Cancer-associated thrombosis

Venous thromboembolism is a complication of cancer that pharmacists should understand to ensure that their patients have the best possible outcomes.

 

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There are a wide range of complications commonly associated with cancer (e.g. neutropenia, metastases and alopecia). However, a lesser-known complication is venous thromboembolism (VTE), or, as it has also been termed, cancer-associated thrombosis (CAT). Despite one in five patients with cancer having a VTE during their cancer journey, awareness of the condition in patients and healthcare professionals is low[1],[2]
.

 

VTE is an umbrella term that comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). A study in the United States has suggested it occurs for the first time in around 1 in 1,000 people each year[3]
. In addition, CAT accounts for 20–30% of all VTEs[2],[4]
. CAT is an important cause of morbidity and mortality in patients with cancer, with a 2.2-fold increase in mortality, compared with patients with cancer without CAT[5]
.

 

Studies comparing patients with cancer to those without the disease have also shown that patients with cancer have a four- to seven-fold increased risk of VTE, combined with a two-fold increased risk of bleeding[6]
. CAT is the second leading cause of death, after disease progression, in patients with cancer, and the leading cause of death while taking chemotherapy (i.e. higher than neutropenic sepsis)[7]
. Not all patients who develop CAT are symptomatic, with as many as half diagnosed incidentally following scans[8]
. Patients with CAT are also at an increased risk of recurrence (9.6 per 100 patient years), with the greatest risk of recurrence in the first few months following diagnosis[9],[10]
. To give the figure some context, this rate of recurrence is similar to that observed for male patients, who do not have cancer, diagnosed with unprovoked proximal DVTs, one of the highest risk groups in terms of re-occurrence of VTE[11]
. Patients with cancer have a three-fold increased recurrence risk compared with non-cancer patients, and a higher rate of readmission to hospital because of VTE recurrence within six months of diagnosis (22% for those with cancer and 6.5% for those without)[12]
.

 

Awareness of CAT has increased in recent years. At the All-Party Parliamentary Thrombosis Group meeting in October 2016, data was published showing that an estimated 4,000 cancer deaths per year in England and Wales may be as a direct result of preventable CAT[1]
. The report highlighted that thrombotic events specifically attributed to CAT are increasing at a higher rate than for total cancer deaths and that the incidence of VTE in cancer may be higher than previously estimated[1]
.

 

This article examines the pharmacist’s role and summarises the evidence underpinning current guidelines, highlighting best practice points throughout to help improve practice.

 

The pharmacist’s role

Although understanding of the clinical elements of CAT are well developed, understanding of the patient’s experience remains limited. The PELICAN study, published in 2015, aimed to explore the understanding and experiences of patients with cancer, from the perspective of CAT[13]
. The study highlighted a lack of awareness of the signs and symptoms of CAT in patients with cancer (e.g. patients attributing shortness of breath to being a side effect of chemotherapy, resulting in delayed access to diagnosis) and an unsatisfactory experience in terms of treatment initiation.

 

The study also identified that patients feel uninformed about their diagnosis, and subsequently feel extremely anxious. One of the key recommendations was the need to raise awareness of the signs and symptoms of CAT, and to develop dedicated CAT pathways[13]
.

 

A study exploring patient preference of anticoagulant strategies in CAT highlighted that patients place greatest value on factors such as the potential impact of anticoagulants on their chemotherapy and efficacy of treatment[14]
. Preference for oral therapy was deemed to be of moderate importance[14]
. Patient education and the development of patient-specific treatment strategies are of paramount importance in the management of CAT.

 

Pharmacy teams can manage CAT patients by:

 

  • Advising on the risks of developing CAT — this may be in specialist oncology clinics, or when issuing chemotherapy within community or hospital pharmacies;
  • Ensuring appropriate VTE risk assessment and thromboprophylaxis for both admitted and ambulatory patients with cancer;
  • Development of CAT pathways, including selection of the most clinically appropriate anticoagulant for the patient (see Figure 1);
  • Counselling on new anticoagulant therapies, including expected and unexpected side effects;
  • Ensuring safe supply of anticoagulants, including monitoring and dose adjustments;
  • Liaising with the wider multidisciplinary team and patients to form patient-specific action plans at the six-month review.

A considerable number of clinical research developments related to CAT have been made in the past few years, yet there is still work to do to improve the patient experience. Data is already emerging that show the impact of dedicated CAT services on patient experience[15]
. There is significant scope for pharmacy to play a vital role in improving the care of this patient group.

 

Figure 1: The Singleton Hospital cancer-associated thrombosis pathway

Why does cancer-associated thrombosis occur?

The association between cancer and thrombosis was first described by Bouillard in 1823 and later in 1865 by Trousseau[3],[16],[17],
[18]
. Since then, numerous studies have illustrated this two-way association[7]
. However, the aetiology and pathophysiology of CAT remains unclear, with most literature suggesting a complex interplay between different factors, as opposed to a single mechanism. Rudolf Virchow’s triad has formed the basis of our understanding of the pathogenesis of VTE for some time[19]
. Virchow’s model proposed that factors that increase the risk of thrombosis may be broadly divided into three categories — endothelial injury/dysfunction, stasis and altered blood constituents — and that cancer can, directly and indirectly, affect each element of the triad (see Table 1) [16],[3],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29]
.

 

Table 1: Virchow’s triad of coagulation and the impact of cancer upon it
Virchow’s triad factor Mechanism Cancer-specific mechanism
Endothelial injury/dysfunctionThe endothelium plays a key role in primary haemostasis through a complex interaction between platelets, the vessel wall and blood proteins. Vascular endothelium is usually anticoagulant in nature (via surface heparan sulfate), and the sub-endothelial membrane pro-coagulant in nature (owing to von Willebrand Factor [vWF]). The subsequent interaction between exposed vWF and platelets leads to clot formation. Direct endothelial damage by:

  • Tumour invasion of the endothelium;
  • Secondary to chemotherapy, erythropoietins or indwelling catheters.

Endothelial dysfunction:

  • Decreased activity of vWF cleaving protein (with a resulting higher level of vWF);  
  • Increased expression of tissue factor (TF). TF is associated with secondary haemostatic process via activation of factor VII and may be up to 67% higher in cancer cells;
  • Cancer pro-coagulant is expressed in tumour cell, which, unlike TF, can directly activate factor X.
StasisStasis describes an alteration in blood flow; however, its role in the development of thrombosis is poorly understood. Some theories associate blood stasis, especially in the area behind venous valves (valvular sinus), with increasing hypoxia, which, in turn, leads to a downregulation of the natural, membrane-based anticoagulants. Direct:

Tumour compression of blood vessels.
Indirect:

Patient immobility (e.g. following hospitalisation, surgery, worsening disease).
Altered blood constituentsChanges in blood constituents results in direct activation of the clotting cascade.
  • Higher levels of certain clotting factors (e.g. V, VII, IX and X);
  • Cancer cell release of pro-inflammatory factors, such as tumour necrosis factor alpha (TNF-α) and interlukin-1-beta (IL-1β), which can stimulate cells to become procoagulant (e.g. by increasing TF expression);
  • Increased vascular endothelial growth factor release;
  • Activation of leukocytes and platelets to expose procoagulant elements.
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The Pharmaceutical Journal, PJ September 2020, Vol 305, No 7941;305(7941):DOI:10.1211/PJ.2020.20208306