Hemophilia C is also known as factor XI (FXI) deficiency, Rosenthal syndrome, and plasma thromboplastin antecedent. It involves patients with severe bleeding after dental extractions. The estimated incidence is 1 in 100,000 in the general population. Hemophilia C in Israel is predicted to be found in up to 8% of Ashkenazi Jews. Hemophilia C is inherited in an autosomal recessive pattern. Both parents must carry mutated genes for their children to be affected. In certain cases, hemophilia C can be inherited in an autosomal dominant pattern. In these patterns, the condition may be inherited from just 1 affected parent. People with only 1 mutated copy of a gene rarely express the symptoms of hemophilia C. Both men and women are affected by hemophilia C equally. FXI plays an important role in the clotting cascade; it leads to clot formation, converts fibrinogen to fibrin, and generates more thrombin.¹

Symptoms Associated With Hemophilia C

Individuals tend to develop nosebleeds and bruises along with rare intestinal or urinary bleeds. FXI levels in the blood do not correlate with the symptoms of hemophilia C as patients with lower levels of FXI in their blood tend to bleed less. It is difficult to predict the frequency and severity of the bleeding based upon FXI in the blood. Major physical trauma such as an accident or surgery can cause prolonged bleeding from the nose, urinary tract, or mouth. Certain medical procedures such as ablation of the uterus or prostate, tooth extraction, and tonsillectomy are related to a high risk of bleeding. Patients suffering from the disorder do not have a risk of bleeding into the joints or muscles. Hence, there are no long-term effects of bleeding and no risk of bleeding inside the skull, or spontaneous intracranial bleeding.²

Blood Coagulation in Hemophilia C

A study showed that low tissue factor (TF) concentration along with FXI deficiency can significantly delay clot formation. The findings also showed that the release of platelet osteonectin was slower in patients suffering from FXI deficiency. Low TF concentration can lead to initial clots for patients suffering from hemophilia C due to thrombin generation in the propagation phase. In the study, patients with FXI deficiency rarely suffered any severe spontaneous bleeding. Patients who suffered extreme trauma or surgical challenge exhibited significant hemorrhage.

The study also revealed no associations between abnormal bleeding and FXII deficiency, even though FXII is a potent activator of FXI. The role of FXI is being investigated during coagulation within in vivo studies. In vitro studies revealed slow activation of FXI by thrombin, and the reaction can be accelerated using negatively charged surfaces like dextran sulfate. A limited amount of thrombin can lead to activation of FXI, which can support TF-initiated thrombin. The study tested theories associated with blood coagulation wherein all the blood components were preserved. It evaluated the role of the potential contributor FXI during whole blood coagulation in vitro using the TF pathway wherein FXIIa was blocked.³

Identifying Patients With Rosenthal Syndrome

FXI deficiency, also known as Rosenthal syndrome, can lead to bleeding in high fibrinolytic activity areas like the genitourinary tract, oral cavity, and pharynx. It is less commonly associated with spontaneous bleeds like hemarthrosis. Individuals engaged in sports with repetitive trauma can suffer from Rosenthal syndrome. This disorder is related to the FXI gene (f11) on chromosome 4, containing 15 exons across a genomic region of 23 kb. There are approximately 253 mutations. It involves amplification of thrombin via positive feedback and inhibition of fibrinolysis leading to stabilization of new clot formation.

A study proposed that variability in bleeding could be due to the thrombin-independent thrombin activatable fibrinolysis inhibitor pathway. Initial investigations for clotting abnormalities included activated partial thromboplastin time (aPTT), platelet function tests, bleeding time, and platelet count. Rosenthal syndrome can prolong aPTT. A normal aPTT can lead to false-negative results as it does not exclude mild deficiency. FXI assay can confirm the diagnosis. If the FXI is significantly reduced <15%, it can lead to prolonged aPTT. Patients with increased bleeding tendency and FXI deficiency can be identified through fibrinolysis assays and novel plasma clotting. The study also pointed toward identifying FXI-deficient patients with an increased bleeding tendency by combining area under the curve in fibrinolysis and rate of clot formation, leading to identifying combined aPTT.⁴

Understanding Coagulation in Hemophilia C

Clot formation requires a TF mechanism as deficiency of FXI and FVIII cannot lead to a self-sustaining wave of thrombin. The mechanism of coagulation propagation can spread the coagulation process for the damaged tissue. It is critical in cases where bleeding is involved. For hemophilia C-diagnosed patients, large-scale injury is involved such as trauma or surgery. In the absence of FXI, the clot is not formed as the thrombin concentration is far from the activator at the time of clot formation.

New concepts that emerge from bleeding in hemophilia can lead to a unique perspective on diagnosis and therapy. This involves experiments with current bypassing agents and potential new ones. A study also revealed that thrombin produced at near-activation sites is not equivalent to thrombin produced far away. The study offers a new point of view and spatial concept to understand bleeding mechanisms in hemophilia and associated treatment strategies. The study also pointed out that FXI is not important in the initiation process but in the TF-independent propagation phase of clot formation.⁵

References

  1. Factor XI deficiency (hemophilia C, plasma thromboplastin antecedent (PTA) deficiency, Rosenthal syndrome). National Hemophilia Foundation. Accessed July 24, 2021.
  2. Hemophilia type C. Hemophilia News Today. Accessed July 24, 2021.
  3. Cawthern KM, van ‘t Veer C, Lock JB, DiLorenzo ME, Branda RF, Mann KG. Blood coagulation in hemophilia A and hemophilia C. Blood. 1998;91(12):4581-4592. doi:10.1182/blood.V91.12.4581
  4. Jayakrishnan T, Shah D, Mewawalla P. Hemophilia C: a case report with updates on diagnosis and management of a rare bleeding disorder. J Hematol. 2019;8(3):144-147. doi:10.14740/jh522
  5. Ataullakhanov FI, Dashkevich NM, Negrier C, Panteleev MA. Factor XI and traveling waves: the key to understanding coagulation in hemophilia?Expert Rev Hematol. 2013;6(2):111-113. doi:10.1586/ehm.13.12

Reviewed by Harshi Dhingra, MD, on 8/10/2021.