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46th Annual UCSF Advances in Internal Medicine

Updates in Hematology:Thrombosis & A Little Anemia

AndrewD.Leavitt,MD

May10,2018

Topic Outline

1. VTE – Comparing notes: What would you do?

2. Review of some AACP/Chest Guidelines

3. Direct Oral Anti-Coagulants (DOACs): A Little Review

4. DOACs and Patients with Cancer

6. Superficial Venous Thrombosis (SVT)

7. Anemia Cases – A Couple Cases from General Medicine

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Ø A 32 year old man comes to your office with 5 days of progressive discomfort in his left leg, and 2 days of swelling from the knee down.

Ø No significant PMH. He takes no Rx. He cannot recall any particular injury other than having been kicked in the left leg while playing soccer 10 days previously. He is afebrile.

Ø History and exam lead you to suspect a DVT. You ssend him for a left leg ultrasound

CASE 1: What Would You Do?

Case 1. Doppler ultrasound demonstrates occlusive thrombosis in the left femoral vein from the mid thigh distally into the popliteal vein. YOU WOULD?...

1. Start him on LMWH with bridge to warfarin.

2. Start LMWH & 1 week later switch to oral Dabigatran (PRDAXA)

3. Start him on oral Rivaroxaban (XARELTO)

4. Start him on oral Apixaban (ELIQUIS)

5. Start LMWH & 1 week later switch to oral Edoxaban (SAVAYSA)

6. Admit him to the hospital for treatment

7. Other

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Case 2. Same story as Case 1, but this time the ultrasound demonstrates occlusive thrombosis in the left posterior tibialand peroneal veins (deep veins of the calf) with no clot in the popliteal or femoral veins. YOU WOULD?...:

1. Start him on LMWH with bridge to warfarin.

2. Start LMWH & 1 week later switch to oral Dabigatran (PRDAXA)

3. Start him on oral Rivaroxaban (XARELTO)

4. Start him on oral Apixaban (ELIQUIS)

5. Start LMWH & 1 week later switch to oral Edoxaban (SAVAYSA)

6. Admit him to the hospital for treatment

7. Other

Case 3. Same guy, but this time, in addition, to the the ultrasound demonstrating occlusive thrombosis in the left femoral vein from the mid thigh distally into the popliteal vein, he admits to pleuritic chest pain over the past two days but denies SOB. A Chest CT Angiogram shows a L upper lobe segmental PE. BP 132/86, HR 89, RR 16, O2 Sat 98% on room air, EKG normal.

1. Start him on LMWH with bridge to warfarin.

2. Start LMWH & 1 week later switch to oral Dabigatran (PRDAXA)

3. Start him on oral Rivaroxaban (XARELTO)

4. Start him on oral Apixaban (ELIQUIS)

5. Start LMWH & 1 week later switch to oral Edoxaban (SAVAYSA)

6. Admit him to the hospital for treatment

7. Other

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In patients with proximal or isolated distal DVT of the leg, or PE, and no cancer, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) anticoagulant therapy.

If not treated with a DOAC, we suggest VKA over low molecular weight heparin (LMWH).

AACP/Chest Guidelines 10th ed. 20161

1. Kearon et al., Chest (2016) 149:315-52

Which Agent?

Chai-Adisksopha et al. Blood (2014) 124:2450-8

DOACsandBleeding– AMeta-analysis

Compared to warfarin, DOACS were associatedwith a reduced rate of:

-Major bleeding by ~28%

-Intracranial and fatal hemorrhage by ~50%

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1. 3 months

2. 6 months

3. 12 months

4. 24 months

5. Indefinitely

6. Other

CASE 3: What Would You Do?

We all agree he needs treatment, but for how long?

In patients with a proximal DVT of the leg, or PE provoked by surgery, or nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period, (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months), or (iii) extended therapy (no scheduled stop date).

AACP/Chest Guidelines 10th ed. 20161

1. Kearon et al., Chest (2016) 149:315-52

How Long? - Provoked

In patients with a isolated distal DVT of the leg provoked by surgery or nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over shorter or longer treatment periods. BUT, it is anticipated that not all patients diagnosed with isolated distal DVT will be prescribed anticoagulants

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In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration, and we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months)

In patients with a unprovoked proximal DVT or PE and who have a (i) low or moderate bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months. If a high bleeding risk, we suggest 3 months over extended therapy (no scheduled stop date).

In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE

AACP/Chest Guidelines 10th ed. 20161

1. Kearon et al., Chest (2016) 149:315-52

How Long? – Unprovoked

Bleeding Risk Assessment

Kearon et al., Chest (2016) 149:315-52 (AACP/Chest Guidelines 10th ed.)

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Guidelines…are Guidelines…not Laws:They are where you start your thinking, not where you end it.

Kearon et al., Chest (2016) 149:315-52 (AACP/Chest Guidelines 10th ed.)

CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.

METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low-(Grade C) quality evidence.

Anticoagulation Care Tips

1. Everyone wants to know ‘how long?’ But you cannot please everyone.

2. I do not say life-long. Extended….indefinite…let’s see…?

3. What are the patient’s wants AND fears?

4. Extended use REQUIRES ongoing risk/benefit assessment.

5. DOACs and renal function!

6. DOACs and anti-platelet agents

7. Much we do not know. Admit and gain the patient’s confidence

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A LITTLE DRUG REVIEW

TFTF

XI XIa

Fibrinogen Fibrin

X-linked FibrinXIIIa

X

II IIa (Thrombin)

XaVaCa++/Pl

TF/VIIa

VIIaTF VIIIX IXaVIIIaCa++/Pl

Coagulation Cascade in PatientsTissue FactorTissue Factor Tissue Factor

Tissue Factor Tissue FactorTissue Factor

TFTF

= Warfarin

DabigaTran

RivaroXabanApiXabanEdoXabanBetriXaban

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DOACs & Laboratory TestingWe Lack Data Correlating Drug Level and Efficacy/Hemorrhage

aPTT and PT: too insensitive, too sensitive, no clear dose response

Direct Thrombin Inhibitor – Dabigatran:

aPTT more sensitive than PT-But, not standardized and prolongation not predictable-And, normal aPTT does not rule out ‘on therapy’ drug level

Thrombin Time is exquisitely sensitiveIf normal, then essentially no clinically significant drug in system

Xa Inhibitors – Rivaroxaban, Apixaban & Edoxaban:

PT is more sensitive than is the aPTT-But a normal PT does not rule out ‘on therapy’ drug level

Need chromogenic Factor Xa activity assay standardized to the Rx

No effect on Thrombin Time

DOACs – A Few Summary Points to StartØ All have a black box warning with two key points:

§ Premature discontinuation increases risk of thrombotic eventsThese findings are from the Atrial Fibrillation trialsTherefore: Parenteral bridging if DOAC to Warfarin

§ Spinal/Epidural HematomaNeed protocols for stopping/starting around procedures

Ø Decline in renal function leads to increased bleeding risk § Think Elderly, NSAIDs, Dehydration/nausea/vomiting (END)

Ø Be sure proceduralist is aware your patient is taking the medication

Ø Not for use with mechanical heart valves

Ø Patients need follow up but you lack the INR clinic connection

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VTE in Cancer Patients

Recurrent VTE & Bleeding on Anticoagulation

Prandoni, et al. Blood 2002;100:3484-8

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The CLOT Trial*

-Recurrent VTE: 17% (OA) vs 9% (D) at 6 months

HR 0.48 (0.3 – 0.77); P = 0.002-Major Bleeding: 4% (OA) vs 6% (D); P = 0.27-Any bleeding: 14% (OA) vs 19% (D); P = 0.09-Mortality: 41% (OA) vs 39% (D)

*Lee et al. NEJM 2003;349(2)146-53

What about beyond 6 months?

What about the belly ache of injections?

KatsushikaHokusai

Raskob GE, et al. for the HOKUSAI VTE Cancer Investigators

N Engl J Med 2018; 378:615-24

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Hokusai VTE Trial – Conclusion

1. Oral edoxaban is noninferior to subcutaneous dalteparin in terms of composite outcome of recurrent VTE or major bleeding

2. The rate of recurrent VTE was numerically lower with edoxaban: 7.9% vs 11.3%; HR 0.71 (0.48-1.06); P=0.09

3. The rate of major bleeding was significantly higher with edoxaban: 6.9% vs 4.0%; HR 1.77 (1.03-3.04); P=0.04

-Mostly due to UGI bleeding in patients with GI tumors-Dalteparin bleeds were lower in this trial than in other trials

Hokusai VTE Trial – Cancer Types

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Hokusai VTE Trial – Patient Characteristics

Hokusai VTE Trial – Results

Combined Major Bleed or VTE

VTE

MAJOR BLEED

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Hokusai VTE Trial – Results

- not a clinical emergency

- not 1, 3, or 4

- yes clinical emergency – hemodynamic or CNS- death before or shortly after hospital admission

Superficial Venous Thrombosis

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MyHealth.Alberta.Ca

VeinsoftheLeg– ABriefOverview

*

*The confusing “superficial femoral vein” segment of the deep vein system.

Ø A 32 year old man comes to your office with a 5 days of a cord-like ‘thing’ on his inner left thigh.

Ø He has no significant past medical history and takes no medications. He cannot recall any particular injury other than having been accidentally kicked in the left leg while playing soccer 2 weeks previously. He is afebrile.

Ø You palpate the cord. It is tender and there is mild erythema. You suspect a blood clot and send him for a Doppler US.

CASE 4: What Would You Do?

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Case 4. A Doppler Ultrasound demonstrates a 6 cm thrombus in the left saphenous vein. No DVT identified. You recommend:

1. Warm soaks, elevation, NSAID, & Follow up US

2. LMWH with bridge to warfarin x 6 weeks.

3. LMWH with bridge to warfarin x 12 weeks.

4. Fondaparinux or LMWH x 6 weeks.

5. Fondaparinux or LMWH x 12 weeks.

6. Rivaroxaban or Apixaban x 6 weeks

7. Rivaroxaban or Apixaban x 12 weeks

8. Other

Superficial Vein Thrombosis: 2 Studies of Note

Decousus, et al., NEJM 363(13):1222-32, 2010.

Cum

ulat

ive

Ris

k (%

)

Years since SVT Diagnosis

PE

DVTHR @ 3mo: 87 (70-108)

HR @ 5 Yr: 6.3 (5.6-7)

HR @ 3 mo: 45 (34-61)

HR @ 5 Yr: 2.9 (2.5-3.5)

Cannegieter, et al., BLOOD 125:1229-35, 2015.Treatment: 2.5mg qD fonda x45D vs placebo

Events: 13/1502 (0.9%) vs 88/1500 (5.9%)(Sx PE, DVT, Extension to Jxn, Recurrence)

Rel Risk Reduction: 85% (95% CI: 74-92)

DVT & PE (0.2% vs 1.3%): Rel Risk Reduction: 85% (50-95)Rel Risk Reduction maintained at day 77.

CALISTO Study Danish National Registry Study

10,973 patients with SVT vs.515,067 in comparison cohort

Again found DVT and PE risk.Increased risk of MI and CVASuggests ‘systemic disorder’

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• Recommends: Fondaparinux 2.5 mg sQ daily for 45 days for a new diagnosis of isolated SVT ≥5 cm in length in the lower extremity.– Grade 2B recommendation

• Recommends: Fondaparinux over LMWH– Grade 3B recommendation

Superficial Vein Thrombosis &American College of Chest Physicians*

*Chest2012;141(2)(suppl):e419S-e494S

-Not all patients will agree due to cost and inconvenience.-In particular, anticoagulant treatment favored if:

(i) extensive (ii) above knee (iii) greater saphenous vein (iv) near saphenofemoral jxn(v) severe symptoms (vi) History of VTE or SVT (vii) active cancer (viii) recent surgery

Did Someone Say Anemia?

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Case #1: Unexpected Pre-op Labs62 yo man admitted for bilateral Total Hip Arthroplasty has the following pre-op CBC that shows an unexpected anemia.

CBC:WBC: 7.1Hgb 7.8Hct 29.2Plt 288

Consult to Heme:1. Why is he anemic?2. Please evaluate ASAP, patient in pain and needs surgery. 3. Surgery cancelled until you give us an answer. 4. He is a physician

How do you proceed?What do you want to know?

The Case Will be Revealed at the Session

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Case 2: Anemia – Need a Marrow Biopsy?

64 yo woman: “Persistent microcytic anemia. Does she need a bone marrow biopsy?”

Most recent CBC that prompted the referral:

3 - 10 x 109/L4 - 5.2 x 1012/L 4.4 – 5.9 x 1012/L12 - 15.5 g/dL 13.6 – 17.5 g/dL36 - 46%; 41 - 53% 80-100 fL

NORMAL VALUES

The Case Will be Revealed at the Session

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Then always

MCV, Retic, Smear*, and…

EMR trends

*Gives insight into marrow and possible need for BM BX

Anemia?

UCSF Non-malignant Hematology Clinic

For Referrals:

415-353-2051 (phone line)

415-353-2467 (fax line)

Andrew D. Leavitt, MD 415-514-3432

andrew.leavitt@ucsf.edu