Annales Franc¸aises d’Anesthe´sie et de Re´animation 33 (2014) e83–e84
Letter to editor Catastrophic antiphospholipid syndrome and heparin-induced thrombocytopenia presenting with adrenal insufficiency caused by bilateral hemorrhagic adrenal infarction during sepsis Insuffisance surre´nalienne aigue¨ secondaire a` une ne´crose bilate´rale des glandes surre´nales re´ve´latrice d’un syndrome catastrophique des antiphospholipides avec thrombope´nie induite a` l’he´parine survenant lors d’un sepsis
A R T I C L E I N F O
Keywords: Catastrophic antiphospholipid syndrome Heparin-induced thombocytopenia Hemorrhagic adrenal infarction Adrenal insufficiency Sepsis Mots cle´s : Syndrome catastrophique des anticorps antiphospholipides Thrombope´nie induite par l’he´parine Ne´crose he´morragique des surre´nales Insuffisance surre´nalienne Sepsis
Bilateral hemorrhagic adrenal infarction (BHA) occurs during intensive stress but is also associated with vascular thrombosis in catastrophic antiphospholipid syndrome (CAPS) and/or heparininduced thrombopenia (HIT) [1,2]. The most common clinical signs are abdominal pain, fever, lethargy or altered mental status and hypotension. The diagnosis is confirmed anatomically by adrenal computed tomography (CT) scan revealing an uniform, rounded enlargement of adrenals with homogeneous enhancement. We report a case of BHA revealing CAPS and HIT, triggered by sepsis. A 63-year-old male patient presented in the emergency department with acute fever, dyspnea for two days and hypoxemia. His past medical history consisted of high blood pressure, type II diabetes mellitus, pulmonary embolism after arterial bypass treated with venal caver filter in 1990, and with acenocoumarol and acetylsalycilic acid since then. On admission, his blood pressure was 142/97 mmHg. Chest X-ray revealed a bilateral alveolar syndrome without lung consolidation. Blood tests are on Day 1: creatinine: 119 mmol/L, prothrombin time (PT) under vitamin K antagonist (VKA) treatment: 28%, procalcitonin: 0.18 UI, activated clotting time (ACT): 109 s, C-reactive protein: 128 UI, B-type natriuretic peptid: 591 pg/ml, platelets count: 310,000/mm3. Troponin, liver function and lipase were normal. Because of an increased respiratory insufficiency, he was then
transfered in ICU to undertake non invasive ventilation. Echocardiogram showed a high cardiac filling pressure without decreased left ventricular function, which was treated with furosemide. A probabilistic antibiotic therapy with IV ceftriaxone and levofloxacine was began after bacteriological sampling. In order to place a central venous catheter and arterial line, VKA was antagonized with 1000 UI of human prothrombin complex concentrate. On D2, VKA are given to have an INR between 2-3. On D3, the patient complained of an interscapular pain with anterior radiation, resistant to morphine administration. Abdominal CT scan and CT pulmonary angiogram highlighted the typical signs of a BHA, a bilateral lung interstitial syndrome without consolidation and a peripancreatic inflammation with fluid collections (Fig. 1). New blood tests displayed a multiple organ failure (MOF) syndrome with respiratory, surrenal, liver and pancreatitis failure associated with clotting trouble (PT: 28%, patient ACT 105s). PaO2/FIO2 ratio was 102, leading to oral intubation and mechanical ventilation. Cortisol level had collapsed with a value of 24 mg/L controlled at 39 mg/L (laboratory range > 50 mg/L), which was substituted by hydrocortisone and fludrocortisone. As the patient had simultaneously thrombocytopenia and BHA and because of his medical history, HIT and APS were both looked for. A substitution treatment with danaparoide sodium was begun, before HIT testing results. The patient status gradually improved, and was extubated on D8. HIT was confirmed on three separate blood tests, and APL diagnosis was assessed on D8 and D90. On D13, blood tests were almost normalized, except for cortisol. Hydrocortisone and fludrocortisone were continued. Patient was transferred to the department of infectiology, where abdominal CT scan displayed stable nodular images on both adrenals, and cortisol level was at 33 nmol/L (38 nmol/L after corticotrophin stimulation test). The search of associated autoimmune diseases and of systemic lupus erymathosus was negative, although anti DNA was positive. The diagnosis of primary APS, associated with HIT, was thus assessed. CAPS differs from classic APS in several ways. In classic APS, a single venous (or arterial medium-to-large blood vessel) occlusion usually dominates the clinical picture while recurrences are rare with adequate anticoagulation. In CAPS however, a severe MOF is characterized by rapid, diffuse small vessel ischemia and thrombosis predominantly affecting the parenchymental organs [3]. Thrombosis in APS occur on vascular endothelium without initial inflamation. In fact, sepsis is associated with CAPS in 25% of cases. The mechanisms of causation and pathogenesis of CAPS are not completely understood, but both sepsis and CAPS have systemic inflammatory response syndrome (SIRS) in common. This evident relationship between APS and infection may explain the developpement of CAPS using the sepsis model, as CAPS looks like severe sepsis in its acute presentation with features of SIRS leading to MOF [4]. HIT is a very rare immunologic adverse effect of heparin therapy (0.1 to 2%). Diagnosis is based on well defined biological tests and clinical signs [5]. In the presented case, search for HIT and APS was
http://dx.doi.org/10.1016/j.annfar.2014.02.021 0750-7658/ß 2014 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved.
e84
Letter to editor / Annales Franc¸aises d’Anesthe´sie et de Re´animation 33 (2014) e83–e84
simultaneously processed because of the association of BHA, thrombopenia and patient’s medical history of thrombosis, although the patient did not receive heparin therapy during hospitalization except for the heparinized arterial line. As his last exposure took place more than 150 days ago, HIT seemed very unlikely. In his past blood tests, ACT was prolonged without any etiology search at that time. As phospholipids antibodies can be found in any septic context, a new blood test had to be performed, which was also positive six weeks later. Several publications already bring out similarities between HIT and APS, which associated paradoxical risks of thrombosis and thombopenia [2]. Some questions remain unsolved in the present case. A high prevalence of antibodies to PF4-heparin in patients with APS has already been described in absence of HIT, which leads to question wether it was a proven HIT or only the presence of auto antibodies in a patient with CAPS, given the short time between the establishment of the heparinized arterial line and thrombosis. Our patient presented with a bilateral hypoxemic pneumonia, however without germs in bacteriological samples, as he did six months earlier. It may be considered that it was both times pulmonary manifestations of APL rather than infectious pneumonias, although infection can not be excluded, knowing that germs are not found in about 20% of infected patients. One of the paradoxes concerns the treatment. Indeed, except in HIT, the heparin therapy must not be stopped to improve the prognosis. Danaparoide sodium was processed for our patient. There are some questions about this therapy: does it show the same results on CAPS as heparin therapy? What are the therapeutic targets with danaparoide? So, many causes of bilateral hemorrhagic adrenal infarction, such as CAPS and HIT, have been described in the past, but the association of those three events had never been described. CAPS has a high mortality rate despite an early treatment; predisposing factors as sepsis can be on the foreground. Diagnosis of HIT and CAPS based on clinical evolution and biological test are difficult, despite a large number of them being available. Additional analysis is needed. Nesting and possible predisposition to TIH in patients with CAPS seems very likely, even if all mechanisms are not identified. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Reverdy F, Freichet M, Grozel JM, Tassin C, Piriou V. Bilateral adrenal hemorrage after heparin induced thrombocytopenia, a rare cause of shock. Ann Fr Anesth Reanim 2013;32:206–7. [2] Levine JS, Ware Branch D, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–63. [3] De Groot PG, Derksen RHWM. Pathophysiology of the antiphospholipid syndrome. J Thromb Haemost 2005;3:1854–60. [4] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [5] Amiral J, Wolf M, Vissac AM, Meyer D. Me´canismes mole´culaires et cellulaires des thrombope´nies induites par l’he´parine. Hematologie 1996;2:279–86.
E. Gelisse, E. Gratia, B. Just, P. Mateu* Intensive care unit, Manchester Hospital, 45, avenue Manchester, 08000 Charleville-Mezieres, France
Fig. 1. A–C. Abdominal CT scan evolution. A. 2011-11-18: initial bilateral hemorrhagic adrenal infarction. B. 2012-04-08: bilateral hemorrhagic adrenal infarction evolution. C. 2012-08-16: regression of adrenal nodule. D. 2013-10-25: after 2 years evolution of adrenal nodule.
*Corresponding author E-mail address: [email protected] (P. Mateu) Available online 5 April 2014
Letter to editor Catastrophic antiphospholipid syndrome and heparin-induced thrombocytopenia presenting with adrenal insufficiency caused by bilateral hemorrhagic adrenal infarction during sepsis Insuffisance surre´nalienne aigue¨ secondaire a` une ne´crose bilate´rale des glandes surre´nales re´ve´latrice d’un syndrome catastrophique des antiphospholipides avec thrombope´nie induite a` l’he´parine survenant lors d’un sepsis
A R T I C L E I N F O
Keywords: Catastrophic antiphospholipid syndrome Heparin-induced thombocytopenia Hemorrhagic adrenal infarction Adrenal insufficiency Sepsis Mots cle´s : Syndrome catastrophique des anticorps antiphospholipides Thrombope´nie induite par l’he´parine Ne´crose he´morragique des surre´nales Insuffisance surre´nalienne Sepsis
Bilateral hemorrhagic adrenal infarction (BHA) occurs during intensive stress but is also associated with vascular thrombosis in catastrophic antiphospholipid syndrome (CAPS) and/or heparininduced thrombopenia (HIT) [1,2]. The most common clinical signs are abdominal pain, fever, lethargy or altered mental status and hypotension. The diagnosis is confirmed anatomically by adrenal computed tomography (CT) scan revealing an uniform, rounded enlargement of adrenals with homogeneous enhancement. We report a case of BHA revealing CAPS and HIT, triggered by sepsis. A 63-year-old male patient presented in the emergency department with acute fever, dyspnea for two days and hypoxemia. His past medical history consisted of high blood pressure, type II diabetes mellitus, pulmonary embolism after arterial bypass treated with venal caver filter in 1990, and with acenocoumarol and acetylsalycilic acid since then. On admission, his blood pressure was 142/97 mmHg. Chest X-ray revealed a bilateral alveolar syndrome without lung consolidation. Blood tests are on Day 1: creatinine: 119 mmol/L, prothrombin time (PT) under vitamin K antagonist (VKA) treatment: 28%, procalcitonin: 0.18 UI, activated clotting time (ACT): 109 s, C-reactive protein: 128 UI, B-type natriuretic peptid: 591 pg/ml, platelets count: 310,000/mm3. Troponin, liver function and lipase were normal. Because of an increased respiratory insufficiency, he was then
transfered in ICU to undertake non invasive ventilation. Echocardiogram showed a high cardiac filling pressure without decreased left ventricular function, which was treated with furosemide. A probabilistic antibiotic therapy with IV ceftriaxone and levofloxacine was began after bacteriological sampling. In order to place a central venous catheter and arterial line, VKA was antagonized with 1000 UI of human prothrombin complex concentrate. On D2, VKA are given to have an INR between 2-3. On D3, the patient complained of an interscapular pain with anterior radiation, resistant to morphine administration. Abdominal CT scan and CT pulmonary angiogram highlighted the typical signs of a BHA, a bilateral lung interstitial syndrome without consolidation and a peripancreatic inflammation with fluid collections (Fig. 1). New blood tests displayed a multiple organ failure (MOF) syndrome with respiratory, surrenal, liver and pancreatitis failure associated with clotting trouble (PT: 28%, patient ACT 105s). PaO2/FIO2 ratio was 102, leading to oral intubation and mechanical ventilation. Cortisol level had collapsed with a value of 24 mg/L controlled at 39 mg/L (laboratory range > 50 mg/L), which was substituted by hydrocortisone and fludrocortisone. As the patient had simultaneously thrombocytopenia and BHA and because of his medical history, HIT and APS were both looked for. A substitution treatment with danaparoide sodium was begun, before HIT testing results. The patient status gradually improved, and was extubated on D8. HIT was confirmed on three separate blood tests, and APL diagnosis was assessed on D8 and D90. On D13, blood tests were almost normalized, except for cortisol. Hydrocortisone and fludrocortisone were continued. Patient was transferred to the department of infectiology, where abdominal CT scan displayed stable nodular images on both adrenals, and cortisol level was at 33 nmol/L (38 nmol/L after corticotrophin stimulation test). The search of associated autoimmune diseases and of systemic lupus erymathosus was negative, although anti DNA was positive. The diagnosis of primary APS, associated with HIT, was thus assessed. CAPS differs from classic APS in several ways. In classic APS, a single venous (or arterial medium-to-large blood vessel) occlusion usually dominates the clinical picture while recurrences are rare with adequate anticoagulation. In CAPS however, a severe MOF is characterized by rapid, diffuse small vessel ischemia and thrombosis predominantly affecting the parenchymental organs [3]. Thrombosis in APS occur on vascular endothelium without initial inflamation. In fact, sepsis is associated with CAPS in 25% of cases. The mechanisms of causation and pathogenesis of CAPS are not completely understood, but both sepsis and CAPS have systemic inflammatory response syndrome (SIRS) in common. This evident relationship between APS and infection may explain the developpement of CAPS using the sepsis model, as CAPS looks like severe sepsis in its acute presentation with features of SIRS leading to MOF [4]. HIT is a very rare immunologic adverse effect of heparin therapy (0.1 to 2%). Diagnosis is based on well defined biological tests and clinical signs [5]. In the presented case, search for HIT and APS was
http://dx.doi.org/10.1016/j.annfar.2014.02.021 0750-7658/ß 2014 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved.
e84
Letter to editor / Annales Franc¸aises d’Anesthe´sie et de Re´animation 33 (2014) e83–e84
simultaneously processed because of the association of BHA, thrombopenia and patient’s medical history of thrombosis, although the patient did not receive heparin therapy during hospitalization except for the heparinized arterial line. As his last exposure took place more than 150 days ago, HIT seemed very unlikely. In his past blood tests, ACT was prolonged without any etiology search at that time. As phospholipids antibodies can be found in any septic context, a new blood test had to be performed, which was also positive six weeks later. Several publications already bring out similarities between HIT and APS, which associated paradoxical risks of thrombosis and thombopenia [2]. Some questions remain unsolved in the present case. A high prevalence of antibodies to PF4-heparin in patients with APS has already been described in absence of HIT, which leads to question wether it was a proven HIT or only the presence of auto antibodies in a patient with CAPS, given the short time between the establishment of the heparinized arterial line and thrombosis. Our patient presented with a bilateral hypoxemic pneumonia, however without germs in bacteriological samples, as he did six months earlier. It may be considered that it was both times pulmonary manifestations of APL rather than infectious pneumonias, although infection can not be excluded, knowing that germs are not found in about 20% of infected patients. One of the paradoxes concerns the treatment. Indeed, except in HIT, the heparin therapy must not be stopped to improve the prognosis. Danaparoide sodium was processed for our patient. There are some questions about this therapy: does it show the same results on CAPS as heparin therapy? What are the therapeutic targets with danaparoide? So, many causes of bilateral hemorrhagic adrenal infarction, such as CAPS and HIT, have been described in the past, but the association of those three events had never been described. CAPS has a high mortality rate despite an early treatment; predisposing factors as sepsis can be on the foreground. Diagnosis of HIT and CAPS based on clinical evolution and biological test are difficult, despite a large number of them being available. Additional analysis is needed. Nesting and possible predisposition to TIH in patients with CAPS seems very likely, even if all mechanisms are not identified. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Reverdy F, Freichet M, Grozel JM, Tassin C, Piriou V. Bilateral adrenal hemorrage after heparin induced thrombocytopenia, a rare cause of shock. Ann Fr Anesth Reanim 2013;32:206–7. [2] Levine JS, Ware Branch D, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–63. [3] De Groot PG, Derksen RHWM. Pathophysiology of the antiphospholipid syndrome. J Thromb Haemost 2005;3:1854–60. [4] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [5] Amiral J, Wolf M, Vissac AM, Meyer D. Me´canismes mole´culaires et cellulaires des thrombope´nies induites par l’he´parine. Hematologie 1996;2:279–86.
E. Gelisse, E. Gratia, B. Just, P. Mateu* Intensive care unit, Manchester Hospital, 45, avenue Manchester, 08000 Charleville-Mezieres, France
Fig. 1. A–C. Abdominal CT scan evolution. A. 2011-11-18: initial bilateral hemorrhagic adrenal infarction. B. 2012-04-08: bilateral hemorrhagic adrenal infarction evolution. C. 2012-08-16: regression of adrenal nodule. D. 2013-10-25: after 2 years evolution of adrenal nodule.
*Corresponding author E-mail address: [email protected] (P. Mateu) Available online 5 April 2014
