Two Novel Mutations (G774A and A1685G) Causing Coagulation Factor XII Deficiency in a Patient with Acute Inferior Myocardial Infarction.

OBJECTIVE: To identify the gene mutation of the coagulation factor XII (FXII) in a patient with FXII deficiency and acute inferior myocardial infarction. METHODS: The proband was a 51-year-old Chinese man who was diagnosed with acute inferior myocardial infarction and had a history of FXII deficiency. The patient presented with a prolonged activated partial thromboplastin time (160 s) and decreased FXII activity (2.3%) and FXII antigen (1%). DNA sequence analysis of the FXII gene was performed by next generation sequencing. The mutant FXII cDNAs were constructed in an expression plasmid vector and transfected into 293T cells. The expression of FXII antigen was detected by western blot. RESULTS: Sequencing of the FXII gene revealed two novel heterozygous mutations, one at exon 8 (G774A; p: W258X) and the other at exon 14 (A1685G; p: D562G). Western blot showed that the FXII antigens were detected only in the supernatant and whole cell lysate of the wild-type and A1685G mutant type, but not in G774A or G774A plus the A1685G mutant type. In addition, the results showed that secretion but not synthesis of A1685G mutant protein was markedly reduced compared to the wild type. CONCLUSION: The present study indicated that the G774A mutation might impair the secretion and synthesis of FXII protein, while the A1685G mutation only influences the secretion of FXII protein. The definition of these new mutations could be useful tools for analyzing the intracellular protein transport and structure-function relationship of FXII protein transport in the future.

Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice.

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.

The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity.

The contact system is a potent procoagulant and proinflammatory plasma protease cascade that is initiated by binding ("contact")-induced, auto-activation of factor XII zymogen. Formed active serine protease FXIIa then cleaves plasma prekallikrein to kallikrein that in turn liberates the mediator bradykinin from its precursor high molecular weight kininogen. Bradykinin induces inflammation with implications for host defense and innate immunity. FXIIa also triggers the intrinsic pathway of coagulation that has been shown to critically contribute to thrombosis. Vice versa, FXII deficiency impairs thrombosis in animal models without inducing abnormal excessive bleeding. Recent work has established the FXIIa-driven contact system as promising target for anticoagulant and anti-inflammatory drugs. This review focuses on the biochemistry of the contact system, its regulation by endogenous and exogenous inhibitors, and roles in disease states. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with severe factor XII deficiency.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited adult-onset microangiopathy caused by missense mutations in the Notch3gene on chromosome 19. However, common vascular risk factors may additionally modify clinical expression and progression of the disease. The role of various prothrombotic factors has also been implied. We report a case of a middle-aged man with typical clinical, neuroimaging and histological features of CADASIL, but with notably prolonged activated partial thromboplastin time. Hematological investigations revealed severe clotting Factor XII deficiency. This case illustrates that the occurrence of vascular risk factors should not be overlooked in patients with CADASIL.

Rosai-Dorfman disease with factor XII deficiency.

A 17-year-old female patient presented with chronic symmetrical oligoarthritis of both knees and ankles, xerostomia, xerophthalmia, multiple bilateral lymphadenopathies in the cervical region, and bilateral parotid enlargement with the histological finding of chronic sialoadenitis. She had been already given methotrexate, chloroquine, and corticosteroids with the diagnosis of rheumatoid arthritis (RA) before referral to our outpatient clinic. Because her complaints and the lumps did not remit and she could be classified as neither RA nor primary Sjögren's syndrome (SS) according to 1987 ACR RA criteria or European preliminary criteria for SS, lymph node biopsy was repeated and revealed the diagnosis of Rosai-Dorfman disease (RDD) with the histological findings of histiocytes, phagocyting lymphocytes in enlarged sinuses, and mature plasma cells infiltrating the pulpa. All the medications were stopped after the pathological diagnosis of RDD and consulting with the Division of Hematology. She was reevaluated with magnetic resonance imaging, which showed dense infiltrative areas around knee and ankle joints, and computed tomography that showed a soft tissue mass surrounding the descending aorta and upper part of the abdominal aorta. Activated partial thromboplastin time was found to be prolonged in prebiopsy examinations, and factor XII deficiency was detected after detailed hematological evaluation. The symptoms of joint involvement were relieved with nonsteroidal antiinflammatory drugs. She has been followed-up without medication without obvious clinical or laboratory change. We herein report a patient with RDD mimicking RA and SS. We consider that RDD should be kept in mind especially in patients with resistant symptoms to conventional therapies, younger disease onset, and predominant parotid and lymph node enlargement.

Factor XII deficiency acquired by orthotopic liver transplantation: case report and review of the literature.

Transmission of congenital clotting factor deficiencies after orthotopic liver transplantation is rare. There are published reports of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia, protein S, factor VII and factor XI deficiencies. We report a case of transmission of factor XII deficiency with liver transplantation in a patient with Budd-Chiari syndrome. There was a persistent elevation of the activated partial thromboplastin time (aPTT), but no evidence of bleeding while the patient was maintained on warfarin. The presence of a persistently abnormal aPTT may raise suspicion for the presence of a clotting factor deficiency; however, deficiencies of other clotting factors may not be readily apparent on routine blood tests performed in a donor. Being aware of the possibilities of transmission of these inherited deficiencies of coagulation factors will aid in their early detection and management in the transplant donor and recipient.

Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor-treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Are hemostasis and thrombosis two sides of the same coin?

Factor XII (FXII), a clotting enzyme that can initiate coagulation in vitro, has long been considered dispensable for normal blood clotting in vivo because hereditary deficiencies in FXII are not associated with spontaneous or excessive bleeding. However, new studies show that mice lacking FXII are protected against arterial thrombosis (obstructive clot formation) and stroke. Thus, FXII could be a unique drug target that could be blocked to prevent thrombosis without the side effect of increased bleeding.

Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID).

We describe two members of a single family, father and son, with mild factor XII deficiency associated to von Willebrand disease (vWD) with aberrant structure in whom distinct multimeric abnormalities and an abnormal proteolytic processing of von Willebrand factor (vWF) after desmopressin (DDAVP) administration were present. They had a mild bleeding history, low levels of vWF-related activities, and a prolonged bleeding time. Low-resolution agarose gel electrophoresis showed a vWF with all size multimers in plasma and platelets. Higher-resolution agarose gels demonstrated that the main band was present, but the relative proportion of the satellite bands was markedly reduced. The smallest oligomer was not increased. After the infusion of DDAVP to the father, a transient increase in the relative proportion of the satellite bands was seen, as described in normal individuals. No difference in the structure of vWF was observed when blood was collected with proteinase inhibitors. The analysis of native subunits of vWF and their proteolytic derived fragments, after DDAVP administration, showed a temporary augmentation of the 176 kDa fragment, as seen in normal subjects, as well as an increase of the 189 kDa fragment. This finding had not been reported previously either in normal individuals or in patients with vWD.