Association of lupus anticoagulant and anticardiolipin antibodies with thrombosis in patients with systemic lupus erythematosus, primary antiphospholipid syndrome and other disorders.

Lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) have been associated with thrombotic events and recurrent fetal loss. In order to assess the role of LA with the thrombotic tendency in various disease states we evaluated 38 patients with confirmed LA [tissue thromboplastin index (TTI) greater than 1.3; circulating anticoagulant index (CAI) greater than 15], subgrouped as follows: a) LA associated with systemic lupus erythematosus (SLE) (n = 13); b) primary antiphospholipid syndrome (PAPS) (n = 16); and c) LA associated with other disorders (n = 9). Male/female ratio differed between the groups: 0/13, 6/10 and 4/5, respectively. Venous and arterial thrombotic events were more common in the PAPS group (87%) compared with the SLE group (61%) and the other disorders group (22%). Serum ACA antiphospholipid IgG levels by ELISA were increased in the SLE and PAPS patients, but did not differ between the groups (167 +/- 24 vs. 190 +/- 28 mu respectively). Antiphospholipid IgM levels were higher in the SLE group compared with the PAPS group (127 +/- 15 vs. 67 +/- 16 mu). Mean TTI and CAI levels did not differ between the SLE, PAPS and other disorders groups (1.8 +/- 0.19, 2.8 +/- 0.9, 2.0 +/- 0.3 for TTI; 25 +/- 4, 33 +/- 4, 32 +/- 5 for CAI). Likewise TTI, CAI and ACA levels did not differ in patients with or without thrombosis. We conclude that the prevalence of thrombotic manifestations varies among patients with similar serum intensities of LA and levels of ACA, suggesting that other factors may be involved in the pathogenesis of thrombosis in these patients.

Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants.

Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.

The effect of combined factor XI deficiency with von Willebrand factor abnormalities on haemorrhagic diathesis.

To account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand's factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXI deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.

The polymerization of fibrin prepared from fibrinogen Haifa (gamma 275Arg----His).

Fibrinogen Haifa is a congenital heterozygous fibrinogen variant (gamma 275 Arg----His) characterized by prolonged thrombin and reptilase times and normal fibrinopeptide (FPA, FPB) release. We compared the polymerization rate (by turbidity measurements at 350 nm) and the ultrastructure of Haifa alpha-, beta-, and alpha, beta-fibrin with that of normal. Haifa alpha, beta-fibrin polymerized less rapidly than did normal and formed a highly branched matrix with a smaller mean fiber diameter; this network closely resembled that of normal alpha, beta-fibrin with EDTA added. In the presence of CaCl2 (1 to 10 mM), Haifa alpha, beta-fibrin polymerized more rapidly than in buffer alone and possessed a matrix structure closely resembling that of normal fibrin. From these observations it appears that the functional defect in Haifa fibrin can be related to the inability of the abnormal molecule to effectively utilize available calcium. The polymerization profile of Haifa alpha-fibrin differed only modestly from that of normal alpha-fibrin, whereas that of Haifa beta-fibrin was markedly impaired. This finding plus similarities in the ultrastructure of Haifa and normal alpha-fibrin specimens suggests that the defective gamma chain structure of Haifa fibrinogen results in greater impairment of the carboxy terminal "b" polymerization domain reacting with the site exposed by cleavage of FPB ("B" site) than it does that of the carboxy terminal "a" domain reacting with the site exposed by cleavage of FPA ("A" site). Whether this effect is due to absolute differences in the degree of impairment of these two types of polymerization sites, or whether proper utilization of the "B" to "b" site is dependent upon participation of the "A" to "a" site remains to be determined.

Additional variant of type I von Willebrand disease.

We introduce a family with a von Willebrand subgroup that has not been described before. All of the eight subjects examined had normal levels of factor VIII coagulant activity (FVIII:C), a moderate reduction in the level of von Willebrand factor antigen (VWF:Ag), which resulted in a high FVIII:C/VWF:Ag ratio, and normal crossed immunoelectrophoresis, with normal multimeric pattern. The ristocetin cofactor in plasma and platelets was very low. Bleeding time was prolonged in two subjects without clearcut linkage to laboratory findings. In addition, an abnormality of platelet aggregation in response to ADP was observed: a decreased initial response was followed by marked disaggregation.

Influence of splenectomy on hemostasis in agnogenic myeloid metaplasia.

The effect of splenectomy on hemostatic tests was studied in 10 patients with agnogenic myeloid metaplasia. Prolonged partial thromboplastin time and abnormal prothrombin consumption were found before splenectomy and were normalized postoperatively in the majority of patients. Prolonged bleeding time and prothrombin time were normalized in some patients. While platelet counts and fibrinogen levels rose significantly following splenectomy, platelet aggregation remained impaired. Thrombocytosis and increased fibrinogen level after splenectomy in patients with agnogenic myeloid metaplasia can enhance a thromboembolic tendency.

Variations in the hereditary patterns of factor VIII complex in a large kindred: coexistence of hemophilia A with Von Willebrand.

Coagulation studies and clinical observations were carried out in 47 members belonging to three generations in one kindred. Classical Hemophilia A, Von Willebrand (VWD) variants, and normal individuals were revealed in this study. The coexistence of Hemophilia A and VWD in different siblings of the same progenitors indicates the difficulty to distinguish between these two major factor VIII abnormalities as two different traits. A hypothesis based on these findings is elaborated.

Multiple acquired haemostatic defects. Case report and review of the literature.

A 14-year-old girl presented with severe haemorrhagic diathesis. Her past history suggested a congenital bleeding disorder. Investigations disclosed severe deficiency of all four vitamin K-dependent factors and a functional defect of platelets. These were caused by simultaneous administration of vitamin K antagonists and anti-inflammatory drugs. A complete clinical and laboratory recovery took place following withdrawal of drugs. The severity of the haemorrhagic diathesis prompted us to describe the case in order to draw the attention of medical personnel to the dangerous potentiation effects of different drugs administered with vitamin K antagonists.