Passovoy Factor Defect

Description

The Passovoy factor defect was originally described as an autosomal dominant bleeding disorder characterized by a prolonged activated partial thromboplastin time (APTT) (Hougie et al., 1975). However, further characterization of supposedly affected individuals has identified other causes for the prolonged APTT, thus casting doubt on the existence of the Passovoy factor defect as a distinct entity (Foster et al., 1992; Hayani et al., 1996).

Clinical Features

Hougie et al. (1975) described the Passovoy family in which 5 sibs and the paternal grandmother had easy bruising and a moderate bleeding diathesis. Laboratory studies showed prolonged partial thromboplastin times and normal levels of all known clotting factors. Male-to-male transmission was noted.

Hougie et al. (1978) provided further analysis of the Passovoy family and presented probands from 4 additional unrelated families with a similar disorder. Bleeding episodes included menorrhagia and excessive bleeding after surgery and minor cuts. All affected individuals had prolonged partial thromboplastin times and normal levels of all known clotting factors. In all cases, admixture of normal plasma corrected the defect, suggesting that no inhibitor was present. However, mixing of plasma among the patients did not correct the defect. Hougie et al. (1975) suggested that the defect was related to the intrinsic coagulation pathway.

Joist (1978) gave reasons to doubt the existence of the Passovoy factor. In a response to Joist (1978), Hougie (1978) noted that the patients in their study (Hougie et al., 1978) had at least 2 determinations of the APTT using different techniques. In addition, platelet function studies were normal, and factor VIII (F8; 300841) and factor VIII-related antigen (VWF; 613160) were normal, thus excluding von Willebrand disease (VWD; 193400).

Ratnoff (1990) studied 'Passovoy plasma' and found that the titer of Hageman factor (F12; 610619) was 44% of the normal standard in his laboratory. He stated, furthermore, that an otherwise unexplained prolongation of the partial thromboplastin time such as was present in these cases, i.e., in asymptomatic individuals, is most often due to heterozygosity for Hageman trait (see 234000).

Castaman et al. (1992) described a 28-year-old man who appeared to have the Passovoy defect. He presented with recurrent bleeding and hematoma after localized surgery, and had a history of gingival bleeding after a dental procedure. Laboratory studies showed consistently prolonged APTT, which was not corrected after mixing with Passovoy-deficient plasma. The addition of as little as 10% normal plasma was sufficient to correct the APTT. There was no family history of the disorder and both parents had normal clinical and laboratory findings, suggesting a recessive trait.

There is only 1 commercially available Passovoy-deficient plasma pool available for diagnosis of the disorder, which is obtained from the proband described in the original report by Hougie et al. (1975). Foster et al. (1992) found multiple coagulation factor abnormalities among 3 different lots of Passovoy-deficient plasma, including low factor VIII, presence of the lupus anticoagulant and anticardiolipin Ig antibodies, and prolonged thrombin time. In particular, all 3 lots had low factor XII. Foster et al. (1992) noted that these defects could potentially contribute to a prolonged APTT. Moreover, as no specific protein had been identified as the Passovoy factor, these results called into question whether the Passovoy defect is truly an established entity.

Hayani et al. (1996) studied blood isolated from 13 children with a diagnosis of Passovoy defect based on a prolonged APTT that corrected with normal plasma but not with Passovoy trait plasma. Five patients had bleeding manifestations, consistent with the diagnosis, and 8 were asymptomatic. Six patients were found to have von Willebrand disease (see 193400, 613554, and 277480), 1 had low factor XII, and 1 had lupus anticoagulant. Testing of the Passovoy trait plasma lot showed low factor VIII and presence of the lupus anticoagulant. Thus, none of the 13 patients had Passovoy defect since they either had another coagulation defect or did not have bleeding manifestations. Hayani et al. (1996) concluded that caution must be taken in diagnosing patients with Passovoy defect by mixing studies, and even questioned whether the defect actually exists.