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Successive bleeding and thrombotic complications in a patient with afibrinogenemia: A case report
Thrombosis Research 128 (2011) 296–298
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Letter to the Editors-in-Chief Successive bleeding and thrombotic complications in a patient with afibrinogenemia: A case report
Dear Editors, Congenital afibrinogenemia is a rare bleeding disorder [1] which can be complicated by rare thrombotic events, whose management is still a subject of debate. We report a case of congenital afibrinogenemia presenting concomitant bleeding and thrombotic complications and discuss the difficulties to achieve appropriate treatment in such a challenging clinical situation. The patient was a 37 year-old male who experienced during his childhood only moderate bleeding episodes such as hematomas treated with cryoprecipitate infusions. Cryoprecipitate was also used as prophylaxis for dental surgery and was complicated with a chronic hepatitis C. Afibrinogenemia was diagnosed in early childhood. Plasma fibrinogen level was undetectable by both Von Clauss and immunological methods. DNA analysis showed two mutations on the gene coding for fibrinogen alpha chain (Aalpha del a4209 het + Aalpha IVS4 +1 G N T het), confirming the diagnosis. The family history revealed a brother with afibrinogenemia who had a mild clinical bleeding phenotype with rare bleeding episodes. He presented an intra cranial-hemorrhage at the age of 28 and received fibrinogen concentrates with a succesful outcome. In January 2003, the patient was hospitalized for severe headache, dizziness and impaired visual acuity, without neurological deficit. On admission, the routine coagulation tests showed aPTT N 200 sec, PT b 10%, fibrinogen b 0.1 g/L, thrombin time N 60 sec and reptilase time N 120 sec. Computed tomography scan (CT scan) showed two cerebral hematomas located on the left intra cerebellar and right occipital hemispheres and also eliminated an aneurysm. The patient initially received fibrinogen concentrate(Clottagen®, Laboratoire Français du Fractionnement et des Biotechnologies, Les Ulis, France), 3 g/day in order to maintain residual plasma fibrinogen level greater than 1.5 g/L. Clinical symptoms were improved after fibrinogen therapy. Two weeks later, while the patient was bedridden and wore elastic stockings for deep venous thrombosis (DVT) prevention, he exhibited a distal DVT of the left tibial and fibular veins. A thrombophilia screening was therefore performed. There was no factor V Leiden, no FII G20210A mutation. The patient had normal plasma AT (113 IU/dL), PC (112 IU/dL) and PS (91 IU/dL) levels. No antiphospholipid syndrom was detected and plasma homocystein level was normal. DVT was treated with low molecular weight heparin (LMWH; Fraxiparine®, GSK, Marly-le-Roi, France) 4750 UI/ 12 h subcutaneously during five weeks with regular monitoring of anti-Xa activity. Two weeks later, a spontaneous right hemothorax occurred while anti-Xa activity was within the target range, e.g. 0.53 IU/mL. Hemothorax was drained with favorable clinical outcome. The compression ultrasound (CUS) exam performed at LMWH withdrawal showed a complete vessel repermeabilization. 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.03.012
Two months after hospitalization, the improvement of clinical symptoms allowed a prolongation of the intervals between the infusions of fibrinogen concentrates, e.g. 1.5 g every 3 days for 10 days then 1.5 g once a week. With this new regimen, the onset and progressive worsening of drowsiness and neurological signs, i.e. nystagmus, homonymous hemianopsia occurring four days after the last fibrinogen infusion justified a magnetic resonance imaging (MRI) examination. MRI diagnosed a recurrent left cerebellar bleeding associated with a right thalamic hematoma. The same day, the plasma fibrinogen level was below 0.3 g/L (trough level). The patient was treated with fibrinogen concentrate at high doses, up to 9 g daily in order to maintain plasma fibrinogen level at 2–3 g/L. Four days later, a systematic CUS exam showed a recurrent left fibular thrombosis. No anticoagulation was prescribed and therapeutical target for fibrinogen level was reduced at 1.5 to 2 g/L with a rapid decrease to 1 to 1.2 g/L because of a better general condition with no drowsiness and improvement of neurological signs. Ten days later, a diagnosis of posterior cerebral vein thrombosis (CVT) was done and anticoagulation with unfractionned heparin (UFH) 100 IU/kg/day was introduced. A multidisciplinary conference recommended to target fibrinogen plasma level between 0.5 and 1 g/L and to stop heparin because of a favorable clinical outcome of CVT with the improvement of headaches. Unfortunately, two days later, a CT scan showed a thrombus in the left pulmonary artery with multiple pulmonary emboli associated with inferior vena cava thrombosis. This severe thrombotic event led to the placement of a vena cava filter and heparin therapy 100 IU/kg/day. Despite therapeutical UFH doses, low anti-Xa activity b 0.15 IU/ml was observed and one week later, the patient presented a phlegmatia coerulea. Fibrinogen replacement therapy was immediately stopped. Concerns about potential bleeding risk related to thrombolysis and the high thrombotic risk of the patient which could be further enhanced by a thrombectomy surgery leaded to prescribe a standard heparin therapy. UFH was given at 300 IU/kg/day during the first day and followed by subcutaneous UFH 500 IU/12 h (Calciparine®, Sanofi-Aventis, Paris, France). After one month of clinical improvement, the patient presented an unusual drowsiness and MRI showed an acute right cerebellar hematoma. Heparin treatment was stopped and fibrinogen 1.5 g/d was introduced aiming to maintain plasma fibrinogenN 0.5 g/L. One week later, the worsening of neurological symptoms prompted to realize a CT scan, which showed a worsening of the recent right cerebellar hematoma associated with peri-lesional oedema. Plasma fibrinogen level was maintained at 1 g/L and the evolution was rapidly favorable. Nine days later, CUS examination showed an extensive DVT of the left leg and a complete thrombosis of the inferior vena cava below the filter without major arterial ischemia. Clottagen® treatment was stopped and the patient’ clinical signs progressively improved. Three weeks later, the patient presented a pleural effusion which was rapidly drained. Blood cultures detected multidrug-resistant Pseudomonas aeruginosa and the patient was treated with large spectrum antibiotics
Letter to the editors-in-chief
during fourteen days. Then, CUS exam showed the persistence of DVT in the iliac and femoral veins. No new hemorrhagic event occurred and the patient required no fibrinogen concentrate. Four days after, the patient had a sudden worsening of the neurological signs and the CT scan visualized a new hemorrhagic area in the brain. Treatment with infusion of fibrinogen concentrates was introduced with a therapeutic target between 0.6 and 1 g/L as a trough level. The clinical course improved within 48 hours, but in the next two days, the patient presented a rapid clinical deterioration progressing to unresponsive coma and death. Discussion Bleeding events encountered in afibrinogenemic patients are mainly cord bleeding at birth, hematomas and ICH [1]. The thrombotic events are more rarely described and can be located in arterial and venous territories [2]. The chronology of events leading to thrombosis in afibrinogenemic patients begins to be better understood. It has been previously suggested that afibrinogenemia can cause an apparent paradoxical thrombotic tendency [3]. In the absence of inactivation by fibrin, free thrombin activity could be increased compared to healthy controls [4,5]. Sensitive markers of thrombin formation such as prothrombin fragment 1+ 2 are increased but normalized after infusion of fibrinogen [6]. Thrombin is an activator of platelets and may lead to the release of von Willebrand Factor (vWF) from platelet α-granules, which may form a thrombus by binding to GPIIb-IIIa complex, despite the absence of fibrin [5,7]. These thrombi were described as large but loosely packed [8], thus confirming the stability conferred by fibrinogen. According to recent recommendations, fibrinogen level of patients with afibrinogenemia encountering surgery or spontaneous bleeding should be greater than 1 g/L until hemostasis is achieved and more than 0.5 g/L until complete healing [9]. In case of thrombosis, associated or not with bleeding, there is no recommendation for patients with afibrinogenemia while the use of LMWH and maintaining plasma fibrinogen level at 1 g/L are recommended in patients with dysfibrinogenemia. A review of the case reports published in recent literature permits to appreciate the variety of thrombotic events in afibrinogenemic patients: vertebral artery dissection [10–12], arterial thrombosis [1,3,5], venous thrombosis [1,13–15]. In most cases, thromboses were often correlated to a predisposing factor: infusion of fibrinogen, thrombophilia, infection, immobilization, arterial stenosis or pregnancy. Only few cases of thrombosis have been described in the absence of any predisposing factor [2]. Treatment strategies used were also variable, i.e. cryoprecipitate, fibrinogen concentrate, LMWH, intraluminal angioplasty or lepirudin. A recent survey confirmed that the therapeutic approaches of physicians for the patients with afibrinogenemia or hypofibrinogenemia were variable [16]. Data remain scarce regarding patients with afibrinogenemia exhibiting thrombosis and bleeding complications [17,18] and in particular, in patients with a quite concomitant bleeding and thrombosis pattern [19–21]. Pati et al. [19] reported a case of spontaneous ICH in a 32 year-old woman who developed, postoperatively, a thrombosis of renal vein and a bilateral pulmonary embolism despite an elevated INR. She was treated with a vena cava filter without anticoagulation and fibrinogen infusions were stopped. Henselmans et al. [20] reported a cerebral hemorrhage treated with cryoprecipitate and complicated with multiple pulmonary emboli for which LMWH 15000 IU/mL/12 h was introduced for 3 months. Finally, Matsumoto et al. [21] reported two cerebellar bleeds in a 35 year-old woman, the latter being complicated with a thrombosis of the femoral central venous catheter. An inferior vena cava filter was placed and she was treated with UFH 20000 IU/d for 2 weeks and 12500 IU/d for the next 2 weeks, while maintaining fibrinogen replacement therapy. Later, she was switched to warfarin. There is no clear evidence on a direct relationship between fibrinogen replacement therapy and the risk of thrombosis in afibrinogenemic patient. However, we can speculate that a high level of free thrombin
297
available in the plasma of these patients, associated to fibrinogen concentrate infusion might be responsible for thromboses in some individuals. Although therapeutic trough levels of fibrinogenemia are relatively well established for the treatment of bleeding episodes, the minimal rate of fibrinogen required to achieve effective haemostasis and being safe regarding the risk of thrombosis is still not known. In our patient, thromboses mostly occurred following fibrinogen infusions despite a use of recommended fibrinogen doses and usual prevention methods e.g. elastic stockings. Interestingly, a similar fibrinogen treatment was previously given to his brother for an ICH with no thrombotic complication. Venous thromboembolism is a multifactorial disease and in this patient with hepatitis C, the impact of auto-immune response on the hemostasis system might also contribute to the pathophysiology of DVTs. Another hypothesis would be the role of rapidly decreased regimen of the fibrinogen which might be responsible for uncomplete wound healing, more prone to ICH recurrency. As in hemophilia patients, the use of continuous fibrinogen infusion at lower doses may avoid peak and trough levels in blood and might be helpful to reduce free thrombin concentration that could continuously be “absorbed” on available fibrinogen. Although this might be considered a safer alternative to the current therapeutical regimen, no clinical data is substantiating this hypothesis. To our knowledge, this case is the first description of an alternation between bleeding and thrombotic events, which were quite concomitant. The implementation of treatment was challenging and difficulties were numerous : i) Difficulties for diagnosis of thrombosis because of an abnormal clot formation with isodense appearance of intraparenchymal bleeding [20]; ii) Difficulties for laboratory follow-up because routine laboratory test (APTT, PT, fibrinogen, anti-Xa activity) can not accurately predict thrombotic or bleeding risk, in particular when the patient is treated with both heparin and fibrinogen; iii) Difficulties to establish safe and efficient treatment protocols for serious bleeding episodes. This case report emphasizes the difficulties in the management of acute severe bleeding episodes in afibrinogenemic patients, where fibrinogen replacement is indispensable but can lead to thromboses because of the high concentrations of free thrombin available in the plasma of these patients. Careful laboratory and clinical monitoring as well as careful dose tailoring might limit thrombotic complications. The report of this particular case can provide useful information with regard to clinical management difficulties in patient with afibrinogenemia.
Conflict of Interest The authors stated that they had no interests which might be perceived as posing a conflict or bias.
References [1] Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999;107:204–6. [2] Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B. Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review. Haemophilia 2006;12:345–51. [3] Schuepbach RA, Meili EO, Schneider E, Peter U, Bachli EB. Lepirudin therapy for thrombotic complications in congenital afibrinogenaemia. Thromb Haemost 2004;91:1044–6. [4] De Bosch NB, Mosesson MW, Ruiz-Saez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost 2002;88:253–8. [5] Dupuy E, Soria C, Molho P, Zini JM, Rosenstingl S, Laurian C, et al. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001;102:211–9. [6] Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig 1994;72: 396–8. [7] De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986;77: 1272–7.
298
Letter to the editors-in-chief
[8] Remijn JA, Wu YP, Ijsseldijk MJ, Zwaginga JJ, Sixma JJ, de Groot PG. Absence of fibrinogen in afibrinogenemia results in large but loosely packed thrombi under flow conditions. Thromb Haemost 2001;85:736–42. [9] Bolton-Maggs PH, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, et al. The rare coagulation disorders–review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia 2004;10:593–628. [10] Bas DF, Oguz KK, Yavuz K, Topcuoglu MA. Spinal cord infarction in congenital afibrinogenemia: a case report and review of the literature. J Stroke Cerebrovasc Dis 2009;18:298–303. [11] Laufs H, Weidauer S, Heller C, Lorenz M, Neumann-Haefelin T. Hemi-spinal cord infarction due to vertebral artery dissection in congenital afibrinogenemia. Neurology 2004;63:1522. [12] Garcia-Monco JC, Fernandez Canton G, Gomez Beldarrain M. Bilateral vertebral artery dissection in a patient with afibrinogenemia. Stroke 1996;27:2325–7. [13] Takasugi Y, Shiokawa Y, Kajikawa R, Oh J, Yamamoto Y, Sakata I, et al. Mesenteric venous thrombosis in a patient with congenital afibrinogenemia and diffuse peritonitis. Ann Hematol 2005;84:129–30. [14] Oruc N, Tokat Y, Killi R, Tombuloglu M, Ilter T. Budd-Chiari syndrome in an afibrinogenemic patient: a paradoxical complication. Dig Dis Sci 2006;51:378–80. [15] Roque H, Stephenson C, Lee MJ, Funai EF, Popiolek D, Kim E, et al. Pregnancyrelated thrombosis in a woman with congenital afibrinogenemia: a report of two successful pregnancies. Am J Hematol 2004;76:267–70. [16] Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006;4:1634–7. [17] Chafa O, Chellali T, Sternberg C, Reghis A, Hamladji RM, Fischer AM. Severe hypofibrinogenemia associated with bilateral ischemic necrosis of toes and fingers. Blood Coagul Fibrinolysis 1995;6:549–52. [18] MacKinnon HH, Fekete JF. Congenital afibrinogenemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971;104:597–9. [19] Pati S, Kombogiorgas D, Anwar A, Price RF. Spontaneous extra-axial intracranial hemorrhage followed by thrombosis in congenital afibrinogenemia: perioperative management of this rare combination. Surg Neurol 2009;71:689–92. [20] Henselmans JM, Meijer K, Haaxma R, Hew J, van der Meer J. Recurrent spontaneous intracerebral hemorrhage in a congenitally afibrinogenemic patient: diagnostic pitfalls and therapeutic options. Stroke 1999;30:2479–82.
[21] Matsumoto T, Wada H, Tamaru S, Sugimoto Y, Fujieda A, Yamamura K, et al. Central venous catheter-related thrombosis after replacement therapy for intracranial bleeding in a patient with afibrinogenaemia. Haemophilia 2008;14: 153–6.
Yoann Chevalier⁎ Yesim Dargaud Unité d'Hémostase Clinique, Hopital Edouard Herriot, Lyon, France ⁎ Corresponding author at: Unité d'Hémostase Clinique, Hôpital Edouard Herriot Pavillon E, 5, place d'Arsonval, 69003 Lyon, France. Tel.: + 33 4 7211 7378; fax: +33 4 7211 7312. E-mail address: [email protected] (Y. Chevalier). Laurent Argaud Service de Réanimation Médicale, Hopital Edouard Herriot, Lyon, France Jacques Ninet Service de Médecine Interne, Médecine Vasculaire, Hopital Edouard Herriot, Lyon, France Emmanuel Jouanneau Service de Neurochirurgie A, Groupement Hospitalier Est, Bron, France Claude Négrier Unité d'Hémostase Clinique, Hopital Edouard Herriot, Lyon, France 12 November 2010
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Letter to the Editors-in-Chief Successive bleeding and thrombotic complications in a patient with afibrinogenemia: A case report
Dear Editors, Congenital afibrinogenemia is a rare bleeding disorder [1] which can be complicated by rare thrombotic events, whose management is still a subject of debate. We report a case of congenital afibrinogenemia presenting concomitant bleeding and thrombotic complications and discuss the difficulties to achieve appropriate treatment in such a challenging clinical situation. The patient was a 37 year-old male who experienced during his childhood only moderate bleeding episodes such as hematomas treated with cryoprecipitate infusions. Cryoprecipitate was also used as prophylaxis for dental surgery and was complicated with a chronic hepatitis C. Afibrinogenemia was diagnosed in early childhood. Plasma fibrinogen level was undetectable by both Von Clauss and immunological methods. DNA analysis showed two mutations on the gene coding for fibrinogen alpha chain (Aalpha del a4209 het + Aalpha IVS4 +1 G N T het), confirming the diagnosis. The family history revealed a brother with afibrinogenemia who had a mild clinical bleeding phenotype with rare bleeding episodes. He presented an intra cranial-hemorrhage at the age of 28 and received fibrinogen concentrates with a succesful outcome. In January 2003, the patient was hospitalized for severe headache, dizziness and impaired visual acuity, without neurological deficit. On admission, the routine coagulation tests showed aPTT N 200 sec, PT b 10%, fibrinogen b 0.1 g/L, thrombin time N 60 sec and reptilase time N 120 sec. Computed tomography scan (CT scan) showed two cerebral hematomas located on the left intra cerebellar and right occipital hemispheres and also eliminated an aneurysm. The patient initially received fibrinogen concentrate(Clottagen®, Laboratoire Français du Fractionnement et des Biotechnologies, Les Ulis, France), 3 g/day in order to maintain residual plasma fibrinogen level greater than 1.5 g/L. Clinical symptoms were improved after fibrinogen therapy. Two weeks later, while the patient was bedridden and wore elastic stockings for deep venous thrombosis (DVT) prevention, he exhibited a distal DVT of the left tibial and fibular veins. A thrombophilia screening was therefore performed. There was no factor V Leiden, no FII G20210A mutation. The patient had normal plasma AT (113 IU/dL), PC (112 IU/dL) and PS (91 IU/dL) levels. No antiphospholipid syndrom was detected and plasma homocystein level was normal. DVT was treated with low molecular weight heparin (LMWH; Fraxiparine®, GSK, Marly-le-Roi, France) 4750 UI/ 12 h subcutaneously during five weeks with regular monitoring of anti-Xa activity. Two weeks later, a spontaneous right hemothorax occurred while anti-Xa activity was within the target range, e.g. 0.53 IU/mL. Hemothorax was drained with favorable clinical outcome. The compression ultrasound (CUS) exam performed at LMWH withdrawal showed a complete vessel repermeabilization. 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.03.012
Two months after hospitalization, the improvement of clinical symptoms allowed a prolongation of the intervals between the infusions of fibrinogen concentrates, e.g. 1.5 g every 3 days for 10 days then 1.5 g once a week. With this new regimen, the onset and progressive worsening of drowsiness and neurological signs, i.e. nystagmus, homonymous hemianopsia occurring four days after the last fibrinogen infusion justified a magnetic resonance imaging (MRI) examination. MRI diagnosed a recurrent left cerebellar bleeding associated with a right thalamic hematoma. The same day, the plasma fibrinogen level was below 0.3 g/L (trough level). The patient was treated with fibrinogen concentrate at high doses, up to 9 g daily in order to maintain plasma fibrinogen level at 2–3 g/L. Four days later, a systematic CUS exam showed a recurrent left fibular thrombosis. No anticoagulation was prescribed and therapeutical target for fibrinogen level was reduced at 1.5 to 2 g/L with a rapid decrease to 1 to 1.2 g/L because of a better general condition with no drowsiness and improvement of neurological signs. Ten days later, a diagnosis of posterior cerebral vein thrombosis (CVT) was done and anticoagulation with unfractionned heparin (UFH) 100 IU/kg/day was introduced. A multidisciplinary conference recommended to target fibrinogen plasma level between 0.5 and 1 g/L and to stop heparin because of a favorable clinical outcome of CVT with the improvement of headaches. Unfortunately, two days later, a CT scan showed a thrombus in the left pulmonary artery with multiple pulmonary emboli associated with inferior vena cava thrombosis. This severe thrombotic event led to the placement of a vena cava filter and heparin therapy 100 IU/kg/day. Despite therapeutical UFH doses, low anti-Xa activity b 0.15 IU/ml was observed and one week later, the patient presented a phlegmatia coerulea. Fibrinogen replacement therapy was immediately stopped. Concerns about potential bleeding risk related to thrombolysis and the high thrombotic risk of the patient which could be further enhanced by a thrombectomy surgery leaded to prescribe a standard heparin therapy. UFH was given at 300 IU/kg/day during the first day and followed by subcutaneous UFH 500 IU/12 h (Calciparine®, Sanofi-Aventis, Paris, France). After one month of clinical improvement, the patient presented an unusual drowsiness and MRI showed an acute right cerebellar hematoma. Heparin treatment was stopped and fibrinogen 1.5 g/d was introduced aiming to maintain plasma fibrinogenN 0.5 g/L. One week later, the worsening of neurological symptoms prompted to realize a CT scan, which showed a worsening of the recent right cerebellar hematoma associated with peri-lesional oedema. Plasma fibrinogen level was maintained at 1 g/L and the evolution was rapidly favorable. Nine days later, CUS examination showed an extensive DVT of the left leg and a complete thrombosis of the inferior vena cava below the filter without major arterial ischemia. Clottagen® treatment was stopped and the patient’ clinical signs progressively improved. Three weeks later, the patient presented a pleural effusion which was rapidly drained. Blood cultures detected multidrug-resistant Pseudomonas aeruginosa and the patient was treated with large spectrum antibiotics
Letter to the editors-in-chief
during fourteen days. Then, CUS exam showed the persistence of DVT in the iliac and femoral veins. No new hemorrhagic event occurred and the patient required no fibrinogen concentrate. Four days after, the patient had a sudden worsening of the neurological signs and the CT scan visualized a new hemorrhagic area in the brain. Treatment with infusion of fibrinogen concentrates was introduced with a therapeutic target between 0.6 and 1 g/L as a trough level. The clinical course improved within 48 hours, but in the next two days, the patient presented a rapid clinical deterioration progressing to unresponsive coma and death. Discussion Bleeding events encountered in afibrinogenemic patients are mainly cord bleeding at birth, hematomas and ICH [1]. The thrombotic events are more rarely described and can be located in arterial and venous territories [2]. The chronology of events leading to thrombosis in afibrinogenemic patients begins to be better understood. It has been previously suggested that afibrinogenemia can cause an apparent paradoxical thrombotic tendency [3]. In the absence of inactivation by fibrin, free thrombin activity could be increased compared to healthy controls [4,5]. Sensitive markers of thrombin formation such as prothrombin fragment 1+ 2 are increased but normalized after infusion of fibrinogen [6]. Thrombin is an activator of platelets and may lead to the release of von Willebrand Factor (vWF) from platelet α-granules, which may form a thrombus by binding to GPIIb-IIIa complex, despite the absence of fibrin [5,7]. These thrombi were described as large but loosely packed [8], thus confirming the stability conferred by fibrinogen. According to recent recommendations, fibrinogen level of patients with afibrinogenemia encountering surgery or spontaneous bleeding should be greater than 1 g/L until hemostasis is achieved and more than 0.5 g/L until complete healing [9]. In case of thrombosis, associated or not with bleeding, there is no recommendation for patients with afibrinogenemia while the use of LMWH and maintaining plasma fibrinogen level at 1 g/L are recommended in patients with dysfibrinogenemia. A review of the case reports published in recent literature permits to appreciate the variety of thrombotic events in afibrinogenemic patients: vertebral artery dissection [10–12], arterial thrombosis [1,3,5], venous thrombosis [1,13–15]. In most cases, thromboses were often correlated to a predisposing factor: infusion of fibrinogen, thrombophilia, infection, immobilization, arterial stenosis or pregnancy. Only few cases of thrombosis have been described in the absence of any predisposing factor [2]. Treatment strategies used were also variable, i.e. cryoprecipitate, fibrinogen concentrate, LMWH, intraluminal angioplasty or lepirudin. A recent survey confirmed that the therapeutic approaches of physicians for the patients with afibrinogenemia or hypofibrinogenemia were variable [16]. Data remain scarce regarding patients with afibrinogenemia exhibiting thrombosis and bleeding complications [17,18] and in particular, in patients with a quite concomitant bleeding and thrombosis pattern [19–21]. Pati et al. [19] reported a case of spontaneous ICH in a 32 year-old woman who developed, postoperatively, a thrombosis of renal vein and a bilateral pulmonary embolism despite an elevated INR. She was treated with a vena cava filter without anticoagulation and fibrinogen infusions were stopped. Henselmans et al. [20] reported a cerebral hemorrhage treated with cryoprecipitate and complicated with multiple pulmonary emboli for which LMWH 15000 IU/mL/12 h was introduced for 3 months. Finally, Matsumoto et al. [21] reported two cerebellar bleeds in a 35 year-old woman, the latter being complicated with a thrombosis of the femoral central venous catheter. An inferior vena cava filter was placed and she was treated with UFH 20000 IU/d for 2 weeks and 12500 IU/d for the next 2 weeks, while maintaining fibrinogen replacement therapy. Later, she was switched to warfarin. There is no clear evidence on a direct relationship between fibrinogen replacement therapy and the risk of thrombosis in afibrinogenemic patient. However, we can speculate that a high level of free thrombin
297
available in the plasma of these patients, associated to fibrinogen concentrate infusion might be responsible for thromboses in some individuals. Although therapeutic trough levels of fibrinogenemia are relatively well established for the treatment of bleeding episodes, the minimal rate of fibrinogen required to achieve effective haemostasis and being safe regarding the risk of thrombosis is still not known. In our patient, thromboses mostly occurred following fibrinogen infusions despite a use of recommended fibrinogen doses and usual prevention methods e.g. elastic stockings. Interestingly, a similar fibrinogen treatment was previously given to his brother for an ICH with no thrombotic complication. Venous thromboembolism is a multifactorial disease and in this patient with hepatitis C, the impact of auto-immune response on the hemostasis system might also contribute to the pathophysiology of DVTs. Another hypothesis would be the role of rapidly decreased regimen of the fibrinogen which might be responsible for uncomplete wound healing, more prone to ICH recurrency. As in hemophilia patients, the use of continuous fibrinogen infusion at lower doses may avoid peak and trough levels in blood and might be helpful to reduce free thrombin concentration that could continuously be “absorbed” on available fibrinogen. Although this might be considered a safer alternative to the current therapeutical regimen, no clinical data is substantiating this hypothesis. To our knowledge, this case is the first description of an alternation between bleeding and thrombotic events, which were quite concomitant. The implementation of treatment was challenging and difficulties were numerous : i) Difficulties for diagnosis of thrombosis because of an abnormal clot formation with isodense appearance of intraparenchymal bleeding [20]; ii) Difficulties for laboratory follow-up because routine laboratory test (APTT, PT, fibrinogen, anti-Xa activity) can not accurately predict thrombotic or bleeding risk, in particular when the patient is treated with both heparin and fibrinogen; iii) Difficulties to establish safe and efficient treatment protocols for serious bleeding episodes. This case report emphasizes the difficulties in the management of acute severe bleeding episodes in afibrinogenemic patients, where fibrinogen replacement is indispensable but can lead to thromboses because of the high concentrations of free thrombin available in the plasma of these patients. Careful laboratory and clinical monitoring as well as careful dose tailoring might limit thrombotic complications. The report of this particular case can provide useful information with regard to clinical management difficulties in patient with afibrinogenemia.
Conflict of Interest The authors stated that they had no interests which might be perceived as posing a conflict or bias.
References [1] Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999;107:204–6. [2] Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B. Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review. Haemophilia 2006;12:345–51. [3] Schuepbach RA, Meili EO, Schneider E, Peter U, Bachli EB. Lepirudin therapy for thrombotic complications in congenital afibrinogenaemia. Thromb Haemost 2004;91:1044–6. [4] De Bosch NB, Mosesson MW, Ruiz-Saez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost 2002;88:253–8. [5] Dupuy E, Soria C, Molho P, Zini JM, Rosenstingl S, Laurian C, et al. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001;102:211–9. [6] Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig 1994;72: 396–8. [7] De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986;77: 1272–7.
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Letter to the editors-in-chief
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Yoann Chevalier⁎ Yesim Dargaud Unité d'Hémostase Clinique, Hopital Edouard Herriot, Lyon, France ⁎ Corresponding author at: Unité d'Hémostase Clinique, Hôpital Edouard Herriot Pavillon E, 5, place d'Arsonval, 69003 Lyon, France. Tel.: + 33 4 7211 7378; fax: +33 4 7211 7312. E-mail address: [email protected] (Y. Chevalier). Laurent Argaud Service de Réanimation Médicale, Hopital Edouard Herriot, Lyon, France Jacques Ninet Service de Médecine Interne, Médecine Vasculaire, Hopital Edouard Herriot, Lyon, France Emmanuel Jouanneau Service de Neurochirurgie A, Groupement Hospitalier Est, Bron, France Claude Négrier Unité d'Hémostase Clinique, Hopital Edouard Herriot, Lyon, France 12 November 2010