Primary hyperfibrinolysis as the presenting sign of prostate cancer – A case report

Introduction. A bleeding syndrome in the setting of primary hyperfibrinolysis in a prostate cancer patient is only 0.40– 1.65% of cases. The laboratory diagnosis of primary hyperfibrinolysis is based on the increase of biomarkers like D-dimer, fibrinogen split products, plasminogen, and euglobulin lysis test. These tests are not specific for primary hyperfibrinolysis. We reported a rare case of hemorrhagic syndrome caused by primary hyperfibrinolysis as the first clinical symptom of metastatic prostate cancer. Case report. A 64-year-old male was admitted to our hospital with large hematomas in the right pectoral and axillary areas (20  7 cm), right hemiabdomen (30  30 cm) and the left lumbal area, (25  5 cm). The patient had no subjective symptoms nor used any medication. Initial coagulation testing, prothrombin time (PT), and activated partial thromboplastin time (APTT) were within the normal range, while fibrinogen level was extremely low (1.068 g/L) (normal range 2.0–5.0) and the D-dimer assay result was high 1.122 mg/L (normal range < 0.23). The results obtained by rotation thrombelastometry pointed to primary fibrinolysis. Further clinical and laboratory examination indicated progressive malignant prostate disease. First line treatment for the patient was a combined administration of tranexamic acid (3  500 mg iv) and transfusion of ten units of cryoprecipitate (400 mL). Next day, fibrinolytic function measurements by rotation thrombelastometry were within the normal ranges. Fibrinogen level was normalized within two days (2.4 g/L). There were no newly developed hematomas. Conclusion. This case report shows primary hyperfibrinolysis with bleeding symptoms, which is an uncommon paraneoplastic phenomenon within expanded prostate malignancy. Rotation thrombelastometry in this severe complication helped to achieve the prompt and proper diagnosis and treatment.


Introduction
Hemostatic capacity of a patient depends on the stability in the processes of formation and degradation of a blood clot.Disturbances in the mechanisms of fibrinolysis may lead in some cases to primarily clinical bleeding without the initial thrombotic events that characterize disseminated intravascular coagulation (DIC) syndromes.Malignant disease results in a prothrombotic imbalance of the host hemostatic system.Hematologic disorders are commonly seen in patients with prostate cancer (PCa).The most frequently observed disorder in PCa patients is acute or chronic DIC.The incidence of DIC complication in PCa ranges from 13% to 30%, and can be presented as catastrophic bleeding or various thrombotic events.In contrast, bleeding symptoms in the setting of primary hyperfibrinolysis in this malignancy are seen in only 0.40-1.65%patients, usually provoked by surgical procedures 1 .Laboratory diagnosis of hyperfibrinolysis is based on the increase of biomarkers like D-dimer; fibrin/fibrinogen degradation products (FDP), plasminogen, and euglobulin lysis test (ELT).These tests are not specific for primary hyperfibrinolysis and they are also elevated in other pathological conditions 2 .We presented a rare case of hemorrhagic syndrome caused by primary hyperfibrinolysis, which was the presenting paraneoplastic phenomenon of metastatic PCa.
The thrombin time was prolonged (24.0 s).A reduced level of fibrinogen, and high positive D-dimer with the absence of dramatic disturbances in coagulation screening tests indicated the high level of fibrinolytic activity.The results obtained by rotation thrombelastometry pointed to primary fibrinolysis.The clotting time, clot formation time, maximum clot firmness, alpha angle, and 60-minute lysis index were pathologically changed in INTEM, EXTEM, FI-BTEM and APTEM tests (Figure 1).First line treatment for the patient was a combined administration of tranexamic acid (3  500 mg iv) and transfusion of ten units of cryoprecipitate (400 mL).Next day, fibrinolytic function measurements by rotation thrombelastometry were within normal ranges.APTEM test was not registered pathological fibrinolysis (Figure 2).The fibrinogen level was normalized within two days (2.4 g/L).There were no newly developed hematomas.

Table 1 Results of coagulation testing
The existence of pathological fibrinolysis with a high value of alkaline phosphatase and lactate dehydrogenase directed the diagnostics to detecting malignancy.Laboratory evaluation of patients included determination of prostate specific antigen (PSA), of the values higher than 150 ng/mL (NV 0-4.5 ng/mL).Digital rectal examination established the enlarged prostate with bumps, painless to palpation.The definitive diagnosis of prostate cancer was only possible after the treatment of hyperfibrinolysis which was the cause of hemorrhagic syndrome.Transrectal biopsy of prostate was successfully performed without any hemorrhagic complications, revealing prostate adenocarcinoma G3, Gleason score 9, and bone scans confirmed bone metastases.Afterwards, the patient was referred to the oncologist for further treatment with androgen deprivation therapy and by per os administration of tranexamic acid.

Discussion
Paraneoplastic syndromes represent a constellation of conditions that are caused by the presence of malignancy, but not associated with direct tumor invasion or compression.In patients with advanced prostate cancer paraneoplastic syndrome is expressed through a variety of different clinical symptoms 3,4 .One of them are disorders of hemostasis ranging from bleeding to thrombosis or embolic complications.This case report presented primary hyperfibrinolysis with bleeding symptoms, which is an uncommon paraneoplasic phenomenon within expanded prostate malignancy.The only clinical manifestation of primary hyperfibrinolysis in the presented patient was the presence of large subcutaneous hematoma.
In malignancy hiperfibrinolysis can be activated in two ways.Firstly, tumor cells can produce all the proteins of the fibrinolytic system including the urokinase-type plasminogen activator (uPA) and the tissue-type plasminogen activator (tPA).Secondly, cancer cells also carry on their membranes the specific urokinase plasminogen activator receptor (uPAR), which favors the assembly of all the fibrinolytic components, facilitating the extreme activation of the fibrinolytic cascade 5 .
The central event of hyperfibrinolysis is the generation of plasmin within the general circulation 6 .The presence of high activity of the plasmin causes a pathological degradation of fibrin and fibrinogen.It leads to rapid clot breakdown with consequent bleeding.Probably, severe hypofibrinogenemia in the presented patient was caused by fibrinogenolysis due to extreme production of uPA and tPA by prostate cancer cells.
Acquired fibrinolysis occurs as primary process during lung, and gland surgery, in malignant diseases of blood and liver disorders 6 .Other type of acquired hyperfibrinolysis is DIC.Fibrinolytic process in DIC is always secondary to another underlying pathological state.Clinical presentation of DIC depends on the underlying condition that triggers this medical disorder.In some patients, activation of the fibrinolytic system may dominate over the excessive coagulation, resulting in massive generation of thromboplastic material and consumption of hemostatic elements 7 .In DIC coagulation test the results are obtained with decreasing probability in this order: platelets decreased, FDP increased, PT prolonged, APTT prolonged and fibrinogen decreased.D-dimer test in DIC is highly positive 7,8 .In patients with prostate cancer DIC is the most frequent coagulation disorder while primary hyperfibrinolysis is unusual.The low fibrinogen with markedly elevated D-dimer and negative test for fibrin soluble monomer complex with no depletion of the coagulation factors can point to primary hyperfibrinolysis.Ddimer is a specific degradation product formed by FXIIa from cross-linked fibrin monomers, followed by plasmin hydrolysis 9 , but elevated D-dimer level can be seen in different diseases and it is not specific for primary hyperfibrinolysis.The diagnosis in the presented case was confirmed by rotation thromboelastometry.
Rotation thromboelastometry (ROTEM ® ) is a viscoelastic point-of-care hemostatic assay designed for full perception of the hemostatic capacity of patients.Also, the method is sensitive for detection and the diagnosis of early fibrinolysis in trauma patients 10 .In contrast to plasmatic coagulation tests, viscoelastic assays like ROTEM ® can estimate speed and quality of clot formation, including detection of hyperfibrinolysis, and are performed in whole blood, thus closely reflecting the in vivo situation 11 .Comparing the pa-rameters in EXTEM and APTEM test we could detect the moderate form of hiperfibrinolysis.
In the literature we could not find similar examples of hyperfibrinolysis in a prostate cancer patient with the diagnosis made using rotation thrombelastometry.Rotation thrombelastometry is intended for perioperative monitoring of coagulation at active bleeding trauma patients.In cancer patients it was applied in order to detect alterations in the hemostatic capacity, primarily in identification of those patients who are at risk of cancer-induced thromboembolic events 12 .Due to the possibility of rotation thrombelastometry to review all elements of the hemostatic system, particularly the role of platelets and fibrinogen in the formation and stability of a blood clot, its wider application can significantly help in the diagnosis of hemostasis disorders in non-trauma patients.
The diagnosis of primary hyperfibrinolysis is complex and requires the knowledge of the fibrinolytic process nature and clinical circumstances of this pathological condition.

Conclusion
This case report presented primary hiperfibrinolysis with bleeding diathesis as the first clinical sign of previously undiagnosed metastatic PCa.Clinical application of rotation thrombelastometry in a combination with coagulation tests at non-trauma patients, especially oncology patients, can greatly facilitate the diagnosis and therapy of primary hiperfibrinolysis.Rotation thrombelastometry in this severe complication helps to achieve the prompt and proper diagnosis.
The management of hyperfibrinolysis was done within a short period of time thanks to the adequate diagnostic procedure.