What is Trousseau Syndrome?
Trousseau syndrome was first described by Armand Trousseau in 1865 as an unexpected or migratory thrombophlebitis (inflammation in the vein related to a blood clot) forewarning a malignancy. In 1977 this definition was extended by including chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial emboli in patients with cancer. This syndrome is considered to be a paraneoplastic syndrome- set of signs and symptoms as a consequence to having a cancer, like Lambert-Eaton syndrome) .
In around 50% of the cases, Trousseau syndrome has an associated cancer. Pancreatic cancer is associated with the highest risk of developing Trousseau syndrome. Other types of cancer, especially adenocarcinomas can also be the underlying cause.
The mechanism for developing Trousseau syndrome is believed to be imbalance in the clotting cascade. This imbalance is caused by the underlying malignancy. Malignant tumors can cause production of various substances that have an effect of the clotting cascade .
The risk factors for Trousseau syndrome can be divided in three groups:
- Patient related
- Old age
- Elevated leukocyte and platelet counts
- Comorbid diseases, like heart disease
- Old age
- Treatment related
- Hormonal agent use, like for treatment of Uterine sarcoma
- Growth factor use
- Central venous catheterization
- Cancer related
- Primary site of cancer
- Stage of cancer
- Direct cancer invasion of large blood vessels
- Mucin production in adenocarcinoma
- Tissue factor expression
The clinical presentation of Trousseau syndrome includes:
- Deep vein thrombosis
- Pulmonary embolism
- Chronic disseminated intravascular coagulopathy associated with non-bacterial thrombo-endocarditis and arterial thrombosis
- Secondary thrombosis associated with chemotherapy and central venous catheterization
The most frequent clinical presentation of Trousseau syndrome is venous thromboembolism. This includes both deep vein thrombosis and pulmonary embolism. It has been reported to occur in 4-20% of all cancer patients. Venous thrombosis is the second largest cause of death in cancer patients, the first being cancer itself .
There have been many theories about the exact pathogenesis of Trousseau syndrome. Research has shown that there are various factors that are responsible for venous thrombosis associated with cancer. All of the mechanisms for developing this syndrome are not fully understood.
There are various carcinomas rich in TF (also known as thromboplastin), like Thymic carcinoma or Cholangiocarcinoma, but TF is also expressed in other types of tumors. Inactivation of tumor suppressors and activation of oncogenes leads to induction of TF level increase and activity, which promotes hypercoagulation and also tumor aggressiveness and increases angiogenesis .
Tumor associated cysteine proteinase
Cysteine protease (also known as cancer pro-coagulant) activates the X factor in the coagulation cascade in the absence of VII factor. The exact mechanism of why this happens is not yet understood .
It has been reported, that tumor hypoxia and stress is likely to produce more pre-coagulants and angiogenetic factors. Tumor hypoxia can increase expression of genes that increase coagulation .
Carcinoma mucins are large, glycosylated molecules that perform the function of carrier molecule. These molecules are believed to take part in hematogenous tumor metastasis phase. Patients with carcinomas secret large amount of these molecules into the bloodstream, and it can lead to series of events causing thrombosis .
Studies done on mice have suggested, that activation of an oncogene can lead to carcinogenesis (for example, growth of Ependymoma) followed by venous thrombosis that later leads to hemorrhages. This mechanism has not yet been proven in humans .
Overlapping of mechanisms
There are many proposed mechanisms for development of Trousseau syndrome. These mechanisms can work together therefore it is better to consider Trousseau syndrome to be a multifactorial disorder .
History and clinical signs
One of the most important parts of diagnosing Trousseau syndrome is clinical examination and patient history. Patients might not know that they have cancer until a thrombotic event occurs. In case of superficial venous thrombosis, patient might complain about redness, swelling and lumps under the skin in the affected area . In case of deep venous thrombosis, patients can complain about severe pain and swelling of a limb. Cyanosis or major swelling is rare . Patients with lung embolism usually complain about sudden onset of shortness of breath, cough, coughing of blood and even loss of consciousness. Symptoms usually appear after standing up (in the morning) [5,7].
To diagnose Trousseau syndrome there is a variety of blood tests that should be performed, such as:
- Resistance to activated protein C
- Protein C deficiency
- Protein S deficiency
- Antithrombin III deficiency
- Antiphospholipid antibodies
- Increased D-dimer levels
- White blood cell count- low levels suggest possible infection
Also, various tests that could suggest possible malignancy should be performed, like cancer marker tests, liver enzyme tests .
Venous thrombosis can be diagnosed by performing magnetic resonance venography. This test is very sensitive and can prove deep vein thrombosis. Usually duplex sonography is performed, since this test is cheaper and easier to use.
X-ray imaging and CT angiography can also be performed to diagnose lung embolism .
The treatment of Trousseau syndrome mostly consists of use of anticoagulants (also used in treatment of Stevens-Johnson syndrome) and treatment of the underlying condition. However there are often risks for bleeding, therefore the use of anticoagulants should always be weighed against the risk of bleeding. Patients with malignancies have even a higher risk of developing hemorrhagic complications.
Initial therapy of acute thrombotic event consists of low molecular weight heparin (LMWH), unfractioned heparin (UFH) and fondaparinux. LMWH is preferred since it doesn’t require monitoring with blood tests and hospitalization, like UFH. Also, LMWH is preferred, since fondoparinux lacks reversal agents.
In cancer patients thrombosis is frequently recurrent therefore long term management is necessary. Oral Warfarin is mostly used for patients with no cancer association, but even in case of Trousseau syndrome, warfarin is preferred to no therapy. Warfarin requires monitoring of International normalized ratio (INR), thus the patient requires frequent blood tests.
There are also new drugs that are promising for treatment of venous thrombosis in patients with cancer, such as factor Xa inhibitors (Edoxaban) and direct thrombin inhibitors (Dabigratan) .
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- General information for patients and health specialists: https://www.jstage.jst.go.jp/article/jjtem/3/2/3_2_40/_pdf
- Causes: http://www.dermnetnz.org/topics/trousseau-syndrome
- Clinical presentation and risk factors: https://academic.oup.com/jjco/article/46/3/204/2384933/Trousseau-s-syndrome-cancer-associated-thrombosis
- Pathogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976377/
- Diagnostics: http://emedicine.medscape.com/article/463256-workup#c9
- Deep vein thrombosis: http://emedicine.medscape.com/article/1911303-clinical#b1
- Lung embolism: http://emedicine.medscape.com/article/300901-overview#a1