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Questions and subquestions asked were about bleeding symptoms, as well as about clotting factor deficiencies. Questions about bleeding symptoms pertained to: 1) Epistaxis, 2) Cutaneous Symptoms, 3) Bleeding from minor wounds, 4) Oral bleeding, 5) Gastrointestinal bleeding, 6) Surgery, 7) Muscle/hemarthrosis, and 8) Menorrhagia. The candidates were to answer 1) Yes or 2) No in response to these questions in accordance with their symptoms.

On the other hand, tests were performed to detect deficiencies for factors II, V, VII, VIII, IX, X, XI, and XIII, while Factor XII was not considered in this study because it is not commonly related with bleeding events.

Only those participants who answered positively to one of the primary questions were sampled for blood coagulation. All tests were performed at Centre of Excellence in Thrombosis and Hemostasis (CETH), Riyadh. Blood samples were collected in 10 cc sodium citrate (3.2%), 10 cc EDTA, and 5 cc sodium heparin tubes to carry out various coagulation tests. All coagulation tests, including prothrombin time (PT), activated prothrombin time (APTT), and all factor assays were performed using reagents from Stago, and STAR Max® Diagnostica Stago instrument at CETH. All samples were processed in 2–4 hours of collection.

Plasma separation was performed by centrifugation, and frozen samples were then transported to CETH for coagulation testing. For efficient testing, those with only prolonged PT (normal range: 11–14.5 seconds) were tested for the extrinsic pathways (Factors II, V, VII and X), while those with only prolonged APTT (normal range: 26–40 seconds) were tested for the intrinsic pathways (Factors VIII, IX, XI).

Only those participants whose factor deficiencies were confirmed after coagulation testing were selected for further analysis. Bleeding symptoms of participants with factor deficiency were examined, and statistical analysis was performed to determine if any correlation were present between the bleeding symptoms of participants and their coagulation factor deficiency.

Our objective was to compare bleeding questionnaire response with coagulation factor, PT and APTT related values.

Bleeding Assessment Tool

A bleeding assessment tool (BAT) for bleeding symptoms was used with coagulation factor deficiency of <50% (10). From the patient data, a symptom-specific score was generated for each bleeding symptom. We assigned the score according to the grading criteria depicted in Table 1, which was devised by the study steering committee and not available to the field physician. Finally, we summed up all symptom scores to achieve the final score.

Statistical Analysis

Descriptive statistics were computed for the categorical variables using frequency and percentages. Continuous variables were converted to categorical using normal ranges as criteria. Fishers Exact test was run to assess the significance between categorical variables related to the questionnaire and clotting factors. Odds ratios were computed between clotting factor and questionnaire, while ROC was computed between clotting factor and bleeding score. We used the software STATA v.13.0 (Stata Corp., College Station, TX, USA) in our analysis. A statistical significance threshold of P<0.05 was adopted.

Results

Out of 1,138 volunteering young adults in the initial survey, coagulation factor data were available for only 194 respondents.

A significant relationship was found between Factor V deficiency and two bleeding questions: GI bleed and Surgery (Table 2). GI bleeding and F-V were significantly related (P–value 0.028), as 6 (35.5%) out of 17 F-V deficient respondents confirmed bleeding, compared to 5 (10.4%) out of 48 with normal F-V value. Surgery and F-V were significantly related (P–value 0.017), as out of 48 respondents with normal F-V value only 6 (12.5%) had bleeding during the surgery, while out of 17 F-V deficient respondents, 7 (41.2%) had bleeding during surgery

Significant relationship was found between bleeding symptom responses and PT and APTT values (Table 3). Epistaxis response, oral bleeding, and surgery were significantly related to PT (P–value 0.02, 0.012, and 0.039, respectively). Cutaneous response, bleeding from minor wounds, and menorrhagia were significantly related to APTT (P–value <0.0001, 0.038, and <0.0001 respectively).

Table 4 shows the score ranges for each symptom and its likelihood. We show the highest likelihood for a factor when a score value is presented. For most clotting factors, the likelihood is highest for score 1.

Figure 1 shows odds ratios of Factor V to symptoms, with GI bleeding and surgery having an odds ratio values greater than 5. Figure 2 shows odds ratios of Von Willebrand factor activity as <2 for epistaxis and cutaneous symptoms, which does not reach the threshold of significance in predicting bleeding.

Figure 3 shows the bleed score and Factor V with ROC AUC 0.6 for Surgery, showing the predictability for surgical bleeding. For a sensitivity of 0.5, the specificity is 0.8. Figure 4 shows Factor V and PT prolongation with ROC AUC 0.67 and 0.5 for GI bleeding, respectively, again showing Factor V deficiency as a predictor of GI bleed. For a sensitivity of 0.55, the specify is 0.8.

Discussion

Rare bleeding disorders (RBDs) are caused by mainly autosomal recessive inherited clotting factor deficiencies of Factors I (fibrinogen), II (prothrombin), V, VII, X, XI, and XIII, as well as combined FV + FVIII. Coagulation factor deficiencies comprise of congenital bleeding disorders with a heterogeneous phenotype. These deficiencies can lead to sudden and chronic bleeding diathesis, which poses a significant impact on quality of life and can be lethal in rare instances. Quantification of bleeding disorders based upon the symptom is itself a challenging task. We utilized a condensed MCMDM-1vWD bleeding questionnaire for efficient screening of bleeding symptoms. The bleeding questions were related to epistaxis, cutaneous symptoms, bleeding from minor wounds, oral, gastrointestinal, surgery, muscle/hemarthrosis, and menorrhagia. To build the correlation insight, we tested blood samples for F II, V, VII, VIII, IX, X, XI, and XIII. A significant correlation was found between gastrointestinal bleeding and Factor V deficiency (P-value 0.019, Fisher exact 0.028); and surgery-related questions and factor V deficiency (P-value 0.011, Fisher exact 0.017).

Coagulation factor V is a glycoprotein that participates in the formation of the prothrombinase complexes, a critical step for clot formation (11). Incidence of Factor V deficiency (Owren’s disease or parahemophilia) is 1 /1,000,000 and is considered a rare bleeding disorder in the general population (12). Although the life-threatening manifestation is rare with factor V deficiency, however, it is manifested in a plethora of bleeding events including mucosal bleeding as the most common manifestation.

Peyvandi, et al. in reporting the results from the European Network of Rare Bleeding Disorders described that on linear regression analysis, there was a strong association between clotting factor activity level and clinical bleeding severity for fibrinogen, F-X, XIII, and combined V and VIII deficiencies. A weaker association was present for V and VII deficiencies [16,17]. These factor deficiencies also have been previously reported in the Saudi population in various regions. Ahmed MA, et al. reported FVII and X deficiency in Eastern Province [13] while Al-Sharief, et al. reported FXIII deficiency in Riyadh [14]. Al-Fawaz, et al. reported FXI, V, and VII deficiency [15] and Madkhali, et al. reported F-II, V, VII, X, XI, and XIII deficiencies [16]. Through a hematological panel assay, Al Numair, et al. was able to identify eleven FV deficiency patients with mutations [17].

A total of 321 cases of rare clotting factor deficiency were reported by Shetty, et al. from India, with 30% of patients having FXIII deficiency, 15.6% of patients with FX, 15% cases with FVII deficiency, 12.1% with fibrinogen deficiency, 9% with FXI deficiency, 5.6% with combined V and VIII deficiency, and 2.1% with congenital multiple vitamin K‐dependent coagulation factor deficiency [18].

Epistaxis is often presented as a common emergency, and routine coagulation studies such as PT and APTT have been questioned as a reliable marker for diagnosis [19]. The current study suggests the notion that prolonged PT and APTT in the presence of bleeding symptoms could be used as screening tests to predict underlying factor deficiency. Yet the absence of abnormal PT APTT doesn’t rule out clotting factor deficiency. In contrast to our study, Elden, et al. reported a limited value of PT and APTT in predicting bleeding disorders in children, arguing that PT, APTT only identify 20% of cases with bleeding disorders [20], while Al Zahrani, et al. demonstrated limited predictability power of routine coagulation testing in pediatric patients undergoing surgery [21]. Such discrepancies signify the ethnic distribution of hereditary elements and indicate the importance of regional studies. The rationale of the current study lies in the fact that specific bleeding symptoms may correlate with underlying genetic defects such as coagulation factor deficiency. A significant relationship between certain bleeding symptoms (GI and Surgery) with factor V deficiency warrant that such association must be studied nationwide to establish a bleeding questionnaire as a diagnostic tool.

Conclusion

Identification of clotting factor deficiency can significantly improve clinical management with better patient outcomes. The current study is an epidemiological survey which aimed to explore the correlation of bleeding symptoms with clotting factor deficiency, and a significant correlation was found between factor V deficiency and bleeding from GI and surgery independently. These correlations demand further studies with greater sample size to increase the power of such associations and establish validated methods to predict factor deficiencies resulting in improved management for patients with bleeding symptoms.

Declarations

Authors’ Contribution

KS & TO designed & developed the study. Both authors were responsible for contents & authenticity. NAN, AS, MZ, AA oversaw data collection, data entry. NAO, EA, NB, AT carried out final review of data and analysis. FZ, FA, AAA were responsible for direction of the study team, and facilitation of the project plan.

Funding and Source of Support

KACST (408-34)

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Center, Kingdom of Saudi Arabia, with approval # RAC KFSHRC (2130036).

Consent for publication

All authors consent for publication.

Availability of data and materials

Furnished upon request.

Competing interests

None declared.