Factor V Leiden mutation triggering four major complications to standard dose cisplatin-chemotherapy for testicular seminoma: a case report

Generally, the occurrence of complications secondary to a chemotherapeutic agent is dependent on both the applied dosage of the drug and the predisposition of the individual patient to acquire particular complications. Accordingly, high dose chemotherapy is associated with a much higher frequency of major complications. With respect to the susceptibility of the patient to acquire complications, older age is clearly one general predisposing factor as well as pre-existing chronic diseases e.g. Diabetes mellitus, renal insufficiency, chronic vascular disease. As most of the patients with testicular GCT are young and otherwise healthy, and as most of the metastasized cases only require standard dose chemotherapy, major complications are rather infrequent. Two or more critical events arising simultaneously or consecutively in one such patient are even more infrequent. Thus, the conjunction of four serious events as experienced by our patient is truly exceptional. O´Reilly reported a 26 year old patient with testicular seminoma and no significant comorbidity who sequentially experienced cerebral stroke, deep vein thrombosis and pulmonary embolism during PVB chemotherapy [11]. A 33 year old Dutch patient with GCT who was otherwise healthy developed cerebral stroke and myocardial infarction upon cisplatin-based therapy [13]. Likewise, in a German series, two patients (36 and 44 years of age) with both, myocardial infarction and cerebral stroke were reported. Also in that report, five cases with multivessel myocardial infarction as well as two cases with pulmonary embolism occurring in conjunction with cerebral stroke and with peripheral arterial thrombosis, respectively, were documented [7].

With respect to the present patient, it is probably the unique combination of a number of particular conditions that instigated this extraordinary pattern of untoward events.

Undoubtedly, the thrombophilic predisposition of this patient documented by the mutation of Factor V Leiden (FVL) represents the paramount pathogenetic factor that triggered the major vascular complications. Heterozygote status of FVL mutation is prevalent in around 5% of the Caucasian population involving a seven-fold increase of the thrombogenic risk in afflicted subjects [14]. Evidently, FVL does also modestly increase the risk of arterial thrombosis [15-17], at least in the presence of additional prothrombotic conditions [18]. Even splenic infarction, one of the events of our patient, has been documented in a case with FVL mutation [19].

Thus, our patient was bearing a genetically determined significantly increased risk of thrombosis which was superimposed by at least four additional synergistic thrombogenic factors: age, cancer, central venous port system, and cisplatin chemotherapy. (I) Firstly, the slightly advanced age of 48 years confers a minor increase of general thrombotic risk by comparison to the average GCT patient. (II) Cancer itself generally increases the risk of thrombosis [20,21]. Moreover, there is also clear evidence of further increased thrombotic risk in those individuals who have both, cancer and FVL mutation [14]. On top of that, our patient had a huge retroperitoneal mass that potentially might compromise venous backflow from the lower limbs thus predisposing to intravasal clotting [4]. (III) Central venous port devices generally involve a high potential of thrombosis due to contact and irritation of vascular walls with the synthetic port material [22]. In the presence of FVL mutation, an additional 3 – 6 fold thrombotic risk has been documented [23,24]. (IV) Cisplatin combination chemotherapy involves considerable thrombogenic risk [25] possibly caused by endothelial damage [6,26,27]. Whether or not anti-emetic steroid therapy and BIP-related corticoid administration may have advanced the thrombotic risk in our patient is at least conceivable [28]. In all, our patient experienced three thrombotic events during or immediately after cisplatin-based chemotherapy. Obviously these complications were initiated and promoted by the conjunction of the patient´s genetically determined increased risk of thrombosis on the one side, and several disease-related as well as treatment related synergistic prothrombotic factors on the other side.

With regard to the Bleomycin-related pulmonary fibrosis the patient used to be a non-smoker and he had no apparent predisposing pulmonary conditions. Yet, two minor precipitating factors could be noted, i.e. the slightly advanced age of 48 years and the impaired renal function developing during the third cycle of chemotherapy, both of these conditions are known to be associated with the occurrence of BIP [8]. At least on the experimental level there is some evidence that FVL mutation may promote pulmonary fibrosis, too [29]. Thus conceivably, the pulmonary and the vascular complications occurring in the present patient may share predisposing factors.

From a clinical point of view, it must be asked how and if at all these events could have been prevented. Probably, the pulmonary complication represents much of a chance event that had not been predictable at the time of treatment. Two of the three vascular complications were endo-arterial events. So, low dose heparin anticoagulation would probably not have been sufficient to prevent further vascular events. If acetylic salicylic acid (ASA) would have been beneficial in this case remains elusive. However, what should be learned from this extraordinary case is that genetic testing for hereditary clotting disorders should be considered in all those GCT patients experiencing one major vascular complication. Then, life-threatening further complications could be prevented by full dose warfarin medication or other modern oral anticoagulation treatment.