralembolism, recurrent thrombosis, traumatic hemolysis, andblood loss may occur.

(a) Aspiration ThrombectomyThe Greenfield embolectomy device has not yet been approvedin Japan. Aspiration thrombectomy using guiding cathetersfor percutaneous transluminal coronary angioplasty (PTCA)has attracted attention because of its simplicity and excellentclinical results.92 On the other hand, catheters designed topercutaneously remove thrombus from the coronary arteriesare not useful in the treatment of acute PTE because of theirlow suction power.

(b) Thrombus FragmentationThrombus fragmentation is performed to directly break athrombotic mass in a proximal pulmonary artery and redis-tribute microemboli into peripheral vessels.93 Although thethrombi are not recovered, small fragments of a thromboticmass will respond better to thrombolytic therapy because thetotal surface area exposed with thrombolytics will be in-creased significantly. Currently used methods of fragmenta-tion include cutting a thrombotic mass by rotating a pigtailcatheter94 and crushing it with a balloon catheter. Hybrid


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treatment techniques combining fragmentation and aspirationthrombectomy using guiding catheters have been proposedto prevent distal emboli associated with fragmentation, andhave achieved excellent results.95

(c) Rheolytic ThrombectomyRheolytic thrombectomy is a theoretically safe method sincethrombi are removed, but is in many cases ineffective whenused alone to treat acute PTE.

[Levels of Recommendations]1. CDT: Class IIb The efficacy of simple injection of a thrombolytic agent

into the affected pulmonary artery does not differ fromthat of systemic administration of the drug.

2. Catheter fragmentation/aspiration thrombectomy: ClassIIb

Aspiration thrombectomy Thrombus fragmentation Rheolytic thrombectomy

(5) Surgical Treatment

1) Indications for Surgery

(a) Treatment Strategies for Acute PTEWhen a diagnosis of acute PTE is made, anticoagulationand/or thrombolytic therapy should be promptly initiated.However, since exacerbation of acute PTE may be observedand cardiac arrest may occur during the course of throm-bolytic therapy, patients should be carefully monitored andconsidered for surgery throughout medical treatment. Manyreports have indicated that surgical treatment improves thecondition of patients with unstable hemodynamics due to mas-sive PTE, and recent surgical techniques may achieve favor-able results in patients with massive PTE.9698 Treatmentstrategies for patients who develop PTE following surgeryshould be determined in accordance with the type of surgeryand the general condition of patients.

(b) Indications for Surgical ThrombectomyIn patients with circulatory failure or shock due to acute mas-sive PTE causing rapid occlusion of the pulmonary arterialtrunk or both right and left main pulmonary arteries, promptrecanalization of the occluded pulmonary arteries is essen-tial.99Surgical pulmonary thrombectomy under cardiopulmo-nary bypass is indicated for these patients. In patients with-out shock, conventional surgical pulmonary thrombectomyis indicated, among other conditions, (1) when tachycardiapersists in the absence of hypotension and medical treatmentis not effective; (2) when thrombus is observed in the pul-monary arterial trunk or both right and left main pulmonaryarteries, and heart failure and/or respiratory failure is rapidlyprogressive; (3) when thrombolytic therapy is contraindicated;and (4) when free thrombus is present in the right atriumand/or ventricle.100

When post-surgical patients or bedridden patients experi-ence the abrupt onset of circulatory collapse before the diag-nosis of acute PTE and medical treatment is not effective,PCPS must immediately be initiated in the ward.101 Whensuch patients are confirmed not to have fatal cerebral com-plications and are diagnosed with shock due to acute PTE,pulmonary thrombectomy should be performed.

2) Methods of SurgerySurgical thrombectomy for the treatment of acute PTE in-volves incision of the affected pulmonary artery to removethrombus under cardiopulmonary support.74When poor car-diopulmonary kinetics are observed before surgery, femoralveno-arterial cardiopulmonary support should be initiatedpromptly as a supportive measure. When shock develops ina patient in the ward, PCPS should be initiated before thepatient is transferred to the operating room.

Following median sternotomy, cardiopulmonary support isinitiated. An incision is made into the pulmonary arterial trunkand, when necessary, the right main pulmonary artery to re-move thrombus. In patients with acute PTE, soft, rod-shaped,relatively fresh red thrombi may be removed. Although throm-bus in peripheral arteries should also be removed wheneverpossible, postoperative thrombolytic therapy is effective indissolving peripheral thrombus when most central thrombusis removed during surgery. Surgical thrombectomy may beperformed during a beating heart procedure. However, whensmall thrombi are located in many segmental arteries orthrombi are tightly adherent to the vascular wall, thrombec-tomy should be performed during an arrested heart procedure.

3) Results of Surgical Pulmonary ThrombectomyStein et al reviewed 46 reports on 1,300 cases of surgical pul-monary thrombectomy performed from 1985 to 2006, andreported that the mortality of patients undergoing pulmo-nary thrombectomy was 20%.102According to annual reportsby the Japanese Association for Thoracic Surgery, a total of539 patients with acute PTE underwent surgical pulmonarythrombectomy during the 7-year period between 2000 and2006, and the in-hospital mortality was 21.2%. The results inJapan are similar to or better than those in foreign countries.The results are fairly good given the severe condition ofpatients. During the period between August 1996 and October2006, the Japanese Society of Pulmonary Embolism Researchconducted a survey in 60 institutions in Japan, and a total of32 patients who underwent pulmonary thrombectomy forthe treatment of acute PTE were registered.103Mean age was5717 years, and 21 patients (66%) were female. The initialpresentation was shock in 23 patients, cardiopulmonary arrestin 3 patients, and syncope in 11 patients. Underlying con-ditions included trauma in 3 patients, malignant tumors in3 patients, cerebrovascular disorder in 3 patients, heart diseasein 1 patient, central line placement in 2 patients, and preg-nancy in 1 patient. Acute PTE developed after surgery in13 patients and during prolonged bed rest status in 8 patients.Seventeen patients were inpatients when PTE developed.Before surgical pulmonary thrombectomy, thrombolytic ther-apy was performed in 10 patients and catheter interventionsfor pulmonary embolus in 4 patients. Ten patients underwentPCPS before surgery. Six patients (18.8%) died in hospital,and 3 patients (30%) under PCPS died. IVC filters were usedin 16 patients (50%).

[Levels of Recommendations]1. Surgical pulmonary thrombectomy under cardiopulmo-

nary bypass in patients with acute massive PTE withcirculatory collapse: Class I

2. Surgical pulmonary thrombectomy for the treatment ofacute massive PTE in patients without shock: Class IIa

(6) Inferior Vena Cava FiltersAlthough the indications for and efficacy of IVC filters haveyet to be fully determined and demonstrated, IVC filters have


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been increasingly recognized as effective in preventing PTEand its complications.104106

1) Indications of Permanent IVC Filters107,108

Class I: Among patients with VTE,Those who are contraindicated for anticoagulation therapyThose who exhibit treatment-related complications and

adverse drug reactions to anticoagulation therapyThose with recurrent VTE during adequate anticoagulation

therapyThose who are unable to continue anticoagulation therapy

Class IIa: Among patients with VTE,Those with venous thrombosis in intrapelvic veins or

branches of the IVCThose with large free thrombi in proximal veinsThose undergoing thrombolytic therapy or thrombectomy

for the treatment of PTEThose with VTE with poor cardiopulmonary reserveThose with recurrent PTE following placement of filtersThose with high risk of complications related to anti-

coagulants (such as ataxia and frequent falls)Those undergoing PEA for the treatment of chronic PTE

Class IIb: Among patients without VTE,Those with trauma associated with a high risk of VTEThose undergoing surgery with a high risk of VTEThose with other conditions associated with a high risk of

VTEClass III:

Patients with acute PTE with neither right heart failurenor DVT who are undergoing anticoagulation therapy

Patients with peripheral type of DVT who are undergoinganticoagulation therapy

Contraindications:Patients with no access to the vena cavaPatients without space to place a filter

*Use of a non-permanent IVC filter may be considered forpatients with conditions for which an IVC filter will nolonger be required after several weeks.

2) Indications for Non-Permanent IVC109111

Class I: NoneClass IIa:

Patients indicated for the placement of a permanent IVCfilter but who need the filter for only several weeks toprevent acute PTE.

Class IIb:Long-term placement of removable filters

Class III:Patients with acute PTE with neither right heart failure nor

DVT who are undergoing anticoagulation therapyPatients with peripheral type of DVT who are receiving

anticoagulation therapy*Since permanent placement of IVC filters increases therisk of venous thrombosis, removable IVC filters should beremoved whenever possible.

[Levels of Recommendations]The indications for permanent and non-permanent IVC filtersare listed as above.

2. Chronic Pulmonary Thromboembolism

1 DiagnosisDiagnosis of idiopathic chronic PTE with PH (CTEPH) as

a condition requiring treatment should be made according tothe criteria for diagnosis provided by the Specific DiseaseRespiratory Failure Study Group of the MHLW (Table 7).CTEPH should be suspected in patients with exertional dys-pnea. Patients in whom CTEPH is suspected should be iden-tified based on the typical symptoms and clinical findingslisted in Table 7. Arterial blood gas analysis should be per-formed not only in patients with abnormal chest X-ray find-ings but also in those without remarkable X-ray findings.

Patients with hypoxemia associated with hypocapnia shouldbe assessed with ECG, echocardiography, and pulmonaryfunction tests to exclude other cardiopulmonary diseases andto confirm the presence/absence of findings of right heartoverload such as right ventricular enlargement and right ven-tricular hypertrophy. In making the diagnosis of CTEPH,physicians should confirm that (1) pulmonary ventilation/per-fusion scintigraphy has revealed maldistribution of pulmonaryblood flow without abnormal ventilation distribution thathas persisted for 6 months; or the patient exhibits at leastone of the five typical findings of pulmonary artery angiog-raphy,112ie, (a) pouch defects (the presence of round pouch-like shadows of thrombi that have been smoothed by bloodflow, (b) webs and bands (band-like stenosis with pulmonaryrecanalization associated with organization of thrombi, (c)intimal irregularities, (d) abrupt narrowing, and (e) completeobstruction; and (2) right heart catheterization reveals normalpulmonary artery wedge pressure and a mean pulmonary arte-rial pressure of 25 mmHg. Cardiac catheterization is usefulfor measurement of pulmonary vascular resistance to deter-mine prognosis.

Although contrast CT (MSCT) has been reported to beuseful in the diagnosis of CTEPH,113pulmonary angiographyis required to assess the condition of subsegmental arteriesand to determine whether surgery is indicated.114

2 TreatmentCTEPH is treated with medical and surgical therapy, andthe results with current methods of PEA are excellent. Onlya few reports have described catheter interventions for thetreatment of CTEPH; use of them is not expected to becomecommon in the future, if they are used at all.

(1) Medical TreatmentThe pathophysiology of CTEPH includes PH due to occlu-sion of pulmonary arteries by organized thrombi, intractableright heart failure, and hypoxemia. Accordingly, surgicalremoval of organized thrombi (PEA) is the only radical treat-ment for CTEPH. However, PEA is limited to the treatmentof central type of CTEPH. Patients with peripheral type ofCTEPH, those with relatively mild CTEPH who do not needsurgery, and those with CTEPH with persistent PH followingsurgery are treated with medical treatment.

In medical treatment, patients with CTEPH who are notindicated for surgery receive anticoagulants for the treatmentof VTE, which is considered the cause of CTEPH, oxygentherapy for hypoxemia, pulmonary vasodilators for PH, andcardiotonics and diuretics for right heart failure, whenevernecessary.

1) Anticoagulation TherapyThe prognosis of untreated CTEPH depends on pulmonaryhemodynamics. It has been reported that even patients withmild CTEPH may exhibit exacerbation of pulmonary hemo-dynamics over time.19 Such exacerbation is believed to becaused by recurrent acute PTE, and to involve mechanisms


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Table 7. Guidelines for the Diagnosis of Idiopathic Chronic Pulmonary Thromboembolism With Pulmonary Hypertension

Chronic pulmonary thromboembolism with pulmonary hypertension is defined as the presence of chronic obstruction of pulmonary arteriesdue to organized thrombi and pulmonary hypertension causing severe exertional dyspnea.

(1) Major symptoms and other clinical findings

1) Exertional dyspnea (Hugh-Jones Grade II or more severe) or fatigability has been observed for >3 months.

2) Clinical symptoms typically associated with acute pulmonary thromboembolism (abrupt onset of dyspnea, chest pain, syncope, etc.)have occurred at least once.

3) Clinical symptoms (swelling in the lower limbs and pain) suspected deep vein thrombosis in the lower limbs have occurred.

4) Pulmonary bruit is auscultated over the lungs. 5) Chest auscultation reveals abnormal sounds suggestive of pulmonary hypertension (including at least one of the following four find-

ings: (1) increase in the pulmonary component of the second heart sound, (2) a fourth heart sound, (3) noise at the pulmonary arterialorifice during the diastolic phase, and (4) noise at the tricuspid orifice during the systolic phase

(2) Laboratory findings

1) Arterial blood gases

(a) Hypoxemia associated with hypocapnia (PaCO218 mm)

(b) Enlargement of cardiac shadow (CTR >50%)

(c) Local differences in pulmonary artery shadows (right vs. left lung, upper vs. lower lung)

3) ECG

(a) Right axis deviation and pulmonary P wave

(b) R >5 mm at V1 or R/S >1, or S >7 mm at V5 or R/S 6 months evenafter thrombolytic or anticoagulation therapy. When findings appear to have persisted, scintigraphy should be repeated 6 months laterto confirm the findings.

6) Pulmonary angiography

As changes due to chronic thrombi, at least one of five findings, including (a) pouch defects, (b) webs and bands, (c) intimal irregulari-ties, (d) abrupt narrowing, and (e) complete obstruction, is observed.

7) Right heart catheterization

(a) Mean pulmonary arterial pressure during the chronic stable phase is >25 mmHg. (b) Pulmonary arterial wedge pressure is normal (


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of formation of thrombus in situ. Accordingly, life-long anti-coagulation therapy with warfarin is required for patients withCTEPH. Warfarin is often administered with a target INR of1.5 to 2.5, which is also recommended for patients with acutePTE.

2) Thrombolytic TherapyPatients with CTEPH may exhibit rapid progression of dis-ease. When levels of coagulation/fibrinolytic molecular

markers such as D-dimer are high during disease progression,thrombolytic therapy may yield improvement. Physiciansshould be aware of this possibility.

3) HypoxemiaAlthough there is no conclusive evidence for it, oxygen ther-apy is expected to improve both the QOL and prognosis ofpatients with CTEPH. In Japan, home oxygen therapy (HOT)for patients with PH including CTEPH is covered by theNHI.

4) Treatment of Right Heart FailureThe presence of clinically significant right heart failure is animportant determinant of the prognosis in CTEPH. Patientswith right heart failure who exhibit pleural effusion, hepa-tomegaly/abnormal hepatic function, thrombocytopenia, legedema, or other typical signs/symptoms are treated with con-ventional regimens for heart failure including bed rest, restric-tion of water intake, diuretics, and oral cardiotonics. Patientsin severe condition also require intravenous administrationof catecholamines such as dopamine and dobutamine as wellas milrinone.

5) VasodilatationAlthough use of classic vasodilators such as calcium blockers,nitrates, and angiotensin converting enzyme (ACE) inhibi-tors to treat CTEPH has been attempted, the efficacy of thesedrugs in patients with CTEPH has not been demonstrated.However, recent studies have evaluated the effects of bera-prost35and epoprostenol,115 drugs indicated for pulmonaryarterial hypertension, on CTEPH. Open-label studies andplacebo-controlled studies of bosentan36,116and sildenafil37have revealed that these drugs may significantly improvepulmonary hemodynamics, six-minute walking distance, andbrain natriuretic peptide (BNP) level, and so on. The efficacyof regimens combining these drugs has also been reported.However, use of these drugs for the treatment of CTEPH iscurrently not covered by NHI in Japan.

[Levels of Recommendations]1. Anticoagulation therapy: Class IIa2. Oxygen therapy/HOT: Class IIb3. Vasodilatation for the treatment of PH: Class IIb4. Cardiotonics and diuretics for right heart failure: Class IIb

(2) Surgical Treatment

1) PEA by Lateral ThoracotomyPEA is almost fully established as a method of treatment ofCTEPH. Lateral thoracotomy had been used before PEA bymedian sternotomy with cardiopulmonary bypass and deephypothermic intermittent circulatory arrest was establishedas the standard technique. The indications for PEA by lateralthoracotomy are similar to those for the method by mediansternotomy, though this procedure is currently considered foronly a limited number of patients.117123

a) SurgeryIncision along the fourth or fifth rib is made to approach thepulmonary artery. Dissection is started from the interlobarfissure to expose the segmental arteries. Taping is performedto control back flow of blood from peripheral vessels. Dissec-tion must be performed carefully so as not to injure the pul-monary parenchyma. After administration of heparin, eitherthe right or left main pulmonary artery is clamped withoutcardiopulmonary bypass to monitor changes over time in pul-

monary arterial pressure for about 5 minutes. After confirm-ing that pulmonary arterial pressure does not exceed systemicblood pressure, an incision is made into the affected lobeartery to initiate thromboendarterectomy. The dissecting planeis determined as in the median sternotomy technique. Thetarget organized thrombus and the intima are held and pulledalong the direction to each segmental artery without cuttingoff the thrombus and the intima. Following removal of thethrombus and the intima, the peripheral taping is removed toconfirm back flow of blood. The incision over the lobe arteryis closed by suturing or using an autologous pericardial patch.

b) Results of Surgery by Masuda et alSince 1986, Masuda et al have performed PEA by lateral tho-racotomy in 16 patients. In all patients, a right lateral tho-racotomy incision was used to access the pulmonary arteries.No patients exhibited serious arrhythmia or right heart failure.No patients required emergency cardiopulmonary bypass forthe treatment of hypoxemia. Two patients underwent throm-boendarterectomy by left lateral thoracotomy as a second-stage procedure in a two-staged operation. Two patients(12.5%) died of surgical complications, due to postoperativepneumonia and postoperative pulmonary edema in one caseeach. The patients who survived surgery exhibited prompt im-provement in mean pulmonary arterial pressure, cardiac index,and pulmonary vascular resistance, and gradual improve-ment in PaO2 over time, resulting in significant improvement6 months after surgery. Three patients died 4,220, 1,891, and1,173 days after surgery, due to sudden death in 2 patientsand heart failure in 1 patient. Relationships were suspectedto exist between these late-phase deaths and CTEPH.

c) SummaryMedian sternotomy, which enables PEA in both right andleft pulmonary arteries in one stage, is used as the standardprocedure for treatment of CTEPH, and has yielded favor-able results, particularly in patients with central type ofCTEPH.16,124 The lateral thoracotomy technique should beconsidered only for patients with predominantly unilateraldisease with peripheral pulmonary lesions.

[Levels of Recommendations]1. PEA by lateral thoracotomy: Class IIb

2) PEA With Deep Hypothermia

(a) Indications for SurgeryFindings of various examinations including pulmonary angi-ography, MSCT, pulmonary perfusion scintigraphy and rightheart catheterization are important in determining treatmentstrategies for CTEPH. Daily et al125,126reported that surgicaltreatment of CTEPH is indicated for patients with a pul-monary vascular resistance of 300 dyneseccm5in whompulmonary angiography reveals occlusive lesions of the lobearteries, while Jamieson et al28,127described this technique asindicated for patients with (1) a mean pulmonary arterial


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pressure of 30 mmHg and a pulmonary vascular resistanceof 300 dyneseccm5; (2) central edges of thrombi locatedin surgically accessible areas; and (3) without serious compli-cations. Important determinants of the use of surgery for thetreatment of CTEPH are the configuration of occluded pul-monary arteries and clinical manifestations (New York HeartAssociation [NYHA] Class III or higher without shock).31,128,129In terms of configuration of affected pulmonary arteries, sur-gery is indicated for patients with central type of CTEPH

that affects central pulmonary arteries including the mainpulmonary artery, interlobar arteries, and segmental arteriesand causes mural thrombi and intimal hyperplasia, whileeffective surgical treatment may not be possible in patientswith peripheral type of CTEPH affecting peripheral portionsof segmental arteries and subsegmental arteries. Appropriateselection of patients is thus important.130

(b) Surgical TechniquesUnlike acute PTE, the thrombi in CTEPH are pale white, andorganized thrombi are attached firmly to the pulmonary arte-rial wall. During surgical treatment of CTEPH, organizedthrombi must be removed together with the intima.129The SanDiego group including Daily et al125and Jamieson et al28de-veloped a technique termed PEA in both lungs, which involvesa median sternotomy with cardiopulmonary bypass and deephypothermic intermittent circulatory arrest. PEA is the stan-dard surgical technique for the treatment of CTEPH,124,130134since CTEPH usually develops in both lungs; the right andleft lungs can be approached simultaneously; cardiac lesionscomplicated by CTEPH can be treated; and the risk of pul-monary bleeding due to thoracotomy is low.

a) Important Aspects of PEATechniques to remove thromboemboli alone without remov-ing the intima are completely ineffective in the treatment ofCTEPH. In removing the intima, it is important first to deter-mine the dissecting plane appropriately. Optimally, the dis-secting plane should be located between the internal elasticmembrane and the media. Second, since organized thrombiare hard and not fragile, the target thrombus and intima shouldbe slowly peeled peripherally to the segmental arteries bypulling the thrombus to remove the tree-like organized throm-bus with intima. Third, it is important to ensure a blood-freesurgical field. Jamieson strippers are useful for this purpose,and intermittent circulatory arrest should be performed asappropriate. The duration of circulatory arrest should be15 minutes each time. When venous oxygen saturation isdecreased to 90%, reperfusion should be performed for atleast 10 minutes before restart of circulatory arrest. Majorchallenges of PEA include the treatment of peripheral occlu-sive lesions for which surgical thromboendarterectomy can-not be performed by median sternotomy and treatment ofpatients with fragile mural thrombi for which traction duringdissection is difficult to perform.

b) Procedures for PEAa. Presurgical preparation: In patients with DVT and those

with a history of it, an IVC filter is placed before PEA.During surgery, patients should be monitored for deep bodytemperature (pharyngeal temperature), arterial pressure, andpulse oximetry. Transesophageal echocardiography andSwan-Ganz catheter placement are performed. Endotrachealtubes are placed in the right and left bronchi to prepare forpulmonary bleeding, and ice bags to wrap the head arealso prepared. Autologous blood recovery systems (Cell

Saver) are used during surgery.b. Following a median sternotomy, cardiopulmonary bypass

is performed with venous drainage from the superior venacava (directly) and the IVC (through the right atrium) andarterial return to the ascending aorta. When ventricularfibrillation occurs after the initiation of cooling, a left atrialvent is inserted from the right upper pulmonary vein.

c. Under hypothermia, the superior vena cava is freed com-pletely from the right atrium to the innominate vein. The

frontal surface of the right main pulmonary artery is ex-posed to the right superior pulmonary vein, and the leftmain pulmonary artery to the pericardial reflection.

d. PEA of the right pulmonary artery: A retractor is placedbetween the superior vena cava and the ascending aorta,and a vertical incision of the right pulmonary artery is madefrom level of mobilized aorta, past right upper lobe branch,and into the right lower lobe artery. On the posterior wall,a dissecting plane is developed to start PEA. In patientswith thrombus in the main pulmonary artery, the dissect-ing plane can be identified at the site of incision. Underhypothermia to a deep body temperature of 18C and inter-mittent circulatory arrest, PEA is performed distally toeach segmental artery using a Jamieson stripper. Follow-ing PEA, the right pulmonary artery is closed by doublerunning suture with monofilament material.

e. PEA of the left pulmonary artery: Using a heart net, theheart is tugged to the lower right-hand side, and the leftpulmonary artery is exposed from the pulmonary trunkto the pericardial reflection. The dissecting plane is de-veloped, and PEA is performed to each segmental arteryunder intermittent circulatory arrest. Following PEA, theleft pulmonary arterial wall is sutured and closed.

f. When an atrial septal defect is present, it is closed. Whencoronary artery bypass grafting (CABG) or surgical treat-ment of valvular disease is required, it is performed duringrewarming. Since tricuspid valve regurgitation is improvedwhen pulmonary arterial pressure is decreased, no surgicaltreatment for it is required, in principle.135

g. Following rewarming, withdrawal from cardiopulmonarybypass is attempted. The patient can be safely withdrawnfrom cardiopulmonary bypass when mean pulmonary arte-rial pressure is 30 mmHg or less. However, when pulmonaryarterial pressure is identical to systemic blood pressure orwhen severe bleeding from the respiratory tract is observed,PCPS is introduced before withdrawal from cardiopulmo-nary bypass, and protamine is administered thereafter.

h. Cardiac tamponade due to pericardial effusion may occurduring the several weeks after surgery. To prevent it, peri-cardial fenestration is performed on the left side, and adrainage tube is inserted into the left thoracic cavity.

c) Postoperative ManagementWhen a patient with PCPS has returned to the intensive careunit (ICU), withdrawal from PCPS is attempted over 2 to3 days. Pulmonary edema and endotracheal bleeding due toreperfusion injury are important postoperative complicationsrequiring careful attention.136 When prolonged respiratoryfailure develops, the patient should be carefully ventilatedusing positive end-expiratory pressure (PEEP) for a sufficientlength of time. After the risk of respiratory tract bleeding orbloody drainage is decreased, the patient should begin hepa-rin therapy and then be switched to oral warfarin. When PHpersists, long-term management of right heart failure withvasodilators (eg, prostaglandin [PG] E1and PGI2) and cate-cholamines is required.


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(c) Results of Surgical TreatmentThe operative mortality of patients undergoing PEA with car-diopulmonary bypass and deep hypothermic circulatory arrestfor the treatment of CTEPH were 11.7% (12/103)125 and12.6% (16/127)126in the case series reported by Daily et al,8.7% (13/150)28and 5.1% as reported by Jamieson et al,12710.1% (7/69) by Tscholl et al,1376% (66/1,100)138and 4.7%(52/1,100)139 by Thistlethwaite et al, 5% by Bonderman etal,1408.0% (7/88) by Ogino et al,32and 8.3% (7 out of 84 pa-tients undergoing elective PEA) by Ando et al.141The resultsof PEA have recently improved.

Although the long-term results of medical treatment ofCTEPH are not favorable, PEA is expected to improve car-diopulmonary hemodynamics and to yield a favorable long-term prognosis.134 It has been reported that the 6-year and5-year postoperative survival rate were 75%,2986%,32respec-tively, and so on. In the patients with persistent PH follow-ing surgery, long-term results are poor.124,131

(d) SummaryCTEPH does not respond to medical treatment. PEA is quiteeffective in the treatment of central type of CTEPH. PEA withcardiopulmonary bypass and deep hypothermic circulatoryarrest, which is performed increasingly often now, signifi-cantly improves pulmonary hemodynamics and pulmonarygas exchange, and is associated with favorable results. How-ever, patients with peripheral type of CTEPH should be care-fully evaluated to determine whether this surgery is indicatedfor them.

[Levels of Recommendations]1. PEA with cardiopulmonary bypass and deep hypother-

mic circulatory arrest for the treatment of central type ofCTEPH: Class I

2. PEA with cardiopulmonary bypass and deep hypothermiccirculatory arrest for the treatment of peripheral type ofCTEPH: Class IIa

3. Deep Vein Thrombosis

1 Diagnosis

(1) Basic ApproachDiagnosis and treatment of DVT should always be per-formed considering the risk of PTE (Figures 1,2). Patientsin the acute phase should be evaluated for the presence andlocation of thrombosis, the characteristics of possible sourcesof emboli, and the severity of venous insufficiency in select-ing appropriate treatment strategies.38,54,142Figure 3shows analgorithm for diagnosis of DVT during the acute phase.142,143DVT should be suspected on the basis of the history and phys-ical examination signs/symptoms, and the presence/absenceof known risk factors. Patients suspected to have acute-phaseDVT44 should be evaluated with appropriate imaging tech-niques that enable the presence of DVT to be promptly deter-mined. Noninvasive venous ultrasonography is the exami-nation of choice for evaluation of DVT in the extremities.53,144Minimally invasive contrast CT or magnetic resonance venog-raphy (MRV) should be performed to evaluate patients sus-pected to have abdominal or chest DVT.145147 When thepresence/absence of DVT cannot be not confirmed with theabove techniques, invasive contrast venography should beperformed.148 Differential diagnosis may be performed byquantitative assay. D-dimer can be used for patients in whomthe possibility of acute-phase DVT is low.149,150Patients withabnormal D-dimer levels should be evaluated with imagingtechniques to confirm the diagnosis. Physicians should beaware that the presence of normal D-dimer levels can excludeacute-phase DVT but cannot exclude chronic-phase DVT.Appropriate imaging techniques should be used to excludethrombosis. Prior to treatment, the causes of DVT should beinvestigated.

(2) History and Present IllnessDuring the history and physical examination, physiciansshould look not only for the symptoms of acute-phase DVTbut also those of PTE and arterial embolism.38,54,142 Acute-phase DVT should be suspected when swelling, pain, or colorchange of the extremities is present. Central type of DVTshould be suspected when unilateral swelling is noted. Cen-tral type of DVT is suspected in patients with femoral pain,while central or peripheral type of DVT is suspected in pa-tients with lower leg pain. Central type of DVT is suspectedwhen red purple skin is observed in the femoral region orlower leg. Patients with peripheral type of DVT are oftenasymptomatic. Physicians should suspect peripheral type of

Figure 3. Algorithm for diagnosis of deep vein thrombosis.CT, computed tomography; MRV, magnetic resonance ve-nography.

Figure 4. Diagnosis of deep vein thrombosis in the lowerlimbs by venous ultrasonography.


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DVT when patients present with dyspnea and/or chest pain.Patients should be evaluated for common known risk factorsof DVT (Table 3).

(3) Medical ExaminationPatients should be inspected visually for color change andswelling in the extremities, and the extremities should bepalpated for pathological changes in the deep veins andmuscles.38,54,142 Central type of DVT should be suspectedwhen color change or swelling is present in the extremities.The presence of palpable thrombotic veins in the groin isa direct finding of central type of DVT in the lower limbs.Stiff muscles in the lower legs are an indirect finding of cen-tral type of DVT, while tender muscles in the lower legs area direct finding of central or peripheral type of DVT. Centraltype of DVT should be strongly suspected when patientsexhibit skin color change and swelling as well as stiffnessand/or tenderness of the lower leg muscles.38,142Severe cen-tral type of DVT should be strongly suspected when dermalnecrosis of the lower legs as well as skin color change andswelling of the legs are present. A lower leg arterial Dopplertest should then be performed to evaluate blood flow inthe leg arteries. Patients in whom acute DVT recurs duringthe chronic phase of DVT exhibit findings of both chronicand acute DVT.

(4) Laboratory Examinations

1) Quantitative ExaminationsQuantitative examinations are used for differential diagnosisof DVT on the basis of blood chemistry findings and bloodflow. D-dimer is the most important item in screening forDVT. Blood flow is evaluated with ultrasonography, whichcan determine vessel blood flow, and plethysmography, whichcan determine blood flow in the lower limbs. Among ultra-sonographic techniques for diagnosis of DVT, continuouswave Doppler is used to check for arterial perfusion dis-order, while color Doppler and pulsed Doppler are used tocheck for occlusion and resumption of blood flow.38,142Airplethysmography is commonly used to evaluate lower limbsvein function.

2) Imaging TechniquesImaging techniques such as ultrasonography,151contrast CT,152MRV, and venography are used to confirm the morphologi-cal diagnosis of DVT. During lower limb venous ultrasonog-raphy (Figure 4), the following four steps of investigationshould be performed: (1) determination of the presence/ab-sence of thrombus in lower limb veins; (2) when thrombus is

detected, evaluation of its characteristics to stage disease;(3) when acute-phase DVT is present, determination of theextent of thrombus to determine the type of DVT; and (4)examination of the central edge of the thrombus to evaluate itas a potential source of emboli. Staging should be performedbased on comprehensive evaluation of noncompressing veins,brightness of thrombus, and perfusion defects, among otherfindings142(Table 8). Although venous ultrasonography is ahighly reliable technique for diagnosis of acute-phase DVT,it is of limited use in the diagnosis of chronic DVT. On con-trast CT, the diagnosis of DVT can be made based on findingsof venous filling defects. MRV can also provide findings ofthrombosis useful in the diagnosis of DVT, though its reli-ability is less than that of contrast CT. Since venographyprovides findings of venous filling defects and delineates theborder of thrombus, it can be used to diagnose DVT reliablyand exclude other possible diseases.153,154

3) Etiological EvaluationEtiological evaluation includes blood tests to check for ten-dency of thrombosis such as the presence of thrombophiliaand autoantibodies. Coagulation/fibrinolytic markers are use-ful in the determination of treatment strategies and the pre-vention of recurrent DVT. Patients should be examined forcongenital conditions such as protein S deficiency, protein Cdeficiency, and antithrombin deficiency as well as for acquiredconditions such as decrease in levels of coagulation inhibi-tors and increase in levels of tissue factors. Antiphospholipidantibodies, which are autoantibodies known to be associatedwith DVT, should also be tested.

[Levels of Recommendations]1. D-dimer: Class IIa2. Venous ultrasonography: Class I3. MRV: Class IIa4. Contrast CT: Class I5. Venography: Class I

2 Treatment

(1) Introduction (Current Concepts)Whether a thrombus developing in a deep vein will grow ornot depends on external factors as well as the balance be-tween the intrinsic and extrinsic coagulation systems and thefibrinolytic system surrounding the thrombus. In order toensure effective treatment of thrombosis, physicians shouldunderstand the effects of mechanical compression of veinssuch as that in pregnancy/delivery and surgical treatment,effects of tissue factors such as cancer on the coagulation

Table 8. Diagnosis of Acute and Chronic Deep Vein Thrombosis by Venous Ultrasonography

Criteria Acute phase Chronic phase

Vein Stenosis (compressibility)

Distention

Occlusion (noncompressing)

Distended

Stenosis (partial compression)

Contracted

Clots Floating

Regression

Consistency

Surface character

BrightnessHomogeneity

Free

None/moderate

Soft

Smooth

Low/middleHomogeneous

Fixed

Severe

Hard

Irregular

High/middleHeterogeneous

Blood flow Defect

Recanalization (in thrombus)

Collateral (in branch)

Total

Absent

Absent

Partial

Present

Present


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system, and abnormality or deficiency of regulatory proteinssuch as proteins C and S and antithrombin (Class I). Theoptimal method of treatment of DVT involves a combinationof techniques to prevent the development of PTE, eliminate ordissolve venous thrombus promptly, and prevent recurrenceof thrombosis, maintain the patency of veins, and preservethe function of venous valves. Physicians must consider theclinical severity and natural course of DVT in selecting drugtreatment, catheter interventions, and/or surgical thrombec-

tomy, among other techniques (Class IIa).

(2) Drug TreatmentHeparin and warfarin are the essential components of anti-coagulation therapy for patients with DVT (Class I).78,155,156Since the anticoagulative effect of unfractionated heparin,which is used in Japan, varies between individuals, the effectof heparin should be monitored with APTT and blood hepa-rin concentration. The target APTT in Europe and the UnitedStates is 1.5 to 2.5 times the control APTT.75,157159This levelappears appropriate in Japanese patients, as well (Class I).Following initial intravenous administration of 5,000 unitsof heparin, 10,000 to 15,000 units of heparin should be con-tinuously infused over 24 hours. The dose should be adjustedaccording to APTT values. When bleeding complicationsoccur, heparin treatment should be suspended or permanentlydiscontinued. Type II heparin-induced thrombocytopenia(HIT) is a serious treatment-related complication associatedwith arterial thrombosis and DVT caused by immune reac-tions. When it is suspected, heparin therapy must be discon-tinued immediately (Class I). Low molecular weight heparin,which is commonly used in Europe and the United States, isnot indicated for the treatment of DVT in Japan. However, theindications for low molecular weight heparin have expanded,and the prevention of VTE in patients undergoing total hipreplacement, total knee replacement, surgery for hip fracture,or abdominal surgery has recently been added to them.

When warfarin is administered to patients with throm-bosis, heparin and warfarin should be combined for 5 daysbefore starting warfarin monotherapy. The dose of warfarinshould be adjusted to achieve a PT-INR of 1.5 to 2.5 (target2.0) (Class IIb). The risk of bleeding complications increasesin patients with a PT-INR of 4. Patients with de novo DVTwith no known risk factors should receive warfarin for 3 to6 months (Class IIa), while patients with recurrent DVT orlong-term risk factors such as cancer, antithrombin deficien-cy, or antiphospholipid antibody syndrome should receivewarfarin as long as the relevant risks continue (Class IIa).Systemic thrombolytic therapy decreases the incidences ofDVT and the sequelae of thrombosis (Class IIa).160163Uro-kinase (UK) should be infused intravenously at a dose of60,000 to 240,000 units/day on Day 1 and at tapered dosesfrom Days 2 to 7 (Class IIa).

[Levels of Recommendations]1. Combined use of of heparin and warfarin in the treatment

of acute DVT: Class I2. Heparin control with a target APTT of 1.5 to 2.5 times

the control in the treatment of acute DVT: Class I3. Warfarin control with a target PT-INR of 2.0 (1.5 to 2.5)

times the control in the treatment of acute DVT: Class IIb4. Systemic thrombolytic therapy in the treatment of acute

DVT: Class IIa

(3) Physical Therapy (Exercise and Compression)During the acute phase of DVT, physicians should carefully

consider clinical severity and the natural course of DVT inselecting appropriate treatment such as drug treatment, cathe-ter interventions, and/or surgical thrombectomy, among othertechniques. Patients should following surgical thrombectomystart

Documents

Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Embolism and Deep Vein Thrombosis (JSC 2009) (1)