Updates in Thrombosis Dr. Ali Y. Al-Muhaini MBBch FRCP(C) - - PowerPoint PPT Presentation

Updates in Thrombosis

• Dr. Ali Y. Al-Muhaini

MBBch FRCP(C) Chairman of the Internal Medicine Department Head of the Division Of Clinical Hematology Jaber Al-Ahmed Al-Sabah Hospital

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Introduction

• What is deep vein thrombosis?
• Thrombus formation within the deep venous system
• It can occur in any vein
• Most clinical events arise in the deep vessels of the

legs, subsequently embolize to the lungs.

• DVT is a frequent occurrence in the general

population, with an estimated annual incidence rate of 0.1-0.2%.

Introduction

• Of those who present with symptoms of possible DVT,

~25% have confirmed DVT

• 80% are proximal and 20% have DVT limited to the calf
• 50% of patients with documented DVT will have PE
• In DVT limited to the calf, 20-30% may extend within 1-2

weeks of presentation

• PE is found in 15% of adult patients who had been

hospitalized

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Introduction

• Risk factors for VTE
• Underlying, such as obesity, increasing age, previous VTE, etc.
• Transient, such as acute trauma, immobility, surgery, etc.
• Virchow’s triad describes the three broad factors that contribute to thrombosis,

which are:

• Vascular wall injury
• Hypercoagulable state
• Circulatory stasis

Classification of Risk factors for Thrombosis ACQUIRED FACTORS

Strong risk (odds ratio > 10)

• Surgery, especially orthopedic
• Spinal cord injury
• Hip or knee replacement
• Major trauma

Moderate risk (odds ratio 2- 9)

• Malignancy
• Presence of a central venous

catheter

• Pregnancy/postpartum
• Oral contraceptives
• Hormone replacement therapy
• Hyperhomocysteinemia
• Antiphospholipid antibody syndrome
• Medical conditions
• Stroke
• Congestive heart failure
• Inflammatory bowel disease

Weak risk (odds ratio < 2)

• Bed rest > three days
• Immobility due to sitting
• Increasing age
• Obesity
• Varicose veins

Classification of Risk factors for Thrombosis

Classification of risk factors for Thrombosis

Hereditary Haemostatic disorders

• 1. Factor V Leiden
• 2. Prothrombin G20210A variant
• 3. Protein C deficiency
• 4. Antithrombin deficiency
• 5. Protein S deficiency
• 6. Dysfibrinogenaemia

Mixed hereditary / acquired disorders

• 1. Raised plasma levels of factor VIII
• 2. Raised plasma levels of fibrinogen
• 3. Raised plasma levels of homocysteine

Who To Test

Why to Test

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Mode of Action

Conventional approach

Dual Drug Approach

Single Drug Approach

• 15mg BID for

the first 3 weeks then 20mg OD

Rivaroxaban

• 10mg BID for 1

week followed by 5mg BID

Apixaban

Reasons Contributing for long term treatment

Reasons Contributing for long term Treatment

DOACs

DOACs

Betrixaban

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Anticoagulation Guidelines 2016

For VTE without an associated cancer diagnosis, all direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban) are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B) and VKA therapy is recommended over low molecular weight heparin (LMWH; Grade 2C). For VTE associated with cancer, LMWH is recommended over VKA (Grade 2B) or any direct oral anticoagulants (all Grade 2C). Anticoagulants should stop after 3 months of therapy in patients with an acute, proximal deep venous thrombosis (DVT) provoked by surgery rather than shorter or longer treatment courses (Grade 1B). Anticoagulants should also be stopped after 3 months in patients with a proximal DVT

• r pulmonary embolism (PE) provoked by a nonsurgical transient risk factor over

shorter or longer courses (Grade 1B for high bleeding risk patients, Grade 2B for low or moderate bleeding risk patients).

Anticoagulation Guidelines 2016

Anticoagulation should be given for 3 months in patients with a first unprovoked VTE and a high risk of bleeding (Grade 1B), but should be extended without a scheduled stop date in patients with a low or moderate risk of bleeding (Grade 2B). For patients with acute VTE who are treated with anticoagulation, the guideline recommends against the use of an inferior vena cava filter (Grade 1B). For patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy, the guideline suggests the use of aspirin over no aspirin to prevent recurrent VTE if there are no contraindications to aspirin therapy (Grade 2B). For patients with acute DVT, the guideline recommends against the use of compression stockings routinely to prevent the post-thrombotic syndrome (Grade 2B).

Anticoagulation Guidelines 2016

For patient with subsegmental PE and no DVT, the guideline suggests clinical surveillance over anticoagulation when the risk of VTE recurrence is low (Grade 2C). The guideline recommends the use of anticoagulation over surveillance when the risk of VTE recurrence is high (Grade 2C). Thrombolysis should almost always be reserved for hypotensive patients, and should be given systemically, rather than catheter-directed. For isolated distal DVT of the leg, the choice between anticoagulation and serial ultrasound at 2 weeks should be made based on risk for thrombus extension, risk for bleeding, and patient preference. Home treatment is recommended for patients with low-risk PE. Patients should be switched to LMWH if they have recurrent VTE on another therapy; patients with recurrent VTE on LMWH should have their dose increased.

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Can DOAC’s be Use in APLS ?

Antiphospholipid Antibody Syndrome (APS) is defined by two major components:

• Presence in the serum of at least one type of

autoantibody (aPL) 3 month apart.

• Lupus anticoagulants (LA)
• Anticardiolipin antibodies
• Antibodies to beta2-glycoprotein
• The occurrence of at least one of the following clinical

features:

• Venous or arterial thromboses
• Pregnancy morbidity.

GENERAL APPROACH TO THERAPY

The mainstay of treatment for APS include:

Heparin Warfarin Aspirin Direct oral anticoagulants (DOACs) only in special situations

GENERAL APPROACH TO THERAPY

The approach to treating antiphospholipid syndrome (APS) varies with the clinical presentation. Recurrance rate with or without warfarin is up to 11% per year. The frequency of recurrent clinical events and the potentially devastating nature of these events are strong arguments for lifelong anticoagulation in most patients.

VTE in APLS

• The initial treatment of VTE in patients with APS is

the same as that for idiopathic thromboembolic disease.

• The standard of care for both of these clinical

complications is treatment with heparin, followed by warfarin.

• The current standard of care for the long-term

management of the APS is to maintain the INR between 2.0 and 3.0 for an initial venous thromboembolic event

Arterial Thrombosis

• There is disagreement among experts regarding the
• ptimal therapy of APS with arterial thrombosis
• The combination of warfarin, with a target INR of 2.0

to 3.0, and low-dose aspirin (81 mg/day).

• Other experts treat to a target INR of greater than

3.0

Duration of VKA Use

• Indefinite antithrombotic therapy in patients with

definite APS and thrombosis is recommended.

• Treating for a more defined period in patients with a

provoked first VTE, and a non- diagnostic or low-risk aPL profile

Treatment Failure

• If thrombotic events recur during warfarin therapy despite INR levels that are

within the target range of 2.0 to 3.0 the treatment alternatives include:

• Increasing the target INR (3.1 to 4.0)
• Adding low-dose aspirin
• Low molecular weight heparin (LMWH)
• HCQ
• The choice between these options is based in part upon patient

characteristics:

• Reliability to maintain a higher INR
• Bleeding risk

Can We Use DOAC’s in APLS ?

• There has been interest in the use of DOACs for APS

due to:

• Convenience
• Lack of need for laboratory monitoring
• Decreased risk of bleeding
• The available evidence suggests:
• They are less effective than VKA for thrombosis

prevention.

Can We Use DOAC’s in APLS ?

• TRAPS Trial
• 120 high-risk patients with APS who were randomly

assigned to receive Rivaroxaban or Warfarin

• Mean follow-up, 569 days
• There were more thromboembolic events in the

Rivaroxaban group (12%) compared to the Warfarin group, resulting in early termination of the study

• There were more major bleeding events in the

Rivaroxaban group (four versus two).

Can We Use DOAC’s in APLS ?

• A meta-analysis of observational studies that included 447 patients with APS

treated with a DOAC (either rivaroxaban, dabigatran, or apixaban) Showed:

• 73 patients (16 percent) experienced a recurrent thrombosis with a mean

duration until thrombosis of 12.5 months.

• A prior history of arterial thrombosis was also associated with a higher risk of

recurrent thrombosis (OR 2.8, 95% CI 1.4-7.7).

• A 2016 systematic review including 122 case reports of patients with APS treated

with DOACs revealed:

• 19 patients who experienced a recurrent thrombosis during treatment with a

DOAC

• Triple positivity for aPL was associated with a 3.5-fold increased risk of

recurrent thrombosis.

Can We Use DOAC’s in APLS ?

• Exceptions to the avoidance of DOACs in APS may

include:

• Individuals who cannot tolerate Warfarin
• In these settings, it is important to inform the

patient about the available evidence.

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

Can DOAC’s be Use in Malignancies ?

• Malignancy is a known risk factor for venous and arterial thrombosis.
• It is the second leading cause of death in cancer patients
• VTE occurs in approximately 5–10% of cancer patients, a 4 to 7-fold

increased risk over patients without cancer.

• Standard-of-care management of cancer-associated VTE for over a decade

has been therapeutic anticoagulation with low molecular weight heparin (LMWH)

• Recent evidence suggesting non-inferiority of oral direct factor Xa inhibitors

to prevent cancer-associated VTE recurrence .

• It’s an attractive option given their oral bioavailability, but are they optimal in

all cancer patient populations.

Summary of Randomized Trials Comparing VKAs with LMWH

Randomized Trials Comparing DOACs with LMWH

• The Hokusai VTE Cancer trial
• Enrolled 1050 cancer patients with acute symptomatic
• r incidental PE or proximal VTE.
• Two groups received either
• LMWH for 5 days followed by edoxaban 60 mg daily
• Dalteparin 200 IU/kg daily for one month followed by

150 IU/kg daily

• Patients were treated for 6–12 months on study.

Randomized Trials Comparing DOACs with LMWH

• The SELECT-D trial
• Enrolled 406 cancer patients with acute symptomatic
• r incidental PE or symptomatic proximal DVT
• Two groups:
• Rivaroxaban (15 mg twice daily for 3 weeks, then 20

mg once daily for a total of 6 months)

• Dalteparin (200 IU/kg daily for 1 month followed by

150 IU/kg daily for 5 months)

Summary of Randomized Trials Comparing DOACs with LMWH

Recommendations for Use of Each Class of Anticoagulant for Treatment of Cancer Associated VTE

Today

• Introduction
• Causes of VTE
• Treatment Options
• DVT & PE Treatment Guidelines ACCP 2016
• Can DOAC’s be Use in APLS ?
• Can DOAC’s be Use in Malignancies ?
• DOACs Reversal
• Conclusion

General Principles of Management of Anticoagulation Associate bleeding

Reversal Of Dabigatran Non-Urgent

Reversal Of Apixaban Non-Urgent

Reversal Of Rivaroxaban Non-Urgent

General Principles of Management of Anticoagulation Associate bleeding

• Idarucizumab for Dabigatran r

eversal.

• Andexanet Alfa for Rivaroxab

an, Apixaban and Edoxaban r eversal.

Take Home Message

• VTE
• DOACs
• APLS
• Cancer