Venous thromboembolism is a common complication in patients with cancer and may be the first manifestation of malignancy.1
The spectrum of haemostatic abnormalities in patients with cancer ranges from abnormal coagulation tests in the absence of clinical manifestations to massive thromboembolism. Clinical presentations include:
- migratory superficial thrombophlebitis (Trusseau's syndrome)
- deep venous thrombosis and other venous thrombosis
- thrombotic endocarditis (marantic endocarditis)
- disseminated intravascular coagulation
- thrombotic microangiopathy
- arterial thrombosis.
Approximately 10% of patients who present with unprovoked or idiopathic thrombosis are diagnosed with cancer within a few years after their thrombotic event.2
Most common cancers associated with venous thromboembolism include lung cancer, colon cancer, brain cancer, prostate cancer in men, and ovarian and breast cancer in women.3,4
Among non-small-cell lung cancers the incidence of venous thrombosis in patients with adenocarcinoma is considerably increased compared to patients with squamous cell carcinoma.5
Observational data indicate that patients with cancer and venous thrombosis have a worse prognosis than those with cancer alone.3,4
Up to 40% of patients with cancer diagnosed within 1 year after venous thrombosis have distant metastases by the time of their cancer diagnosis.6
Considering these observations, earlier cancer diagnosis is likely to be associated with improved treatment possibilities and prognosis. However, there is no evidence for better prognosis due to earlier diagnosis. One recent randomised controlled trial (RCT) of 201 patients with symptomatic idiopathic thromboembolism showed no survival benefit with extensive screening compared to routine testing for malignant disease in patients with idiopathic venous thromboembolism.7
In this trial, extensive screening included ultrasound of the abdomen, followed by CT scan of the abdomen, gastroscopy or double contrast barium swallowing, colonoscopy or sigmoidoscopy followed by barium enema, haemoccult, sputum cytology, tumour markers (including carcionembryonic antigen, α-fetoprotein and cancer antigen 125), mammography and Pap smear for women, and transabdominal ultrasound of the prostate and total specific prostatic antigen for men. Although in the extensive screening group a single (1%) malignancy became apparent during 2-year follow-up whereas in the control group a total of 10 (9.8%) malignancies became symptomatic, it is uncertain whether the earlier detection of the cancer improves the prognosis due to the limited sample size. Despite the extensive screening, one of the overall detected fourteen malignancies of the extensive screening group was not identified for a sensitivity of 93%. This shows the difficulty of finding the suspected malignancy as, in our case, no definite diagnosis could be established although repeated CT scans and biopsies were performed.
During hospitalisation we did not perform a positron emission tomography (PET) scan despite its increasing value in diagnostics of malignancies. It possibly would have helped us to locate the primary; however, PET scan still has hardly any significance in screening for unknown malignancy in Germany due to its costs. As all findings possibly indicating malignancy via CT scan did not provide evidence performing invasive diagnostics, we would have considered a PET scan as one of our next steps. Anyway, the rapid aggravation of the clinical condition left no opportunity to complete the diagnostic workup.
The FV Leiden mutation is an established thrombophilic risk factor that increased the cancer-associated risk of thrombosis. A large population-based case control study of 3220 consecutive patients showed a twofold increased risk of venous thrombosis for patients with FV Leiden mutation with cancer compared to non-carriers with cancer.8
However, the enormous activation of the coagulation system in this case cannot be explained by the FV Leiden mutation.
The patient developed recurrent deep vein thrombosis while on full-dose anticoagulant treatment. Therefore, we suspected an underlying malignancy of unknown origin. As the clinical condition of the patient worsened rapidly we discussed treatment with chemotherapeutic agents like 5-FU and carboplatin as a last resort. Retrospectively, chemotherapy probably leading to a reduction of tumour size and, therefore, to an improvement of thrombophilia could have ameliorated her condition as autopsy showed the recurrent lung microembolism with subsequent right heart failure were direct causes of death. However, the use of chemotherapeutic agents should be considered carefully as these agents are also associated with increased risk of venous thrombosis. Cytotoxic agents can alter coagulation protease levels and may directly injure the endothelium. Clinical data prospectively collected on the population of Olmsted County, Minnesota, suggest a 4.1-fold risk of thrombosis for cancer alone compared to the absence of cancer. Chemotherapy increased the risk for thrombosis 6.5-fold;9
thereby, questioning the empiric use of chemotherapy in our case without a definite diagnosis. Further investigation using a multivariate model to estimate the attributable risk in this study showed 18% of venous thromboembolism cases were attributable to active malignant neoplasm. Malignant neoplasm without chemotherapy was responsible for a larger percentage of the risk of venous thromboembolism (12%) than was malignancy with chemotherapy (6%).10
Although there are few comments in literature indicating an improvement of thrombophilia by chemotherapy,11
this effect is poorly proved and all recent studies suggest an increase of risk within populations with neoplasms by using chemotherapeutic agents.12,13
Existing studies focus on anticoagulant treatment rather than the use of chemotherapeutic agents. Concerning anticoagulation, the largest reported RCT study (CLOT) comparing LMWH with vitamin K antagonist treatment in patients with cancer with venous thrombosis showed a RR reduction of 49% for treatment with dalteparin compared to vitamin K antagonists.14
Recent guidelines recommend treatment with LMWH rather than with vitamin K antagonists or UFH as several studies demonstrate a positive effect on survival.14
Current evidence suggests that the best-characterised cancer procoagulant tissue factor is also an important mediator between activation of coagulation and tumour growth. LMWH releases tissue factor pathway inhibitor, a physiological inhibitor of the tissue factor pathway,15
and should even be considered in patients with cancer without venous thromboembolism.14,15
After the occurrence of pericardial effusion we temporary changed antithrombotic regimen to heparin and argatroban due to facilitate monitoring during invasive procedures. This also led to an adequate reduction of d-dimers but probably did not have the same effect on tumour growth compared to LMWH.
In summary, our case illustrates that despite the knowledge of a metastatic disease with multiple bone metastases and paraneoplastic hypercoagulation no definite diagnosis could be established in vivo. We considered chemotherapeutic treatment but could not decide for it due to the additional risk and the lack of experience in using chemotherapeutic agents in such special cases. Diagnosis and management of these patients still remains a challenging issue in medical care and further experience is needed.
- Venous thromboembolism is a common complication in patients with cancer and may be the first manifestation of malignancy.
- The case illustrates the difficulty of establishing a definite diagnosis despite the knowledge of a metastatic disease with multiple bone metastases and paraneoplastic hypercoagulation.
- Concerning anticoagulative treatment existing guidelines recommend treatment with LMWH rather than with vitamin K antagonists or UFH as several studies show a positive effect on survival.
- The impact of chemotherapy on cancer-related recurrent thromboembolism is poorly investigated. Considering the negative effects of chemotherapeutic agents on protease levels and the endothelium with potentially increased risk of venous thrombosis further experience is needed.