Thromboembolism, Skin Lesions, and

Fibrinolytic Activity Nicholas G. Kounis M.D., F.I.C.A.



The association of thromboembolism with some specific skin disorders, such as psoriasis, has been reported recently, 1,2 and several factors have been implicated.I-5 Thrombus formation due to inadequate removal of fibrin deposition may be the result of reduced fibrinolytic activity. The fibrinolytic mechanism is activated by damage of the vessel wall, which is followed by formation of thrombus and deposition of fibrin. Blood fibrinolytic activity has been found to be reduced in some patients with pulmonary embolism, coronary thrombosis, acquired valvular heart disease, congenital heart disease, hypertension, multiple myeloma, polycythemia, the nephrotic syndrome, rheumatoid arthritis, and thyrotoxicosis.1 Patients with skin disorders were also found to have diminished fibrinolytic activity. These skin disorders are systemic lupus erythematosus, systemic sclerosis, erythema nodosum, erythema multiforme, Raynaud’s disease, and skin lesions with cutaneous vasculitis (polyarteritis nodosa, Wegenener’s granulomatosis, hypersensitivity angiitis, and granulomatous arteritis).’7 The following report discribes patients with thromboembolism associated with reduced fibrinolytic activity and skin lesions resembling mycosis fungoides. The aim of this report is to emphasise that the lack of a factor activating fibrinolysis is possible in patients with skin lesions, and that these patients are prone to develop thromboembolism. Materials and Methods

observed in 2 of 20 patients who were suffering from thromboembolic disease and who were admitted to the hospital over a period of 1 year. All patients underwent routine investigations, and the fibrinolytic activity was measured in the patients with skin lesions. Blood fibrinolytic activity was assessed by measuring the dilute whole blood clot lysis time (DWBCLT),8 the fibrin plate lysis area (FBLA ),9,10 the euglobin clot lysis time (ECLT),11,12 and the plasma fibrinogen level.&dquo;-15 Knowing that venous congestion has some effect on the fibrinolytic activity Skin lesions


From the Department of Cardiorespiratory Diseases, East Birmingham Hospital, Birmingham, England, and the Department of Cardiology, Royal Victoria Hospital, Belfast, Northern Ireland.


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of venous blood,16 we collected blood specimens before and after venous stasis. Venous blood was taken during the course of the disease at 2-day intervals. A 5ml sample was taken from an arm vein without compressing the veins, 2 ml was used for the ECLT, 0.9 ml for the FBLA, 0.1 ml for DWBCLT, and 2 ml for measuring the fibrinogen levels. The blood was collected at 9:30 AM. After the first specimen was brought to the laboratory, an infant sphygmomanometer cuff was applied to the upper arm and was inflated to a pressure of 80 mm Hg. After 10 minutes, and to avoid discomfort and maintain the venous stasis for 20 minutes, another infant sphygmomanometer was inflated above the first for 10 minutes. The first cuff was deflated immediately when the second was fixed. After 20 minutes, another sample of blood was taken and the cuff was deflated. With this method the stasis was maintained for 20 minutes, the time necessary for maximum release from the stores. Apart from the quantitative measurement of the fibrinogen, it was also observed in 75 X 12 mm glass tubes with liquid paraffin on the top of the blood to help the support of the clot. Both patients with skin lesions underwent histologic examination of their lesion, and in the first patient pictures of bone marrow and liver were also taken. Results

patients suffering from thromboembolism and admitted to the hospiperiod of 1 year, 2 were found to have skin lesions resembling mycosis fungoides. The first of these 2 patients developed acquired icthyosis during the course of the disease, and his thromboembolism ensued as terminal episode. This patient’s skin was dry and scaly. The scales covered the extensor aspects of arms and legs as well as the trunk and scalp, and were small, fine, and white. There were some areas of darker color, especially in the abdomen and thighs, as well as some erythematous areas which were more itchy and scaly. Bone marrow aspiration revealed very cellular marrow, with lymphocytes constituting about 30% of the total nucleated population, (normal lymphocytes about 10%) as shown (Figure 1). Skin biopsy from an erythematous area revealed perivascular dermal infiltration by lymphocytes but no Pautrier’s abscesses (Figure 2). Although there were no palpable lymph nodes, the liver was enlarged and was found to be infiltrated by fatty round cells (Figure 3). The diagnosis of this patient’s malady was acquired ichthyosis and premycotic mycosis fungoides, with possible transition to a poorly differentiated lymphocytic lymphoma. Despite treatment with corticosteroids and cyclophosphamide, the patient collapsed and died suddenly. Postmortem examination revealed deep venous thrombosis and pulmonary embolism. The second patient’s skin lesion was a darker area over the lower sternum, measuring 10 cm in diameter with superficial crusting and ulceration (Figure 4). Of 20


over a

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FIG. 1. Bone


showing hypercellularity


lymphocytic predominance.

This lesion appeared 18 months before his admission. Skin biopsy from the darker sternal area showed a malignant, infiltrative, highly cellular lesion involving the dermis and subcutaneous tissues and consisting of very pleomorphic reticulum cells with hyperchromatic nuclei. Other cells were lymphocytes, plasma cells, neutrophils, and histiocytes. Mitotic figures were also seen, but there were no Pautrier’s abscesses (Figure 5). The patient was admitted with chest pain, and the diagnosis of pulmonary embolism was confirmed by lung scan and angiography. With conventional anticoagulant treatment, the patient made a good recovery, and with radiotherapy his skin lesion remains localized without sequelae. Both of the patients had diminished fibrinolytic activity, as shown in Table 1. Discussion

fibrinolytic activity depends on the mobilization and release of endogenous plasminogen activator from the vascular endothelium into the occluded venous blood.&dquo; Venous occlusion of a limb is probably the most widely recognized and reproducible method of assessing the fibrinolytic response of the endothelium.l8 Blood fibrinolytic activity has been found to be diminished in patients after major operations, but not after minor operations.&dquo; It has also been suggested that after myocardial infarction and fracture of the femur there is an endothelial failure to release plasminogen activator.&dquo; This failure has been Blood

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FIG. 2. Skin

biopsy showing perivascular infiltration by lym-


attributed to an exhaustion of supplies resulting from the pronounced increase in systemic fibrinolytic activity. Skin disorders may be associated with cutaneous vasculitis and this results in decreased fibrinolytic activity. The formation of the thrombus and so the development of thromboembolism are due to inadequate removal of fibrin deposition resulting from diminished fibrinolytic :

activity. Thromboembolism has occurred in patients with other skin disorders such as psoriasis. This has been attributed to the high levels of cholesterol and/or triglyceride, 1,5 or to the treatment with Azaribine,2-4 which inhibits the enzyme orotidylic acid decarboxylase and thereby blocks the pyrimidine synthesis. Skin lesions with systemic involvement may affect the coagulation mechanism and

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FIG. 3. Liver lesion at autopsy showing marked fatty the portal tract. Sinuses contain excessive lymphocytes.

FIG. 4. Cutaneous






with moderate round cell infiltration in

of lower sternum with

superficial crusting

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and ulceration.


FIG. 5. Skin biopsy showing subcutaneous and dermal infiltration reticulum cells, lymphocytes, plasma cells, neutrophils, and histiocytes.


thus induce intravascular clotting and depletion of plasminogen activator from blood and vascular endothelium.11,11 A certain group venous disorders display diminished fibrinolytic activity.9 These include idiopathic superficial thrombophlebitis, deep venous thrombosis, varicose veins, and liposclerosis (a condition characterized by severe varicose veins with pigmentation, induration, thickening, eczema, and ulcers in the lower medial third of the leg due to superficial thrombophlebitis and extravasation of plasma proteins into the tissues). In these venous disorders in which the skin is always involved, a deficiency in some

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Fibrinolytic Activity Expressed as Means (and Standard Deviations)

DWBCLT dilute whole blood clot FBLA fibrin plate lysis area. ECLT euglobin clot lysis time. =

lysis time.



other factor activating fibrinolysis is postulated and a thrombotic diathesis is created. It has been known, for over 100 years,22 that malignant diseases are associated with thromboembolism, and some alteration in hemostatic factors have been described in patients with malignancy. They include increased platelet adhesiveness,23 increased factor X activity, 14 increased concentration of factor VIII,25 and an increase of factors V, IX, and XI.26 The administration of prednisolone in the first patient might have had an effect on his fibrinolytic activity. Corticosteroids inhibit clot lysis experimentally27,2S and reduce fibrinolytic activity in cirrhotic patients,29 although the latter action is not established with certainty and their effect of fibrinolysis is dose-related.30 The association of thromboembolism with skin lesions and low fibrinolytic activity seems now to constitute an entity. However, the precise mechanism of this association is still unknown. Its occurrence might be accidental, but a common pathogenetic basis cannot be excluded. Nicholas G. Kounis, M.D., F.I.C.A.

Department of Cardiology Royal Victoria Hospital Belfast, Northern Ireland

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666 al.: Skin fibrinolytic and systemic vasculitis. et

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1963, p. 79. 12. Menon, I. S.: Fibrinolysis infiltrated and oxalated blood. Lancet, 1: 116, 1967. 13. Ratnoff, O. D., Menzie, C.: A new method for the determination of fibrinogen in small samples of plasma. J. Lab. Clin. Sci., 37 : 316, 1951. 14. Reid, H. A., Chan, K. E., Thean, P. C.: Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite. Lancet, 1: 621, 1963. 15. Kounis, N. G.: Contribution to the Treatment and Prevention of Thromboembolic Disease with Arvin, Heparin, Phenformin, Ethyloestrenol and Warfarin. M.D. Thesis (in Greek). Athens University, Athens, Greece, 1976. 16. Rosenberg, S.. A., Diamond. H. D.. Taslowitz, B., et al.: Lymphosarcoma: A review of 1263 cases. Medicine (Baltimore), 40: 31, 1961. 17. Griffiths, N. J., Woodford, M., Irving, M. H.: Alteration in fibrinolytic capacity after operation. Lancet, 2: 635, 1977. 18. Clifton, E., Clarke, R., Murphy, J.: Studies on fibrinolytic activity with venous occlusion: Treatment of thrombophlebitis. Surgery, 50: 644, 1961. 19. Rawles, J. M., Warlow, C., Ogston, D.: Fibrinolytic capacity of arm and leg veins after femoral shaft fracture and acute myocardial

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R. A.: The effect of cortithe Shwartzman reaction: The production of lesions resembling the dermal and generalized Shwartzman reaction by a single injection of bacterial toxin in cortisonetreated rabbits. J. Exp. Med., 25: 409, 1952. 29. Kwaan, H. L., McFadzean, A. J. C., Cook, J.: Plasma fibrinolytic activity in cirrhosis of the liver. Lancet, 1: 132, 1956. 30. Chakrabarti, R., Fearnley, G. R., Hocking, E. D.: Effect of corticosteroid therapy on fibrinolysis in patients with inflammatory and noninflammatory conditions. Br. Med. J., 1: 534, 1964.


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Thromboembolism, skin lesions, and fibrinolytic activity.

Thromboembolism, Skin Lesions, and Fibrinolytic Activity Nicholas G. Kounis M.D., F.I.C.A. BELFAST, NORTHERN IRELAND The association of thromboemb...
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