Final Diagnosis -- Hyperfibrino(geno)lysis, Secondary to Metastatic Prostatic Carcinoma

DIAGNOSIS:  HYPERFIBRINO(GENO)LYSIS, SECONDARY TO METASTATIC PROSTATIC CARCINOMA.

DISCUSSION:

Fibrin formation (coagulation) and dissolution (fibrinolysis) are carefully coordinated physiologically. Hyperfibrino(geno)lysis occurs when there is greater fibrinolytic activity than fibrin formation, thus leading to hemorrhage. The central event of hyperfibrino(geno)lysis is the generation of plasmin within the general circulation (plasminemia). Plasmin, which is a protease converted from plasminogen, degrades fibrin, fibrinogen, coagulation factors V and VIII, complement components and other plasma proteins. The fibrinolytic activity of plasmin is initiated by the plasminogen activators (tissue plasminogen activator (t-PA) and urokinase (u-PA)) and down-regulated by plasminogen activator inhibitors (PAI-1 and 2) and plasmin inhibitors (α₂-antiplasmin).

Hyperfibrino(geno)lysis has been reported in various pathologic conditions. Examples include hypotension, trauma, heatstroke, cardiac bypass surgery and severe liver diseases. In these cases, excessive amounts of plasminogen activators may be released into the blood from body stores (mainly endothelial cells) and exceed the capacity of inhibitors. Occasionally, patients with disseminated neoplasms, such as acute promyelocytic leukemia or metastatic prostate cancer, also exhibit enhanced fibrinolytic activities with symptoms of GI or GU bleeding, epistaxis or other forms of hemorrhage. It has been demonstrated that the tumor tissue or cells contain plasminogen activators, especially u-PA. The secretion of these activators into the circulation may rapidly lead to plasminogen activation and, occasionally, to hyperfibrino(geno)lysis. The coagulation profiles in these patients usually show: (1) normal or slightly prolonged PT and PTT due to the anticoagulation effects of FDP (fibrinogen degradation product); (2) normal platelet count; (3) normal plasma levels of clotting factors, except for factors V and VIII which are more sensitive to the proteolytic action of plasmin; (4) hypofibrinogenemia; (5) depletion of plasminogen or a2-antiplasmin and the presence of a2-antiplasmin-plasmin complexes in the plasma; (6) normal plasma level of antithrombin III; (7) increased plasma level of FDP with normal level of D-dimer; (8) normal erythrocyte morphology shown by peripheral blood smear. The laboratory findings in hyperfibrino(geno)lysis are summarized in Table 2.

It should be noted that the fibrinolytic activation seen in DIC is a secondary response to microvascular thrombosis. It has been shown that there is an acute release of large quantities of t-PA into the circulation in patients with DIC. The abnormal hemostasis, therefore, is due to a combination of activation of coagulation and accelerated fibrinolysis. The clinical picture and laboratory findings of DIC are similar to those of hyperfibrino(geno)lysis, and distinction between the two is not always possible using routine laboratory assays . However, in cases of DIC, (1) the platelet count is usually low; (2) there is depletion of clotting factors, and thus prolonged PT and PTT; (3) there is decreased plasma level of antithrombin III and increased level of D-Dimer; (4) schistocytes and microspherocytes are present in the peripheral blood (Table 2).

In this report, we described a 77-year-old patient with acute onset of epistaxis and a medical history of metastatic prostate cancer. The patient's coagulation profile showed normal platelet count, borderline PT and PTT, levels of clotting factors within normal ranges, hypofibrinogenemia, significant increase of FDP, decreased activities of plasminogen and antiplasmin, and normal level of antithrombin III. These results are consistent with the diagnosis of hyperfibrino(geno)lysis, which is most likely secondary to the patient's underlying malignant neoplasm that may secret plasminogen activators into the blood. The elevated plasma level of D-Dimer in this patient may be explained by the degradation of fibrin generated from the tissue damage related to his metastatic carcinoma.

The treatment of choice for hyperfibrino(geno)lysis is antifibrinolytic agents. EACA (epsilon aminocaproic acid) and related agents are specific and potent inhibitors of plasminogen activation and action of plasmin. However, such antifibrinolytic agents are potentially dangerous in the presence of DIC. Therefore, the diagnosis of DIC should be ruled out before administering these agents to the patients.

REFERENCES:

1. Francis CW, and Marder VJ. Physiologic Regulation and Pathologic Disorders of Fibrinolysis. Hemostasis and Thrombosis. pp. 975-1002. 4th Ed., 2001.
2. Bennett B, and Ogston D. Fibrinolytic Bleeding Syndromes. Disorders of Hemostasis. pp. 296-322. 3rd ED, 1996.
3. Grosset, ABM, and Rodgers GM. Primary Fibrinolysis (Fibrinogenolysis). Wintrobe's Clinical Hematology. pp. 1753-1754.10th Ed., 1999.
4. Tagnon HJ, Whitmore WF, et al. Fibrinolysis in metastatic cancer of the prostate. Cancer, 5:9, 1952.
5. Okajima K, Kohno I, et al. Direct evidence for systemic fibrinogenolysis in a patient with metastatic prostatic cancer. Thrombosis Research, 66:717, 1992.
6. Bennett B, Booth NA, et al. The bleeding disorder in acute promyelocytic leukemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol, 71:511, 1989.
7. Wilson EL, Jacobs P, el al. The secretion of plasminogen activators by human myeloid leukemic cells in vitro. Blood, 61:568, 1983.
8. Bennett B, Croll AM, et al. Tumor cell u-PA as a cause of fibrinolytic bleeding in metastatic disease. Br J Haematol, 99:570, 1997.
9. Kirchheimer, JC, Pfluger H, et al. Plasminogen activator activity in bone metastasis of prostatic carcinomas as compared to primary tumors. Invasion and Metastasis, 5:344, 1985.
10. Bennett B, Croll A, et al. Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin and C1 inhibitor: Studies on patients with defibrination and a fibrinolytic state after electroshock or complicated labor. Blood, 75:6

Contributed by Su Zheng, MD, PhD, and Andrea Cortese Hassett, PhD