Venous Thromboembolism ASH2017 · Perform clinical assessment and measure D-Dimer Full compressibility Non-diagnostic Exclude DVT Treat Re-consider clinical assessment Whole-leg Compression

Venous Thromboembolism

ASH2017

Wichai Prayoonwiwat

January 13, 2018

Outline

• To treat or not to treat :

- Superficial vein thrombosis

- Distal deep vein thrombosis

- Subsegmental pulmonary embolism

• How I treat recurrent DVT

• How I treat catastrophic syndrome

• How I use anticoagulant in AF

• Oral VTE 6 abstracts

Deep veins

Superficial veins

Superficial Vein Thrombosis

• Incidence: 0.3-0.6/1,000 py in younger and 0.7-1.5/1,000 py in older patients

• Most common manifestations: lower extremities and arm veins

• Risk factors similar to DVT/PE

• Patient with history of SVT had 6 times higher to develop DVT and 4 times to develop PE than controls

How I treat recurrent DVT? DVT: Chronic disease, often recurs

Case 1 59-year-old man presented for pain and swelling of Lt calf. ~ 3 years ago diagnosed with posterior tibial vein thrombosis treated with blood thinner 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 DVT Sensitivity >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 DVT Consider serial CUS or 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/VKA Do not use VKA in cancer/pregnancy

Discontinue Continue

DVT triggered by a persistence risk factor

Continue as long as risk factor persist 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

DOACs 1. 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 edoxaban 60 mg once daily

Pregnancy • LMWH at therapeutic dose until 24 hours before induction of labor or caesarean section, 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 it is 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 risk dose 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 risk reductions 64% - 92% compared with placebo • DOACs effectively prevent recurrent VTE at an acceptable bleeding 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 plan 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 for recurrence

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 treatment 1st step • Asses the quality of treatment by checking INR 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 folds higher risk of recurrent VTE than non cancer

- >80% occurred at therapeutic range - VKA recurrent 17% - LMWH recurrent 9%

• Unknown hidden malignancy

Recurrent DVT during anticoagulation While 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 twice daily 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 dose together 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

Start LMWH/VKA

Start DOAC

Give Vitamin K

Start LMWH/VKA

High-dosa LMWH

Start LMWH/ High intensity VKA

Start LMWH/VKA Plus aspirin

Start LMWH

Start Fondaparonux

While on LMWH • LMWH one or twice daily dose increase by ~ 25%

Case 2 INR 1.4 The patient had stopped INR monitoring several months before. He refused to take VKA any longer → DOAC regimen

How I treat catastrophic thrombotic syndrome

• A 14-year-old young man developed progressive headache, nausea, vomiting, and tonic-clonic seizure several days ago.

• He had extensive dural sinus thrombosis and started on anticoagulant therapy, but DIC and thrombocytopenia developed, limiting treatment with anticoagulants.

• Testing for APA and HIT were negative, and heparin was restarted at the coagulopathy resolved.

How I treat catastrophic thrombotic syndrome

• Despite aggressive efforts, severe brain swelling with herniation developed, and effort to save him were withdrawn after documenting lack of blood flow above the internal carotid arteries

• Autopsy: Bilateral pulmonary emboli and iliac vein occlusion in addition to extensive intracranial venous thrombosis

Thrombotic storm (Kitchens 1998)

• Underlying hypercoagulable state

• Provocative factor is frequently associated with initiation of thrombotic process.

• New thrombotic events develops rapidly

• Prompt initiation of antithrombotic therapy

• Long-term is good, if the cycle of thrombosis is interrupted early

Kitchens CS, et al. Am J Med 1998;104:381-5.

What are the “catastrophic” thrombotic syndrome?

• Catastrophic APS

• Atypical TTP

• Cancer-associated thrombosis

• Delayed or spontaneous HIT

• Idiopathic catastrophic thrombosis

Catastrophic APS • Asherson 1992 ……..10 cases

• Multiple vascular occlusive events

• Small vessels of internal organs (brain, lungs, kidneys)

• Precipitating factor: Infection, medication, surgery, anticoagulant withdrawal

• Rare 1% of APS

• Treatment: Anticoagulants, plasma exchange, corticosteroids, IVIg, rituximab, cyclophosphamide

Asherson RA, et al. J Rheumatol 1992;19:508-12.

Asherson RA, et al. Medicine1998;77:195-207.

Atypical TTP • Acute thromboembolic stroke, acute

coronary syndrome

• Precipitating factor: Pancreatitis, surgery, infection, medication, pregnancy

• Decreased ADAMTS13, schistocytes, thrombocytopenia

• Treatment: Plasma exchange, immunosuppression

.

HITT • Transient

• Immune-mediated disorder caused by Ab bind PF4-heparin complex

• Affect large vessels, VTE > arterial events

• Multiple thrombotic events

• Anticoagulant with non heparin agents

• Plasma exchange in refractory HIT

.

Cancer-associated thrombosis

• VTE is a leading cause of death

• Know and unknown cancer at presentation

• Superficial and deep venous thrombosis and arterial thrombosis

• Associated with DIC

• Anticoagulant with LMWH

• Treat underlying malignancy

.

Other disorders

• Idiopathic hypereosinophilic syndrome

• Kimura disease

• Inflammatory bowel disease

• Behcet disease……DVT

• Homozygous protein C deficiency

.

Diagnostic approach to CT

• History and physical examination

• Diagnostic imaging

• Laboratory studies: CBC, PBS, BUN Cr, LFT, LDH, PT, APTT, fibrinogen, D-dimer

• Special tests: Anti-PF4/heparin Ab, ADAMTH13, APL, antithrombin

.

Therapeutic management

• Frist, therapeutic anticoagulation

• Second, additional therapies: plasmapheresis, immunomodulators

• Third, ongoing management, review response, new complication

• Fourth, collaborative of specialists

• Indefinite anticoagulant therapy

.

• Frist, therapeutic anticoagulation

• Second, additional therapies: plasmapheresis, immunomodulators

• Third, ongoing management, review response, new complication

• Fourth, collaborative of specialists

• Indefinite anticoagulant therapy

.

Acute onset multiple thromboembolic events

History/PE, diagnostic imaging, and initial laboratory studies

MAHA,TP LDH

Normal

Data not suggestive of malignancy

Additional diagnostic laboratory studies

TTP or other TMA

HITT Catastropic APS

Cancer/Trousseau’s syndrome

Data suggestive of malignancy

Additional diagnostic evaluations

APL, +TP TP Positive

Negative

Idiopathic Catastropic TE

IVC Filter USE: Summary • Dramatic increased use 1970s-2010

(but rate now decreasing)

• Wide variation in practice patterns

• No proven benefit for any indication

• Many filters are being placed for inappropriate indications

• Most retrievable filters are not removed

• Post-insertion complications are common

• Almost all filters are removable

Choose wisely!

How I use anticoagulant in AF

• Most common cardiac arrhythmia

• Conveys a significant risk of morbidity/mortality due to related stroke and systemic emboli

• Oral anticoagulant: mainstay of TE prevention

Decision for anticoagulation

• Stroke risk

• Bleeding risk


• NOACs over warfarin, safer and more effective in non valvular and normal renal function

• No direct randomized comparison

CHA2DS2-VSc • Congestive heart failure (1 point)

• Hypertension (1 point)

• Age >75 years (1 point)

• Diabetes (1 point)

• Stroke or TIA (2 point)

• Vascular disease (1 point)

• Age 65-74 years (1 point)

• Sex category (1 point-female/0 point-male)

Lip GY et al. Chest 2010;137:263-72.

HAS-BLED

• Hypertension (1 point)

• Abnormal liver or renal function (1 point each)

• Stroke (1 point)

• Bleeding (1 point)

• Labile INR (1 point)

• Elderly age >65 years (1 point)

• Drugs or alcohol (1 point each)

Pister R, et al. Chest 2010;138:1093-100.

Valvular AF or

non valvular AF + CHA2DS2-VSc > 2

CHA2DS2-VSc =1

No therapy

Warfarin vs NOAC

No Yes

Consider no Therapy, ASA

Alone, or OAC in Selected patient

No

Mechanical valve or Mod/severe MS or

severe CKD

Warfarin 1. NOAC 2. Warfarin

Yes

Yes No

How I use anticoagulant in AF A 74-year-old woman with new-onset palpitation and history of hypertension and hypothyroidism PE: AF 130/min, no sign of CHF, CBC, coagulogram, and blood chemistries were normal, CrCl 66 mL/min normal thyroid function studies She was administed Ca channel blockade for rate control and therapeutic-dose SC enoxaparin and a synclonized cardioversion Home medication: enoxaparin and warfarin Follow up as OPD patient


• New diagnosis of AF • No reversible cause of AF • Current guideline recommend

systemic OAC for at least 4 weeks following cardioversion

• CHA2DS2-VASc = 3 • Need long-term OAC • Switch to NOACs

Oral VTE Abstracts 1. RNA sequencing approaches to identify novel biomarkers for VTE in Lung Cancer

Tamara A. Sussman, MD, Cleveland Clinic

2. Aging-associated inflammation due to elevated levels of TNF-a increases

activation of the integrin aIIbß3 and the procoagulant potential of platelets

Pavel Davizon-Castillo, MD, University of Colorado

3. Development and external validation of thrombosis lymphoma score - Interim

Analysis

Darko Antic, Clinical Center Serbia

4. Elevated Gas6 plasma level as a predictor of VTE recurrence and mortality in a

prospective multicenter cohort of elderly patients with VTE

Annatina Schnegg-Kaufmann, MD, Inselspital, Bern University Hospital

5. Rebound hypercoagulability following a conventional course of

anticoagulation and the risk of recurrent VTE in young patients: First analysis of

the kids-DOTT multicenter trial-derived biobank

Marisol Betensky, MD,MPH, Johns Hopkins All Children's Hospital

6. The identification of high risk APS patients for thrombosis with triple

antiphospholipid antibody positivity Is platform dependent

Walid Chayou, MSc, Maastricht University

RNA Sequencing Approaches to Identify Novel

Biomarkers for VTE in Lung Cancer Tamara A. Sussman, MD, Cleveland Clinic

• To identify novel biomarkers of cancer-

associated VTE

• 6 each with or without VTE with a median

age of 67 years

• 6 patients with VTE, 50% had PE, 33%

had lower extremity DVT, and 17% had

catheter-associated thrombus

• Revealed a total of 1037 genes with statistically significant (p <0.05) differential expression.

• In patients with VTE, 869 genes were over-expressed and 168 were under-expressed compared to patients without VTE

• Genes of interest over-expressed in patients with VTE included complement receptors: CECR1, CR1, MIAT, SHC4, NLRP14, IL5RA, IL16 , CLNK, and XCL1

RNA Sequencing

RNA Sequencing

• GSEA revealed over-expression of genes

involved in IL2-STAT5 signaling, IL6-JAK-

STAT3 signaling, IFN-gamma response,

inflammatory response, KRAS signaling,

and complement pathway.

• In lung cancer patients without VTE,

GSEA revealed over-expression of genes

involved in apoptosis and epithelial

mesenchymal transition pathways.

Conclusions

• Complement and inflammatory pathways are upregulated in lung cancers that develop VTE

• These differentially expressed genes and pathways provide novel biologic insight into cancer-associated VTE

• May lead to development of new risk stratification as well as therapeutic strategies.

Aging-Associated Inflammation Due to Elevated Levels

of TNF-a Increases Activation of the Integrin aIIbß3 and

the Procoagulant Potential of Platelets

Pavel Davizon-Castillo, MD, University of Colorado

• Aging: Independent risk factor for VTE

• Increased TNF-a levels during aging alter

platelet function to promote thrombosis

remains unexamined

• TNF-associated inflammation of aging is an

important factor in the development of platelet

hyperreactivity during aging and may

contribute to the increased incidence of age-

associated thrombosis

Aging-Associated Inflammation Due to Elevated Levels

of TNF-a Increases Activation of the Integrin aIIbß3 and

the Procoagulant Potential of Platelets Pavel Davizon-Castillo, MD, University of Colorado

• Integrin aIIbß3 activation was significantly

greater in activated platelets from older

adults (mean age 78.0 ± 8.4) compared to

younger adults (mean age 35.0 ± 10.1).

• MK reprogramming in aging, due to chronic

inflammation, and serve to identify potential

candidates regulating aging-associated

platelet hyperactivity

Development and External Validation of Thrombosis

Lymphoma /Throly/ Score - Interim Analysis


• Lymphoma patients are at increased risk of

thromboembolic events

• Thromboprophylaxis in these patients is

largely underused

• Study population: NHL, HL, and CLL/SLL

• Data were collected form Serbia, USA,

France, Spain and Macedonia

• Internal (584 patients) and external validation

cohort (822 patients)

• The incidence of VTE was 81 (5.3%) in the

newly diagnosed patients and 18 (6.2%) in

relapsed patients.

• Overall, 35.4% (35/99) of the patients with

thromboembolism experienced the event

before the start of chemotherapy.

• The majority of patients (64.6%) had TE

events during chemotherapy or within 3

months after chemotherapy.




• The variables independently associated with

risk for VTE

- previous venous and/or arterial events

- mediastinal involvement

- BMI >30 kg/m2

- reduced mobility

- extranodal localization

- development of neutropenia

- hemoglobin level < 100g/L




• we can conclude that developed

prognostic Thrombosis Lymphoma –

ThroLy score is more specific for

lymphoma patients than any other

available score targeting thrombosis in

cancer patients.

• Model calibration will be needed based

on data from large prospective cohort

studies.




Elevated Gas6 Plasma Level As a Predictor of Venous Thromboembolism

Recurrence and Mortality in a Prospective Multicenter Cohort of Elderly

Patients with Venous Thromboembolism


• Growth arrest-specific gene 6 (Gas6) is a pro-

hemostatic protein with multiple functions, including

an effect on coagulation and platelet function,

enhancing platelet aggregation and expression of

tissue factor in endothelial cells as well as

promoting the recruitment of platelets and

leukocytes to the endothelial cell membrane.

• The goal of this study was the assessment of the

predictive ability of Gas6 levels for recurrent venous

VTE and mortality, as well as the comparison to D-

Dimer levels

• Gas6 levels measured at diagnosis of acute VTE

were associated with higher risk of VTE recurrence

and mortality in an elderly population.

• 12 month after the first VTE episode, only Gas6

levels were associated with higher risk of VTE-

recurrence, whereas higher D-Dimer levels were

associated with higher mortality.

• Our findings suggest that a clinical decision to avoid

prolonged anticoagulation could be made based on

Gas6 plasma level in the elderly.

Elevated Gas6 Plasma Level As a Predictor of Venous Thromboembolism

Recurrence and Mortality in a Prospective Multicenter Cohort of Elderly

Patients with Venous Thromboembolism


Rebound Hypercoagulability Following a Conventional Course of

Anticoagulation and the Risk of Recurrent Venous

Thromboembolism in Young Patients: First Analysis of the Kids-DOTT

Multicenter Trial-Derived Biobank


• Limited knowledge of prognostic factors for

recurrence in adult and pediatric VTE

• Elevated D-dimer levels following a 6-month course

of anticoagulation in adults with unprovoked VTE are

associated with a heightened risk of VTE recurrence,

warranting prolonged therapy.

• Provoked VTE, and young VTE patients prognostic

factors remain largely undefined.

• We observed a phenomenon of rebound

hypercoagulability at 3 months post-diagnosis,

relative to 4-6 weeks post-diagnosis, in a group of

children with provoked VTE

• To evaluate the prevalence of relative

rebound hypercoagulability at 3

months status-post acute VTE in

patients <21 years old

• To investigate an association of relative

rebound hypercoagulability with

recurrent VTE






• Conclusions: Relative rebound

hypercoagulability, as measured by

change in MA in the CloFAL assay,

developed in 13% of a multicenter

study population of patients <21 years

old with predominantly-provoked VTE,

and was associated with a 4-fold

increased risk of recurrent VTE.






The Identification of High Risk APS Patients for Thrombosis with

Triple Antiphospholipid Antibody Positivity Is Platform Dependent


• APS is characterized by thrombosis and/or specific

pregnancy morbidity with the persistent presence of

aPL.

• Laboratory criteria include aPL detection by LAC or

aß2GPI and aCL IgG/IgM antibodies.

• Triple positivity (positivity for LAC, aCL and aß2GPI

Abs is associated with a high risk for both a first

thrombotic event and recurrence.

• To investigate the variability in triple positivity

detection and its clinical association between

different aPL platforms.

• Our study confirmed the high-risk profile for thrombosis

associated with triple positivity, independent of the

platform used to detect aß2GPI, aCL, and aPL.

• Number of triple positives is dependent on the platform

used, resulting in varying sensitivities of triple positivity

for thrombosis over the different platforms.

• The high risk on recurrent clinical complications in triple

positive APS patients often requires them to take

indefinite oral anticoagulant treatment.

• Therefore, to avoid misclassification of high-risk APS

patients, standardization/uniformity of solid phase

assays for the diagnosis of APS is urgently warranted.

The Identification of High Risk APS Patients for Thrombosis with

Triple Antiphospholipid Antibody Positivity Is Platform Dependent


Thank you for your attention

Documents

Venous Thromboembolism ASH2017 · Perform clinical assessment and measure D-Dimer Full compressibility Non-diagnostic Exclude DVT Treat Re-consider clinical assessment Whole-leg Compression