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Recurrent Deep Vein Thrombosis
Case 159-year-old man presented for pain and swelling of Lt calf. 3 years ago diagnosed with posterior tibial vein thrombosis treated with warfarin for several months. PE: Tenderness and warmth of the calf and increase in calf diameters of 3 cm compared with the other leg. Deep palpation of the calf muscles was painful. Recurrent DVT was suspected.What are the next diagnostic step?
Recurrent DVT: Strong risk factors
- Recent surgery- Trauma- Prolonged bed rest- Active cancer- Previous VTE
Recurrent DVT ½ occur in the unaffected contralateral leg
Lindmarker P, et al. J Intern Med 2000;247:601-6.
Diagnosis of 1st DVT- D-dimer- Compression ultrasonography (CUS)
CUS gold standard for diagnosis 1st DVTSensitivity >90% (proximal)
60% (distal) Specificity 100%
Goodacre S, et al. BMC Med Imaging 2005;5:6.
Diagnosis of recurrence DVT• Venography• Compression ultrasonography• CT venography • MR direct thrombus imaging
Venography- Invasive- Associated serious complications - Technical problem- Expertise declined
Diagnosing recurrent DVT in a previously affected vein segment - Increase in thrombus diameter of at
least 4 mm on serial CUS- Combination with D-dimer measurement
Proximal CUS should be performed at time of withdrawal of anticoagulation to obtain a baseline measurement
Suspected Recurrent DVT
Perform clinical assessment and measure D-Dimer
Full compressibility Non-diagnostic
Exclude DVT Treat
Re-consider clinical assessment
Whole-leg Compression Ultrasonography
Non-compressibility of vein not affected by 1st DVT
Likely Unlikely
D-Dimer+ D-Dimer- D-Dimer-D-Dimer+
Treat Exclude DVTConsider serial CUSor alternative imaging
Case 1• High clinical likelihood of recurrent DVT• Whole leg CUS, non compressibility of
femoral vein and popliteal vein • D-dimer positive supported thrombosis
What are the treatment options for a patient with a recurrent DVT?
Confirmed Diagnosis of Recurrent DVT
Start DOACs Consider of all-oral regimen if admission is not required
Evaluate duration of anticoagulation after 3 months
DVT triggered by a transient risk factor
DVT unprovoked
Start LMWH/VKADo not use VKA in cancer/pregnancy
Discontinue Continue
DVT triggered by a persistence risk factor
Continue as long as risk factorpersist and/or it is safe to do so
Anticoagulant treatment of recurrent DVT
How to estimate the bleeding risk?• Evaluate the bleeding risk before and
regular interval there after
• Estimation of bleeding risk relies on treating physician rather than on scientific evidence
How to estimate the bleeding risk?• Long-term major bleeding risk <1%->65% depend on
- advanced age- previous bleeding- cancer- thrombocytopenia- antiplatelet therapy- recent surgery- previous stroke- other comorbidities
Which anticoagulant regimen should be used for acute treatment?
• Similar to the first DVT• Immediate and intensive• UH, LMWH, or fondaparinux followed by
VKA• DOACs
- Direct Xa inhibitor: rivaroxaban,apixaban edoxaban
- Direct thrombin inhibitor: dabigatran
DOACs1. Apixaban 10 mg twice daily for 1 week
followed by 5 mg twice daily for month then 2.5 mg twice daily
2. Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
3. LMWH once or twice daily at therapeutic dose for at least 5 days followed by dabigatran 150 mg twice daily or edoxaban60 mg once daily
Pregnancy• LMWH at therapeutic dose until 24 hours
before induction of labor or caesareansection, and restart LMWH at reduced dose
Cancer• LMWH at therapeutic dose reduced to about
75% at 4 weeks for 6 months or as long as itis safe to do so
Transient risk factors
Surgery, trauma, prolonged bed rest, oral contraceptives, HRT, pregnancy/puerperium
Discontinue anticoagulants after 3 months
Persistent risk factors:- Inflammatory bowel syndrome- APS- Nephrotic syndrome- PNH- MPN - Behcet syndrome- Post thrombotic syndrome- Congenital venous malformation
Continue as long as risk factor persists and/or it is safe to do so
What is the optimal duration of anticoagulant?- Depend on risk of recurrent VTE- 1st provoked recurrent < 1st unprovoked- Transient risk 3-6 months- Persistent risk long-term
anticoagulant as long as bleeding riskdose not increase
1st unprovoked VTE have recurrence risk 30% over 5 years after discontinue anticoagulants
Prandoni P et al. Haematologica 2007;92:199-205.Rodger MA, et al. CMAL 2008;179:417-26.
Kyrle PA, et al. Lancet 2010;376:2032-9.
2nd unprovoked VTE recurrent >1.5 time of 1st unprovoked VTE 50% over 5 years
KearonC, et al. Chest 2012 141:e419S-e494S.
Unprovoked VTE• Treat 6 months --- recurrence 20.7%
one major bleeds• Treat infinitely --- recurrence 2.6%
2 fatal bleeds and 8 major bleeds
Long-term anticoagulant treatment• Patient’s preferences and concerns• Major life-style implications • Regular follow-up• Evaluate the quality of anticoagulation
and the adherence to treatment• Capture the appearance of new risk
factors of bleeding
Which anticoagulant regimen should be used for long-term treatment?
• DOACs conferred substantial riskreductions 64% - 92% comparedwith placebo
• DOACs effectively preventrecurrent VTE at an acceptablebleeding risk
• DOACs are alternative to VKA
The patient was healthy and no risk of bleeding, no need to admission, an all-oral DOAC regimen was started
The patient consented to long-term anticoagulant therapy after having been informed his 2nd unprovoked VTE with high risk of recurrent DVT and low bleeding risk
Adviced to take medicine regularly missing dose could result in thrombus progression, embolization or recurrent
Case 2 Recurrent DVT during anticoagulant therapy
A 27-years-old presented with swelling and pain of the right leg. PE: Revealed warmth, edema from the distal thigh downward to the ankle and tenderness on palpation of the calf. He often traveling by plane over long distances.
Case 2 Recurrent DVT during anticoagulant therapy
The D-dimer was elevated and CUS showed femoral vein thrombosis. He had already diagnosed with unprovoked proximal DVT of left leg 1 year earlier and long-term anticoagulation had been recommended. At the time of presentation he was still on VKA treatment.
What could be the reason for a recurrent DVT during anticoagulation?
• Insufficient intensity of anticoagulation• Non adherence to the medication• DOACs have short half-life missing dose
may increase the susceptibility forrecurrence
Possible underlying conditions for recurrent VTE during anticoagulation
• Insufficient intensity of anticoagulation
• Active cancer
• Anatomical abnormalities (M-T syndrome)*
• Myeloproliferative neoplasms (PV, ET)*
• Paroxysmal nocturnal hemoglobinuria*
• Phospholipid antibody syndrome*
• Heparin-induced thrombocytopenia
* Low level of scientific evidence
Recurrent VTE during VKA treatment1st step• Asses the quality of treatment by checkingINR at the time and earlier • ผปวยอาจหยดกนยาและมากนตอนทมาพบแพทย
ใหคา INR ด• Hypercoagulability risk factor potent
enough to over come the usual intensity of anticoagulation
• Cancer patient have more 3 foldshigher risk of recurrent VTE thannon cancer
- >80% occurred at therapeutic range- VKA recurrent 17%- LMWH recurrent 9%
• Unknown hidden malignancy
Recurrent DVT during anticoagulationWhile on VKA at INR <2 or on DOACs• Start LMWH once or twice daily at therapeutic
dose (at least 5 days) then VKA INR 2-3• Apixaban 10 mg twice daily for 1 week then
5 mg twice daily• Rivaroxaban 15 mg twice daily for 3 weeks
then 20 mg once daily• LMWH once or twice daily at therapeutic dose
for at lest 5 days then 150 mg dabigatran twicedaily or edoxaban 60 mg once daily
At INR ≥ 2• Vitamin K 10 mg orally or IV• LMWH once or twice daily at therapeutic dose
together with VKA INR 2.5-4.0 continue LMWH until a stable INR has reached (at least 5 days)
• LMWH once or twice daily at therapeutic dosetogether with VKA INR 2.0-3.0 and aspirin 100 mg one daily and continue LMWH until a stable INR reach (at least 5 days)
• LMWH once or twice daily at therapeutic dose• Fondaparinux weight-adjust at therapeutic dose
Recurrent DVT During Anticoagulation
While on VKA While on DOACs While on LMWH
INR < 2 INR < 2
StartLMWH/VKA
StartDOAC
GiveVitamin K
StartLMWH/VKA
High-dosaLMWH
Start LMWH/High intensity VKA
Start LMWH/VKAPlus aspirin
Start LMWH
Start Fondaparonux
While on LMWH• LMWH one or twice daily dose increase
by ~ 25%
Case 2INR 1.4The patient had stopped INR monitoring several months before. He refused to take VKA any longer→ DOAC regimen