Managing coagulopathies in critical care

Transcription

1 Managing coagulopathies in critical care Prof Beverley Hunt Thrombosis & Haemostasis, King s College Consultant, Guy s & St Thomas Trust Medical Director of Lifeblood: the thrombosis charity

2 Coagulopathy a condition in which the blood s ability to clot is impaired + for some thrombotic states too Complexity of the haemostatic pathways both can co-exist A clinicopathological diagnosis Tools: history & examination, FBC/blood film & coagulation screen

3 First principle of Rx of a coagulopathy: don t treat a coagulopathy UNLESS there is bleeding &/or a major procedure

4 OUT OF DATE!

5 The cell-based model of coagulation Initiation + activates various factors VIIIa IXa Amplification Propagation Hoffman M & Munroe DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85:

6 Prothrombin time International Normalised Ratio (INR) Activated partial Thromboplastin time KCCT etc Thrombin time Fibrinogen levels (Claus)

7 Causes of Bleeding among Patients in the ICU. Hunt BJ. N Engl J Med 2014;370:

8 Thrombocytopenia in critical care 20% of medical & 30% surgical CC patients Usually multifactorial & long list of causes Thrombocytopenia tend to be sicker Identify those requiring specific & urgent action e.g. HIT & TTP Excluding drug-induced is challenging because usually on so many drugs If stable no need to Rx if > 10,000 x 10 9 /L If bleeding maintain > 50,000 x 10 9 /L

9 Differential Diagnosis of Thrombocytopenia in the ICU. Young platelets are large & counted as red cells Immunoplatelet counts give true count

10 Disseminated intravascular coagulation Definition An acquired syndrome characterised by the intravascular activation of coagulation with loss of localisation arising from different causes. It can originate from and cause damage to the vasculature, which if sufficiently severe, can produce organ dysfunction. ISTH, 2000.

11 Clinical conditions associated with DIC Sepsis (any microorganism) Trauma e.g. polytrauma, neurotrauma, fat embolism Organ destruction e.g pancreatitis Malignancy Obstetric -amniotic fluid embolism -abrutio placentae Vascular Kasabach Merritt syndrome - Large vascular aneurysms Severe toxic or immunological reactions - snake bites - recreational drugs - transfusion reactions - transplant rejection March 2012

12 Concepts around haemostasis in sepsis The coagulation system evolved as an effector pathway of the immune response: laying down fibrin around bacteria to physically entrap them & prevent their dissemination

13 Underlying disorder Systemic activation of coagulation Widespread fibrin deposition Consumption of platelets & clotting factors Microvascular thrombotic obstruction Organ failure Thrombocytopenia & coagulation factor deficiency Bleeding March 2012

14 Blood film & renal biopsy specimen from a patient with DIC

15 Pathogenesis of Disseminated Intravascular Coagulation in Sepsis. Hunt BJ. N Engl J Med 2014;370:

16 Importance of tissue factor in septic DIC Anti TF/FVIIa abrogates DIC in baboon model TF antigen in plasma of patients with DIC Monocyte TF prognostic for survival in meningococcal sepsis (Osterud)? TF on endothelium In > 1000 patients Plasma TF levels & genetic variation within TF gene associated with outcome in severe sepsis Shi et al. Crit Care 2014; 18: 631 Computor modelling of docking of TF (white) with FVIIa (green)

17 The haemostatic effects of endothelial cell activation The five key changes of endothelial cell activation 1. Shape change 2. Adhesion molecules 3. Production of cytokines 4. Prothrombotic changes 5. self antigens

18 Antithrombin in DIC Activated 10,000 fold by heparinoids Produced by the liver Plasma levels reduced in DIC, and precede clinical manifestations Consumption, degradation by neutrophil elastase Loss of GAGs from endothelium reduces activation Low levels associated with increased mortality (Fourrier 1992) Studies of antithrombin concentrate show beneficial effect on laboratory parameters BUT Cochrane Meta analysis 20 trials, 3,458, Afshari et al 2008: no improvement in mortality & increased bleeding (RR 1.52, 95% CI )

19 Tissue factor pathway inhibitor Phase III RCY of 1754 patients with severe sepsis and high INR -no change in 28 day mortality & increased rate of bleeding (Abraham E et al, JAMA 2003; 290: 238)

20 The effect of cytokines on the Protein C pathway IL-1/TNF- Thrombomodulin - endocytosis of surface TM & transcription for >24 hours Increased IL-6 production levels of C4bB protein free Protein S levels of antitrypsin Protein C inactivation Neutrophil activation releases elastase, cleaving TM & O - species oxidise surface methionine on TM Activation of coagulation

21 Protein C pathway clinical trials in sepsis Activated Protein C showed no survival benefit. Ranieri et al. New Engl J Med 2012 Recombinant human thrombomodulin rhtm Yamakawa JTH 2015 systematic/meta analysis 12 studies (3RCTS), none sign trend to 28 day mortality

22 (Hermans PW, Lancet 1999; 354: 556) Fibrinolysis in DIC Schematic illustration of physiologic fibrinolysis Shut down due to increased PAI-1 BUT not all good Polymorphism, 4G/5G, in the promoter area of PAI-1influences plasma levels & survival in 226 children after meningococcal sepsis 4G/4G had higher levels )1051 [ ] vs 436 [ ] ng/ml; p=0.03 & increased risk of death (RR 2.0 [ )

23 Platelets in sepsis Histones can bind to platelet through Toll-like receptors & induce thrombin generation on platelet surface Semeraro Blood 2011; 118:

24 CT (seconds) The bleeding time with PFA- 100 Effect of Platelet Count Platelet Count Coll/Epi Coll/ADP

25 Anaemia in sepsis Reduced red cell production Multiple reasons -cytokines blunt erythropoietin production and increase apoptosis of erythroid precursors -increased hepcidin reduces iron absorption - production of epo if kidney damage Increased loss -Shortened red cell survival -Haemolysis if DIC -Iatrogenic venesection SEPSIS Effect Prolongation of bleeding time if Hb<75g/l

26 CT (seconds) Effect of Haematocrit Haematocrit (%) CEPI CADP

27 Two-way talk between haemostasis & inflammation some examples: Thrombin can cause endothelial activation and thus the synthesis of proinflammatory cytokines (van der Poll 2001) Activated Protein C inhibits endotoxinproduction of TNF-, IL- 1, IL-6 & IL-8 by cultured monos (Grey 1994) APC abrogates inflammatory activation & improves survival in baboon E Coli sepsis model (Taylor 1995)

28 Diagnosis of DIC A clinicopathological diagnosis- go to the bedside! No single test- soluble fibrin and D-dimers have % sensitivity but low specificity. apttwaveform is specific and reasonable sensitive (Toh 2002) March 2012

29 The ISTH diagnostic algorithm for DIC Risk assessment: Does pt have an underlying disorder known to be associated with DIC? If yes order and score the following: Platelet count >100 =0, <100=1, < 50 =2 Elevated fibrin-related marker e.g FDPs No increase = 0, moderate = 2, strong = 3 Prolonged prothrombin time <3 secs =0, 1-6 secs = 1, >6 secs =2 Fibrinogen >1g/l =0, <1.0 =1 Total score > 5 overt DIC < 5 suggestive, repeat in 1-2 days Prognostic value

30 Management of DIC Treat underlying disorder Coagulopathy needs no treatment UNLESS there is bleeding or thrombosis If bleeding or thrombosis: Maintain fibrinogen >1.5g/l cryoprecipitate or fibrinogen concentrate Maintain APTT/IPT <1.5 - fresh frozen plasma, Maintain platelets > 50 x 10 9 /l - platelet pool plt x 50 Anticoagulants & vasodilators???? ABSOLUTE CONTRAINDICATIONS rviia Antifibrinolytics

31 Using heparin in DIC due to sepsis Uncontrolled case series have claimed success in those with thrombotic DIC Safety is debatable in those prone to bleeding Therapeutic heparin indicated in clinically overt thrombosis e.g. purpura fulminans but difficulty monitoring use anti Xa assay as APTT already prolonged In non-bleeders prophylactic LMW heparin recommended to reduce high risk of hospitalacquired VTE (Levi et al, 2007). March 2012

32 March 2012 Bacterial have their own unique effects

33 Conclusions DIC is a syndrome characterised by systemic intravascular activation of coagulation in the (micro) circulation which contributes to organ failure Recent knowledge has illuminated understanding of the pathogenesis Using a scoring system an accurate diagnosis can be made Management: treatment of the underlying disorder Pharmacological doses of physiological anticoagulants are not beneficial in SIRS in adults is there hope in using soluble thrombomodulin March 2012

34 Hemostasis in Hepatic Failure and Renal Disease.

35 Causes of Bleeding among Patients in the ICU. Hunt BJ. N Engl J Med 2014;370:

36 von Willebrand factor Cross section of the human heart, Stained for von Willebrand factor EM: a Weibel Palade body

37 von Willebrand s disease in critical care Inherited Unexplained persistent oozing Inherited (1 in 100-1,000) autosomal dominant Acquired Autoantibodies -often other autoimmune disease or -lymphoproliferative disease -myeloproliferative disease Breakdown of high MW forms due to high shear stresses - aortic stenosis (can lead to GIT bleeding =Heyde s syndrome) -Extracorporeal circuits esp ECMO & Ventricular Assist Devices -Ideally treat the cause

38 Too much High Molecular Weight vwf = TTP Sadler, J. E. Blood 2007;109:3

39 Pathogenesis of acquired TTP

40 Thrombotic Thrombocytopenic Rare: 4-6/million Female: 70% cases. Peak incidence: 4 th decade Purpura Acute, life threatening disorder >70% cases-due to an acquired TTP- an antibody to vwf- CP/ADAMTS 13. IgG primarily, IgM/IgA described. Significant minority have congenital TTP, which can present for the first time in pregnancy Mortality 90% without treatment, <10% with Rx.

41 Management of acquired TTP Progress monitored by plt count & LDH level This is a medical emergency!! Urgent plasma exchange 1-11/2 plasma volumes daily Methylprednisolone If acquired, more durable response ritoximab In desperation- vincristine, cyclosporin, cyclophosphamide, splenectomy Rock et al, 1991

42 Differential diagnosis of TMAs with a normal coagulation screen

43 TTP, essentially a clinical diagnosis Fever Renal impairment Severe Thrombocytopenia Neurological symptoms MAHA microangiopathic haemolytic anaemia, red cell fragments NB. HUS, also a thrombotic microangiopathy, is a triad, with different pathophysiology.

44 Or secondary TMAs!

45 Deaths due to acquired thrombotic thrombocytopenic purpura. Hunt BJ, Thomas-Dewing RR, Bramham K, Lucas SB. J Obstet Gynaecol Res Anti-CD61

46 Analysis for TTP ADAMTS13 levels (5 hour turn around) ADAMTS13 antibodies Molecular analysis Genetic analysis in Molecular Haemostasis Lab: 3 polymorphisms in ADAMTS13 gene, one known to cause congenital TTP

47 Key points on TTP if in doubt treat until alternative diagnosis confirmed 1. TTP is rare BUT 2. In view of the high risk of preventable, early death in TTP, treatment with plasma exchange (PEX) should be initiated if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause. 3. The diagnosis of TTP is a medical emergency. Patients must be offered plasma exchange as soon as the diagnosis is made, preferably within at least 4-8 hours of presentation, whatever time of day they present.

48 37 year old woman Known thrombotic APS. Developed PET/eclampsia at 28/40 Delivered by C/S, problems during operation Septic, ventilated and haemodialysis BP required help CT scan of abdomen showed infarction of adrenals, splenic wedge infarcts,? bowel infarct Diagnosis and management?

49 Catastrophic APS Multiple thromboses in any organ associated with apl (lupus anticoagulant &/or ACA &/or anti beta2 glycoprotein 1) 50% mortality Often precipitated by infection &/or surgery Ideally prevent Rx- no trials. Plasma exchange, IV Igs, steroids, anticoagulation (hirudin). anticomplement monoclonals??

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