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Coagulation disturbances in the critically ill patient with special reference to prediction of outcome

Nilsson, Gunnar LU (2006)
Abstract
Critically ill patients in intensive care units (ICU) often have coagulation disturbances. Clinical manifestations such as thromboembolism and/or bleeding may result from activation and consumption of coagulation factors and inhibitors. Disseminated intravascular coagulation (DIC) is a severe condition with an often-poor prognosis. Global haemostatic tests are inexpensive, widely available, and may be performed 24 hours a day. In contrast, more sophisticated coagulation tests, such as protein C, antithrombin, and activated protein C-protein C inhibitor (APC-PCI) complex, are expensive, can be performed only in a limited number of healthcare facilities specializing in coagulation disorders, and often only during office hours.

... (More)
Critically ill patients in intensive care units (ICU) often have coagulation disturbances. Clinical manifestations such as thromboembolism and/or bleeding may result from activation and consumption of coagulation factors and inhibitors. Disseminated intravascular coagulation (DIC) is a severe condition with an often-poor prognosis. Global haemostatic tests are inexpensive, widely available, and may be performed 24 hours a day. In contrast, more sophisticated coagulation tests, such as protein C, antithrombin, and activated protein C-protein C inhibitor (APC-PCI) complex, are expensive, can be performed only in a limited number of healthcare facilities specializing in coagulation disorders, and often only during office hours.



In the present study 92 patients admitted to a general ICU constituted the study group. The inclusion criteria consisted of one or more of the following: platelet count <100×10e9 /L; International Normalized Ratio (INR) >1.36; or activated partial thromboplastin time (APTT) >45 seconds. A control group with a comparable age and sex distribution, but not fulfilling the laboratory criteria, was established. Groups were followed up to 180 days. Survival upon discharge from the ICU and hospital was significantly lower in the study group, especially in patients with disorders that can be related to internal medicine. Odds ratios showed that prolonged APTT, in particular, predicted a lower survival rate at the time points evaluated.



The coagulation inhibitors protein C and antithrombin were also analysed. Univariate analysis of variance showed that INR and APTT were independent predictors of protein C and, to some extent, antithrombin. Using a Cox regression model, decreased protein C, but not antithrombin, predicted lower survival at 5 years.



Using the same patient material in a theoretical model assuming best-case scenario, we hypothesized that protein C treatment of patients with low levels would increase survival to the same level as a cohort with higher protein C. Total costs per life saved at 30 days (upper limit of 95 % CI) were calculated at SEK 408,000 [recombinant human activated protein C; drotrecogin alfa (activated)] and 435,000 (protein C zymogen), which may be compared to the value of a statistical life at the same age (SEK 7.66 million).



We also studied 38 patients who underwent aortic surgery. The level of the coagulation test APC-PCI complex was very high immediately following surgery and remained so, although declining, during the first two days. Higher complex levels at 6-12 hours and 12-18 hours after admission to the ICU were observed in patients who did not survive their stay in the unit. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Kritiskt sjuka patienter på intensivvårdsavdelningar (IVA) har ofta störningar i blodets levringsförmåga (koagulation). Kliniska tecken som blodpropp (djup ventrombos eller blodpropp i lungorna) och/eller blödning kan vara resultatet av aktivering och konsumtion av koagulationsfaktorer och koagulationshämmare. Disseminerad intravaskulär koagulation (DIC, som är en samtidig kombination av blodproppsbildning och blödningsbenägenhet) är ett allvarligt tillstånd med en ofta mycket dålig prognos. Screeningprover för blödningsbenägenhet (blodplättar, INR och APTT) är billiga, överallt tillgängliga och kan analyseras dygnet runt. Däremot är mer sofistikerade koagulationsprover som protein C, antitrombin... (More)
Popular Abstract in Swedish

Kritiskt sjuka patienter på intensivvårdsavdelningar (IVA) har ofta störningar i blodets levringsförmåga (koagulation). Kliniska tecken som blodpropp (djup ventrombos eller blodpropp i lungorna) och/eller blödning kan vara resultatet av aktivering och konsumtion av koagulationsfaktorer och koagulationshämmare. Disseminerad intravaskulär koagulation (DIC, som är en samtidig kombination av blodproppsbildning och blödningsbenägenhet) är ett allvarligt tillstånd med en ofta mycket dålig prognos. Screeningprover för blödningsbenägenhet (blodplättar, INR och APTT) är billiga, överallt tillgängliga och kan analyseras dygnet runt. Däremot är mer sofistikerade koagulationsprover som protein C, antitrombin och komplexet mellan aktiverat protein C och dess hämmare protein C inhibitor (APC-PCI-komplexet) dyra, analyseras vanligen bara vid ett litet antal koagulationslaboratorier och utförs oftast enbart under kontorstid.



I det första delarbetet skapades den så kallade studiegruppen av 92 patienter som lades in på en allmän intensivvårdsavdelning. För att ingå i studiegruppen skulle ett eller flera av följande blodprovsresultat vara uppfyllda: blodplättar <100×10e9/L, INR >1,36 eller APTT >45 sekunder (referensområde 125-340 ×10e9/L, <1,2 respektive 24-37 sekunder). En kontrollgrupp med samma könsfördelning och liknande åldersfördelning skapades också, men där var kravet att inte något blodprovsresultat för att ingå i studiegruppen fick vara uppfyllt. Grupperna följdes under 180 dagar. Överlevnaden vid utskrivning från IVA och från sjukhuset var lägre i studiegruppen, särskilt hos patienter med diagnoser som tillhör den internmedicinska sfären. I synnerhet förlängd APTT förutspådde lägre överlevnad vid de undersökta tidpunkterna (upp till 180 dagar).



Koagulationshämmarna protein C och antitrombin undersöktes också. Matematiska metoder (univariat variansanalys) visade att INR och APTT oberoende av varandra kunde förutspå nivån på protein C och i viss mån antitrombin. Med andra matematiska metoder (Cox regressionsmodeller) visades att sänkt protein C, men inte sänkt antitrombin, kunde förutspå sämre överlevnad i upp till 5 år.



Vi använde samma patient-data i en teoretisk modell, där vi förutsatte bästa möjliga utfall (resultat). Vi antog att behandling av patienter med sänkta protein C-nivåer skulle öka deras överlevnad till samma nivå som en grupp med högre protein C-nivåer. Den totala kostnaden per räddat liv vid 30 dagar beräknades vara 408 000 SEK vid användning av aktiverat protein C och 435 000 SEK om icke-aktiverat protein C användes. De angivna kostnaderna utgör det högre pris man får då man tar hänsyn till slumpmässig spridning och osäkerhet i beräkningarna. Dessa framräknade kostnader kan jämföras med ?värdet av ett statistiskt liv?, som beror på åldern, och är SEK 7,66 miljoner för en person som är lika gammal som patienterna i undersökningen.



Vi följde också 38 patienter som hade opererats i stora kroppspulsådern (aorta). Blodprovet APC-PCI-komplex var kraftigt förhöjt omedelbart efter operationen och, trots att nivåerna sjönk, var värdena förhöjda under de två första dygnen efter operationen. Extra höga nivåer sågs vid 6 till 12 timmar och 12 till 18 timmar efter operationen hos de patienter som inte överlevde vistelsen på IVA. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Ingerslev, Jørgen, Århus Universitetshospital/Skejby Sygehus, Århus, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicine (human and vertebrates), protein C, mortality, intensive care, health economics, global haemostatic tests, blood coagulation disorders, APC-PCI complex, abdominal aortic aneurysm operation, antithrombin, Medicin (människa och djur)
pages
132 pages
publisher
Department of Coagulation Disorders and Department of Anaesthesiology and Intensive Care, Malmö University Hospital, Lund University, Malmö, Sweden
defense location
Jubileumsaulan, Medicinskt Forskningscentrum, ingång 59, Universitetssjukhuset MAS, Malmö
defense date
2006-05-30 09:15:00
ISBN
91-85481-88-2
language
English
LU publication?
yes
additional info
G Nilsson, J Astermark, S Lethagen, E Vernersson and E Berntorp. 2002. The prognostic value of global haemostatic tests in the intensive care unit setting. Acta Anaesthesiol Scand, vol 46 pp 1062-7.
G Nilsson, J Astermark, S Lethagen, E Vernersson and E Berntorp. 2005. Protein C levels can be forecasted by global haemostatic tests in critically ill patients and predict long-term survival. Thromb Res, vol 116 pp 15-24.
G Nilsson, S Höjgård and E Berntorp. . Treatment of the critically ill patient with protein C: aspects on survival and cost. (manuscript)
G Nilsson, K Strandberg, J Astermark, E Vernersson, J Stenflo and E Berntorp. . The APC-PCI complex concentration predicts outcome of aortic surgery. (submitted)
id
8008c26b-120b-41cc-a6af-3f61af64051e (old id 546808)
date added to LUP
2016-04-01 16:44:35
date last changed
2018-11-21 20:43:51
@phdthesis{8008c26b-120b-41cc-a6af-3f61af64051e,
  abstract     = {{Critically ill patients in intensive care units (ICU) often have coagulation disturbances. Clinical manifestations such as thromboembolism and/or bleeding may result from activation and consumption of coagulation factors and inhibitors. Disseminated intravascular coagulation (DIC) is a severe condition with an often-poor prognosis. Global haemostatic tests are inexpensive, widely available, and may be performed 24 hours a day. In contrast, more sophisticated coagulation tests, such as protein C, antithrombin, and activated protein C-protein C inhibitor (APC-PCI) complex, are expensive, can be performed only in a limited number of healthcare facilities specializing in coagulation disorders, and often only during office hours.<br/><br>
<br/><br>
In the present study 92 patients admitted to a general ICU constituted the study group. The inclusion criteria consisted of one or more of the following: platelet count &lt;100×10e9 /L; International Normalized Ratio (INR) &gt;1.36; or activated partial thromboplastin time (APTT) &gt;45 seconds. A control group with a comparable age and sex distribution, but not fulfilling the laboratory criteria, was established. Groups were followed up to 180 days. Survival upon discharge from the ICU and hospital was significantly lower in the study group, especially in patients with disorders that can be related to internal medicine. Odds ratios showed that prolonged APTT, in particular, predicted a lower survival rate at the time points evaluated.<br/><br>
<br/><br>
The coagulation inhibitors protein C and antithrombin were also analysed. Univariate analysis of variance showed that INR and APTT were independent predictors of protein C and, to some extent, antithrombin. Using a Cox regression model, decreased protein C, but not antithrombin, predicted lower survival at 5 years.<br/><br>
<br/><br>
Using the same patient material in a theoretical model assuming best-case scenario, we hypothesized that protein C treatment of patients with low levels would increase survival to the same level as a cohort with higher protein C. Total costs per life saved at 30 days (upper limit of 95 % CI) were calculated at SEK 408,000 [recombinant human activated protein C; drotrecogin alfa (activated)] and 435,000 (protein C zymogen), which may be compared to the value of a statistical life at the same age (SEK 7.66 million).<br/><br>
<br/><br>
We also studied 38 patients who underwent aortic surgery. The level of the coagulation test APC-PCI complex was very high immediately following surgery and remained so, although declining, during the first two days. Higher complex levels at 6-12 hours and 12-18 hours after admission to the ICU were observed in patients who did not survive their stay in the unit.}},
  author       = {{Nilsson, Gunnar}},
  isbn         = {{91-85481-88-2}},
  keywords     = {{Medicine (human and vertebrates); protein C; mortality; intensive care; health economics; global haemostatic tests; blood coagulation disorders; APC-PCI complex; abdominal aortic aneurysm operation; antithrombin; Medicin (människa och djur)}},
  language     = {{eng}},
  publisher    = {{Department of Coagulation Disorders and Department of Anaesthesiology and Intensive Care, Malmö University Hospital, Lund University, Malmö, Sweden}},
  school       = {{Lund University}},
  title        = {{Coagulation disturbances in the critically ill patient with special reference to prediction of outcome}},
  year         = {{2006}},
}