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Factor XI (FXI) deficiency (hemophilia C or Rosenthal disease) was first described in the 1950s in a multigenerational family experiencing bleeding related to surgery and dental procedures. Managing patients with FXI deficiency presents several challenges, including a lack of correlation of bleeding symptoms with FXI activity levels, the large volume of fresh frozen plasma required to achieve hemostatic FXI levels, lack of availability of FXI concentrate in certain regions of the world, and the inherent thrombotic risk associated with replacement therapy. This article summarizes presentation, diagnosis, and management of patients with FXI deficiency in a variety of clinical settings.

SummaryPlasma thromboplastin antecedent is a beta-globulin which is essential to normal coagulation. Its deficiency results in a hemorrhagic disease which is relatively less severe than either AHG or PTC deficiency. Transmitted as an autosomal dominant gene with variable expression and penetrance, the disease occurs in both males and females. The incidence of PTA deficiency seems to be high in comparison with the other hereditary clotting protein abnormalities. At present, our series numbers 39 cases (29 families). Since PZA is a catalytic, stable factor, which is present in serum, it is well corrected by both fresh or stored blood or plasma (15% replacement). The correction gradually disappears over the period of one week.

We report a 74-year-old woman presenting with vaginal bleeding and hepatomegaly and was found to have plasma thromboplastin antecedent deficiency and alpha 1 antitrypsin deficiency. She also had liver and lung disease of the type associated with the antiprotease deficiency. The relative rarity of the two deficient states led to family and genetic studies. The possibility of a new genetic syndrome is entertained.

Factor XI (plasma thromboplastin antecedent) deficiency is a blood coagulation abnormality occurring in high frequency in Ashkenazi Jews. Three independent point mutations that result in a blood coagulation abnormality have been identified in the factor XI gene of six unrelated Ashkenazi patients. These mutations either disrupt normal mRNA splicing (type I), cause premature polypeptide termination (type II), or result in a specific amino acid substitution (type III). The three different genotypes were present in the six patients as type I/II, type II/III, and type III/III. Thus far no correlation was found between the three genotypes and the bleeding tendency in these patients.

Fourteen patients with PTA deficiency are reviewed, including a family with six bleeders in the past two generations. Data are presented which show that the bleeding tendency in this disorder is often mild, as hitherto emphasized, but may also be of moderate or severe degree. Heredity appears to be by an autosomal dominant gene with variable expressivity and incomplete penetrance.

Rosenthal, Dreskin and Rosenthal (1953) described a familial haemorrhagic disorder due to plasma thromboplastin antecedent (PTA) deficiency. Further studies have established the properties of this factor and its action in the early phase of thromboplastin generation (Rosenthal, 1954; Rosenthal, Dreskin and Rosenthal, 1955; Ramot, Angelopoulos and Singer, 1955; Campbell, Mednikoff and Dameshek, 1957; Cavins and Wall, 1960). The mode of hereditary transmission of this deficiency has been discussed by various authors (Cavins and Wall, 1960; Campbell et al., 1957; Rosenthal et al., 1955). Recently Rapaport, Proctor, Patch and Yettra (1961), using a quantitative assay of PTA, suggested that this deficiency is transmitted by an intermediate gene, which produces major PTA deficiency in the homozygote and minor PTA deficiency in the heterozygote. In the present communication, 10 families with PTA deficiency will be described and the mode of its inheritance will be discussed.

A total of 10 patients with factor XI deficiency underwent prostatectomy: 3 who underwent suprapubic prostatectomy and 3 who underwent transurethral resection received fresh frozen plasma preoperatively, while 4 received fresh frozen plasma only in response to bleeding. We conclude that all patients who present with partial or severe factor XI deficiency should receive fresh frozen plasma preoperatively and for at least 10 to 14 days postoperatively. We believe that all Ashkenazi Jews who are about to undergo a urological operation should be screened for factor XI deficiency even when a history of a bleeding tendency is not present.

Publisher Summary Factor XI is a plasma glycoprotein that participates in the early stage of intrinsic blood coagulation. It is absent, or present as an inert protein, in plasma of individuals with a congenital bleeding disorder called plasma thromboplastin antecedent deficiency. In normal plasma, factor XI is present in a precursor form and is converted to an active form (factor XIa) by another coagulation factor(s). The purification of factor XI has been difficult by conventional methods of protein fractionation since its concentration in plasma is low and it is also very sensitive to protease degradation. This chapter describes the isolation method in which, heparin-agarose column chromatography and benzamidine–agarose column chromatography play an important role in the procedure. It also details each purification step which is performed in the presence of several protease inhibitors, making it possible to isolate a highly purified preparation in a precursor form. It describes the purification process and the general properties of Factor XI.

The preoperative preparation of patients manifesting a systemic hemorrhagic diathesis has always presented the physician with a serious and often difficult problem. Very few reports dealing with the correction of the coagulation defect of plasma thromboplastin antecedent (PTA) deficiency are to be found in the literature. Rosenthal et al. have been able to correct the PTA deficiency of some patients with a single transfusion of 500 cc. of seven-day-old plasma. 1 , 2 The correction, as measured by in vitro techniques, persisted for seven days in one patient. Another patient was normalized for 24 hours after infusion of only 50 cc. of plasma. 3 The patient reported in this article required transfusions of large amounts of blood for correction of the in vitro test. This patient was previously reported from this department as a well-documented case of PTA deficiency. 4 Methods The routine hematologic tests were performed with the usual methods.

Summary Two cases of previously undiagnosed plasma thromboplastin antecedent deficiency are reported. The problems associated with the diagnosis and management of this condition are discussed. Recommendations are made for the control of this deficiency in routine cases.

Until recently, male persons with a severe hemorrhagic diathesis characterized by (1) a prolonged clotting time, (2) normal Quick plasma prothrombin time, but (3) a poor prothrombin consumption were unhesitatingly diagnosed as suffering from classic hemophilia. This disease is still widely attributed to a deficiency of antihemophilic factor (AHF) 1 essential for the formation of blood thromboplastin. However, it has been emphasized that the demonstrable decrease of AHF activity in these patients may be functional rather than real, owing to the presence of an inhibitor (antithromboplastin). 2 In 1952, Aggeler and co-workers 3 described a syndrome, clinically and genetically indistinguishable from classic hemophilia, which is apparently caused by the absence or marked diminution of a previously unrecognized plasma constituent. They named this factor plasma thromboplastin component (PTC). PTC is also essential for the formation of blood thromboplastin. The PTCdeficiency syndrome is now known under a variety of names, such as

• A patient had bilateral cataracts and severe plasma thromboplastin antecedent deficiency (factor XI deficiency). This patient underwent successful cataract extraction in both eyes without complication. The problems inherent in performing eye surgery with factor XI deficiency are discussed.

Es wird uber eine Sonderform der Hamophilie bei 2 Brudern berichtet, die sich klinisch nicht von der klassischen Hamophilie unterschied. In beiden Fallen handelt es sich um Mangel an einem Plasmafaktor, der nicht an Bariumsulfat adsorbiert wird und auch im Serum erhalten bleibt. Dieses Verhalten entspricht der vonRosenthal beschriebenen PTA-Mangel-Hamophilie.

In Reply.— Dr Soloway presents a number of pertinent questions and comments, certain of which were spoken to in the original editorially scrutinized manuscript, later contracted for publication. Answers to his specific questions are as follows: (1) 45 seconds; (2) kaolin; (3) no, specific factor analyses were performed, and only factor XI was below the generally accepted norms for the several factors; (4) no; and (5) no. In 1953, Rosenthal described a type of hemophilia owing to plasma thromboplastin antecedent deficiency (PTA), or hemophilia C.1Following elucidation of this defect, other cases were reported in the literature. Two types of patients were defined. The first group was severely affected with multiple episodes of bleeding and hemorrhage; a second group was much less symptomatic, often only identifiable by clotting factor analysis. The severely affected group on clotting factor analysis was noted to have a factor XI level of 20% of

This is an unusually complete and enlightened discussion of hemorrhagic states in terms which will really help the practicing physician in his understanding and treatment of these problems. Emphasis is placed on bleeding states associated with hereditary deficiencies of clotting factors and includes such recently described coagulation defects as plasma thromboplastin antecedent deficiency and Hageman trait. Hageman trait is of special interest in that it is characterized by lack of a clotting activity easily demonstrated in the laboratory, but is unassociated with a bleeding tendency. In all these conditions the patterns of inheritance are reviewed together with the problems of daily living which face a family fated to one of these conditions. The thrombocytopenias are considered very logically. Discussion extends to such conditions as scurvy, purpura with dysproteinemia, autoerythrocyte sensitization, and also the hemorrhagic complications of extracorporeal circulation. Items of importance in making a clinical diagnosis are covered, which include

An increasing number of hereditary hemorrhagic diseases caused by deficiencies in plasma clotting factors has been recognized in recent years. In addition to classic hemophilia or antihemophilic globulin deficiency, two other similar diseases have been described: plasma-thromboplastin-component deficiency, or Christmas disease, 1 and plasma-thromboplastin-antecedent deficiency. 2 In comparison with antihemophelic-globulin and plasma-thromboplastin-componentdeficiencies, hemorrhagic manifestations have been generally less severe in plasma-thromboplastin-antecedent deficiency. Spontaneous hemorrhage has been rare. This paper presents an unusual case of plasmathromboplastin-antecedent deficiency in which spontaneous cerebral hemorrhage produced bizarre neurological symptoms. The prompt disappearance of symptoms after the administration of plasma emphasized the importance of establishing the diagnosis of plasma-thromboplastin-antecedent deficiency. A 38-year-old housewife had an extensive history of abnormal bleeding. At the age of 17, she had had severe postpartum bleeding. At the age of 28, she required five blood transfusions for hemorrhage after mastoid surgery. Three years before the present studies, she bled