European Journal of Cardiovascular Medicine

Cancer is a complex systemic disease that involves not only uncontrolled cellular proliferation and metastatic spread but also widespread disruption of physiological systems, including the hemostatic system. A prothrombotic state is a well recognized feature of malignancy and predisposes patients to venous thromboembolism, arterial thrombosis, intravascular coagulation and fibrinolysis (ICF), and disseminated intravascular coagulation (DIC). These coagulation disturbances contribute to increased morbidity, mortality and poorer oncologic outcomes. [1]

The pathogenesis of cancer-associated coagulopathy is multifactorial and includes tumor-mediated endothelial injury, systemic inflammation, and release of procoagulant substances such as tissue factor and cytokines. Certain malignancies, including pancreatic, lung, ovarian and mucin-secreting gastrointestinal tumors, are particularly thrombogenic. Cancer

treatments such as chemotherapy, surgery, radiotherapy and hormonal therapy may further exacerbate coagulation dysfunction by inducing vascular damage and altering the synthesis of coagulation factors. [2]

D-dimer and fibrinogen are widely studied biomarkers of hypercoagulability and have demonstrated prognostic value in advanced-stage cancers. Platelet activation and thrombocytosis also contribute to tumor progression and coagulation activation, and platelet count in combination with D-dimer can be used to classify ICF syndromes. Routine assessment of PT, APTT, fibrinogen, D-dimer, FDP and platelet counts provides valuable insight into the hemostatic status of cancer patients.[3]

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The relationship between cancer and coagulation varies across tumor sites and histologic types. Understanding these patterns may help identify markers for early detection of cancer-related ICF and refine risk stratification strategies. [4]

The principal objectives of this study were to analyze coagulation parameters and platelet counts in patients with various solid malignancies, and to evaluate their association with tumor site, histopathology, metastatic status, lesion size and ICF categorization.

2.1 Study design and setting This prospective observational study was conducted over 18 months at a tertiary care teaching hospital. The study period consisted of 12 months of patient recruitment and sample collection followed by 6 months of data analysis. Institutional Ethics Committee approval was obtained prior to initiation of the study, and written informed consent was taken from all participants. 2.2 Study population A total of 150 indoor patients of all ages and both sexes with histopathologically or cytologically confirmed solid malignancies were enrolled. Patients with hematologic malignancies, known congenital or acquired bleeding diatheses and history of hemorrhagic stroke were excluded. For each patient, detailed demographic and clinical information, including age, sex, primary tumor site, histologic type, lesion size, and presence of lymph node or organ metastasis, was recorded. Imaging and histopathology reports were reviewed to confirm diagnosis and staging. 2.3 Sample collection and laboratory analysis Two milliliters of venous blood were collected into EDTA vacutainers and two milliliters into citrate vacutainers and processed within two hours of collection. Platelet counts were measured using a 5-part hematology analyzer (Horiba Yumizen 2500) and cross-checked with peripheral smear findings. Coagulation tests including PT, international normalized ratio (INR), APTT, fibrinogen and D-dimer were performed on an ACL TOP 350 coagulometer. FDP was detected using a qualitative and semi-qualitative latex slide agglutination test (TULIP XL FDP kit) performed on citrated plasma. The normal reference ranges used were: platelet count 150,000 to 400,000/µL; PT 11 to 15 seconds; APTT 29 to 35 seconds; fibrinogen 250 to 450 mg/dL; FDP <5 µg/mL; and D-dimer <0.5 µg/mL (local laboratory cut-off 243 ng/mL). 2.4 Definition of ICF categories D-dimer and platelet counts were used to categorize patients into four ICF groups: 1) No ICF: normal D-dimer with normal platelet count. 2) Overcompensated ICF: elevated D-dimer with elevated platelet count. 3) Compensated ICF: elevated D-dimer with normal platelet count. 4) Decompensated ICF: elevated D-dimer with decreased platelet count. D-dimer was prioritized for the diagnosis of ICF because of its higher specificity for cross-linked fibrin degradation products, representing breakdown of fibrinogen and fibrin into FDP fragments. 2.5 Statistical analysis Sample size was calculated using the formula n = 4pq/L², where n is sample size, p the estimated prevalence, q = 100 − p, and L the allowable error. Data were entered in Microsoft Excel and analyzed using SPSS version 19.0 (IBM Corp, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as frequencies and percentages. One-way ANOVA was used to compare mean coagulation parameters across tumor systems and between metastatic and non-metastatic groups. Independent samples t-test was used for pairwise comparisons where appropriate. Chi-square test was applied for categorical associations. Pearson correlation analysis was performed to assess the relationship between lesion size and coagulation parameters. A p-value <0.05 was considered statistically significant.

3.1 Baseline characteristics and tumor distribution

A total of 150 patients with solid malignancies were included, with ages ranging from 15 to 77 years. Most patients were between 36 and 65 years. Males constituted 60% of the cohort and females 40%. The most frequently involved systems were gastrointestinal, head and neck, female reproductive tract, respiratory tract and breast. Less common sites included the genitourinary tract, soft tissue, thyroid, skin and others (Table 1). Adenocarcinomas of the gastrointestinal system (well and moderately differentiated) and squamous cell carcinomas of the oral cavity were predominant. Nearly half of the patients (47.9%) had lesions ≥5.00 cm³, while 38.4% had lesions ≤1.99 cm³. Metastatic disease involving lymph nodes or distant organs was present in 27 patients (18.0%), while 123 patients (82.0%) had no evidence of metastasis at the time of evaluation.

3.2 Frequency of coagulation abnormalities

Key coagulation parameters, including PT, APTT, fibrinogen, D-dimer, FDP and platelet count, were compared with standard reference values. Abnormal results are summarized in Table 2. Prolonged PT (>15 seconds) was present in 25.3% of patients and prolonged APTT (>35 seconds) in 34.7%. Elevated D-dimer (>243 ng/mL) was found in 60.0% of patients. Fibrinogen levels were elevated (≥450 mg/dL) in 25.3% and low (<250 mg/dL) in 14.0%. FDP was positive in 32.7%. Thrombocytopenia (platelet count <150,000/µL) occurred in 14.0%.

3.3 Systems with higher coagulation activation

System-wise analysis suggested that certain tumor groups had more pronounced coagulopathy. Respiratory tumors showed the highest D-dimer and APTT elevations, gastrointestinal tumors showed marked D-dimer and fibrinogen rise, and metastatic cancers from any site demonstrated combined derangement in PT, APTT, D-dimer and FDP. Soft tissue sarcomas frequently had elevated APTT and fibrinogen. These patterns and clinical implications are summarized in Table 3.

3.4 Coagulation profile and metastasis

Patients with metastasis had significantly more deranged coagulation profiles compared with those without metastasis (Table 4). Mean PT, APTT, fibrinogen and D-dimer levels were all significantly higher in the metastatic group. FDP positivity was also more frequent in metastatic patients (66.7% vs 25.2%, p < 0.001), and thrombocytopenia was present in one third of metastatic cases, suggesting active coagulation–fibrinolysis imbalance and early DIC-like states.

3.5 Lesion size and coagulation parameters

Pearson correlation analysis was performed to assess the impact of tumor burden on coagulation markers. Lesion size showed no meaningful correlation with PT (r = 0.097, p = 0.245), APTT (r = 0.105, p = 0.205) or D-dimer (r = 0.022, p = 0.796). However, there was a moderate and statistically significant positive correlation between lesion size and fibrinogen levels (r = 0.265, p = 0.001), indicating that larger tumors are associated with higher fibrinogen, likely due to chronic inflammation and cytokine-mediated hepatic stimulation.

3.6 ICF classification

Based on D-dimer and platelet counts, patients were stratified into four ICF categories (Table 5). No ICF was seen in 60 patients (40.0%) who had normal D-dimer and platelet levels. Overcompensated ICF was present in 11 patients (7.3%), characterized by elevated D-dimer and high platelet counts. Compensated ICF was the most frequent pattern and was seen in 62 patients (41.3%) with elevated D-dimer and normal platelet counts. Decompensated ICF was present in 17 patients (11.3%), with elevated D-dimer and thrombocytopenia, indicating advanced coagulopathy. Overall, 59.3% of patients exhibited some degree of ICF.

Table 1. Distribution of malignancies by primary system (N = 150)

Table 2. Frequency of coagulation abnormalities in patients with malignancy

Table 3. Systems showing higher coagulation activation severity

Table 4. Comparison of coagulation parameters according to metastatic status

Table 5. Distribution of intravascular coagulation and fibrinolysis (ICF) categories and associated parameters (N = 150)

The present study evaluated coagulation abnormalities in patients with solid malignancies and explored their association with tumor distribution, metastatic status, tumor burden and stages of intravascular coagulation and fibrinolysis. By comparing our findings with previously published cohorts, important insights emerge regarding the clinical applicability of routine coagulation profiling in oncology.

System wise cancer distribution

 Gastrointestinal cancers accounted for the largest proportion of cases in our series followed by head and neck, female reproductive, respiratory and breast malignancies. This pattern parallels observations from Gaurav et al who reported a predominance of head and neck, cervical and breast cancers although the proportions varied slightly due to regional and institutional factors [7]. Mohammed et al reported stomach and breast cancer as the most frequently encountered sites while Ernaald et al described lung, breast and cervical cancers as the most common diagnoses in their study population [4, 8]. These variations across studies indicate considerable geographic heterogeneity in malignancy profiles which must be considered when interpreting coagulation patterns.

Metastatic burden and tumor size

Metastatic disease was documented in 18 percent of patients in our cohort which is considerably lower than the 55 percent reported by Mohammed et al [4]. This difference may reflect earlier diagnosis in our setting or variable referral pathways. Patients with metastasis demonstrated significantly higher levels of APTT, D dimer, fibrinogen and FDP positivity. These findings support the concept that systemic coagulation activation intensifies as malignancy progresses.

Nearly half of the patients had tumor volumes greater than or equal to 5 cubic centimeters. Larger tumor size correlated positively with fibrinogen levels which is consistent with previous findings by Lee et al who reported a prognostic role of fibrinogen in assessing tumor burden and survival outcomes [9]. Fibrinogen elevation may result from hepatic stimulation by cytokines and reflects a heightened inflammatory milieu associated with advanced disease.

Prothrombin time & Activated partial thromboplastin time

Prolonged PT was seen in 25.3 percent  & prolonged APTT was observed in 34.7 percent in our study. This frequency is lower than that reported by Singh et al who documented PT prolongation in 90 percent of patients & APTT in 58 percent [10] While  Ernaald et al who recorded PT abnormalities in 71 percent & APTT abnormality in 65 % [8].  The variability across studies suggests that PT abnormalities may depend on tumor type distribution and disease stage. Our findings align with reports by Mohammed et al and Shen et al who linked PT & APTT prolongation with metastatic disease and aggressive tumor biology [4, 12].

Fibrinogen alterations

Fibrinogen behaved as an indicator of systemic inflammation and tumor induced cytokine activity. High fibrinogen levels were noted in 25.3 percent and low levels in 14 percent of patients. Compared with the 40 percent elevation rate reported by Ernaald et al and the results from Shen et al our cohort demonstrated a lower frequency of high fibrinogen levels which may reflect earlier stage disease in some patients [7, 8, 12]. Importantly, fibrinogen elevation correlated positively with tumor size which confirms its role as a surrogate for tumor load and a component of the cancer related inflammatory response.

D dimer and fibrin degradation products

D dimer elevation was observed in 60 percent of the cohort which is consistent with results from Zhang et al Shen et al and Ernaald et al who reported elevated levels in up to 73 percent of their patients [8, 11, 12]. FDP positivity was found in 32.7 percent which aligns with the documented hyper fibrinolytic state frequently associated with gastrointestinal, respiratory and high grade tumors. Elevated D dimer and FDP jointly indicate active fibrin turnover and may serve as early indicators of aggressive malignancy or impending coagulopathic complications.

Platelet abnormalities

Thrombocytopenia was present in 14 percent of patients whereas thrombocytosis was recorded in 9 percent. This differs from patterns described by Mohammed et al who observed more frequent thrombocytosis [4]. Singh et al reported only 4 percent thrombocytopenia but generally higher platelet counts [10]. In our study thrombocytopenia was most pronounced in patients with decompensated ICF which suggests significant platelet consumption during advanced stages of intravascular coagulation.

Organ specific coagulation patterns

Distinct coagulation signatures were evident across malignancy types. Gastrointestinal cancers particularly mucinous or signet ring subtypes exhibited marked elevation in D dimer and FDP which supports earlier findings by Lee et al and Shen et al [9, 12]. Metastatic respiratory cancers demonstrated considerable APTT and D dimer elevation which indicates widespread intrinsic pathway activation. High grade prostate cancers also demonstrated PT and D dimer abnormalities. Mucinous tumors are known to promote coagulation via tumor associated mucins that trigger platelet activation and thrombin generation [9, 11, 12].

ICF syndrome and stratified coagulopathy

The classification of patients into ICF categories revealed that 59.3 percent exhibited some degree of intravascular coagulation and fibrinolysis. Compensated ICF was the most common pattern whereas decompensated ICF characterized by elevated D dimer and thrombocytopenia represented 11.3 percent of cases and indicated advanced coagulopathy. These findings closely parallel those published by Mohammed et al who established D dimer and platelet count as reliable markers for identifying early stages of DIC and thrombo hemorrhagic stress in cancer patients [4]. Progressive elevation in D dimer and corresponding decline in platelet count across ICF categories highlights the usefulness of this classification scheme for clinical risk assessment.

 From a practical standpoint, routine measurement of D-dimer and platelet counts at diagnosis and during follow-up may help identify high-risk patients who require closer monitoring, thromboprophylaxis or early intervention to prevent thrombo-hemorrhagic complications

Coagulation abnormalities are highly prevalent in patients with solid malignancies and are particularly pronounced in metastatic disease and in certain tumor systems such as gastrointestinal and respiratory cancers. Elevated D-dimer and fibrinogen levels, together with platelet counts and FDP positivity, reflect ongoing intravascular coagulation and fibrinolysis and can be used to classify ICF states. Lesion size correlates positively with fibrinogen and may serve as a surrogate of tumor burden. Routine assessment of coagulation profiles at the time of cancer diagnosis and during follow-up may assist clinicians in risk stratification, early detection of subclinical ICF and optimization of supportive management in oncology practice. 6. Declarations Ethics approval and consent to participate The study protocol was approved by the Institutional Ethics Committee of SMIMER, Surat, India. Written informed consent was obtained from all individual participants included in the study.

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