12.4 () Assessment and Management of Thrombotic Complications

Question 1

List the 3 risk factors in Virchow’s triad for development of VTE

Answer 1

1. venous stasis
2. endothelial injury
3. hypercoagulable state

Question 2

For cancer associated thrombosis, list:
i) 2 intrinsic (direct) risk factors
ii) 3 extrinsic (indirect) risk factors

Answer 2

i) Cancer induces hypercoagulable state via direct and indirect release of:
- procoagulants (i.e tissue factor)
- inflammatory mediators (i.e. IL-1)

ii)
- anti-cancer treatments (chemo, immunoRx, hormones, brachyRx)
- surgery
- central access
- immobility
- local stasis

Question 3

i) List 4 primary tumour types with highest hypercoagulable state

ii) List 2 tumour types with lowest hypercoagulable state

Answer 3

i) brain, lung, upper GI, ovary
ii) breast and prostate

Question 4

How does VTE risk change with metastatic disease progression?

Answer 4

The presence of distant metastases increases VTE rate up to 19-fold

Question 5

What are the gold standard investigations for DVT and PE?

Answer 5

i) DVT - doppler U/S
ii) PE - CT angiogram

Question 6

List 4 confounding factors in diagnosing VTE in cancer patients

Answer 6

1. Symptoms could be explained by other etiologies*
2. Co-existing diagnoses could mask the symptoms of VTE
3. Clinical prediction tools (ie. Wells score) have limited exclusory utility in cancer (specific but not sensitive)*
4. Elevated D-dimer common in cancer (due to relationship between metastasis and fibrin activity) so only useful as exclusory test (sensitive but not specific)*
5. Limited access to imaging in hospice/PCU settings +/- inappropriate to put patient through transfer near EOL*
6. Incidental PE’s found on e.g. staging imaging - to anticoagulate or not?

Question 7

1. How common are incidental PE’s in cancer patients?
2. What does the evidence suggest regarding whether to anticoagulate for incidental PE’s

Answer 7

1. Incidental PE’s occur in 3% of all cancer patients
2. Use same approach to type and duration of anticoagulation as symptomatic cancer-associated PE as far down as segmental branches
   Current data suggests no advantage in anticoagulating isolated incidental subsegmental PE. So if no radiologial evidence of leg DVT, most clinicians don’t anticoagulate

Question 8

How does anticoagulation treat VTE?

Answer 8

Prevents further thrombus development, therefore allowing body’s fibrinolytic system to stabilize and resorb the acute clot.

Inhibition of clot formation: Anticoagulant medications interfere with the blood clotting cascade, specifically targeting factors that promote clot formation. By inhibiting these clotting factors, anticoagulants help prevent the formation of new blood clots in the pulmonary arteries, reducing the risk of the PE becoming larger or causing additional complications.
Preventing clot extension: Anticoagulation helps prevent the existing clot from extending further into the pulmonary arteries. This is crucial as large clots can obstruct blood flow to the lungs, leading to serious complications such as right heart strain or failure.
Facilitating natural clot breakdown: The body has its mechanism to break down blood clots naturally. Anticoagulation supports this process by preventing the clot from growing larger, allowing the body’s natural fibrinolytic system to work on dissolving the clot over time.
Preventing new clots: In patients with PE, there is a risk of developing new blood clots in other areas of the body, particularly in the deep veins of the legs (deep vein thrombosis or DVT). Anticoagulation helps reduce this risk by inhibiting clot formation throughout the body.
The choice of anticoagulant medication and duration of treatment depends on various factors, such as the severity of the PE, the presence of other medical conditions, and the patient’s risk profile for bleeding. Commonly used anticoagulant medications for PE include heparin, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). In some cases, long-term anticoagulation may be necessary to prevent recurrent PE or manage underlying conditions that increase the risk of clot formation.

Regenerate response

Question 9

List 4 goals of anticoagulation for VTE

Answer 9

Improve symptoms (pain, chest pain, SOB)
Prevent clot extension
Preventing embolic events
Prevent early recurrence
Decreasing upfront mortality
Minimize bleeding

Question 10

1. What is the risk of PE with untreated DVT?
2. What is the risk of mortality with untreated PE?

Answer 10

1. Untreated symptomatic DVT carries 50% risk of PE
2. Untreated PE is associated with 30% mortality, usually due to recurrent embolism

Question 11

The concept of fatal PE’s being asymptomatic is erroneous.

i) How likely is a PE to cause a sudden asymptomatic death?

ii) What do we know about the duration and symptom burden of deaths from PE?

Answer 11

i) Sudden asymptomatic death in only 10% of patients

ii) Majority (90%) will have prolonged symptomatic death lasting an average of 2 hours and dominated by SOB, tachycardia, and distress

Question 12

List 4 disadvantages with choosing warfarin in cancer-associated VTE

Answer 12

1. increased risk of recurrent thrombosis
2. increased risk of bleeding
3. reduced QOL with frequent INR monitoring
4. significant drug drug interactions (eg chemo) - unstable INR

** increased risk of thrombosis/bleeding was related to severity of cancer, not over/under anticoagulation

Question 13

1. What is first line anticoagulation for cancer associated thrombosis and why?
2. What alternative is supported by data?
3. What remains the most frequently prescribed anticoagulant and why?

Answer 13

1. LMWH - greater efficacy with respect to recurrent thrombosis without increasing bleed risk (vs. warfarin)
   Therefore, recommed 3-6 months of LMWH as 1st line
2. data support use of specific DOAC’s for some patients with CAT
3. Warfarin, due to cost + lack of coverage by insurance bodies

Question 14

List 3 advantages of DOAC’s for management of VTE (vs. warfarin)

Answer 14

1. No monitoring or dose adjustment
2. Fewer drug drug interactions
3. superior safety profile wrt major bleeding

** check #3 - is this in CAT or extrapolated from non-cancer data?

Question 15

List 3 challenges of VTE treatment in the cancer patient population (compared to non cancer)

Answer 15

1. Increased VTE recurrence (vs. noncancer) esp with warfarin
2. Increased bleeding (vs. noncancer), up to 20% at 12 months*
3. Ongoing, varying risk of VTE due to extrinsic factors or disease progression/regression*
4. Drug drug interactions from ongoing anti-cancer treatments:
   - increased risk of VTE with chemo/targeted/hormonal Rx*
   - chemo-related thrombocytopenia can make AC hazardous

Question 16

What does data show about concerns that sc administration of LMWH may negatively impact patient QOL?

Answer 16

Qualitative studies show that patients find LMWH acceptable and quickly adapt to it

(conditional on patient understanding of purpose of medicine and education on technique)

So LMWH should not be considered overly burdensome. While oral med convenient, patients prioritize safety/efficacy of LMWH.

Question 17

List 2 skin side effects of subcutaneous LMWH administration

Answer 17

1. Bruising
2. Subcutaneous fibrosis (reassurance that lumps are not metastatic spread)

Question 18

List 3 scenarios in which patients may not tolerate sc LMWH administration

Answer 18

1. limited injectable surfaces due to stoma or scarring
2. extensive subcutaneous fibrosis from longterm use
3. Lower body fat

Question 19

1. List 2 classes of DOACs and 1 example of each.

Answer 19

1. Factor IIa inhibitor - dabigatran
2. Factor Xa inhibitors - rivaroxaban, apixaban, edoxaban

FS:
Dabigatran = dos
RAE all have X

Question 20

How do DOACs compare with warfarin in terms of efficacy and safety for management of VTE

Answer 20

• have demonstrated non-inferiority with warfarin
• some show superior safety profile with respect to major bleeding

Question 21

List 3 conditions in which to use DOAC’s with caution

Answer 21

1. Frail and elderly
2. Hepatic dysfunction
3. Impaired renal function (avoid DOAC altogether in those with CrCl <30 mL/min)

Also if high risk of bleeding / drug drug interactions

Question 22

List 2 disadvantages of DOAC’s

Answer 22

1. Specific reversal agents + monitoring tests of anticoagulation are expensive/not widely available
2. Multiple drug-drug interactions lead to increased or decreased DOAC plasma levels (although still less interactions than warfarin). Common interactions:
   - chemo
   - immunoRx
   - hormonal Rx
   - TKI’s
   - dexamethasone

Question 23

List 2 types of malignancies in which major bleeding with DOAC’s was higher than LMWH

Answer 23

1. Gastrointestinal
2. Urothelial

Question 24

How do DOAC’s compare with LMWH in efficacy and bleed risk when treating cancer associated thrombosis?

Answer 24

1. Efficacy:
   Rivaroxaban and edoxaban showed fewer recurrent VTE events (vs. LMWH)
2. Bleed risk:

Rivoroxaban had similar major bleeds but more clinically relevant non-major bleeds vs LMWH

Edoxaban had more major bleeding episodes vs LMWH

FS: more efficacious but more bleeding

Question 25

List 3 points of guidance for the use of DOAC's vs LMWH in the treatment of cancer-related thrombosis

Answer 25

1. Recommend individualized treatment regimens after shared decision making with patient 2. Suggest specific DOAC's for cancer patients with acute VTE +low risk of bleeding, and no d-d interactions with systemic therapy. LMWH is acceptable alternative 3. Suggest LMWH for cancer patients with acute VTE + high risk of bleeding , including those with: - luminal GI cancers with intact primary - cancers at risk of bleeding from GU tract - nephrostomies - or active GI mucosal abnormalities (duodenal ulcers, gastritis, esophagitis, colitis).

Question 26

Data on VTE recurrence with or without long term anticoagulation (i.e. > 6 months) are limited. Therefore, it is impossible to advise with accuracy whether a patient's risk of VTE recurrence exceeds bleed risk of ongoing anticoagulation. List 3 important considerations when making a decision about continuing anticoagulation longer than the standard 3-6 months

Answer 26

1. Perceived bleeding risk: - 0.7% major bleeding risk for every month beyond 6 months (higher in more vascular tumours) - risk increased if thromobcytopenia/marrow, liver failure 2. Ongoing thrombotic risk: - higher risk in UGI, gyne, and lung cancers - higher risk if distant metastases 3. Patient wishes: - patient with distressing VTE sx at diagnosis will often want to continue - those with low sx burden do not wish to continue

Question 27

1. List 4 possible reasons cancer patients are highly thrombotic at end of life. 2. What is the evidence for continuing anticoagulation in the last days of life?

Answer 27

1. disease progression, immobility, dehydration, possible infection 2. Little evidence to inform best practice. Decision to cease A/C should involve patient and family.

Question 28

What is a major limitation of clinical trials in cancer associated thrombosis with respect to recurrent VTE?*

Answer 28

1. Trials excluded patients with poor PPS, prognosis < 3 months, thrombocytopenia, increased bleed risk, renal impairment, and wt < 40 kg Recurrent VTE is seen most often in those with advanced disease, as above + seen by pall care specialists who may need to modify their A/C

Question 29

List 3 steps to managing recurrent VTE despite anticoagulation

Answer 29

1. If on warfarin, switch to therapeutic LMWH 2. If on LMWH, increase dose by 25% (or back to therapeutic weight adjusted dose if on non-therapeutic dose) 3. If no symptomatic improvement, use peak anti-Xa level to estimate next dose escalation

Question 30

List 4 steps to management of cancer associated thrombosis (CAT) + thrombocytopenia

Answer 30

1. Plt > 50: - give full dose of LMWH 2. Plt 25-50 + acute CAT - plt transfusion to >50 —> full dose LMWH - if plt transfusion not possible —> IVC filter 3. Plt 25-50 + subacute/chronic CAT - reduce therapeutic dose by 50% or use prophylactic dose 4. Omit LMWH if plts <25

Question 31

What is the evidence for twice daily dosing of LMWH in recurrent VTE

Answer 31

1. Little supporting data 2. Half-life of 5 hours for most LMWHs, so thought that twice daily dosing may = less time subtherapeutic but overall little guidance

Question 32

List 3 steps to managing patients who are anticoagulated then bleeds

Answer 32

1. Assess each bleeding episode: source, severity, impact, and reversibility 2. Provide supportive RX to stop bleeding, including PRN transfusion and stopping anticoagulant/reversing agents 3. For major or life-threatening bleeding episode: - IVC filter in patients with acute or subacute CAT (not for chronic CAT) - once bleeding resolves, remove retrievable IVC filter and resume anticoagulation Tx source, to symptom, tx complication

Question 33

There is substantial controvery and disagreement regarding use of IVC filters. 1. List 2 absoluate indications for an IVC filter 2. List 2 relative indications

Answer 33

1. Absolute: - contraindication to anticoagulation* (bleeding, thrombocytopenia) - complication of anticoagulation* - inability to achieve/maintain therapeutic anticoagulation - recurrent VTE while on therapeutic anticoagulation* 2. Relative: - massive PE - limited cardiopulmonary reserve - free floating IVC thrombus* - poor compliance with anticoagulation therapy*

Question 34

1. List 2 major disadvantages to IVC filter use 2. List at least 4 known complications of IVC filters

Answer 34

1. Disadvantages: - Variable evidence that they prevent fatal PE - high complication rate 2. Complications: - improper anatomical placement* - migration* - angulation of filter - caval stenosis or filter narrowing* - caval occlusion - air embolism - penetration of caval wall* - lower extremity edema

Question 35

1. What is the DVT rate with CVCs or PICCs 2. What are 3 risk factors for catheter-related DVT 3. List 4 treatment guidelines for catheter-related DVT

Answer 35

1. 1% to 5% (asymptomatic may be up to 50%) 2. type of CVC tip location* side of placement history of VTE* presence of metastases* 3. - Catheter should remain in-situ if functional and still required (unless infection) - continue AC as long as catheter remains - Receive 3-5 days of AC prior to removal - minimum 3-6 months of total AC (even if catheter removed)

Question 36

1. In cancer patients with non-valvular atrial fibrillation, list 2 anticoagulation options for stroke prophylaxis 2. What should be done in patients with AF, and unstable anticoagulation or interactions with cancer therapies? 3. List 2 scenarios in cancer patients with AF where use of LMWH may be reasonable

Answer 36

1. Warfarin and DOAC's (no data supporting LMWH in stroke prophylaxis except for peri-op bridging) 2. Consider conversion to alternative AC (i.e. warfarin to DOAC or DOAC to wafarin) 3. Patient unable to take oral meds Anticoagulation has become subtherapeutic

Question 37

Antiembolism stockings in palliative care patients - What is the evidence? - Name 3 SEs What is the role of pneumatic compression devices in palliative care?

Answer 37

1. -No data supporting their use in medical patients (vs surgical) - no better at preventing VTE than no stockings -worsen QOL -associated with discomfort -5x increased risk of skin necrosis, ulcers, blisters 2. No clear role, yet to be evaluated

Question 38

What is the evidence for prophylaxis anti-coagulation in palliative care settings (hospice/PCU)?

Answer 38

Based on data available so far, up to 55% of palliative care patients have contraindiation to thromboprophylaxis Remainder have increased risk of bleeding weighed against limited evidence of survival or symptomatic benefit Role of TPX in select patients with good PPS and temporary increse in VTE risk requires exploration