Safety of plasma‐derived protein C for treating disseminated intravascular coagulation in adult patients with active cancer
Authors: Alessandra Malato, Giorgia Saccullo, Lucio Lo Coco, Clementina Caracciolo, Simona Raso, Marco Santoro, Valentina Zammit, Sergio Siragusa
Journal: American Journal of Hematology (2011)

Cancer-related disseminated intravascular coagulation (DIC) is a life-threatening condition for which no effective treatment is currently available. Protein C (PC), a modulator of coagulation as well as the inflammatory system, has been successfully tested (in its activated recombinant form [a-rPC]) in sepsis-related coagulopathy, but with an increased risk for major bleeding. Plasma-derived PC (pd-PC) is more suitable than a-rPC in patients at high risk from bleeding due to its self-limiting process. We carried out a single-arm study evaluating the role of pd-PC in adult cancer patients with overt DIC. Over a period of 3 years, we treated 19 patients with overt DIC and a PC plasma concentration <50%; all received PC concentrate (Ceprotin®, Baxter) for 72 hr in adjusted doses to restore normal PC values (70–120%). Blood coagulation, haematological tests, and the DIC score were recorded after 12, 24, 48 hr, 7 and 10 days, while clinical outcomes (bleeding, thrombosis and mortality) were recorded up to 28 days. Within 48 hr of starting pd-PC therapy, laboratory tests as well as the DIC score improved in all patients. At 28-days follow-up, no bleeding or thrombosis was observed. This is the first study to investigate the use of pd-PC for treatment of cancer-related overt DIC. Disseminated intravascular coagulation (DIC) is a syndrome characterized by the systemic activation of blood coagulation, thrombosis of the small and medium size vessels, and multiorgan dysfunction leading to consumption of coagulant factors and platelets; bleeding is usually the overt clinical picture while thrombosis produces organ damage [ 1]. There are many causes of DIC, such as sepsis, cancer, or pregnancy [1, 2]. Its management, still unsatisfactory due to the lack of an effective therapy, is mainly based on the treatment of the underlying condition along with the administration of fresh-frozen plasma (FFP) and replacement therapy (such as anti-thrombin [AT]) [3, 4]. Recently, the correlation between sepsis and coagulation abnormalities has been intensively investigated [5-7]; in septic patients with DIC, substitution therapy with activated recombinant protein C (ar-PC) has been proven to be effective, but with an increase in bleeding [8, 9]. The protein C pathway is a modulator of the coagulation system, and PC itself plays an integral role in the host response to infection, immune system, and cancer cells [1, 2]. The extent of PC deficiency assessed at the time of diagnosis has been found to correlate with increased morbidity and mortality [6, 7]. Less is known regarding the correlation between active cancer and coagulation consumption leading to DIC in patients without signs or symptom of sepsis [ 10-13]. As the presenting condition, DIC occurs in 2–5% of patients suffering from solid neoplasm [10]. Many factors can contribute to coagulopathy in tumors. Cancer cells express different procoagulant molecules as well as fibrinolytic proteins [10-13], and chemotherapy may enhance the risk of thrombosis due to its damaging effect on the endothelium [11]. Some clinical differences exist between the coagulopathy that occurs in sepsis in comparison to the one occurring in cancer. In general, a less severe picture occurs in cancer patients where chronic activation of coagulation can proceed with few clinical events. This process usually leads to exhaustion of platelets and coagulation factors, thus making bleeding (e.g., at the site of the tumour) the first clinical symptom of DIC, while in other cases, cancer-related coagulopathy occurs in the form of thrombotic microangiopathies [10-13]. In cancer-related DIC, conventional treatment is related to high mortality also due to the difficulty in properly treating the underlying neoplasm [10]. In this situation, pd-PC seems a suitable treatment, due to its ability to modulate coagulopathy, inflammation and cancer activity, and its self-limiting process in activating anticoagulation [1, 2]. However, there is little information in the literature regarding the appropriateness of such an approach within cancer populations. For this purpose, we conducted a single arm study evaluating the role of pd-PC in cancer patients with overt DIC showing no signs or symptoms of sepsis. From February 2006 to June 2009, 49 consecutive adult cancer patients with overt DIC were considered; 30 patients were excluded because of: normal PC levels at the baseline (n = 14), signs/symptoms of sepsis (n = 8), reluctance to give consent (n = 3), acute promyelocytic leukemia (APL) (n = 2), and initial treatment with substitutive AT (n = 3). Thus, 19 patients were enrolled. At study entry, all had active cancer and plasma values of PC activity lower than 50%. Patient characteristics are reported in Table I. Six patients received fresh frozen plasma and one (4.5%) received red blood concentrates; seven patients had clinical manifestations of muco-cutaneous and/or genitourinary bleeding. Twelve patients had solid cancer (six gastrointestinal, two pulmonary, four genitourinary) and six had a haematological cancer (three lymphoproliferative disorders, two myeloma, and one acute myeloid leukaemia). Most had an advanced/metastatic neoplasm (Table I), and six had recently undergone previous surgery (within <1 month). Baseline plasma PC activity was 31.4% ± 8.1% (range 19–48%). Our therapeutic approach increased plasma PC activity in all patients. Plasma PC activity normalized after 48 hr and remained stable over the following days. Average bolus dose and daily total amount are reported in Table I. At baseline, most patients showed abnormal PT, aPTT, platelets and D-dimer levels, and had high DIC scores. During the study period, there was a progressive and significant increase in platelets, fibrinogen, and AT, and a progressive and significant decrease in D-dimer, PT/INR, aPTT, and DIC scores (Table II). No adverse reactions or events were observed during PC replacement therapy. Baseline PC levels were lower in nonsurvivors than in survivors (23.4% vs. 31.6%, respectively), although the difference was not statistically significant (P = 0.08); there was no difference between PC levels in patients who died and those who survived. On average, the total amount of infused PC concentrate was similar in survivors and nonsurvivors. No difference was found among all other laboratory tests among patients who died in comparison to survivors. In both groups, baseline AT levels were similar, mean D-dimer concentrations decreased significantly over the following days. At baseline, the mean DIC score was 6.26 ± 1.12; 14 patients had overt DIC, (DIC score =5). Regarding the baseline DIC score, we found a significant difference (P < 0.05) between survivors (mean DIC score of 6.2) and patients who died (mean DIC score of 8.5). The DIC score decreased significantly after 72 hr in all patients. At the 7-day follow-up, only two patients had laboratory and clinical characteristics of an overt DIC status. No patients developed signs or symptoms of bleeding or thrombosis. Five patients (26.3%) died within 28 days of DIC diagnosis. The use of PC has been shown to be effective for reducing mortality in adult patients with severe sepsis (in its activated form) and in children with concomitant PC deficiency (plasma-derived zymogen) [ 8, 9, 14-16]. Regarding pd-PC, this form acts only when it is converted to activated PC and requires the presence of the thrombin–thrombomodulin complexes. The physiological self-limitation of this process may reduce the risk of bleeding in respect to ar-PC and, to our knowledge, no adverse events on the use of pd-PC have been reported so far [8, 9, 14-16]. This evidence supports the use of pd-PC zymogen in acquired PC deficiency in septic patients [14] and in adults with purpura fulminans [16]. While nonovert chronic DIC is quite common in cancer patients (and usually does not require any specific therapeutic approach), there are no reliable data regarding the incidence and management of overt DIC. In fact, this complication, although rare, is extremely severe and difficult to treat properly [ 10, 13, 17]. Based on the notion that depression of the PC system may contribute significantly to the beginning of DIC in cancer patients, supplementation of PC may be of benefit [1, 2, 10, 12]. However, the role of restoring defective physiological anticoagulant in patients with cancer has not been evaluated and extrapolation from other settings of patients is difficult; this is considering that patients with severe thrombocytopenia (as commonly occurs during cancer treatment) were excluded from the available trials for the use of ar-PC [9]. Therefore, the role of PC (either plasma-derived or activated) for treating cancer-related coagulopathy is unclear. We are the first to evaluate PC concentrates for managing cancer patients with overt DIC. The observed results of our series are limited to the effectiveness of the dosage and the lack of side effects; our regimen of pd-PC therapy was effective in restoring physiological plasma PC activity, to normalize coagulation laboratory tests and to decrease the DIC score. No adverse events were recorded. Our study has some limitations. First, we had to conduct a single arm study due to the rarity of the disease; in the absence of a control group, it is not possible to comment on the efficacy of treatment. To reinforce our findings, we compared the mortality rate in the present investigation with historic control values from our hospital. The latter comprised a population of 24 cancer patients with DIC, similar to the present series in respect to median age, tumor type and burden, and severity of coagulopathy, all of whom received substitutive AT and FFP for a median period of 72 hr. Mortality at the 28-days follow-up was around 70% in comparison to 26% reported in the present investigation. Although direct comparisons are not possible, this difference would appear to be clinical relevant. Second, cancer patients differ in terms of prognosis, cancer spread, organ involvement, and staging. We are aware that our population may not be fully comparable between survivors and nonsurvivors; however, only patients with advanced cancer (solid or haematological) were included in the analysis to reduce the risk of considering patients with different degrees of severity. We excluded patients suffering from APL since the associated-coagulopathy is well controlled by -trans-retinoic-acid treatment [ 18]. In conclusion, we report for the first time the use of pd-PC concentrates for managing advanced cancer patients with overt DIC. Our results demonstrate the feasibility of pd-PC therapy for normalizing laboratory values and ameliorating the DIC score without bleeding or thrombosis during the study period. Eligible patients were those with active cancers (solid or haematological except than APL) [ 18], overt DIC score and PC plasma levels below 50%. Patients were excluded in the case of laboratory or clinical findings suggesting multiorgan failure (MOF) and/or severe sepsis. In these cases, patients were admitted to the local ICU and managed accordingly. Treatment was performed at the University Hospital of Palermo, Italy. A diagnosis of DIC was established according to the Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society of Haemostasis and Thrombosis [19]. An evolving DIC score was given to each patient: a DIC score = 5 was compatible with overt-DIC, while a score < 5 was suggestive (not affirmative) for nonovert DIC. Overt DIC was defined as the alteration of laboratory parameters according to current international guidelines resulting in a DIC score ≥ 5 with or without bleeding or thrombosis [18, 19]. Enrolled patients were treated with pd-PC concentrate (Ceprotin®, Baxter) with the aim of obtaining 100% of the plasma PC activity. The infusion was given for 72 hr at a starting dose of 50 UI kg−1 daily−1, adjusted to maintain a plasma PC activity between 70 and 120%. Laboratory measurements of PC activity were performed every 24 hr with a chromogenic method (amidolytic assay protein C assay, Chromogenix, Milan, Italy; range 70–140%). Fresh-frozen plasma, AT concentrates, and red packed cells or platelet transfusions were given when appropriate. White blood cells, platelets, D-dimer, fibrinogen, PT, aPTT, AT, and DIC score (20) were evaluated before PC infusion (baseline), after 24, 48, 72 hr, and on the 7th and 10th day of treatment. Mortality was evaluated within 28 days. Parameters evaluated during the study period were analyzed by repeated measures ANOVA and post-hoc comparison (LSD test). A P < 0.01 was considered statistically significant. The study design was a single-arm study and approved by the Internal Review Board. Protein C concentrate (Ceprotin®, Baxter) was administered according to the ethical principles of the Declaration of Helsinki for medical research involving human subjects. Sergio Siragusa designed the study, analyzed the data, and contributed to writing the article. Alessandra Malato performed the research, analyzed the data, and contributed to writing the article. Giorgia Saccullo analyzed the data and helped perform the study. Clementina Caracciolo, Simona Raso, Marco Santoro, and Valentina Zammit performed the research. Lucio Lo Coco contributed essential reagents and analyzed samples. Alessandra Malato*, Giorgia Saccullo*, Lucio Lo Coco*, Clementina Caracciolo*, Simona Raso*, Marco Santoro*, Ambra Di Piazza*, Valentina Zammit*, Sergio Siragusa*, * Cattedra ed U.O. di Ematologia con trapianto, Dipartimento di Medicina Interna e Specialistica (DIMIS), Università degli Studi di Palermo, Italy.