Bleeding and Coagulopathies in Critical Care Beverley J

The new england journal of medicine

review article

critical care medicine Bleeding and Coagulopathies in Critical Care Beverley J. Hunt, M.D.

he definition of coagulopathy is “a condition in which the From King’s College London and Guy’s blood’s ability to clot is impaired.” However, for some clinicians, the term and St. Thomas’ Trust — both in London. Address reprint requests to Dr. Hunt at T also covers thrombotic states, and because of the complexity of the hemo- the Thrombosis and Haemophilia Centre, static pathways, the two conditions can exist simultaneously. Some practitioners St Thomas’ Hospital, Westminster Bridge would consider that mildly abnormal results on coagulation screening without Rd., London SE1 7EH, United Kingdom, or at [email protected]. bleeding can also indicate a coagulopathy. This review is confined to the original definition of coagulopathy as given above. Such states are common in patients in N Engl J Med 2014;370:847-59. DOI: 10.1056/NEJMra1208626 the intensive care unit (ICU) and require a clinicopathological approach to ensure Copyright © 2014 Massachusetts Medical Society. that the correct diagnosis is made and the appropriate treatment administered. The lack of evidence for managing coagulopathies in critical care is striking. This review will highlight selected areas in which there is high-quality evidence and at the same time point out areas for which there is poor evidence. In the latter case, there is little consensus on management.

Differential Diagnosis

A medical history taking and physical examination are vital, since many different conditions can produce similar laboratory abnormalities. For example, end-stage liver failure and disseminated intravascular coagulation produce thrombocytopenia and similar changes in standard tests of coagulation, and yet the management of and prognosis for these conditions are very different. A peripheral-blood smear is a vital investigation tool in most cases to confirm a low platelet count and the presence or absence of other diagnostic features, such as red-cell fragmentation, platelet morphologic abnormalities, or evidence of dysplasia or hematinic deficiency. Table 1 and Figure 1 highlight the relationship between laboratory findings and various coagulopathies. Once it has been determined that the underlying cause is not a response to therapeutic agents meant to modify the coagulation response (e.g., treatment with vitamin K antagonists, heparinoids, or direct factor Xa or IIa inhibitors), practitioners need to evaluate the pattern of bleeding, which may include widespread petechiae and mucosal bleeding in platelet disorders, generalized oozing from de-epithelialized surfaces, and fast bleeding from damaged major vessels.

Management of Coagulopathies

The first principle of the management of coagulopathies in critical care is to avoid the correction of laboratory abnormalities with blood products unless there is a clinical bleeding problem, a surgical procedure is required, or both.

Major Bleeding The lack of good-quality evidence is most marked in the use of blood components to manage major bleeding. When blood components were introduced into critical care practice decades ago, their benefit was never assessed in randomized clinical trials.

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Table 1. Laboratory Findings in Various Platelet and Coagulation Disorders in the ICU.

Prothrombin Activated Partial- Fibrinogen d-Dimer Bleeding Platelet Findings on Condition Time Thromboplastin Time Level Level Time Count Blood Smear Vitamin K deficiency or use Normal or of vitamin K antagonist Prolonged mildly prolonged Normal Unaffected Unaffected Unaffected Aspirin or thienopyridines Unaffected Unaffected Unaffected Unaffected Prolonged Unaffected Liver failure Early stage Prolonged Unaffected Unaffected Unaffected Unaffected Unaffected End stage Prolonged Prolonged Low Increased Prolonged Decreased Uremia Unaffected Unaffected Unaffected Unaffected Prolonged Unaffected Disseminated intravascular Prolonged Prolonged Low Increased Prolonged Decreased Fragmented coagulation red cells Thrombotic thrombocytopenic Unaffected Unaffected Unaffected Unaffected Prolonged Very low Fragmented purpura red cells Hyperfibrinolysis Prolonged Prolonged Low Very high Possibly Unaffected prolonged

Later, concern about transfusion-transmitted infec- an increase by a factor of 6 in the multiple organ tions (human immunodeficiency virus infection, dysfunction syndrome.5 hepatitis, and a new variant of Creutzfeldt–Jakob The critical transfusion ratio of fresh-frozen disease) and limitations in the blood supply led to plasma to red cells in the management of major a more restrictive use of blood components. bleeding is not known. This question is being In the absence of randomized, controlled trials, evaluated in the North American Pragmatic, Ran- retrospective studies of military casualties1 and, domized Optimal Platelets and Plasma Ratios later, similar studies of civilian casualties2 show- study (ClinicalTrials.gov number, NCT01545232). ing improved survival with transfusion of 1 U of This multicenter, randomized trial is comparing fresh-frozen plasma for each unit of red cells the effect of various ratios of blood products have resulted in earlier administration of an in- administered to trauma patients who are pre- creased number of units of fresh-frozen plasma. dicted to require massive transfusion (>10 U of However, these studies have been criticized, packed red cells within the next 24 hours) on particularly for methodologic flaws that include rates of death at 24 hours and 30 days. In the survival bias (i.e., patients who did not survive interim, a North American–European divide in were not transfused with fresh-frozen plasma) the practice of using blood components to sup- and heterogeneity between studies.3 port hemostasis has emerged. Although in North Despite the lack of evidence that bleeding America there has been increased use of fresh- after surgery and gastrointestinal or obstetric frozen plasma in patients with major hemor- hemorrhage are associated with hemostatic rhage, some European practitioners have aban- changes similar to those in acute traumatic co- doned the use of fresh-frozen plasma, relying on agulopathy, the early use of a transfusion ratio the exclusive use of factor concentrates on the of fresh-frozen plasma to red cells of 1:1 or 1:2 basis of rotational-elastometry–guided interven- has become widespread. This increased use of tion with prothrombin complex concentrate, plasma is not risk-free, since the incidence of factor XIII, and fibrinogen.6 In contrast, other transfusion-related acute lung injury is increased,4 practitioners believe that the treatment of major as may be the risk of the acute respiratory dis- hemorrhage should begin with fibrinogen sup- tress syndrome (ARDS). In one study involving plementation with tranexamic acid, a synthetic trauma patients requiring a nonmassive transfu- derivative of the amino acid lysine that acts as an sion (<10 U of packed red cells within 12 hours antifibrinolytic agent by competitively inhibiting after admission), the administration of more than plasminogen, with red cells and intravenous fluid 6 units of fresh-frozen plasma, as compared used on an as-needed basis.7 with no transfusion, was associated with an in- Fibrinogen is a critical molecule in coagula- crease by a factor of 12 in the rate of ARDS and tion. It is the protein that ultimately forms fibrin,

848 n engl j med 370;9 nejm.org february 27, 2014 The New England Journal of Medicine Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. critical care medicine the ligand for platelet aggregation, and in pa- outcomes in patients with major bleeding. Future tients with major bleeding, it is required to a randomized, controlled trials should assess the larger extent than any other hemostatic protein.8 overall benefit and safety, including the rate of In such patients, this requirement reflects in- hospital-acquired venous thromboembolism.10,11 creased consumption, loss, dilution, and fibrin- Similarly, the use of recombinant factor VIIa, o genolysis. On the basis of these multiple roles, which has been shown to reduce the use of red even in the absence of evidence from random- cells in bleeding but not to reduce mortality, ized, controlled trials, guidelines for the man- needs further evaluation. Data from placebo- agement of traumatic bleeding now indicate that controlled trials have shown that the off-label the trigger level for supplementing fibrinogen use of recombinant factor VIIa significantly in- should be 1.5 to 2.0 g per liter rather than 1.0 g creased the risk of arterial thrombosis.12,13 per liter.9 It is unknown whether early fibrino- Tranexamic acid should be administered to gen supplementation and the use of prothrom- all patients with major bleeding after trauma. This bin complex concentrate, as compared with the recommendation is supported by a large, random- use of fresh-frozen plasma, improves clinical ized, controlled trial, the Clinical Randomization

History: Rule out inherited defect or use of antithrombotic drugs.

Examination: Is bleeding general or local? General bleeding Local bleeding

Coagulation screening and full blood count

Low platelet count with normal Low platelet count and Normal platelet count with Low platelet count with results on coagulation screening fragmented red coagulation deficiencies coagulation deficiencies cells (microangiopathic hemolytic anemia)

Disseminated Reduced intravascular survival Failed production of coagulation coagulation factors

Failed production Reduced Underlying of platelets survival disorder Increased splenic Schistocyte pooling Stem cell Factor VIII Antibody-mediated Consumption of Widespread Acquired hemophilia platelet destruction platelets and fibrin deposition clotting factors Splenomegaly Megakaryocytosis

Thrombocytopenia and coagulation factor Microvascular thrombotic obstruction Release of deficiency platelets

Megakaryocyte Bleeding Organ failure

Figure 1. Causes of Bleeding among Patients in the ICU. After the presence of inherited disorders and the use of antithrombotic drugs have been ruled out, the first major question (“IsCOLOR the FIGURE bleeding general or local?”), combined with a platelet count and coagulation screening, will assist in the identification of the pathogenesisDraft 7 of bleeding.2/11/14 Author Hunt Fig # 1 Title Bleeding and coagulopathies in critical care n engl j med 370;9 nejm.org february 27, 2014 ME 849 DE Drazen The New England Journal of Medicine Artist N Koscal Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Copyright © 2014 Massachusetts Medical Society. All rights reserved. Please check carefully Issue date 02/27/2014 The new england journal of medicine

of an Antifibrinolytic in Significant Hemorrhage of vitamin K1 (at a dose of at least 1 mg orally (CRASH-2) study, in which 20,000 trauma patients daily or 10 mg intravenously weekly) for critical with bleeding or at risk for major bleeding were care patients at risk. randomly assigned to receive either tranexamic acid or placebo. Patients who received tranexamic Disseminated Intravascular acid within 3 hours after injury had a one-third Coagulation reduction in deaths from bleeding.14 After a sec- ondary analysis of their data, the CRASH-2 in- Disseminated intravascular coagulation is a clini- vestigators recommended that tranexamic acid copathological diagnosis21 of a disorder that is de- be administered as soon as possible after injury, fined by the International Society on Thrombosis since the drug ceased to confer benefit and ap- and Hemostasis (ISTH) as “an acquired syndrome peared to be associated with increased mortality characterized by the intravascular activation of co- if it was administered more than 3 hours after agulation with loss of localization arising from injury.15 Reassuringly for a hemostatic drug, the different causes.” This condition typically origi- incidence of thrombosis after trauma was not nates in the microvasculature and can cause dam- increased in the study patients. Strong evidence age of such severity that it leads to organ dysfunc- that tranexamic acid reduced the need for blood tion (Fig. 2). It can be identified on the basis of a transfusion in surgery has been available for scoring system developed by the ISTH (Table 2). years, although the effect of tranexamic acid on Disseminated intravascular coagulation usually thromboembolic events and mortality in such presents as hemorrhage, with only 5 to 10% of patients remains uncertain.16 cases presenting with microthrombi (e.g., digital ischemia) alone. Whether the condition presents Hemostatic Support for with a thrombotic or bleeding episode depends Invasive Procedures on its cause and host defenses. Sepsis is the most common cause of disseminated intravascu- There is no supportive evidence for the prophy- lar coagulation in critical care; systemic infec- lactic use of fresh-frozen plasma to correct ab- tion with a range of bacteria from Staphylococcus normal results on coagulation screening (for pro aureus to Escherichia coli is known to be associated thrombin time, activated partial-thromboplastin with this condition. The complex pathophysiology time, and fibrinogen) before an invasive proce- is mediated by pathogen-associated molecular pat- dure. Coagulation screening has no predictive terns, which generate an inflammatory response value for later bleeding, and the use of fresh-fro- in the host through signaling at specific recep- zen plasma may not correct abnormal results on tors. For example, signaling by means of toll-like coagulation tests. There is currently no consensus and complement receptors initiates intracellular on what coagulation-screening results should trig- signaling, which results in the synthesis of sev- ger the use of fresh-frozen plasma, which has led eral proteins (including proinflammatory cyto- to variation in the use of fresh-frozen plasma by kines). These proteins trigger hemostatic chang- critical care physicians.17,18 Thrombin generation, es, leading to the up-regulation of tissue factor22 although delayed, is normal or enhanced19 when and impairment of physiologic anticoagulants the prothrombin ratio is 1.5 or less, so I suggest and fibrinolysis. Tissue factor plays a critical role that a prothrombin ratio of 1.5 or less is satisfac- in this process, as shown in meningococcal septi- tory for the insertion of a central venous or an cemia, in which the level of tissue factor on mono- arterial catheter in patients in whom direct com- cytes at presentation may be predictive of sur- pression can assist with hemostasis without the vival.23 Another study of meningococcal sepsis need for prophylactic supplementation with fresh- showed that a large amount of tissue factor was frozen plasma. found on monocyte-derived circulating micropar- As a general rule, dietary intake of vitamin K, ticles.24 The up-regulation of tissue factor activates which is necessary for the formation of coagu- coagulation, leading to the widespread deposition lation factors II, VII, IX, and X, may be inade- of fibrin and to microvascular thromboses and quate in critical care settings.20 Despite the may contribute to multiple organ dysfunction. lack of high-quality evidence and the inability Complex abnormalities of the physiologic anti of vitamin K to correct a coagulopathy caused coagulants occur, and pharmacologic doses of by liver disease, I recommend supplementation activated protein C, antithrombin, and tissue

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Sepsis

Microparticles Monocyte

Tissue factor Microvascular expression Fibrin deposition Proinflammatory thrombus cytokines

Insufficient Impairment of removal anticoagulant mechanisms

Plasminogen activator inhibitor 1 Endothelial cell Activation of endothelial cells

Figure 2. Pathogenesis of Disseminated Intravascular Coagulation in Sepsis. Through the generation of proinflammatory cytokines and the activation of monocytes, bacteria cause the up-regulation of tissue factor as well as the release of microparticles expressing tissue factor, thus leading to the activation of coagulation. ProinflammatoryCOLOR FIGURE cytokines also cause the activation of endothelial cells, a process that impairs anticoagulant mechanisms and down-regulatesDraft fibrinolysis 4 by1/30/14 gener- Author Hunt ating increased amounts of plasminogen activator inhibitor. Fig # 2 Title Bleeding and coagulopathies in critical care ME DE Drazen Table 2. Diagnostic Scoring System for Disseminated Intravascular Coagulation (DIC).* Artist N Koscal AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC? Please check carefully Issue date 02/27/2014 If yes, proceed with this algorithm If no, do not use this algorithm Order global coagulation tests (prothrombin time, platelet count, fibrinogen, fibrin-related marker) Score the test results as follows: Platelet count: 50,000 to 100,000 per mm3, 1 point; <50,000 per mm3, 2 points Elevated fibrin-related marker (e.g., d-dimer, fibrin degradation products): no increase, 0 points; moderate increase, 2 points; strong increase, 3 points Prolonged prothrombin time: <3 sec, 0 points; ≥3 sec but <6 sec, 1 point; ≥6 sec, 2 points Fibrinogen level: ≥1 g per liter, 0 points; <1 g per liter, 1 point Calculate the score as follows: ≥5 points: compatible with overt DIC; repeat scoring daily <5 points: suggestive of nonovert DIC; repeat scoring within next 1 to 2 days

* Data are adapted from Toh and Hoots21 on the basis of the scoring system developed by the International Society on Thrombosis and Hemostasis.

factor pathway inhibitor appeared to be benefi- activated protein C,25 antithrombin,26 and tissue cial in a study of endotoxemia in animals. These factor pathway inhibitor27 in patients with sepsis. promising studies led to major randomized, con- However, the studies showed no reductions in the trolled trials of the supplementation of physio- rates of death and increased bleeding episodes. logic anticoagulants with pharmacologic doses of The consumption of the coagulation proteins

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The cornerstone for managing this condition Table 3. Differential Diagnosis of Thrombocytopenia in the ICU. remains the management of the underlying cause First, rule out pseudothrombocytopenia by asking the following question: (e.g., sepsis). Further management may not be Is the blood sample clotted? necessary in patients with mild abnormalities in Check for EDTA-dependent platelet antibodies by collecting the sample in coagulation and no evidence of bleeding. Guide- an anticoagulant (e.g., citrate) lines for management are based mainly on ex- If pseudothrombocytopenia has been ruled out, ask the following: pert opinion, which suggests replacement of Is the patient taking drugs that could lower the platelet count? coagulation proteins and platelets in patients Check for receipt of: who are bleeding. Platelet transfusion is indi- Heparin, which may be associated with heparin-induced thrombocytopenia cated to maintain a platelet level of more than IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, tirofiban) 50,000 per cubic millimeter, along with the admin- Adenosine diphosphate (ADP)–receptor antagonists (e.g., clopidogrel) istration of fresh-frozen plasma to maintain a pro Acute alcohol toxicity thrombin time and activated partial-thromboplas- Does the patient have a hematinic deficiency (particularly, acute folate deficiency)? tin time of less than 1.5 times the normal control Does the patient have any of the following: time and a source of fibrinogen to maintain a fi- Sepsis (especially consider) brinogen level of more than 1.5 g per liter.28 Human immunodeficiency virus (HIV) infection The use of antifibrinolytic agents is contra Disseminated intravascular coagulation indicated in the management of disseminated in- Major blood loss and hemodilution travascular coagulation, since the fibrinolytic sys- Mechanical fragmentation tem is required in recovery to ensure the dissolution Post-cardiopulmonary bypass of the widespread fibrin. Some guidelines recom- Intraaortic balloon pump mend the administration of therapeutic doses of Renal dialysis unfractionated heparin in patients with a throm- 28 Extracorporeal membrane oxygenation botic phenotype (e.g., gangrene), but such rec- Immune-mediated disorder ommendations remain controversial because of Immune thrombocytopenic purpura the difficulties in monitoring treatment in a pa- Antiphospholipid syndrome tient who already has a prolonged activated partial- Post-transfusion purpura thromboplastin time; in addition, heparin admin- Microangiopathic hemolytic anemia istration may provoke hemorrhage. Currently, there is insufficient clinical evidence to make a firm Disseminated intravascular coagulation recommendation on the use of heparin in patients Thrombotic thrombocytopenic purpura with disseminated intravascular coagulation. Hemolytic–uremic syndrome Hypersplenism Other disorder Thrombocytopenia Myelodysplastic syndrome Pathophysiological Mechanisms Cancer Thrombocytopenia may arise because of de- Hereditary thrombocytopenia creased production or increased destruction (immune or nonimmune) of platelets, as well as from and platelets produces a bleeding tendency, with sequestration in the spleen. Among patients who thrombocytopenia, a prolonged prothrombin time are admitted to an ICU, the condition occurs in and activated partial-thromboplastin time, hypo about 20% of medical patients and a third of sur- fibrinogenemia, and elevated levels of fibrin deg gical patients. The cause of this condition is of- radation products, such as d-dimers. The physi- ten multifactorial. Patients with thrombocytope- ologic anticoagulants are also consumed in the nia tend to be sicker, with higher illness-severity process of inhibiting the many activated coagu- scores, than those who are admitted with normal lation factors.19 In fulminant disseminated intra platelet counts.29 Table 3 lists the differential di- vascular coagulation, the consumption and dimin- agnoses of thrombocytopenia in the critical care ished supply of platelets and coagulation proteins setting. Given the long list, it is important to iden- usually results in oozing at vascular access sites tify patients in whom thrombocytopenia requires and wounds but occasionally causes profuse specific and urgent action (e.g., heparin-induced hemorrhage. thrombocytopenia and thrombotic thrombocyto

852 n engl j med 370;9 nejm.org february 27, 2014 The New England Journal of Medicine Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. critical care medicine penic purpura). Drug-induced thrombocytopenia Post-Transfusion Purpura is a diagnostic challenge, because critically ill Post-transfusion purpura is a rare bleeding dis patients often receive multiple medications that order caused by a platelet-specific alloantibody can cause thrombocytopenia. (usually, anti–human platelet antigen 1a [HPA-1a]) A platelet threshold of 10,000 per cubic milli in the recipient. HPA-1a reacts with donor plate- meter for platelet transfusion in patients who lets, destroying them and also the recipient’s are in stable condition is both hemostatically own platelets. The majority of affected patients efficacious and cost-effective in reducing platelet- are multiparous women who have been sen transfusion requirements.30 Patients with sustained sitized during pregnancy. Treatments for post- failure of platelet production, such as those with transfusion purpura include intravenous immune myelodysplasia or aplastic anemia, may remain (gamma) globulin, glucocorticoids, and plasma- free of serious hemorrhage, with counts below pheresis. High-dose intravenous immune globu- 5000 to 10,000 per cubic millimeter. However, a lin (2 g per kilogram of body weight administered higher platelet transfusion trigger should be set over either 2 or 5 days) produces an increased in patients with other hemostatic abnormalities platelet count in about 85% of patients. Large or increased pressure on platelet turnover or numbers of platelet transfusions may be required platelet function. If the patient is actively bleed- to control severe bleeding before there is a re- ing, then a platelet count of 50,000 per cubic mil- sponse to intravenous immune globulin. There is limeter should be maintained. Among patients limited evidence that the use of HPA-1a–negative who have or are at risk for bleeding in the central platelets is more effective than the use of plate- nervous system or who are undergoing neurosur- lets from random donors.33 gery, a platelet count of more than 100,000 per cubic millimeter is often recommended, although Thrombotic Microangiopathies data are lacking to support this recommenda- Profound thrombocytopenia and microangiopathic tion.29,30 hemolytic anemia (red-cell fragmentation) charac- Standard platelet counts are produced by terize the thrombotic microangiopathies, which cell counters that categorize the cells according includes three major disorders: thrombotic throm- to size, but large platelets may be the same size bocytopenic purpura, the hemolytic–uremic syn- as red cells and thus be categorized as such. drome, and the HELLP syndrome (characterized Therefore, an immunologic method of platelet by pregnancy-related hemolysis, elevated liver- counting, in which platelet antigens are labeled enzyme levels, and low platelet count). The major- with markers that can be detected with the use ity of cases of thrombotic thrombocytopenic pur- of flow cytometry, may be helpful in providing pura are due to a deficiency of a disintegrin and a true count.31 Since platelet transfusions may metalloproteinase with thrombospondin type 1 lead to immune platelet refractoriness owing motif 13 (ADAMTS13), a disorder that may be to the formation of anti-HLA antibodies, the hereditary or caused by autoimmune destruction. use of HLA-matched platelets, if available, The absence of ADAMTS13 results in the persis- should produce better platelet counts after trans- tence of high-molecular-weight von Willebrand fusion. factor, which can cause spontaneous platelet aggregation when the protein is subjected to high Immunologic Causes shear stress. The rate of death in untreated cases As a general rule, an abrupt reduction in platelet is nearly 95%, but with early plasmapheresis, the counts with a history of recent surgery suggests survival rate is 80 to 90%. The use of rituximab, an immunologic cause or adverse transfusion re- a chimeric monoclonal antibody against the sur- action (post-transfusion purpura or drug-induced face B-cell protein CD20, which leads to destruc- thrombocytopenia). Heparin-induced thrombo- tion of those cells, has been shown to reduce the cytopenic thrombosis is an uncommon, transient, rate of recurrence of the autoimmune form of drug-induced, autoimmune prothrombotic disor- this disorder from 57% to 10%.34 Thrombotic der caused by the formation of IgG antibodies thrombocytopenic purpura is a medical emer- that cause platelet activation by the formation of gency and in untreated cases is associated with a antibodies to complexes of platelet factor 4 and rate of death of 90%, usually from myocardial heparin.32 infarction due to platelet thrombi in the coronary

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arteries. Thus, an active diagnosis of this disor- However, in parallel with the reduction in der or failure to rule it out should lead to urgent coagulation factors, there is a similar reduction plasmapheresis. in the production of physiologic anticoagulants. Thus, patients with chronic liver disease and a Liver Disease prolonged prothrombin time are no longer considered to have a deficiency of coagulation fac- Thrombopoietin and most hemostatic proteins tors, since their coagulation is rebalanced and are synthesized in the liver. Thus, reduced he- thrombin generation is usually normal.35 In patic synthetic function results in prolongation such cases, there is no need to treat prolonged of the screening tests of coagulation (particularly coagulation times in the absence of bleeding. If the prothrombin time) and reduced platelet counts, bleeding does occur in liver disease, then con- although levels of factor VIII and von Willebrand sensus guidelines, which are largely based on factor are increased.35 Acute alcohol intake in- consensus expert opinion, recommend blood- hibits platelet aggregation. In chronic liver dis- component management as determined by the ease, there is also increased fibrinolytic potential results of testing of the platelet count, prothrom- due to the failure of the liver to metabolize tissue bin time, activated partial-thromboplastin time, plasminogen activator. In cholestatic liver dis- thrombin time, and fibrinogen. In a recent ran- ease, there is reduced absorption of lipid-soluble domized, controlled trial, investigators com- vitamins, so reduced amounts of the vitamin K– pared a liberal red-cell transfusion strategy dependent coagulation factors II, VII, IX, and X (hemoglobin level, <9 g per deciliter) and a re- are produced. Furthermore, in liver disease, the strictive strategy (hemoglobin level, <7 g per failure of the normal enzymatic removal of si- deci liter) in patients with acute upper gastro- alic acid from fibrinogen results in dysfibrino- intestinal bleeding. Patients who were treated genemia36 (Fig. 3A). with the restrictive strategy had longer survival

A Hepatic failure Acute alcohol Liver failure and drug intake

Splenic sequestration Platelet dysfunction or Splenomegaly with or without thrombocytopenia hypersplenism

↓ Production of ↓ Production of Sialic acid not removed ↑ t-PA due to ↓ Thrombopoietin coagulation factors to physiologic from fibrinogen impaired metabolism about 30% (except anticoagulants to

fibrinogen and factor VIII) about 30% OH OH 100% 100% O OH OH COOH 30% 30% O

H3C N H OH ↑Fibrinolysis

↓ α -Antiplasmin Hemostatic balance preserved 2 Impaired polymerization of fibrin

Plasminogen Plasmin

Poor coagulation reserve ↓ TAFI if bleeding occurs Dysfibrinogenemia Fibrin Fibrin-degradation products

Fibrinogen Fibrinogen-degradation products and ↓fibrinogen levels Routine testing shows ↓Functional fibrinogen prolonged PT or APTT ↑Total fibrinogen Factor V ↓Factor V levels

854 n engl j med 370;9 nejm.org february 27, 2014 COLOR FIGURE The New England Journal of Medicine Draft 6 2/11/14 Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses withoutAuthor permission.Hunt Copyright © 2014 Massachusetts Medical Society. All rights reserved. Fig # 3a Title Bleeding and coagulopathies in critical care ME DE Drazen Artist N Koscal AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully Issue date 02/27/2014 critical care medicine

B Renal disease Uremic toxins Diseased produced kidney Erythropoiesis

Normal axial red-cell flow, Anemia, resulting in loss of axial Platelet dysfunction due to hematocrit ≥30% red-cell flow, hematocrit <30% platelet adhesion and granule release Subendothelial matrix von Willebrand factor Glycoprotein Ib Adhesion

Platelet Fibrinogen

Aggregation

Glycoprotein IIb/IIIa

Granule release

Figure 3. Hemostasis in Hepatic Failure and Renal Disease. Liver failure (Panel A) leads to complex hemostatic changes, since the liver is the producer of coagulation factors, physiologic anticoagulants, and thrombopoietin, as well as the site of the metabolism of sialic acid residues from fibrinogen, activated coagulation factors, and tissue plasminogen activator. These defects result in poor coagulation reserve, dysfibrinogenemia, and increased fibrinolytic potential. In renal failure (Panel B), decreased production of erythropoietin produces anemia, which results in a loss of axial flow so that the bleeding time is prolonged. The accumulation of uremic toxins results in platelet dysfunction. APTT denotes activated partial-thromboplastin time, PT prothrombin time, TAFI thrombin-activatable fibrinolysis inhibitor, and t-PA tissue plasminogen activator. COLOR FIGURE Draft 5 2/11/14 Author Hunt Fig # 3b Title Bleeding and Coagulotherapies (6 weeks) and a lower rate of rebleeding than in Critical Care Renal Disease ME did those who were treated with the liberal DE Drazen strategy.37 In this study, portal circulation Uremic bleeding typically presents with ecchy-Artist N Koscal AUTHOR PLEASE NOTE: pressures increased significantly among pa- moses, purpura, epistaxis, and bleeding fromFigure has been redrawn and type has been reset Please check carefully tients in the liberal-strategy group. Although puncture sites due to impaired platelet function.Issue date 02/27/2014 there are no similar studies addressing chang- The platelet dysfunction is a result of complex es in coagulopathy or thrombocytopenia, it changes that include dysfunctional von Wille- seems sensible to adopt a restrictive approach brand factor, decreased production of throm- to the use of fresh-frozen plasma and platelets boxane, increased levels of cyclic AMP and cyclic in patients with acute upper gastrointestinal GMP, uremic toxins, anemia, and altered plate- bleeding. The role of tran examic acid in pa- let granules, all of which are necessary for ade- tients with gastrointestinal bleeding is under quate formation of a platelet plug (Fig. 3B). The investigation in the ongoing randomized, con- anemia that commonly accompanies renal dis- trolled Hemorrhage Alleviation with Tran- ease leads to the loss of laminar flow in arteri- examic Acid–Intestinal System (HALT-IT) trial oles so that red cells no longer push platelets (NCT01658124). In patients with liver disease and plasma to the endothelium, leading to pro- and laboratory tests indicating abnormal syn- longation of the bleeding time; treatment of the thesis of coagulation factors, vitamin K should anemia partially corrects this problem. There is be routinely administered to aid in the synthe- also some evidence of impaired fibrinolysis in sis of coagulation factors. patients with renal disease.

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In the past, the bleeding time was considered proliferative disorders,44 or the breakdown of high- to be the most useful clinical test of coagulation molecular-weight von Willebrand factor multimers in patients with renal disease, but much of the owing to high intravascular or extracorporeal cir- evidence supporting testing and treatment was cuit shear stresses, may also occur in patients in derived from poor-quality studies performed more the ICU. This disorder can also be caused by than 30 years ago. We now know that dialysis, shear stresses on blood flow in extracorporeal especially peritoneal dialysis, improves platelet circuits, such as those caused by extracorporeal function. Erythropoietin, cryoprecipitate, conju- membrane oxygenation44 and left ventricular assist gated estrogens, desmopressin, and tranexamic devices. Intravascular shear stress from aortic- acid have all independently been shown to reduce valve stenosis can cause acquired von Willebrand’s bleeding time.38,39 In the past decade, citrate has disease, leading to gastrointestinal bleeding risen in popularity as a replacement anticoagulant (Heyde’s syndrome).45 in continuous renal-replacement therapy, with a Acquired von Willebrand’s disease is treated reduction in bleeding, although data on its safety with the use of either desmopressin, which stimu- in patients with liver failure are lacking.40 lates the release of residual stores of von Wille- brand factor by endothelial cells, or von Willebrand Fibrinolytic Bleeding factor concentrates, with the latter considered to be the more effective therapy.46 The use of antifibri- Excessive fibrinolysis that threatens clot integrity nolytic agents may be considered to alleviate muco is known as hyperfibrinolysis.41 Abnormal fibri- cutaneous bleeding. Acquired von Willebrand’s nolytic activity may be overlooked as a cause of disease due to high shear stresses requires the bleeding, particularly in liver disease, and the removal of the cause of the condition whenever condition is difficult to diagnose because of the possible. absence of a specific routine assay. Clinical sus- picion should be high in cases in which bleeding Bleeding Associated with continues despite hemostatic replacement therapy, Antithrombotic Therapy platelet levels are relatively conserved but fibrinogen levels are disproportionately low, and d-dimer Table 4 summarizes the current antithrombotic levels are disproportionately high for disseminat- drugs, their mechanisms of action, and reversibil- ed intravascular coagulation. Thromboelastogra- ity.47,48 It is difficult to treat a bleeding patient phy, which may help differentiate fibrinolytic ac- who is receiving an oral anticoagulant such as tivation from coagulation factor deficiency, is a dabigatran and rivaroxaban, since there is no crude tool, since it detects only the most marked specific antidote. Studies that have evaluated the changes.42 Fibrinolytic bleeding should be con- reversal of the new oral anticoagulants have been sidered particularly in patients with liver disease limited to reversal of drug effect with the use of and disseminated cancers. The use of tranexamic recombinant activated factor VII and prothrom- acid, either by infusion or orally (depending on bin complex concentrate. Current evidence sug- the severity of the problem and the state of the gests that prothrombin complex concentrate may patient), is beneficial in controlling bleeding. be the best option and that it reverses the effects of rivaroxaban better than the effects of dabiga- Von Willebrand’s Disease tran.49,50 General measures such as stopping the antithrombotic medication, documenting the time If unexplained bleeding occurs, consideration and amount of the last drug dose, and noting the should be given to the late presentation of an presence of renal and hepatic impairment are inherited bleeding disorder. A personal and fam- suggested. Management may be aided by obtain- ily history of easy bruising and bleeding should ing a full blood count and hemostatic screening, be sought. Occasionally, a condition such as mild along with a specific laboratory test to measure von Willebrand’s disease may present with per- the antithrombotic effect of the drug, if avail- sistent oozing after an injury or surgery.43 able. If the medication has been recently ingested Acquired von Willebrand’s disease, which can and there is no specific antidote, oral activated be caused by several potential mechanisms due charcoal may be given to absorb any residual to autoantibodies, myeloproliferative and lympho drug in the stomach.

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Procedure for Immediate Reversal administered within 2 hr after receipt of drug; con drug; of receipt after hr 2 within administered life-threateningif hemodialysis; hemofiltration, sider concentrate,complex prothrombin consider bleeding, andconcentrate, complex prothrombin activated VII factor activated recombinant dabigatran for as plex concentrate (25 to 50 U/kg); use of fresh frozenfresh of use U/kg); 50 to (25 concentrate plex isconcentrate complex prothrombin if only plasma available not recombinant activated factor VII if there is continuedis there if VII factor activated recombinant suggestsframe time the and bleeding life-threatening effect residual is there bleeding critical for bleeding critical for considered be should VII bleeding critical considered for be may plasmapheresis unfractionated heparin Platelet transfusion; consider use of desmopressin of use consider transfusion; Platelet No specific antidote; use of oral activated charcoal if charcoal activated oral of use antidote; specific No same bleeding, life-threatening if antidote; specific No Intravenous vitamin K (1 to 5 mg) and prothrombin com - prothrombin and mg) 5 to (1 K vitamin Intravenous No specific antidote; plasmapheresis may be consideredbe may plasmapheresis antidote; specific No factor activated recombinant of use antidote; specific No or hemofiltration, hemodialysis, antidote; specific No antidote specific No Protamine reverses 60% of effect; consider the use of use the consider effect; of 60% reverses Protamine Platelet transfusion Platelet U 80–100 neutralizes mg) 1 of dose a (at Protamine

24 hr 24 45 min 45 Half-Life 17–20 hr 17–20 6 to 15 hr 15 to 6 45–90 min 45–90 for 5 days 5 for apixaban, 9–14 hr 9–14 apixaban, with creatinine clearancecreatinine with hr 22–35 ml/min, <30 with phenprocoumon with aceno - and longest the shortest the coumarol ability among products among ability 25 min; 1 hr in renal failure renal in hr 1 min; 25 20 min but effect will persist will effect but min 20 Rivaroxaban, 7–9 hr; 7–9 Rivaroxaban, 13 hr (range, 11–22 hr); 11–22 (range, hr 13 Varies according to drug, to Varies according Approximately 4 hr, with vari - with hr, 4 Approximately Renal Renal Renal Hepatic Hepatic Hepatic 80% renal 80% Site of Clearance Hepatic and renal and Hepatic with 20% renal excretion renal 20% with renal Proteolysis by thrombin (80%)thrombin by Proteolysis Cellular and (at higher doses)higher (at and Cellular

antagonists 12 inhibitor anti-Xa to anti-IIa of >20 of anti-IIa to anti-Xa anti-Xa indirect with effect K–dependent vitamin of VII, (II, factors clotting X) and IX, heparin but mainly anti- mainly but heparin effect Xa effect; increases the actionthe increases effect; factorby antithrombin of 10,000 of Mechanism of Action Irreversible cyclooxygenase Irreversible P2Y Direct anti-Xa inhibition anti-Xa Direct A direct thrombin inhibitor thrombin direct A A heparinoid with ratio of ratio with heparinoid A pentasaccharide Synthetic effect antithrombin Direct inhibitor thrombin Direct levelsfunctional in Reduction Same as for unfractionated for as Same Indirect anti-Xa and anti-IIa and anti-Xa Indirect

ticagrelor edoxaban (e.g., warfarin, phen - warfarin, (e.g., acenocou - procoumon, marol, phenindione) heparin Aspirin prasugrel, Clopidogrel, Common Antithrombotic Agents, Mechanisms of Action, and Reversibility. and Action, of Mechanisms Agents, Antithrombotic Common 4. Table Agent Rivaroxaban, apixaban, Rivaroxaban, Dabigatran Danaparoid Fondaparinux Bivalirudin Argatroban K antagonists Vitamin Low-molecular-weight Unfractionated heparin Unfractionated

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Conclusions quired bleeding disorders is very striking and points to the need for studies to address the The management of bleeding in critically ill pa- many evidence gaps that currently exist. tients remains a major clinical challenge. The Dr. Hunt reports receiving consulting fees from Haemonetics and serving as medical director of Lifeblood: the Thrombosis cause of a bleeding problem may be complex and Charity, which receives funds from pharmaceutical companies only partially understood, with limited diagnos- to help educate health care professionals and the public. No tic tools and management strategies currently other potential conflict of interest relevant to this article was reported. available. The absence of robust evidence from Disclosure forms provided by the author are available with clinical trials to guide the management of ac- the full text of this article at NEJM.org.

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