Hepatocellular carcinoma associated with acquired von Willebrand disease and extreme thrombocytosis

Reactive thrombocytosis (RT) is a common clinical condition and can be seen in patients with malignancies. On the other hand, acquired von Willebrand disease (AvWD) is a rare bleeding disorder and its occurrence in patients with solid tumors is even more unusual. Here we report a victim of hepatocellular carcinoma (HCC) who manifested both.

A 50-year-old man was referred for treatment of unresectable HCC. He presented with bleeding diathesis. The hemogram showed marked thrombocytosis (1413 x 109/l). His prothrombin time was normal, but both the activated partial thromboplastin time and bleeding time were significantly prolonged. Levels of coagulation factors and biochemical profiles were essentially normal.

The patient denied past and familial histories of bleeding tendency. His plasma thrombopoietin (TPO) level was extraordinarily high, while interleukin-6 level was low. Platelet aggregation tests showed mildly impaired capabilities of aggregation with various agonists. No inhibitors of coagulation factors were detectable. Levels of von Willebrand factor (vWF) antigen and fibrinogen were high, but the functional property of vWF assessed by ristocetin cofactor activity (vWF:RCo) assay reached 30% of that of normal reference plasma only.

The possibility of inhibitor-induced AvWD was confirmed by a subsequent inhibition test. We mixed the patient's plasma and pooled normal plasma in a 1:1 ratio, incubated it at 37°C for 2 h, and repeated the ristocetin cofactor activity assay. The mixture showed similarly decreased activity.

The patient then received therapy with epirubicin and interferon-alpha, with satisfactory response. Clinically, his bleeding diathesis abated. Laboratory work-up showed an improved hemostatic profile. His platelet count dropped dramatically without a concurrent fall of white cell count, which ruled out the possibility of marrow suppression effects of chemo-immunotherapy.

Our patient here exhibited two unique features: AvWD due to presence of vWF inhibitors and RT mediated by increased TPO production.

Non-hematological malignancies with coexisting AvWD are most commonly seen in patients with Wilms tumor. Other cancers sporadically reported include adrenocortical carcinoma, lung cancer, grastric carcinoma and primitive neuroectodermal tumor [1Go]. There have not been similar reports in patients with HCC. Generally, excessive tumoral adsorption of vWF was the pathogenesis of AvWD in cancer patients [1Go]. Nevertheless, we demonstrated vWF inhibitors as the underlying causes in our case.

Autoantibody-induced AvWD was typically associated with autoimmune or hematoproliferative disorders. In most patients, the antibody–vWF immune complexes were cleared from the circulation, which resulted in low levels of factor VIII and vWF antigen and reduced vWF:RCo activity [2Go]. Sometimes, these antibodies had restricted specificity, interfering with the binding of vWF to platelet glycoprotein Ib receptors without causing clearance of vWF antigen [3Go]. This could lead to normal antigen level with disproportionately reduced functional activity of vWF, as in our patient.

Various neoplasms have been associated with RT. The most widely accepted mechanism is that the endogenously increased IL-6 in cancer patients leads to excessive TPO production and resultant thrombocytosis [4Go]. Newer evidence has also revealed that tumor cells could over-express TPO. In a large series, thrombocytosis occurred in 2.7% of HCC patients and was the result of overproduction of TPO by HCC [5Go]. The contrast levels of IL-6 and TPO in our patient suggest a similar mechanism.

Both thrombocytosis and AvWD are rare paraneoplastic syndromes of HCC patients. Although RT rarely causes bleeding, hemorrhagic complications associated with AvWD could be problematic. When bleeding occurs, careful evaluation of hemostatic parameters is mandatory. If AvWD is documented, treatment must be planned accordingly.

C.-C. Chen1,2, J.-Y. Chang1, K.-J. Liu1, C. Chan1, C.-H. Ho2,3, S.-C. Lee3 and L.-T. Chen1,4,*

1 National Cancer Research Center, National Health Research Institutes; 2 School of Medicine, National Yang-Ming University Taipei; 3 Division of Hematology, Department of Internal Medicine, Veterans General Hospital-Taipei, Taipei; 4 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Email: leochen{at}nhri.org.tw; Email: twleochen{at}nhri.org.tw

References

1. Tefferi A, Nichols WL. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med 1997; 103: 536–540.[CrossRef][ISI][Medline]

2. Michiels JJ, Budde U, van der Planken M et al. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001; 14: 401–436.[CrossRef][ISI][Medline]

3. Goudemand J, Samor B, Caron C et al. Acquired type II von Willebrand's disease: demonstration of a complexed inhibitor of the von Willebrand factor-platelet interaction and response to treatment. Br J Haematol 1988; 68: 227–233.[ISI][Medline]

4. Heits F, Katschinski DM, Wilmsen U et al. Serum thrombopoietin and interleukin 6 concentrations in tumour patients and response to chemotherapy-induced thrombocytopenia. Eur J Haematol 1997; 59: 53–58.[ISI][Medline]

5. Hwang SJ, Luo JC, Li CP et al. Thrombocytosis: a paraneoplastic syndrome in patients with hepatocellular carcinoma. World J Gastroenterol 2004; 10: 2472–2477.[Medline]





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