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Background: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione., Case Report: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued., Discussion: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

We report a family with history of deep and superficial venous thrombosis. A large number of siblings had numerous episodes of deep venous thrombosis and less frequently arterial thrombosis. The most frequent site was lower limb. Dysfibrinogenaemia seems to play an essential role in predisposition to thromboembolism in this family, other known aetiologies having been excluded. Genetic studies of fibrinogen gene show a point mutation in the gamma chain (364 Asp-Val), the site close to gamma 363 one of the sites involved in fibrin monomers polymerisation, although fibrinogen polymerisation is normal. Review of the 250 families with dysfibrinogenaemia published up to now shows that the prevalence of dysfibrinogenaemia in patients with a history of thromboembolism is about 0.7%, and that thrombosis is observed in about 10% of cases of dysfibrinogenaemia. Abortion risk seems to be increased in women with dysfibrinogenaemia. In contrast thromboembolism risk does not seem to be higher during pregnancy, but may be increased after delivery. The main mechanisms which have been proposed to explain thromboembolism observed in dysfibrinogenaemia are: resistance of the clot to thrombolysis; defective thrombin binding; enhanced platelet aggregation; increased blood viscosity, alteration of clot architecture. This family study together with the previously reported cases supports the hypothesis that there is a link between thrombosis and dysfibrinogenaemia in a small number of patients.

Erythrocyte aggregation is one of the principal determinants of blood viscosity at low shear rates (low flow). Anatomical and hemodynamical characteristics make retinal venous circulation particularly dependent on hemorheological factors. Erythrocyte aggregation and other laboratory parameters (haematocrit, fibrinogen, plasma proteins, clotting) were measured in 85 patients presenting with retinal vein occlusion and 64 controls matched for age, sex and vascular risk factors (hypertension, diabetes, smoking). Statistical analysis of the results demonstrated a significant difference between the retinal vein occlusion group an the control group for erythrocyte aggregation (p less than 0.001 for the aggregation index at 10 sec and for the threshold of dissociation). The fibrinogen level, haematocrit and plasma proteins (albumin, IgA, IgG, IgM, total proteins, 2-macroglobulin) were similar in the two groups. No statistically significant difference for erythrocyte aggregation was observed between occlusions of the venous branch and occlusions of the central retinal vein or between ischaemic and non-ischaemic forms. These results suggest that raised erythrocyte aggregation mainly explains the increase in blood viscosity previously demonstrated, and could play a role in the constitution of retinal vein occlusion.

Cutaneous necrosis of the breast is a rare complication of oral antivitamin K drugs. It occurs shortly after instituting therapy with well-limited, irreversible skin necrosis developing rapidly. The scar is superficial and only involves the subcutaneous tissue; early and extensive surgery does not therefore seem to be justified. Normal scarring is the eventual spontaneous outcome but this is always a long process. Several arguments are advanced in favour of a toxic effect of the drug itself on the vascular walls of the vessels in the dermis.

Testing for soluble fibrin complexes was performed using a sensitive and reliable haemagglutination assay, with red cells sensitized by fibrin monomers. The principle is based on the fact that the monomers linked to red cells and induce their agglutination. This test, used in clinical trials, has revealed the presence of soluble complexes in every confirmed case of acute DIC, but also in Chronic DIC where diagnosis is difficult to establish (negative ethanol gelation test, normal or sub-normal levels of fibrin breakdown products). In Cirrhosis of the liver, the test gives positive results in a non negligible number of cases. Several hypotheses are made to explain why in certain confirmed cases of DIC, low fibrin breakdown products levels are found.

Acquired von Willebrand syndrome is reported in four patients with monoclonal IgG: benign gammapathy in three cases, multiple myeloma in one case; to our knowledge, this last association has not been previously reported. Coagulation abnormalities included a borderline bleeding time, a low platelet retention on glass beads, decreased levels of factor VIII coagulant activity (VIII: C), factor VIII related-antigen (VIII R: Ag) and ristocetin induced agglutination cofactor (VIII R: RC). The late clinical onset, the negative family history and the immunological abnormality suggest an acquired von Willebrand syndrome. After cryoprecipitate infusion the patients did not show the expected rise and there was no secondary increment in factor VIII: C. Time-dependent inhibition of factor VIII R: RC and factor VIII: C was found in one case only and was associated with qualitative abnormality of factor VIII R: Ag demonstrated by crossed-immunoelectrophoresis. It was not possible to interpret this last test in the other cases, due to the very low level of factor VIII R: Ag. The factor VIII abnormalities might be related to the binding and/or destruction of factor VIII by a circulating antibody, or to the adsorption of this factor on the malignant lymphocytes.

An 85-year-old woman without personal history of haemorrhages was found to have qualitative and quantitative deficiency of Factor VIII persisting at least 6 months. Asymptomatic monoclonal IgG kappa gammopathy was also discovered in the same patient, together with a circulating inhibitor of ristocetin co-factor. The fact that the inhibitory effect was reduced after the patient's serum IgG's were bound to staphylococcal protein A suggests that the inhibitor belonged to that category of immunoglobulins, although the authors were unable to detect it after elution.

Haemorrhage is the most frequent complication of oral anticoagulant therapy (OAT) and a resistance to these drugs is rarely reported. The following classification of OAT resistance is proposed: primary or secondary resistance according to the delay of onset (at the initiation of therapy or later); selective or generalized according to the number of drugs involved (only one or several); absolute or relative as judged by the prolongation of the prothrombin time (absent or moderate). Six cases are reported and the mechanisms of resistance are discussed: no intake, variations in the vitamin K availability (diet, intestinal absorption and synthesis of vitamin K), variations in the pharmacokinetics of oral anticoagulants (drug interactions, abnormal hepatic metabolism) and variations in the receptor affinity (hereditary resistance). Resistance is often overcome by progressive increase of the doses of oral coagulant, or by changing drugs, to warfarin or coumadin (long acting drugs).

A congenital deficiency in protein C (physiological inhibitor of coagulation) was identified in 57 patients: the deficiency was quantitative (type I) in 20 families, qualitative (type II) in two families. The transmission was autosomal dominant in 21 families but was suspected to be recessive in one family: the 18 years old homozygous propositus has a severe deficiency (protein C = 16 p. 100): both parents are heterozygous (consanguinity was present) and 5 other family members with heterozygous deficiency are asymptomatic. In the 49 patients (25 women, 24 men) belonging to the 21 other families, 9 men and 4 women (27 p.100) are asymptomatic although precipitating factors had existed in 5 patients. In the remaining 36 symptomatic patients, a deep venous thrombosis was observed in 34, a pulmonary embolism in 18. Recurrent arterial thromboses were diagnosed in 3 patients. The first thrombotic episode was observed at the mean age of 27 +/- 11 years and a triggering factor was found in 26 patients (72 p. 100). Thrombosis was recurrent in 21 (60 p. 100). In the patients without oral anticoagulant treatment, mean protein C antigen concentrations were 47 +/- 9 p. 100 and mean protein C activity was 46 +/- 10 p. 100. In 4 patients with type II deficiency, protein C antigen levels were normal (113 +/- 15 p. 100), contrasting with decreased protein C activity (43 +/- 6 p. 100). Thirty-eight patients have been treated with oral anticoagulants and a skin necrosis developed in the homozygous patients only.(ABSTRACT TRUNCATED AT 250 WORDS)

A 62 year old man presented a diffuse hemorrhagic syndrome related to the presence of an acquired factor VII inhibitor (proconvertin). Autoantibodies were of the IgG class and no subjacent disease was detected during a 7-month follow up. Treatment with high-dose polyvalent immunoglobulins was ineffective, and the onset of an intracerebral hemorrhage required therapy by a series of plasma exchanges combined with immunosuppressive treatment. The plasma inhibitor was no longer present after the first exchange and clinical and biological remission was rapid.

A 45 years old woman with AL amyloidosis presented with a hypofibrinogenemia (fibrinogen 100 mg/dl) without severe bleeding. There was laboratory evidence of fibrinolysis with shortened euglobulin lysis time, decreased alpha-2 plasmin inhibitor and decreased plasminogen. The mechanism of this primary fibrinolysis remains unclear, since there is no enhancement of the tissue-type plasminogen activator. Analysis of the 8 cases related in the literature of excessive fibrinolysis associated with amyloidosis demonstrated improvement of bleeding manifestations and abnormal fibrinolysis following the administration of antifibrinolytic agents.

When adapted to the Dideco Vivacell cell separator, the eccentriplate system allows preparation of leukocyte-poor platelet concentrates. Results of its use on 84 procedures showed that a mean of 4.51 x 10(11) platelets were removed in less than 2 hours with a particularly low level of leukocyte contamination: 2.6 x 10(8). Study of platelet function showed them to be altered more by eccentriplate than by conventional removal with the same apparatus. Analysis of recirculation in vivo corroborated the functional anomalies observed with all aggregating agents (with the exception of arachidonate). These anomalies were associated with a quantity of platelets collected at the lower limit of French norms: 30% of the concentrates contained less than 4 x 10(11) platelets. These findings indicate the need for improvement in the eccentriplate system.

Congenital dysfibrinogenaemia is a rare disorder related to an abnormality in the behaviour of the fibrinogen molecule. The diagnosis may be made with the aid of simple tests, including prothrombin'time, even though this examination may be normal in a small number of cases. Two new cases are reported here. Neither of the two women involved had a past history of severe haemorrhage, the diagnosis being made at the time of routine coagulation studies. According to the international nomenclature, we suggest the names fibrinogen Paris IV and fibrinogen Buenos-Aires II. In order to avoid missing the diagnosis, fibrinogen should be estimated by different methods in the presence of hypofibrinaemia. There is disagreement between fibrinogen levels estimated by the thrombin chronometric method, in general low, and levels obtained by gravimetric and immunological methods, usually normal.

beta-thromboglobulin (beta TG), a platelet-specific protein, was measured in the plasma of 53 healthy subjects (20 men and 33 women), 53 women using estrogen-progestogen contraceptives, 31 patients with cardiac valve disease (including 19 with prosthesis) and 71 patients about to undergo scintigraphy for suspected pulmonary embolism. Compared with levels in healthy subjects, beta TG levels were significantly increased in oral contraceptive users and in cardiac patients with or without prosthesis. High beta TG levels were also found in 20 out of 28 patients with pulmonary embolism confirmed by scintigraphy, but also in some of the .9 lung patients with chronic bronchopulmonary disease. Cardiac patients treated with heparin had higher beta TG levels than non heparin-treated patients, which raises queries about a possible influence of heparin on this particular blood protein.

Heparin may be administered either prophylactically (to prevent postoperative thromboembolic complications) or therapeutically (when thrombosis has occurred) and the dosages are very different. In addition, low molecular weight heparins are now available, and usually reserved only for prevention of thrombosis. The biological monitoring of these different therapies has evolved, and in addition to the classical tests like the recalcified plasma clotting time or the APTT, it is now possible to use more specific tests like the amidolytic activity of anti-IIa or anti-Xa. None of the simple tests alone is satisfactory for the verification of the efficacy of the treatment on a formed thrombosis or for detecting patients at high risk of haemorrhage. At this present state of our knowledge, the association of two of the preceding tests is recommended as any discrepancy could lead to the detection of an associated, unrecognised abnormality such as a circulating anticoagulant factor or thrombocytopaenia. The monitoring of classical prophylactic treatment generally only requires a very limited monitoring.

The aim of this retrospective study was to evaluate the efficacy and tolerance of a moderate dose of urokinase (UK : 2000 IU/kg/h) for at least 24 h in a series of 23 patients with massive pulmonary emboli (PE) (mean pulmonary vascular obstruction = 70 +/- 7%). All patients received heparin in conjunction with UK. A control pulmonary angiography, performed at the end of UK therapy, revealed an important decrease in pulmonary obstruction (-50%). One patient died before the end of UK therapy from shock due to PE (early mortality = 4.3%). Severe hemorrhagic complications occurred in 3 patients (13%) and dictated the stoppage of UK administration, but bleeding was never the cause of death or sequelae. Thus, moderate doses of UK associated with heparin appear to effectively induce clot lysis in patients with massive pulmonary emboli. The incidence of hemorrhagic complications should be decreased by strictly respecting all contraindications to the use of thrombolytic agents and by avoiding excessive heparinization.

Fibrinolytic therapy is effective in reducing the extent of myocardial infarction by lysing intracoronary clots. An overview of twelve trials of prolonged intravenous infusion of SK showed a highly significant reduction in short term mortality. Intra coronary SK infusion achieved reperfusion of the coronary artery in 60 to 90 p. 100 of patients and improvement of left ventricular function was reported. Mortality was also significantly reduced at 6 months. The frequency of bleeding was relatively low and ventricular arrhythmias were not a serious problem. High dose brief duration intravenous SK therapy achieved reperfusion of the occluded coronary artery in 44 to 60 p. 100 of patients. Left ventricular function was also improved. An Italian multicentre trial has shown a significant decrease in the overall hospital mortality of a randomized population. There is no evidence that UK was more effective than SK. New fibrinolytic agents (T-PA, acylated SK-plasminogen activator), with more fibrin specific activity, were successful in inducing coronary thrombolysis in patients with acute myocardial infarction. The rate of reocclusion was about 20 p. 100 and additional stabilising procedure (percutaneous transluminal coronary angioplasty) was necessary in many patients.

Streptokinase was administered to 98 patients, 75 of them with arterial occlusion of the limbs, in accordance with the classical protocol of high and continuous doses (150,000 international units per hour for 48 to 78 hours after an initial standard dose of 500,000 units). There were a total of 15 haemorrhagic complications: --related to a non-respected contraindication (1 case) --traumatic (4 cases) --spontaneous (10 cases), responsible for or contributing to a fatal outcome in 4 instances. In addition, there were 13 spontaneous or provoked haemorrhagic side effects. Retrospective analysis of laboratory results shows that it is difficult to predict haemorrhage: the degree of fibrinopaenia and fibrin breackdown product levels are not closely related to the onset of bleeding. Nevertheless, the combination of a residual fibrin level of less than 1.50 g/l approximately with an amount of fibrinogen broken down (difference between fibrinogen levels before treatment and during treatment) of more than 3 grams was present in the great majority of patients in whom complications developed. The absence of bleeding seen when plasma thrombolytic activity, assessed by the Blix test, is inadequate, suggests the existence of a relationship between biological effectiveness and the risk of haemorrhage. In practice, apart from strict observation of contraindications, the risk of haemorrhage must be born in mind when the therapeutic decision is made. Careful clinical surveillance is today more important than laboratory studies in the prevention of haemorrhagic complications, the price which must be paid for the thrombolytic activity of streptokinase. The latter is capable of acting not only upon the vascular obstruction but also upon haemostatic clots.