Warfarin-induced skin necrosis is a rare and serious adverse effect of oral anticoagulant therapy, occurring in only 0.01 to 0.1% of patients and is especially related to coagulation protein C and S deficiency.

46-year-old woman with a history of rheumatic valve disease, requiring mitral valve replacement with a mechanical prosthesis. The initial postoperative evolution is favorable. However, after starting treatment with acenocoumarol, she develops a picture of skin necrosis affecting the abdominal region and extremities. Which of the following alterations would justify this picture?

[Role of thrombolytic treatment in thrombosis of valvular prostheses. Apropos of 2 cases and review of the world literature].

The authors report 2 cases of thrombolytic therapy by Urokinase at the dose of 4 500 U/kg/hour, for 24 hours, in patients with thrombosis of a Bjork aortic and Lillehei mitral valve prostheses, and assess the efficacy with a review of the world literature. The first case was a 65 year old woman who received a Bjork No 25 aortic valve prosthesis for aortic regurgitation. Two years later oral anti-vitamin K anticoagulants were replaced by an association of Aspirin-Persantine. She developed acute pulmonary oedema secondary to thrombosis of her valve during the fifth postoperative year. Treatment with Urokinase was successful (4 500 U/kg/hour for 24 hours). The second cases was a 33 year old woman who received a Lillehei No 27 mitral valve prosthesis for mitral regurgitation due to infective endocarditis. Six years later, during a period of apparently ineffective oral anticoagulation, she developed subacute pulmonary oedema due to thrombosis of her prosthesis. Urokinase therapy was successful after 4 hours, but the valve surface area on cardiac catheterisation was decreased and elective reoperation to change the prosthesis was decided upon. Prosthetic valve thrombosis is a serious complication with an operative mortality of 68.6% (35 deaths out of 51 reoperations in the worl literature) whilst the efficacy of thrombolytic therapy would appear to be about 80%. When thrombosis is progressive, the valve has to be changed surgically, but when it is secondary, thrombolytic therapy at least helps the patient survive the acute phase.

Multiple-shower thromboembolism in an artificial mitral valve patient.

Late acute left atrial thrombosis is a rare life-threatening complication that mostly appears with predisposing primary coagulopathy, such as Protein C, Protein S, antithrombin 3 deficiency, antiphospholipid syndrome or hyperhomocysteinemia. We present grave outcome due to lack of anticoagulation in a patient with artificial mitral valve. A 47-year-old male known to have an artificial valve was hospitalized in another hospital due to an acute illness. Anti-coagulation therapy was not provided during that hospitalization. He was transferred to our hospital due to lower limb weakness and diagnosed by us as having extensive emboli disease with complete occlusion of the distal aorta. Multiple infarcts were found in the abdominal organs and leg muscles. He suffered from multiple organ failure and eventually died. Neglecting the common practice of anticoagulation to a patient with a mechanical heart valve may, in rare cases, lead to immediate catastrophic event caused by shower thrombemboli with disseminated vascular occlusion from the left atrium to the abdominal aorta causing complete occlusion, spleen, kidney and muscle infarcts.

[Skin necrosis during long-term fluindione treatment revealing protein C deficiency].

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. 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. 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.

[The best in 2000 on valve diseases].

During the year 2000, publications on valvular heart disease have concerned all aspects of this field of cardiology at a time when old and dated therapeutic procedures are being reassessed. The ageing population of the developed world has led to aortic stenosis playing a large part, and the study of its natural history has provided two keynote publications. Aortic valve replacement, increasingly involving older patients, led to the evaluation of this surgery in this age group in which bioprostheses are often associated with coronary bypass surgery. Conversely, in younger patients, there is a regain in interest in autograft (Ross' procedure) or homograft valve replacement which requires a rigorous infrastructure of supply. In mitral valve disease, the indications of conservative surgery of mitral incompetence, ideal in degenerative forms of the posterior leaflet, have been progressively extended to include bacterial endocarditis in many cases and ischaemic mitral regurgitation according to some authors. Rheumatic lesions are not commonly treated by this technique although some encouraging results have been reported. Percutaneous mitral commissurotomy has attained maturity in the treatment of mitral stenosis, even in the less favourable forms such as restenosis after an initial percutaneous procedure or even after surgical commissurotomy. Valve replacement surgery by prosthetic valves is forty year old and many long-term retrospective and prospective evaluations of the results on large patient population either with one type of prosthesis or comparing different bioprostheses or bioprostheses with mechanical valves have been performed. The ideal age for implanting bioprostheses remains uncertain, between 60 and 70, depending on the authors. Finally, problems of anticoagulation in patients with prosthetic valves were the object of three interesting publications about the use of low molecular weight heparin, aspirin and the risks during pregnancy. 2000 was a year of steady and regular progress in the study of valvular heart disease without any major revolutionary contributions.

[New approaches for treating skin necrosis in protein C deficiency].

A 62-year-old woman with a 8-month-history of recurrent deep and superficial vein thrombosis developed multiple areas of skin necrosis during warfarin treatment initiation. Routine coagulation tests did not revealed any abnormalities. Protein C plasma activity and concentration were significantly decreased (59.9% and 63.3% of the normal value, respectively). Antithrombin III and protein S (total and free) content were in the normal range. Initially, the adjusted dosage of standard heparin and fresh frozen plasma was administered. Thereafter, the treatment with low doses of oral anticoagulant (acenocoumarol) was reinstalled simultaneously with Protein C Concentrate (Immuno, Vienna) intravenous administration. After six days of the oral anticoagulation the therapeutic value of prothrombin time was obtained and administration of Protein C Concentrate could have been discontinued. No adverse reactions and post-transfusions complications were observed.

Cutaneous necrosis revealing the coexistence of an antiphospholipid syndrome with acquired protein S deficiency, factor V Leiden and hyperhomocysteinemia.

We report an exceptional case of cutaneous necrosis due to the coexistence of 4 thrombophilic factors, inherited and acquired. We would like to draw attention to these unrecognized associations. A 72-year-old woman was admitted with a 5 month history of necrotic nonhealing, painful ulcer of both legs and recently a purple toe. She had a history of 3 deep venous thromboses of the leg complicated by pulmonary embolism. A skin biopsy of the ulcer and purple toe showed only thrombosis in the dermal vessel. Laboratory findings showed a circulating lupus anticoagulant, positive anticardiolipin antibodies, antinuclear antibodies (1/320 dilution) and an anti Sm. Moreover, activated protein C resistance associated with factor V Leiden mutation and hyperhomocysteinemia was found; protein S was transiently low. With iloprost, oral anticoagulant, vitamin B12 and folic acid, the evolution was good, with healing of ulcer. cutaneous necrosis can reveal hypercoagulable states, sometimes complex. We find 4 thrombophilic factors in our case, i.e. antiphospholipid antibodies, factor V Leiden, protein S deficiency and hyperhomocysteinemia. This is exceptional but highlights the role of several constitutional and acquired thrombophilic factors in the genesis of thrombosis. Extended protein C pathway disturbances could explain the mechanism that leads to cutaneous necrosis, in this patient, with an antiphospholipid syndrome. This case shows that it is necessary in some circumstances to make a complete hemostatic laboratory search to detect several thrombophilic factors. If they are present they can justify an oral anticoagulant treatment and a familial screening.

[Study of hemostasis in patients with a recent thromboembolic complication].

The clinical history of well-documented personal or familial episodes of thromboembolism with systematic construction of a genealogical tree orients the diagnosis of hereditary or acquired thrombophilia. The presence of favorable medical or surgical conditions for pulmonary embolism (surgical operation, prolonged bed rest, oral contraception, pregnancy, etc) are commonly observed in thrombophilia. Young age, under 40, at the time of the first episode, the recurrent nature of thromboses and a positive family history are three criteria in favour of the diagnosis of hereditary thrombophilia. Laboratory tests should be performed, if possible anticoagulant therapy, or taking into account its effect on the results, heparin reducing the antithrombin level and the oral anticoagulants those of proteins C and S and affecting the "classical" test of resistance to activated protein C. This abnormality is observed in nearly 20% of patients with previous thromboembolism in familial thrombophilia whereas it is twice less common in deficits of antithrombin, protein C and protein S. The other more or less acknowledged causes, alteration of plasminogen, dysfibrinogenaemia, homocysteinaemia, particular blood diseases, indicating systematic association of a full blood count with blood clotting tests, are much more rare. Of the acquired thrombophilias, the commonest is the presence of circulating anticoagulant and/or anticardiolipine antibodies, these two conditions also requiring systematic investigation. Biological examinations for determining the cause of unexpected pulmonary embolism is essential but should not delay instauring treatment. It should be associated with a familial enquiry if the patient has a hereditary thrombophilia. Interpretation of the results should obey the rule of the 3 cs: is the biological abnormality the cause, a coincidence or the consequence of the affection?

Pulmonary embolism

The development of thrombosis is classically due to a group of causes named Virchow's triad (alterations in blood flow, factors in the vessel wall, and factors affecting the properties of the blood). Often, more than one risk factor is present. Alterations in blood flow: immobilization (after surgery, long-haul flight), injury, pregnancy (also procoagulant), obesity (also procoagulant), cancer (also procoagulant) Factors in the vessel wall: surgery, catheterizations causing direct injury ("endothelial injury") Factors affecting the properties of the blood (procoagulant state): Estrogen-containing medication (transgender hormone therapy, menopausal hormone therapy and hormonal contraceptives) Genetic thrombophilia (factor V Leiden, prothrombin mutation G20210A, protein C deficiency, protein S deficiency, antithrombin deficiency, hyperhomocysteinemia and plasminogen/fibrinolysis disorders)

[Disclosure of protein C deficiency with pulmonary embolism followed by cardiac arrest during the recovery period].

A case of unexpected cardiac arrest occurring in a 17-year-old male patient is reported. The patient had been admitted after sustaining hand trauma. A first emergency surgical procedure was carried out, followed about three weeks later by another one. No incidents occurred during or after either of these two operations. A third procedure was required about two months after the accident (free toe graft to the thumb of the left hand). The twelve-hour operation was carried out under general anaesthesia and axillary block. The patient was given intravenous heparin (800 IU.h-1) during the procedure on the arm. The patient recovered quickly, and was extubated before his transfer to the recovery room. Fifteen minutes later, the patient's heart rate decreased to 40 b.min-1, followed by a transient cardiorespiratory arrest. The suspicion of pulmonary embolism was confirmed by pulmonary scintigraphy. Thrombolysis was carried out with 2,000 IU.kg-1.h-1 of urokinase for a 72 h period, combined with continuous heparin administration (16 to 36 x 10(3) IU.day-1). The patient recovered after one week. No thrombophlebitis was found for origin of the emboli. Biological investigations carried out both before and after 10 minutes of anoxia revealed a normal fibrinolytic system, but a deficit in protein C (62% antigen, 64% activity). Two years after the episode of pulmonary embolism, the patient, still taking acenocoumarol, remained free from any sequela. Current perioperative management of patients with a known protein C deficit is discussed.

Protein C, S and antithrombin III levels in patients with acute mechanical valve thrombosis.

Mechanical prosthetic heart valve thrombosis is a serious complication with an incidence of 1-6%. The reduction in active vitamin-K dependent protein C and S levels caused by warfarin treatment also results in a prothrombotic state. This study was conducted to investigate the connection between protein C (PC), protein S (PS), antithrombin III (ATIII) deficiency and prosthetic mechanical valve thrombosis. Twenty-nine of the 283 patients who underwent valve replacement with St. Jude medical prosthesis had mechanical valve thrombosis (group 2). The rest were considered as group 1. Twelve of the 29 patients (41.4%) had isolated aortic valve replacement, 12 had isolated mitral valve replacement (41.4%) and 5 patients had double valve replacement (17.2%). Most of the patients had rheumatic valve disease at their 1st operation. The mean time of occurrence for mechanical valve occlusion was 4.1+/-1.0 years following surgery. The values of PC, PS and ATIII were obtained when the mechanical valves stuck or at routine follow-up. PC, PS and ATIII levels were significantly lower in the mechanical valve thrombosis group. PC levels were 75.4+/-37.6% and 49.9+/-32.2% in group 1 and 2, respectively (p=0.001). PC, PS and ATIII values were mostly lower in the 2nd group but this difference only became significant after at least 2 years of warfarin usage. Natural anticoagulant levels can be low during the use of warfarin. In which case the dose can be increased in order to hold the international normalized ratio (INR) at 3-3.5. However, more frequent follow-up is required and patients should be investigated for hypercoagulation states or deficiency in anticoagulant proteins. Patients referred to hospital with any mechanical valve thrombosis or recurrent thromboembolism should be evaluated for hypercoagulant proteins.

[Changes in the clinical profile of patients treated with oral anticoagulants in the 1990's].

During the last few years the efficacy of oral anticoagulant treatment in the prevention of thromboembolic complications among patients with cardiac diseases has been well established. This has determined an increase in the number of patients undergoing this therapy and a change in the clinical profile of these patients. To determine the number and the changes in the clinical characteristics of patients treated with oral anticoagulants during the last decade. The charts of 5,771 hospitalized patients between January 1, 1991 and December 31, 1999, were retrospectively reviewed. We analyzed the number of patients discharged with anticoagulant treatment, the clinical profile and the evolution during the decade. 761 (13.1%) patients were discharged with anticoagulants. The therapy was prescribed to 7.4% of the patients from 1991-1993 and to 15.1% of the patients from 1998-1999. The mean age of the patients was 60.4 from 1991-1993 and 67.1 from 1998-1999 (p < 0.001). At the beginning of the decade, 90% of the patients had prosthetic valves, suffered from rheumatic heart disease or had had thromboembolic phenomena previously. At the end of the decade, only 49% could be included in these groups. a) The use of oral anticoagulants among our hospitalized patients has been duplicated during the past ten years; b) the clinical profile has changed, patients are now older and with different morbidity; c) the rheumatic heart disease and the prosthetic valves are no longer the predominant indications, and d) the use of therapy as secondary prevention has decreased significantly.

Warfarin necrosis

Notably, the prothrombin time (or international normalized ratio, INR) used to test the effect of warfarin is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state. In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. The condition is related to purpura fulminans, a complication in infants with sepsis which also involves skin necrosis. These infants often have protein C deficiency as well. There have also been cases in patients with other deficiency, including protein S deficiency, activated protein C resistance (Factor V Leiden) and antithrombin III deficiency. Although the above hypothesis is the most commonly accepted, others believe that it is a hypersensitivity reaction or a direct toxic effect. Diagnosis

Evolution of antithrombin III during the postoperative period.

In a prospective study, antithrombin III (AT III) was performed preoperatively, peroperatively immediately after the surgical procedure and daily during the 8 postoperative days in 57 consecutive patients who underwent major abdominal surgery without prophylactic anticoagulant therapy. On d 8, according to the results of a bilateral radiological phlebography, the patients were divided into 2 groups: Group I: presence of deep venous thrombosis (DVT): n = 28 (49%) and Group 2: absence of deep venous thrombosis: n = 29 (52%). The results of the study showed that the preoperative AT III value did not constitute a marker of the postoperative DVT risk. During the postoperative period, AT III level decreased immediately following the intervention and resumed its preoperative value within 8 d. Nevertheless, this evolution was not different in the 2 groups and was not related to the presence of postoperative DVT.

Venous thrombosis

Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency (type I) Factor V Leiden Prothrombin G20210A Dysfibrinogenemia Non O-blood type Mixed Low free protein S Activated protein C resistance High factor VIII levels Hyperhomocysteinemia High fibrinogen levels High factor IX levels High factor XI levels

[Recurrent thrombosis of an aortic valve prosthesis in a pregnant woman. Treatment with urokinase].

A 36 year old woman developed two thromboses on aortic valve prosthesis. The first thrombus at the 14th week of pregnancy was treated with urokinase (2,000 U/kg/h) plus heparin (700-1,000 U/h) over 24 hours and normal wing kinetics were obtained. The second thrombus developed at the 36 th week of pregnancy when the patient was receiving calciparin, and only transient improvement was obtained with similar doses of urokinase hourly over 72 hours. Progressive worsening resulted in higher doses (4,000 U/kg/h) being given without heparin and the thrombus then resolved. The use of urokinase for the first time in this indication allowed therefore, on two occasions and without hemorrhagic complications the cure of this recurrent thrombosis on aortic prosthesis, and the birth, by caesarean, of a healthy baby.

Fourth mitral valve replacement in a 15-year span in a woman of childbearing age.

There is no report of four valve replacement surgeries in a woman during 15-year follow-up. A 23-year-old female was diagnosed at 7 years with rheumatic fever. She developed severe mitral regurgitation and at the same age a prosthetic valve was placed. In the next 15 years her mitral valve was changed 3 times because of clinical, echocardiographic, and histopathologic evidence of thrombosis. Her coagulation tests all showed infratherapeutic international normalized ratio and by the age of 15 years she had had an ischemic stroke with total recovery. She developed a normal pregnancy by the age of 19 years with no complications. This case exposes the complexity of the decision making that cardiologists face in terms of choosing the type of prosthetic valve that should be indicated in a woman of childbearing age. With each surgical valve replacement prognosis is less favorable and choosing the best therapy remains a challenge for the heart team. <<bLearning objective:</b Valvular heart disease remains a challenging problem due to anticoagulation issues. Prosthetic valvular replacements need a thorough follow-up for anticoagulation goals. Women of childbearing age can both have mechanic and biologic prosthesis.>.

[Venous thrombosis. Experience in treatment, problems and perspectives].

Venous thromboembolic disease is a recurring reason for death, it is often well-known but sometimes misunderstood. The right treatment for this pathology should not follow one approach only, but several strategies with respect to the seriousness and extension of the several clinical pictures. In particular the pharmacological therapy tries to find the balance between risks and benefits. It is well-known that a weak treatment may cause an increase in the risk of the pathology extension or of recurrence; on the other hand, a therapy exceeding the well known ranges exposes to important hemorrhagic risk. This work presents the personal seven years' experience in patients affected by limb venous thrombosis, in some cases combined with pulmonary embolism. For all patients the pathology seriousness has been assessed by echoduplex scanner and angio-CT, and routine serum electrolite and enzymes analysis and blood counts have been carried out. Different therapies have been investigated, their evolution over the years (on the basis of international and personal experience) and the follow-ups. The foudamental implications of this experience are: the more remarkable use of vena cava filters do not improve clinical findings' follow-up. On the contrary, it can cause the extension of pathology; heparin therapy must start early and the therapeutic range must be reached as soon as possible. Any delay, together with immobilization, can cause the extension of the pathology; diagnosis research cannot stop at the acuity moment but it should study also the etiopathogenetic picture. This affects the future therapeutic strategy in the follow-up; fibrinolitic therapy, once recommended for extended femoral-iliac thrombosis, should be used for serious levels of the same pathology and only for patients with low haemorrhage risk, or for patients affected by periodic pulmonary thromboembolism which may compromise haemodynamic system.

Anticoagulation Resumption in a Patient With Mechanical Heart Valves, Antithrombin Deficiency, and Hemorrhagic Transformation Following Thrombectomy After Ischemic Stroke.

Anticoagulation is essential for patients undergoing mechanical heart valve replacement; however, the timing to reinitiate the anticoagulant could be a dilemma that imposes increased risk for bleeding events in patients suffering from the life-threatening hemorrhagic transformation (HT) after ischemic stroke. Such a situation was presented in this case report. A 71-year-old woman was transferred directly to the Neurocritical Care Unit because of a HT that occurred following the mechanical thrombectomy for ischemic stroke. Since she had a history of prosthetic metallic valve replacement, how the anticoagulating therapy could balance the hemorrhagic and thrombotic risks was carefully evaluated. On day 6 after the onset of hemorrhage transformation, the laboratory results of coagulation and fibrinolysis strongly suggested thrombosis as well as antithrombin deficiency. The short-acting and titratable anticoagulant argatroban was immediately initiated at low dose, and thrombosis was temporarily terminated. On day 3 of anticoagulation resumption, argatroban was discontinued for one dose when the prothrombin time and activated partial thromboplastin time significantly prolonged after argatroban infusion. Aortic valve thrombosis was detected the next day. The anticoagulation was then strengthened by dose adjustment to keep mitral valve intact, to stabilize the aortic valve thrombosis, and to decrease the aortic flow rate. The intravenous argatroban was transited to oral warfarin before the patient was discharged. This study is the first report of administering argatroban and titrating to its appropriate dose in the patient with valve thrombosis, antithrombin deficiency, and HT after mechanical thrombectomy for acute ischemic stroke. Notably, the fluctuations argatroban brings to the coagulation test results might not be interpreted as increased bleeding risk. This case also suggested that the reported timing (day 6 to day 14 after hemorrhage) of anticoagulant resumption in primary intracerebral hemorrhage with mechanical valves might be late for some patients with HT.

[The risk of hemorrhage versus the thromboembolic risk in patients with prosthetic valve].

376 adults were followed up for between 2 and 153 months after surgery (mean: 3.8 years); all of them, with the exception of 8, received anticoagulant treatment. The results were subjected to statistical analysis using several tests. Thromboembolic complications occurred in 16 per 100 after 5 years, and 8.5. per 100 of them were fatal. Among the factors favoring this complication are the type of valvular disorder (the rate of throembolism being 4 times greater with mitral valve defects), the type of prosthesis, and the efficiency of the anticoagulant therapy (the risk of thromboembolism being four times greater in those patients whose treatment has been inneffective). Against the vitamin antagonists must be set the haemorrhages: the incidence of lethal haemorrhage in this series was 6.4 per 100 patients per treatment year. There was a proven hypoprothrombinaemia to below the desirable level in two thirds of these cases, and in one case out of four an additional predisposing factor could be demonstrated. Haemorrhage and thromboembolism are together responsible for one in four of the late deaths. In order to reduce the mortality, several solutions are considered, one of which is to utilise anti-aggregation treatment. However, the vitamin K antagonists remain an essential part of treatment in the majority of cases; it can only be justifiable to withhold them in those patients in whom the risks of haemorrhage are for various reasons considered to be too high. The introduction of biological valves or of valves with a lessened risk of embolism is highly desirable in such cases.

Factor V and VIII deficiency treated with therapeutic plasma exchange prior to redo mitral valve replacement.

A 33-year-old male was admitted to the hospital for a repeat mitral valve replacement. The original surgery, performed in India in 2008 due to rheumatic heart disease, required massive amounts of plasma replacement during and after the surgery. The patient was admitted to our hospital with extremely low Factor V and Factor VIII activities due to a rare combined Factor V and Factor VIII deficiency. His clinical condition on admission was grave due to severe pulmonary hypertension. It was decided to replace the patient's Factor V using therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) just prior to surgery, and his Factor VIII with Factor VIII concentrate. The patient tolerated the valve replacement surgery very well, without excessive bleeding, and received several more TPE procedures postoperatively. He was successfully made replete with both coagulation factors with little to no bleeding during the procedure and postoperatively. TPE is a promising modality for the treatment of patients with similar factor deficiencies for which a specific factor concentrate is not available, especially those at risk of fluid overload from plasma transfusion. J. Clin. Apheresis 32:196-199, 2017. © 2016 Wiley Periodicals, Inc.

[Impact of biochemisty on the duration of treatment for pulmonary embolus].

Can the biochemical evidence for "new thrombophilic factors" influence the duration of AVK treatment following the occurrence of a first pulmonary embolus? Certainly for the classic but very rare antithrombin defects as well as for the existence of circulating anticoagulant. Possibly for protein C and S defects. On the other hand, the existence of a heterozygotic "Leiden" mutation of factor V, or factor II, and an increase of factors VIII, IX, or XI, do not at present warrant a change in AVK prescription. In effect, in the case where the existence of a thrombogenic state implies a prolongation of AVK treatment with its significant potential complications, it is indispensable that the risk/benefit ratio is well founded, which is not the case for these "new" thrombophilic states. The coexistence of several of these new biochemical anomalies (for example the association of a factor V and factor II mutation) probably represents an excess risk of thrombosis, but in this situation the reasoning remains the same. On the other hand, faced with a confirmed recurrence, the studies in the literature tell us that very long term treatment should be debated independently from the biochemical results. It is conceivable that there are biochemical anomalies (sometimes quite frequent which should be viewed as "normal variants") which, although they have great significance for improving the understanding of venous thrombo-embolic disease, do not at present warrant a change in our therapeutic protocols. Another facet of the problem concerns the use of D-dimers following the first months of AVK treatment in order to possibly distinguish patients at low risk of recurrence. The first results of this approach are interesting, but require confirmation before they can be used in practice.

Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud's phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis.

Necrosis of the digits is a rare complication of warfarin therapy of obscure pathogenesis. We report a 61-year-old woman with a 12-month history of Raynaud's phenomenon who developed multiple digital necrosis following aortic valve replacement with mechanical prosthesis for aortic insufficiency caused by nonbacterial thrombotic endocarditis. Exacerbation of Raynaud's phenomenon occurred during the postoperative period, with daily episodes of ischemia of the fingers and toes that improved with local warming. However, coincident with the occurrence of immune heparin-induced thrombocytopenia, and while undergoing routine warfarin anticoagulation because of the mechanical valve prosthesis, the patient abruptly developed progression of digital ischemia to multiple digital necrosis on postoperative day 8, at the time the international normalized ratio reached its peak value of 4.3. All limb pulses were readily palpable, and vascular imaging studies showed thrombosis only in the superficial femoral and popliteal veins of the right leg. Coagulation studies showed greatly elevated levels of thrombin-antithrombin complexes and prothrombin fragment F1.2 levels, consistent with uncontrolled thrombin generation. After vitamin K administration, no abnormalities of the protein C anticoagulant pathway were identified, consistent with previous studies of other patients with warfarin-induced necrosis complicating heparin-induced thrombocytopenia. Subsequently, the patient was shown to have metastatic breast adenocarcinoma, which explained the patient's initial presentation with nonbacterial thrombotic endocarditis. This patient case suggests that multiple digital gangrene can result from the interaction of various localizing and systemic factors, including compromised microvascular blood flow (Raynaud's phenomenon), increased thrombin generation (heparin-induced thrombocytopenia, adenocarcinoma), and warfarin-induced failure of the protein C natural anticoagulant pathway.

[Postoperative pulmonary embolism].

Post-operative thrombo-embolic disease remains a frequent occurrence in spite of advances in their prophylaxis. Evaluation of 60 case-reports of this disease which often includes peripheral manifestations and always pulmonary manifestations, enables to specify the role of the procedure itself (mostly orthopaedic surgery 60%), pelvic surgery 20%, the chronology of events (possibility of early embolism between D1 and D3 and usual occurrence of manifestations between D8 and D18, and the importance of the background, whether investigated or not: deficiencies in anti-thrombin III, protein C and S: 4 cases. The diagnosis is based on clinical signs (non-specific) and the laboratory tests, especially scintigraphy (screening) and angiography, absolutely necessary for the diagnosis and evaluation of the amputation coefficient (Miller index). With a diagnosis of pulmonary embolism, it is always necessary to look for a proximal venous thrombosis. The treatment, calls for heparin (quite seldom), thrombolytics (Urokinase, Plasminogen in our experience), the indication of which must take into consideration the delays and the nature of the previous procedure, and finally surgery (massive forms where thrombolytics are contraindicated). The thrombo-embolic manifestations with thrombogenic thrombopenia secondary to heparin are quite frequent, in a surgical environment (10 cases) and difficult to treat.

Warfarin necrosis

Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis (tissue death) occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (4-hydroxycoumarins, such as warfarin). Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants. The typical patient appears to be an obese, middle aged woman (median age 54 years, male to female ratio 1:3). This drug eruption usually occurs between the third and tenth days of therapy with warfarin derivatives. The first symptoms are pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechial, then hard and purpuric. They may then resolve or progress to form large, irregular, bloody bullae with eventual necrosis and slow-healing eschar formation. Favored sites are breasts, thighs, buttocks and penis, all areas with subcutaneous fat. In rare cases, the fascia and muscle are involved.

[Upper limb deep venous thrombosis. Risk factors, outcome, and posthrombotic syndrome].

Our objective was that of describing a series of episodes of upper limb deep venous thrombosis, with special emphasis on the incidence of posthrombotic syndrome and its impact in the quality of life of the patients. 33 episodes (29 patients) of upper limb deep venous thrombosis were studied, between January 1995 and January 2002; episodes until September 1999 (18 episodes) were considered retrospectively while those which took place starting in this date (15 episodes) were considered prospectively. In all, 24 patients were cared in hospital clinic. It was possible to obtain complete data in 16 cases, in which evolution toward posthrombotic syndrome, venous revascularization, and impact of the pathological process in the global quality of life of patients were studied. Average age of patients was 58.9 years. In 25 episodes (75.8%) some risk factor for venous thrombosis existed, the presence of a venous catheter being the most frequent. Subclavian axillary affectation was predominant (18 episodes, 55%) and in the left side (25 episodes, 76%). Twenty-eight episodes were diagnosed with echography (84.8%). Mean D-dimers concentration (N = 16) was 1,046 ng/ml (standard deviation [SD]: 826.9). One of the episodes (3%) was associated to lung thromboembolism. Treatment consisted on the administration of low molecular weight heparin during the acute phase in 70% of the cases. In 13 episodes (39%) additional treatment of thrombosis (endovascular in most) was carried out. In 29 episodes (88%) chronic treatment was administered with acenocoumarol, while in 4 episodes (12%) the administration of low molecular weight heparin was kept. No patient died during hospitalization. In 15 patients (52%) control of revascularizacion was performed. We detected complete revascularization in 6 patients (40%), revascularization with collateral circulation in 4 patients (27%), partial revascularization in other 4 patients (27%) and presence of permeability but with expansion and tortuosity of deep venous system in 1 case (6%). Posthrombotic syndrome was considered mild or nonexistent in 10 patients (62.5%) and moderate in 6 patients (37.5%). Quality of life of patients with moderate posthrombotic syndrome was significantly worse than that of patients with mild posthrombotic syndrome (73 vs 90, p < 0.035). Most of upper limb deep venous thrombosis are associated to the use of intravenous catheters. Echography is the primary diagnostic technique. At the time of the diagnosis, patients tend to show elevation in D-dimers levels. Evolution toward posthrombotic syndrome is frequent; this syndrome does not use to be serious but indeed influences the quality of life of patients.

[Mechanic valve prosthesis and pregnancy: Is Phenprocoumon replaceable?].

We report the case of a 30-year-old pregnant patient with mechanical valve replacement in mitral and aortic position. She had discontinued Phenprocoumon-treatment in the 5+4 week of pregnancy by herself. Because of rheumatic fever she had undergone a mechanical aortic and mitral valve replacement 12 years ago. Due to a thrombosis of the mitral valve, an acute reoperation had to be done 5 years later. 2 years ago, a partially re-thrombosis of the mechanical mitral valve was treated by intravenous thrombolysis. These complications had been probably due to incomplicance. The patient had experienced 3 abortions before. The vaginal sonography determined an intact gestation. The laboratory test revealed an INR of 1.2. The transesophageal echocardiography showed a partially thrombosed mechanical mitral valve. The abdominal ultrasonography detected an embolic splenic infarction. These findings were consistent with partially thrombosed mechanical mitral valve with thromboembolic splenic infarction among incompetent oral anticoagulation. After initial heparinization with under twice daily control of the partial thromboplastin time the joint decision was made to restart Phenprocoumon (target INR 2.5 to 3.5, and additional ASS 100 mg /day). 9 days later the patient had a missed abortion. An uncomplicated curettage was performed under therapeutic i.v. heparinization. The use of coumarins in pregnancy carries a fetal risk. But it is the most secure anticoagulation after a mechanical valve replacement, especially in high-risk patients. Alternatives are heparins. They don't cross the placenta but are associated with a slightly elevated risk of thromboembolism.

[Mitral valve prosthesis without anticoagulant treatment. Apropos of 46 cases].

Out of a total of 90 patients with valvular prosthesis not treated with anti-coagulants, 46 only had a prosthesis in the mitral position. These patients were treated in Professor Ben Ismail's department for an average of 58 months (extreme limits 26 and 116 months). The average age of these patients at the time of the operation was 13.6 years. It is important to note that these patients greatly improved as attested to by the evolution of the functional symptoms, cardiac volume, capillary and pulmonary arterial pressure. 7 patients had a thromboembolism (15.5 per cent or 3 embolisms per 100 patient-years). Three cases were minor or rapidly regressed and out of four major cases, one died. This complication is much more frequent in patients treated with anti-coagulants as is the risk of haemorrhage which is sometimes serious or even mortal. In view of these results, it seems legitimate, in these young patients, especially when they are in sino-astrial rhythm, have a good clinical history and are haemodynamic to forego anti-coagulant treatment which may be dangerous in these undisciplined patients under irregular and unusual treatment.

Progressive hemolytic anemia due to delayed recognition of a Beall mitral valve prosthesis.

In addition to a working knowledge of general complications such as thromboembolism and infective endocarditis, optimal care of the patient with a prosthetic valve requires specific knowledge concerning the characteristics of a given patient's prosthesis. This may need to include the ability to identify the valve roentgenographically when history and records are unavailable. A 53-year-old woman with mitral stenosis secondary to rheumatic heart disease and status post a reported Bjork-Shiley mitral valve (MV) replacement 17 years prior to hospital admission was referred for evaluation of severe hemolytic anemia. Previous cinefluoroscopy in 1986 at the time of a cerebrovascular accident revealed a normally functioning caged disc prosthesis and not the tilting disc of a Bjork-Shiley prosthetic valve. The valve was not further characterized and she continued receiving warfarin therapy until May 1989 when she presented with laboratory findings showing a marked hemolytic anemia with a hemoglobin of 6.5 mg/dl and lactate dehydrogenase (LDH) value of 2100 IU. Echocardiography revealed normal valvular function without evidence of perivalvular leak. The patient was referred for further evaluation with chest roentgenogram at the time of hospital admission revealing a valve configuration characteristic of the Beall model 103/104 series that has been found to manifest progressive disc variance with a high degree of hemolytic anemia (despite normal noninvasive evaluation of MV function), disc tilting with intermittent regurgitation, and catastrophic disc embolization in extreme cases. The precise identification of valvular prosthesis in patients after valve replacement is crucial for optimal management. As in our case, the mere identification of a particular valve may necessitate certain management and therapy based on the natural history of that valve. In the absence of reliable history and/or records, the roentgenographic examination should lead to the precise identification.

[Thrombosis of mechanical heart valve prosthesis. Predisposing factors and results of surgical treatment].

Heart valve thrombosis is a serious complication. From February, 1995 to January, 1996, 19 patients were studied to identify predisposing factors and results of surgical management. Mean age was 47.3 years. Thirteen patients (73.6%) had an irregular surveillance of anticoagulation therapy. Fifteen patients showed low anticoagulation effect during their evolution. Sixteen patients were in functional class III and 80% (15 patients) showed imaging of thrombus in the echocardiographic study. All patients presented thrombus on both sides of the prothesis. There were no deaths, and 15 patients returned to functional class I. It was concluded that the main predisposing factor in this series of patients was deficient anticoagulation therapy, and surgical results are comparable to those other authors.

[Multiple mitral valve aneurysms, mycotic arterial embolism and aneurysms with infective endocarditis].

A 30-year-old woman with a more than 6-month history of fever, weight loss, general fatigue and dysesthesia of lower extremities was admitted to our hospital with a diagnosis of infective endocarditis. Blood cultures revealed Staphylococcus oralis. Echocardiography revealed severe mitral and moderate tricuspid regurgitation, as well as massive vegetations and aneurysms on the mitral valve. Computed tomography revealed an abdominal aortic aneurysm, left common and external iliac arterial aneurysms, and occlusion of the left common iliac, the deep femoral arteries and the bilateral tibioperoneal trunk. The ankle brachial pressure indices (ABI) were 0.94 (right) and 0.61 (left). She initially underwent mitral valve replacement and tricuspid annuloplasty. On postoperative day 24, the affected segments of the arteries were replaced with a woven Dacron bifurcated graft after resection of the mycotic abdominal and the iliac arterial aneurysms. We could not obtain a sufficient amount of omental pedicle to wrap the prosthesis. Her postoperative course was uneventful and mycotic arterial embolism and aneurysm did not recur.

Outcomes and associated risk factors for mitral valve replacement in children.

We aim to report time-related outcomes following mitral valve replacement (MVR) in children and to identify factors affecting outcomes. Clinical records from 307 children who underwent MVR between 1985 and 2004 were reviewed. Competing-risks methodology determined time-related prevalence of three mutually exclusive end-states: death, mitral reoperation and survival without subsequent MVR, and their associated risk factors. Mean age was 11.4 ± 5.6 years including 36 (12%) patients < 2 years old. There were 154 (50%) males. Underlying pathology was rheumatic fever (n = 195, 64%), congenital (n = 83, 27%) and other (n = 29, 9%) with congenital pathology predominant in younger children while rheumatic fever predominant in older children. Hemodynamic manifestation was regurgitation (83%), stenosis (5%), or mixed disease (12%). One hundred and twenty-six patients (41%) had undergone a prior cardiac surgery including mitral surgery (n = 96, 31%). Initial mitral prosthesis was mechanical (n = 229, 75%), tissue (n = 71, 23%), or homograft (n = 7, 2%). Concomitant cardiac surgery was required in 141 patients (46%). Competing-risks analysis predicted that 20 years following MVR, approximately 17% of patients have died, 51% have undergone mitral reoperation and only 33% were alive and free from mitral reoperation. Risk factors for death without mitral reoperation included younger age < 3 years [PE (parameter estimates): +1.66 ± 0.31, p < 0.001], longer cross-clamp time (PE: +0.11 ± 0.04/10 min, p = 0.005), postoperative complications (PE: +1.5 8 ± 0.31, p < 0.001), and higher prosthesis size/body surface area (BSA)-predicted mitral annulus ratio (PE: + 0.48 ± 0.10, p < 0.001). Risk factors for mitral reoperation included implantation of homograft or tissue prosthesis (PE: +1.12 ± 0.23, p < 0.001) and smaller prosthesis size (PE: +0.06 ± 0.03/1 mm, p = 0.05). Fifteen-year freedom from pacemaker implantation, endocarditis, bleeding, and thromboembolism was 92%, 96%, 82%, and 92%, respectively. Mortality and mitral reoperation are common after MVR in children and outcomes can be predicted based on patient's age, prosthesis size, and other associated factors. Some modifiable factors such as avoiding oversized prostheses may improve outcomes especially in the smallest children.

[An uncommon cause of severe soft tissue bleeding during phenprocoumon treatment].

A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation. Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak. The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device. The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.