Hematologic Disorders in Critically Ill Patients

ABSTRACT

Hematologic disorders are frequently encountered in the intensive care unit. Thrombocytopenia, often defined as a platelet count below 100,000/μL, is common in critically ill patients and may be associated with adverse outcomes. A systematic evaluation of clinical and laboratory findings is necessary to ascertain the cause of the thrombocytopenia and to determine the correct therapy. Recognition of heparin-induced thrombocytopenia (HIT) is particularly important, given the risk of thrombosis associated with this condition. Prompt cessation of all heparin products is required, and anticoagulation with a direct thrombin inhibitor is recommended if HIT is strongly suspected. Coagulopathies are also common in the critically ill, and are often due to vitamin K deficiency or disseminated intravascular coagulation (DIC). A careful history and interpretation of clotting studies are useful in defining the coagulation defect. Advances in understanding the pathogenesis of DIC have generated new treatment approaches, such as the use of recombinant activated protein C. Recombinant factor VIIa (rFVIIa) is a novel drug approved for use in patients with congenital hemophilias and inhibitors. Although its use as a hemostatic agent is currently being evaluated in several off-label scenarios, including trauma, intracerebral hemorrhage, and liver disease, there are limited data to guide therapy in these conditions.

KEYWORDS

Thrombocytopenia - coagulopathy - heparin-induced thrombocytopenia - disseminated intravascular coagulation - recombinant factor VIIa

REFERENCES

• 1 Bonfiglio M F, Traeger S M, Kier K L, Martin B R, Hulisz D T, Verbeck S R. Thrombocytopenia in intensive care patients: a comprehensive analysis of risk factors in 314 patients.  Ann Pharmacother. 1995;  29 835-842
• 2 Hanes S D, Quarles D A, Boucher B A. Incidence and risk factors of thrombocytopenia in critically ill trauma patients.  Ann Pharmacother. 1997;  31 285-289
• 3 Baughman R P, Lower E E, Flessa H C, Tollerud D J. Thrombocytopenia in the intensive care unit.  Chest. 1993;  104 1243-1247
• 4 Vanderschueren S, De W A, Malbrain M et al.. Thrombocytopenia and prognosis in intensive care.  Crit Care Med. 2000;  28 1871-1876
• 5 Stephan F, Hollande J, Richard O, Cheffi A, Maier-Redelsperger M, Flahault A. Thrombocytopenia in a surgical ICU.  Chest. 1999;  115 1363-1370
• 6 Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn E G. Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome.  Crit Care Med. 2002;  30 1765-1771
• 7 Chakraverty R, Davidson S, Peggs K, Stross P, Garrard C, Littlewood T J. The incidence and cause of coagulopathies in an intensive care population.  Br J Haematol. 1996;  93 460-463
• 8 Cawley M J, Wittbrodt E T, Boyce E G, Skaar D J. Potential risk factors associated with thrombocytopenia in a surgical intensive care unit.  Pharmacotherapy. 1999;  19 108-113
• 9 Shalansky S J, Verma A K, Levine M, Spinelli J J, Dodek P M. Risk markers for thrombocytopenia in critically ill patients: a prospective analysis.  Pharmacotherapy. 2002;  22 803-813
• 10 Bogdonoff D L, Williams M E, Stone D J. Thrombocytopenia in the critically ill patient.  J Crit Care. 1990;  5 186-205
• 11 Drews R E, Weinberger S E. Thrombocytopenic disorders in critically ill patients.  Am J Respir Crit Care Med. 2000;  162(2 Pt 1) 347-351
• 12 Bizzaro N. EDTA-dependent pseudothrombocytopenia: a clinical and epidemiological study of 112 cases, with 10-year follow-up.  Am J Hematol. 1995;  50 103-109
• 13 Babcock R B, Dumper C W, Scharfman W B. Heparin-induced immune thrombocytopenia.  N Engl J Med. 1976;  295 237-241
• 14 Warkentin T E, Levine M N, Hirsh J et al.. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
• 15 Warkentin T E. Heparin-induced thrombocytopenia: pathogenesis and management.  Br J Haematol. 2003;  121 535-555
• 16 Francis J L. Detection and significance of heparin-platelet factor 4 antibodies.  Semin Hematol. 2005;  42(3, Suppl 3) S9-14
• 17 Rauova L, Poncz M, McKenzie S E et al.. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;  105 131-138
• 18 Visentin G P, Ford S E, Scott J P, Aster R H. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.  J Clin Invest. 1994;  93 81-88
• 19 Girolami B, Prandoni P, Stefani P M et al.. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study.  Blood. 2003;  101 2955-2959
• 20 Prandoni P, Siragusa S, Girolami B, Fabris F. The incidence of heparin-induced thrombocytopenia in medical patients treated with low molecular weight heparin.  Blood. 2005;  106(9) 3049-3054
• 21 Wallis D E, Workman D L, Lewis B E, Steen L, Pifarre R, Moran J F. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia.  Am J Med. 1999;  106 629-635
• 22 Warkentin T E, Kelton J G. A 14-year study of heparin-induced thrombocytopenia.  Am J Med. 1996;  101 502-507
• 23 Wester J P, Haas F J, Biesma D H, Leusink J A, Veth G. Thrombosis and hemorrhage in heparin-induced thrombocytopenia in seriously ill patients.  Intensive Care Med. 2004;  30 1927-1934
• 24 Bartholomew J R. The incidence and clinical features of heparin-induced thrombocytopenia.  Semin Hematol. 2005;  42(3, Suppl 3) S3-S8
• 25 Warkentin T E, Sheppard J A, Horsewood P, Simpson P J, Moore J C, Kelton J G. Impact of the patient population on the risk for heparin-induced thrombocytopenia.  Blood. 2000;  96 1703-1708
• 26 Verma A K, Levine M, Shalansky S J, Carter C J, Kelton J G. Frequency of heparin-induced thrombocytopenia in critical care patients.  Pharmacotherapy. 2003;  23 745-753
• 27 Martel N, Lee J, Wells P S. Risk of heparin induced thrombocytopenia with unfractionated and low molecular weight heparin thromboprophylaxis: a meta-analysis.  Blood. 2005;  106(8) 2710-2715
• 28 Warkentin T E. Heparin-induced thrombocytopenia: pathogenesis and management.  Br J Haematol. 2003;  121 535-555
• 29 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(Suppl 3) 311S-337S
• 30 Warkentin T E. New approaches to the diagnosis of heparin-induced thrombocytopenia.  Chest. 2005;  127(Suppl 2) 35S-45S
• 31 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 1286-1292
• 32 Warkentin T E, Roberts R S, Hirsh J, Kelton J G. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study.  Chest. 2005;  127 1857-1861
• 33 Warkentin T E. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia.  Arch Pathol Lab Med. 2002;  126 1415-1423
• 34 Kuo K H, Kovacs M J. Fondaparinux: a potential new therapy for HIT.  Hematology (Am Soc Hematol Educ Program). 2005;  10 271-275
• 35 Rice L. Evolving management strategies for heparin-induced thrombocytopenia.  Semin Hematol. 2005;  42(3, Suppl 3) S15-S21
• 36 Crowther M A, McDonald E, Johnston M, Cook D. Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study.  Blood Coagul Fibrinolysis. 2002;  13 49-52
• 37 Staudinger T, Locker G J, Frass M. Management of acquired coagulation disorders in emergency and intensive-care medicine.  Semin Thromb Hemost. 1996;  22 93-104
• 38 Alperin J B. Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients.  JAMA. 1987;  258 1916-1919
• 39 Cohen H, Scott S D, Mackie I J et al.. The development of hypoprothrombinaemia following antibiotic therapy in malnourished patients with low serum vitamin K1 levels.  Br J Haematol. 1988;  68 63-66
• 40 Krasinski S D, Russell R M, Furie B C, Kruger S F, Jacques P F, Furie B. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders.  Am J Clin Nutr. 1985;  41 639-643
• 41 O'Shaughnessy D F, Atterbury C, Bolton M P et al.. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  Br J Haematol. 2004;  126 11-28
• 42 Penning-van Beest F J, van Meegan E, Rosendaal F R, Stricker B H. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation.  Thromb Haemost. 2001;  86 569-574
• 43 Raj G, Kumar R, McKinney W P. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione.  Arch Intern Med. 1999;  159 2721-2724
• 44 Crowther M A, Douketis J D, Schnurr T et al.. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial.  Ann Intern Med. 2002;  137 251-254
• 45 Wilson S E, Watson H G, Crowther M A. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review.  CMAJ. 2004;  170 821-824
• 46 Watson H G, Baglin T, Laidlaw S L, Makris M, Preston F E. A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin.  Br J Haematol. 2001;  115 145-149
• 47 Hung A, Singh S, Tait R C. A prospective randomized study to determine the optimal dose of intravenous vitamin K in reversal of over-warfarinization.  Br J Haematol. 2000;  109 537-539
• 48 Riegert-Johnson D L, Volcheck G W. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review.  Ann Allergy Asthma Immunol. 2002;  89 400-406
• 49 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(Suppl 3) 204S-233S
• 50 Esmon C T. The impact of the inflammatory response on coagulation.  Thromb Res. 2004;  114 321-327
• 51 Levi M. Current understanding of disseminated intravascular coagulation.  Br J Haematol. 2004;  124 567-576
• 52 Hambleton J, Leung L L, Levi M. Coagulation: consultative hemostasis.  Hematology (Am Soc Hematol Educ Program). 2002;  335-352
• 53 Mesters R M, Mannucci P M, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.  Blood. 1996;  88 881-886
• 54 Mesters R M, Helterbrand J, Utterback B G et al.. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications.  Crit Care Med. 2000;  28 2209-2216
• 55 Yan S B, Helterbrand J D, Hartman D L, Wright T J, Bernard G R. Low levels of protein C are associated with poor outcome in severe sepsis.  Chest. 2001;  120 915-922
• 56 Fourrier F, Chopin C, Goudemand J et al.. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C, and protein S deficiencies.  Chest. 1992;  101 816-823
• 57 Biemond B J, Levi M, ten Cate H et al.. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades.  Clin Sci (Lond). 1995;  88 587-594
• 58 Mesters R M, Florke N, Ostermann H, Kienast J. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis.  Thromb Haemost. 1996;  75 902-907
• 59 Watanabe R, Wada H, Miura Y et al.. Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.  Clin Appl Thromb Hemost. 2001;  7 229-233
• 60 Kobayashi T, Terao T, Maki M, Ikenoue T. Diagnosis and management of acute obstetrical DIC.  Semin Thromb Hemost. 2001;  27 161-167
• 61 Gando S. Disseminated intravascular coagulation in trauma patients.  Semin Thromb Hemost. 2001;  27 585-592
• 62 Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia.  Semin Thromb Hemost. 2001;  27 593-604
• 63 Toh C H, Samis J, Downey C et al.. Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca( + + )-dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation.  Blood. 2002;  100 2522-2529
• 64 Fernandes B, Giles A. An abnormal activated partial thromboplastin time clotting waveform is associated with high mortality and a procoagulant state.  Lab Hematol. 2003;  9 138-142
• 65 Yu M, Nardella A, Pechet L. Screening tests of disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis.  Crit Care Med. 2000;  28 1777-1780
• 66 Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation.  Thromb Haemost. 1999;  82 695-705
• 67 Horan J T, Francis C W. Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation.  Semin Thromb Hemost. 2001;  27 657-666
• 68 Taylor Jr F B, Toh C H, Hoots W K, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.  Thromb Haemost. 2001;  86 1327-1330
• 69 Bakhtiari K, Meijers J C, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation.  Crit Care Med. 2004;  32 2416-2421
• 70 Slofstra S H, van't Veer C, Buurman W A, Reitsma P H, ten Cate H, Spek C A. Low molecular weight heparin attenuates multiple organ failure in a murine model of disseminated intravascular coagulation.  Crit Care Med. 2005;  33 1365-1370
• 71 du Toit H J, Coetzee A R, Chalton D O. Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon.  Crit Care Med. 1991;  19 1195-1200
• 72 Feinstein D I. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy.  Blood. 1982;  60 284-287
• 73 Okabayashi K, Wada H, Ohta S, Shiku H, Nobori T, Maruyama K. Hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit.  Am J Hematol. 2004;  76 225-229
• 74 Baudo F, Caimi T M, de C F et al.. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study.  Intensive Care Med. 1998;  24 336-342
• 75 Eisele B, Lamy M, Thijs L G et al.. Antithrombin III in patients with severe sepsis: a randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis.  Intensive Care Med. 1998;  24 663-672
• 76 Warren B L, Eid A, Singer P et al.. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial.  JAMA. 2001;  286 1869-1878
• 77 Abraham E, Reinhart K, Svoboda P et al.. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.  Crit Care Med. 2001;  29 2081-2089
• 78 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis.  Crit Care Med. 2000;  28(Suppl 9) S31-S33
• 79 Abraham E, Reinhart K, Opal S et al.. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.  JAMA. 2003;  290 238-247
• 80 Esmon C T. The protein C pathway.  Chest. 2003;  124(Suppl 3) 26S-32S
• 81 Bernard G R, Ely E W, Wright T J et al.. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis.  Crit Care Med. 2001;  29 2051-2059
• 82 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
• 83 Ely E W, Laterre P F, Angus D C et al.. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.  Crit Care Med. 2003;  31 12-19
• 84 Abraham E, Laterre P F, Garg R et al.. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.  N Engl J Med. 2005;  353 1332-1341
• 85 Roberts H R, Monroe D M, White G C. The use of recombinant factor VIIa in the treatment of bleeding disorders.  Blood. 2004;  104 3858-3864
• 86 Hoffman M, Monroe III D M. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis.  Semin Hematol. 2001;  38(4, Suppl 12) 6-9
• 87 Monroe D M, Hoffman M, Oliver J A, Roberts H R. Platelet activity of high-dose factor VIIa is independent of tissue factor.  Br J Haematol. 1997;  99 542-547
• 88 Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa.  Lancet. 1999;  354 1879
• 89 Martinowitz U, Kenet G, Lubetski A, Luboshitz J, Segal E. Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma.  Can J Anaesth. 2002;  49 S15-S20
• 90 Martinowitz U, Kenet G, Segal E et al.. Recombinant activated factor VII for adjunctive hemorrhage control in trauma.  J Trauma. 2001;  51 431-438
• 91 Dutton R P, Hess J R, Scalea T M. Recombinant factor VIIa for control of hemorrhage: early experience in critically ill trauma patients.  J Clin Anesth. 2003;  15 184-188
• 92 Dutton R P, McCunn M, Hyder M et al.. Factor VIIa for correction of traumatic coagulopathy.  J Trauma. 2004;  57 709-718
• 93 Geeraedts Jr L M, Kamphuisen P W, Kaasjager H A, Verwiel J M, van Vugt A B, Frolke J P. The role of recombinant factor VIIa in the treatment of life-threatening haemorrhage in blunt trauma.  Injury. 2005;  36 495-500
• 94 Boffard K D, Riou B, Warren B et al.. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials.  J Trauma. 2005;  59 8-15
• 95 Qureshi A I, Tuhrim S, Broderick J P, Batjer H H, Hondo H, Hanley D F. Spontaneous intracerebral hemorrhage.  N Engl J Med. 2001;  344 1450-1460
• 96 Mayer S A, Brun N C, Broderick J et al.. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage.  Stroke. 2005;  36 74-79
• 97 Mayer S A, Brun N C, Begtrup K et al.. Recombinant activated factor VII for acute intracerebral hemorrhage.  N Engl J Med. 2005;  352 777-785
• 98 Kujovich J L. Hemostatic defects in end stage liver disease.  Crit Care Clin. 2005;  21 563-587
• 99 Bernstein D E, Jeffers L, Erhardtsen E et al.. Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study.  Gastroenterology. 1997;  113 1930-1937
• 100 Shami V M, Caldwell S H, Hespenheide E E, Arseneau K O, Bickston S J, Macik B G. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy.  Liver Transpl. 2003;  9 138-143
• 101 Pavese P, Bonadona A, Beaubien J et al.. FVIIa corrects the coagulopathy of fulminant hepatic failure but may be associated with thrombosis: a report of four cases.  Can J Anaesth. 2005;  52 26-29
• 102 Bosch J, Thabut D, Bendtsen F et al.. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial.  Gastroenterology. 2004;  127 1123-1130
• 103 Jeffers L, Chalasani N, Balart L, Pyrsopoulos N, Erhardtsen E. Safety and efficacy of recombinant factor VIIa in patients with liver disease undergoing laparoscopic liver biopsy.  Gastroenterology. 2002;  123 118-126
• 104 Anantharaju A, Mehta K, Mindikoglu A L, Van Thiel D H. Use of activated recombinant human factor VII (rhFVIIa) for colonic polypectomies in patients with cirrhosis and coagulopathy.  Dig Dis Sci. 2003;  48 1414-1424
• 105 Hendriks H G, Meijer K, de Wolf J T et al.. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study.  Transplantation. 2001;  71 402-405
• 106 Lodge J P, Jonas S, Jones R M et al.. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation.  Liver Transpl. 2005;  11 973-979