Epidemiology

Malignancies of various types may be associated with thromboses and it has recently become clear that a proportion of patients who suffer from malignancy-associated thrombosis have elevated aPL. The clinical association of cancer with thrombosis was first documented over 100 years ago by Trousseau [4].

The work of Bowie and his colleagues from the Mayo Clinic in the 1970s stressed the high prevalence of overt or subclinical intravascular coagulation in cancer patients [5, 6] and recent reviews have also stressed this occurrence [7, 8],

Agents which activate blood coagulation tend to promote tumour growth and spread in experimental animals. Conversely, inhibitors of coagulation may lead to tumour regression and this latter aspect has been supported by the Veterans Administration Co operative Study (CSP#75) utilizing warfarin treatment for small cell carcinoma of the lung [9],

The generation of fibrin has been associated with tumour growth [10] and tumour cells themselves or accompanying inflammatory cells may be responsible for the generation of this compound.

Indeed, serum fibrinopeptide A (FPA) levels were found to be elevated in 60% of cancer patients by Rickles et al. [11].

The levels of FPA, when serially determined, may parallel progression of disease and when persistently elevated, suggests treatment failure.

FPA levels may be reduced by the administration of warfarin. A warfarin-sensitive protease which is vitamin K dependent has been discovered in Lewis lung carcinoma cells and this functions as a powerful procoagulant [12]. This enzyme is heparin-resis-tant.

In addition to coagulation abnormalities described, other causes of vascular occlusions in cancer patients include vasculitis and this encompasses cutaneous leu-cocytoclastic vasculitis associated with various carcinomas [13-19], temporal arteritis and polyarteritis nodosa with hairy cell leukaemia, Churg-Strauss vasculitis with melanoma [22], Henoch-Schonlein purpura with carcinoma of the lung [23-24], central nervous system angiitis preceding Hodgkin's disease [25], Raynaud's phenomenon antedating the diagnosis of a malignant tumour [26] and digital gangrene [27-32],

Estimates of the frequency of antiphospholipid antibodies (aPL) in malignancies vary. Zuckerman et al. [33] studied the prevalence of aCL in patients with malignancy as well as investigating the possible association of aCL with thromboembolic events in these patients. They included 216 patients in their group and an age matched control group of 88 healthy subjects. Forty-seven (22%) of the cancer patients were found to be aCL positive compared with only 3 (3%) of the control group. The aCL positive cancer patients had a significantly higher rate of thromboembolic events than the aCL negative cancer patients (13/47 = 28% vs 24/169 = 14%, respectively (p < 0.05)).

Interestingly, when aCL levels were followed, in four patients, the levels decreased after successful surgery/chemotherapy treatment and remained negative with the patients being thromboembolism free for 12 months of follow-up. High titres of either IgG aCL or IgM aCL were found in 10/13 patients with throm boembolic complications, but in only 2/34 patients without thromboembolic complications.

Lupus anticoagulant (LA) positivity was detected in 2-12% of their series by Gastineau et al. [34], while Love and Santoro [35] found 3% aPL positivity in their series.

Studies on aPL positivity in haematological malignancies particularly have also been undertaken. Stasi et al. [36] found 10 aPL positive patients only in their group of patients with acute myeloid leukaemia (AML) and non-Hodgkins' lymphoma (NHL). Five out of 19 patients with AML (26.3%) and 5 out of 14 with NHL (35.7%) had elevated aPL levels at the time of diagnosis. aPL normalised in all patients responding to treatment, whereas the nonresponders retained their elevated levels. In addition, 6 patients (4 with AML and 2 with NHL) who had normal aPL at the time of diagnosis and who were either refractory to treatment or in relapse, subsequently developed LA and/or aCL positivity.

These investigators also measured the cytokines IL-6, TNF-a and IL-2r and found that the levels of these cytokines correlated with IgG-aCL. They postulated that the aPL may have a role as markers of disease activity and progression in these haematological malignancies.

The prevalence of malignant disease in aPL positive patients has also been extensively investigated and was found to be 20 and 17% in two consecutive series of patients [37, 38],

A large prospective epidemiological study on the occurrence of malignant disease in aPL positive patients was recently conducted in Montpelier, France [37]. One thousand and fourteen patients were tested at entry and, interestingly enough, carcinoma was the most frequently associated disease. Among the 72 aPL positive patients, 14 had a history of carcinoma, 9 had active malignant disease while 5 were in clinical remission. The types of malignant diseases are reproduced in Table 1.

One patient in the above study, with NHL was aPL positive when first tested, but was found to be negative on repeat testing, once complete remission had been achieved.

None of the patients who were positive and had malignant disease had a history of thrombosis, nor did any of the aPL positive patients have a history of drug exposure associated with induction of aPL (e.g., phenothiazines).

Table 1. APA positive patients: Malignant disease

Table 2. Malignancies with aPL

Table 1. APA positive patients: Malignant disease

Patient

Sex

Age

Malignant disease

Remission

No.

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