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SummaryA new dysfibrinogenemia associated with thrombophilia has been identified in a Venezuelan kindred. Thrombin and Reptilase times were prolonged and the accelerating capacity of the patient’s fibrin on the t-PA-induced plasminogen activation was decreased. In addition the affinity of fibrinogen for plasminogen was diminished. Permeability and electron microscopy studies revealed that the abnormal clot was made up of thin and densely packed fibres giving rise to a reduced fibrin gel porosity. This was confirmed by turbidity studies showing a decreased fibre mass/length ratio. Affected members were heterozygous for an Aα 532 Ser→ Cys mutation as demonstrated by genetic analyses. This abnormal fibrinogen has been designated as Fibrinogen Caracas V. The family study showed a convincing association between the mutation and thrombotic manifestations. The thrombotic tendency may be ascribed to lack of accelerating capacity of fibrin to induce fibrinolysis caused by an abnormal clot structure with thin fibres and reduced porosity.

Summary. Fibrinogen Lima is an abnormal fibrinogen with an Aa Arg141 fi Ser substitution resulting in an extra N-glycosylation at Aa Asn139, which seems to be responsible for the impairment of fibrin polymerization. We have studied the polymerization and properties of clots made from both plasma and purified fibrinogen of both the homozygous and heterozygous forms. The clot permeation studies with both plasma and purified protein revealed a normal flux through the network for the heterozygous form but very decreased permeation in the homozygous form. Consistent with turbidity results, the clot network of the homozygous form, seen by scanning electron microscopy, was tight and composed of thin fibers, with many branch points, while the appearance of clots from the heterozygous form was similar to that of control clots, but in both cases the fibers were more curved than those of control clots. The rheological properties of clots from the homozygous form were also altered, with rigidity being increased in plasma clots, but decreased in the purified system, a consequence of the balance between numbers of branch points and fiber curvature. From these results it seems that the extra carbohydrate moiety, located in the a coiled-coil region close to the bC domains, impairs the protofibril lateral association process, giving rise to thinner, more curved fibers, with the structural anomalies being most pronounced in the clots from the homozygous plasma. These studies support a model for fibrin polymerization in which the bC-bC interactions are involved in lateral aggregation.

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Dengue virus is a mosquito-borne human viral pathogen that has recently become a major public health concern particularly in tropical and subtropical countries, predominantly in urban and periurban areas. Plasma from five patients infected by the virus was selected since they have in different degrees prolonged thrombin times: +2.1, +3.4, +5.7, +7.1 and +18.5 s, like a transitory acquired dysfibrinogenemia. The serotype could be determined in only two patients, being DEN-1 and DEN-3. The fibrinogen concentration was normal ranging from 2.5 to 3.2 g/l. In general, the fibrin degradation products of the patients were high, reaching values of 6000 ng/ml. The polymerization process was quite similar to that of the control, except in two cases where the final turbidity was almost half the control value. In one of these patients, the fibrinogen was purified and mixed with normal fibrinogen (v : v); the patients' fibrinogen impaired normal fibrin polymerization. Studies of the fibrinolytic process revealed that clots from dengue patients started to lyze before they have reached the maximum turbidity, although this was not reflected in the time needed for complete clot dissolution, which was similar to that of the control for all the patients. Fibrinolysis of clots made by mixing normal and patient purified fibrinogen (2.5 : 1) was impaired. Clot images obtained by scanning electron microscopy showed that the patients' fibrin network had some degree of degradation and the fibers were thicker than those of the control (P < 0.05). This preliminary study seems to indicate that the dengue virus infection modifies the balance of coagulation-fibrinolysis toward hyperfibrinolysis and could modify the normal fibrinogen molecule.

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SummaryIdentifying coagulation abnormalities in patients with combined bleeding and thrombosis history is clinically challenging. Our goal was to probe the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. The patient is a 56-year-old female with a history of haematomas, poor wound healing, and thrombosis (retinal artery occlusion and transient cerebral ischaemia). She had a normal activated partial thromboplastin time, prolonged thrombin and reptilase times, and decreased functional and antigenic fibrinogen levels, and was initially diagnosed with hypodysfibrinogenaemia. This diagnosis was supported by DNA analysis revealing a novel FGB mutation (c.656A>G) predicting a Q189R mutation in the mature chain that was present in the heterozygote state. However, turbidity analysis showed that purified fibrinogen polymerisation and degradation were indistinguishable from normal, and Bβ chain subpopulations appeared normal by two-dimensional difference in-gel electrophoresis, indicating the mutated chain was not secreted. Interestingly, plasma thrombin generation testing revealed the patient’s thrombin generation was higher than normal and could be attributed to elevated levels of factor VIII (FVIII, 163–225%). Accordingly, in an arterial injury model, hypofibrinogenaemic mice (Fgn+/−) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline-infused Fgn+/− mice. Together, these data associate the complex bleeding and thrombotic presentation with combined hypofibrinogenaemia plus plasma hypercoagulability. These findings suggest previous cases in which fibrinogen abnormalities have been associated with thrombosis may also be complicated by co-existing plasma hypercoagulability and illustrate the importance of “global” coagulation testing in patients with compound presentations.