Coagulation Disorders Pathology

Quick Answer

CICM Exam Focus

Key Points

---

Disseminated Intravascular Coagulation (DIC)

Definition and Overview

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterised by systemic intravascular activation of coagulation leading to widespread fibrin deposition, microvascular thrombosis, and consumptive coagulopathy with bleeding complications (PMID: 11816725).

DIC Pathophysiology

1. Coagulation Activation

The central driver of DIC is inappropriate, systemic tissue factor (TF) expression (PMID: 17096707):

Tissue Factor Expression

• Normally sequestered on sub-endothelial cells
• In DIC: Expressed on monocytes, macrophages, endothelial cells
• Triggers: Inflammatory cytokines (TNF-α, IL-1β, IL-6), LPS, DAMPs
• Initiates extrinsic coagulation pathway

Thrombin Generation ("Thrombin Storm")

• TF-VIIa complex activates Factor X
• Factor Xa (with Va) generates massive thrombin
• Thrombin effects:
  • Converts fibrinogen to fibrin
  • Activates platelets
  • Activates Factors V, VIII, XI, XIII
  • Cleaves protein C (when bound to thrombomodulin)

Microvascular Fibrin Deposition

• Widespread intravascular fibrin mesh formation
• Microvascular obstruction → organ ischaemia
• Red cell fragmentation → microangiopathic haemolysis (schistocytes)
• End-organ damage: kidneys, lungs, liver, brain, skin

2. Natural Anticoagulant Depletion

DIC exhausts the body's natural anticoagulant systems (PMID: 11236773):

3. Fibrinolysis Dysregulation

DIC involves complex fibrinolytic changes that vary by aetiology (PMID: 18796009):

Initial Activation

• Plasminogen activators (t-PA, u-PA) released
• Plasmin generated → degrades fibrin clots
• D-dimer elevation (fibrin degradation products)

Fibrinolytic Shutdown (Sepsis-DIC)

• PAI-1 (plasminogen activator inhibitor-1) massively upregulated
• Prevents plasmin generation
• Results in persistent microvascular thrombosis
• Characteristic of sepsis-induced DIC
• Explains thrombotic phenotype

Hyperfibrinolysis (Trauma/Obstetric DIC)

• Overwhelming t-PA release
• Excessive plasmin generation
• Rapid clot dissolution
• Cannot maintain haemostasis
• Characteristic haemorrhagic phenotype
• Target for tranexamic acid therapy

4. Consumptive Coagulopathy

As clotting factors and platelets are consumed in microvascular thrombosis:

• Thrombocytopenia: Platelet consumption exceeds production
• Factor depletion: Factors I, II, V, VIII, XIII consumed
• Fibrinogen depletion: Converted to fibrin, degraded by plasmin
• Bleeding tendency: Despite ongoing thrombosis, haemostatic capacity exhausted
• Paradox: Simultaneous thrombosis and bleeding

DIC Aetiology

DIC is always secondary to an underlying condition. Aetiologies include:

ISTH DIC Scoring System

The International Society on Thrombosis and Haemostasis (ISTH) developed a scoring system for overt DIC (PMID: 11816725):

Non-Overt (Pre-DIC) Scoring

For early detection before overt DIC develops:

Score ≥5 suggests non-overt DIC - monitor closely, treat underlying cause

---

Thrombotic Microangiopathies: TTP and HUS

Overview of Thrombotic Microangiopathies

Thrombotic microangiopathies (TMAs) are characterised by:

1. Microangiopathic haemolytic anaemia (MAHA) - schistocytes
2. Thrombocytopenia
3. Organ dysfunction from microvascular thrombosis

The two classic TMAs are TTP and HUS, but other causes include DIC, malignant hypertension, scleroderma renal crisis, and drug-induced TMA (PMID: 24892643).

Thrombotic Thrombocytopenic Purpura (TTP)

Pathophysiology of TTP

TTP results from severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13), also known as von Willebrand factor-cleaving protease (PMID: 12435261):

Clinical Features of TTP

Classic Pentad (complete in <10% of cases):

1. Microangiopathic haemolytic anaemia (100%)
2. Thrombocytopenia (100%)
3. Neurological symptoms (65%) - confusion, headache, seizures, stroke, coma
4. Renal impairment (50%) - usually mild (cf. HUS)
5. Fever (25%)

Laboratory Features:

• Severe thrombocytopenia (<30 × 10⁹/L common)
• Anaemia (Hb often <80 g/L)
• Schistocytes on blood film (>1%)
• Elevated LDH (haemolysis marker)
• Elevated indirect bilirubin
• Low/undetectable haptoglobin
• Normal coagulation (PT, APTT, fibrinogen) - distinguishes from DIC
• ADAMTS13 activity <10% (diagnostic)
• ADAMTS13 inhibitor (antibody) present in acquired TTP

Haemolytic Uraemic Syndrome (HUS)

Typical HUS (STEC-HUS)

Shiga toxin-producing E. coli (STEC) HUS, also called D+ HUS (diarrhoea-associated) (PMID: 15726497):

Pathophysiology:

1. STEC infection (E. coli O157:H7 most common; also O104:H4)
2. Shiga toxin (Stx1, Stx2) binds Gb3 receptor on renal endothelium
3. Direct endothelial cell damage and apoptosis
4. Thrombotic microangiopathy predominantly in kidneys
5. Complement activation amplifies injury

Clinical Features:

• Prodromal bloody diarrhoea (3-10 days before HUS)
• Predominantly paediatric (peak 6 months - 5 years)
• Severe AKI (oliguria/anuria, dialysis often required)
• Less neurological involvement than TTP
• ADAMTS13 activity normal (>10%)

Prognosis:

• Mortality 3-5% with supportive care
• Recovery of renal function in majority
• ~10% develop CKD

Atypical HUS (aHUS)

Complement-mediated HUS, not related to STEC infection (PMID: 22410951):

Pathophysiology:

1. Genetic mutations in complement regulatory proteins:
   • Factor H (most common, ~25%)
   • Factor I
   • Membrane cofactor protein (MCP/CD46)
   • C3, Factor B (gain-of-function mutations)
2. Uncontrolled alternative complement pathway activation
3. Endothelial damage from C3b and MAC deposition
4. TMA predominantly affecting kidneys

Clinical Features:

• No diarrhoeal prodrome (D-)
• Any age (bimodal: childhood, adulthood)
• Severe AKI
• High recurrence rate (especially Factor H mutations)
• ADAMTS13 activity normal

Treatment:

• Eculizumab (anti-C5 monoclonal antibody) - transforms prognosis
• Plasma exchange (historically used, less effective than eculizumab)

Differentiating TTP, HUS, and DIC

---

Heparin-Induced Thrombocytopenia (HIT)

Pathophysiology of HIT

HIT is an immune-mediated adverse drug reaction caused by antibodies against complexes of platelet factor 4 (PF4) and heparin (PMID: 28410963):

Types of HIT

HIT Laboratory Diagnosis

Immunoassays (Screening):

• ELISA for anti-PF4/heparin antibodies
• High sensitivity (~99%), lower specificity (~75%)
• Many positives are not clinically significant ("iceberg effect")

Functional Assays (Confirmatory):

• Serotonin release assay (SRA) - gold standard
• Heparin-induced platelet aggregation (HIPA)
• High specificity (>95%)

HIT Treatment

---

Acquired Haemophilia

Pathophysiology

Acquired haemophilia is caused by autoantibodies (inhibitors) against clotting factors, most commonly Factor VIII (PMID: 25494753):

Mechanism:

• IgG autoantibodies neutralise Factor VIII activity
• Type 1 kinetics (complete neutralisation) or Type 2 (incomplete)
• Results in severe bleeding diathesis
• APTT prolonged, PT normal
• Mixing study does not correct (presence of inhibitor)

Aetiology:

• Idiopathic (50%)
• Autoimmune disorders (SLE, rheumatoid arthritis)
• Malignancy (solid tumours, lymphoproliferative)
• Postpartum (1-4 months after delivery)
• Drug-induced (penicillins, phenytoin, fludarabine)

Clinical Features

• Severe, often life-threatening bleeding
• Pattern different from congenital haemophilia:
  • Soft tissue/muscle haematomas
  • Retroperitoneal bleeding
  • GI/urological bleeding
  • Post-procedural bleeding
  • Less joint bleeding (haemarthrosis)
• Mortality 10-22% (haemorrhage or immunosuppression complications)

Diagnosis

Treatment Principles

Bleeding Control:

• Bypassing agents if high-titre inhibitor:
  • rFVIIa (recombinant activated Factor VII)
  • FEIBA (factor eight inhibitor bypassing activity)
• High-dose Factor VIII if low-titre inhibitor

Inhibitor Eradication:

• Immunosuppression: corticosteroids + cyclophosphamide
• Rituximab for refractory cases
• ~70% achieve remission

---

Vitamin K Deficiency

Physiology of Vitamin K

Vitamin K is essential for gamma-carboxylation of glutamate residues in vitamin K-dependent clotting factors, enabling calcium binding and membrane phospholipid interaction (PMID: 22315259):

Vitamin K Cycle

1. Vitamin K (quinone form) → Vitamin K epoxide during gamma-carboxylation
2. Vitamin K epoxide reductase (VKOR) regenerates vitamin K
3. Warfarin inhibits VKOR → blocks recycling → functional vitamin K deficiency

Causes of Vitamin K Deficiency

Clinical Features

• Bleeding: Bruising, mucosal bleeding, GI haemorrhage, intracranial haemorrhage
• PT prolonged (Factor VII depletes first - shortest half-life)
• APTT prolonged later
• Corrects with vitamin K (distinguishes from liver synthetic failure)

Treatment

Vitamin K Replacement:

• IV vitamin K 10 mg (onset 6-12 hours, peak 24-48 hours)
• Oral vitamin K (if absorptive capacity intact)
• Repeat as needed

Urgent Reversal (Warfarin or Bleeding):

• Prothrombin complex concentrate (PCC) - immediate effect
• FFP if PCC unavailable (larger volume, infection risk)
• Plus IV vitamin K for sustained effect

---

Liver Disease Coagulopathy

The Concept of "Rebalanced Haemostasis"

Liver disease affects both pro-coagulant and anti-coagulant pathways, creating a precarious "rebalanced" state (PMID: 21390322):

Why PT/INR is Misleading in Liver Disease

• PT/INR only measures pro-coagulant pathway
• Does not account for reduced anticoagulants (protein C, S, AT)
• "Normal" haemostasis maintained at lower factor levels due to balanced reduction
• INR of 1.5-2.0 in cirrhosis ≠ INR 1.5-2.0 on warfarin (different implications)

Thromboelastography in Liver Disease

TEG/ROTEM better reflects true haemostatic capacity:

• Often shows normal or hypercoagulable pattern despite prolonged PT
• Guides transfusion more accurately than conventional tests
• Avoids unnecessary FFP transfusion

Bleeding Risks

Despite "rebalanced haemostasis," bleeding occurs in liver disease due to:

• Portal hypertension (varices, gastropathy) - mechanical cause
• Thrombocytopenia (splenic sequestration)
• Impaired platelet function (acquired von Willebrand dysfunction)
• Hyperfibrinolysis (reduced PAI-1, tPA clearance)
• Renal dysfunction (uraemic platelet dysfunction)

Thrombotic Risks

Patients with cirrhosis also have increased thrombotic risk:

• Portal vein thrombosis (20-25% of cirrhotics)
• Deep vein thrombosis
• Pulmonary embolism
• Do NOT withhold anticoagulation based on elevated INR alone

---

Dilutional Coagulopathy

Massive Transfusion and Dilutional Coagulopathy

Massive transfusion is variably defined as (PMID: 28085617):

• ≥10 units pRBC in 24 hours
• Replacement of entire blood volume in 24 hours
• ≥4 units pRBC in 1 hour with ongoing bleeding

Mechanisms of Dilutional Coagulopathy

Factor Dilution:

• pRBC contain negligible clotting factors
• Crystalloid contains no factors
• Historical 1:1:1 (RBC:FFP:platelet) ratio developed to prevent dilution

Platelet Dilution:

• pRBC contain no platelets
• Stored platelets lose function over time
• Thrombocytopenia develops rapidly with massive transfusion

Fibrinogen Depletion:

• First factor to reach critical levels
• Critical threshold: <1.5 g/L (some suggest <2.0 g/L in major haemorrhage)
• FFP contains only ~2 g/L fibrinogen
• Cryoprecipitate or fibrinogen concentrate more effective

Critical Thresholds

Massive Transfusion Protocols (MTP)

---

Hypothermic Coagulopathy

Temperature Effects on Coagulation

Hypothermia profoundly impairs enzymatic coagulation processes (PMID: 8989172):

Laboratory Considerations

Standard PT/APTT:

• Performed at 37°C in laboratory
• Do NOT reflect true in vivo coagulation at patient temperature
• Patient may be severely coagulopathic with "normal" lab values

Thromboelastography:

• Can be performed at patient temperature
• Better reflects true haemostatic capacity
• Shows prolonged R time, reduced MA at hypothermia

Clinical Significance

• Part of "lethal triad" in trauma (hypothermia, acidosis, coagulopathy)
• Each component worsens the others
• Aggressive rewarming is essential component of haemostatic resuscitation

---

Acidotic Coagulopathy

pH Effects on Coagulation

Acidosis significantly impairs thrombin generation and platelet function (PMID: 17653136):

The Lethal Triad

In trauma, acidosis, hypothermia, and coagulopathy form a vicious cycle:

1. Haemorrhage → tissue hypoperfusion → lactic acidosis
2. Acidosis → impaired coagulation → more bleeding
3. Bleeding + exposure → hypothermia
4. Hypothermia → impaired enzymes → worse coagulopathy
5. Coagulopathy → continued bleeding → more acidosis

Breaking the Cycle:

• Damage control surgery (haemorrhage control)
• Damage control resuscitation (permissive hypotension, minimal crystalloid, blood products)
• Aggressive rewarming
• Correction of acidosis (primarily by restoring perfusion)

---

Trauma-Induced Coagulopathy (TIC)

Acute Traumatic Coagulopathy (ATC)

ATC is an endogenous coagulopathy that develops immediately after injury, BEFORE dilution, hypothermia, or acidosis (PMID: 17898336):

Fibrinolysis Phenotypes in Trauma

TEG/ROTEM has identified three fibrinolysis phenotypes (PMID: 24351685):

Implications:

• Hyperfibrinolysis: Tranexamic acid potentially beneficial
• Fibrinolysis shutdown: TXA may increase VTE risk
• Time-dependent: Hyperfibrinolysis early, shutdown later

Tranexamic Acid in Trauma

CRASH-2 trial (PMID: 20554319):

• TXA 1g bolus then 1g over 8 hours
• Reduced all-cause mortality (14.5% vs 16%, RR 0.91)
• Bleeding death reduced (4.9% vs 5.7%)
• Most benefit if given within 3 hours
• HARM if given after 3 hours (increased bleeding death)

---

Laboratory Assessment of Coagulation

Conventional Coagulation Tests

Viscoelastic Haemostatic Assays

TEG (Thromboelastography) and ROTEM (Rotational Thromboelastometry) provide real-time, whole-blood assessment (PMID: 22011002):

TEG/ROTEM-Guided Transfusion Algorithms

Example Algorithm:

Benefits of TEG/ROTEM in ICU

• Real-time results (15-30 minutes)
• Whole blood (includes cellular contributions)
• Detects hyperfibrinolysis (not detected by PT/APTT)
• Can be performed at patient temperature (hypothermia assessment)
• Reduces transfusion in cardiac surgery, liver transplant, trauma
• Cost-effective through reduced blood product use

---

Histopathology of Coagulation Disorders

DIC Histopathology

Characteristic findings at autopsy in DIC (PMID: 2020553):

Microvascular Thrombosis:

• Fibrin thrombi in arterioles and capillaries
• Most prominent in: kidneys (glomeruli), lungs, liver sinusoids, brain, adrenals
• "Fibrin strands" in small vessels

Organ-Specific Changes:

Red Cell Fragmentation:

• Schistocytes (helmet cells, fragments) in blood film
• Result of RBC shearing on fibrin strands

TTP Histopathology

• Platelet-rich thrombi (cf. fibrin-rich in DIC)
• Predominantly in arterioles and capillaries
• Most common in brain, kidneys, heart, pancreas, adrenals
• Thrombi contain VWF and platelets ("white clots")
• Minimal fibrin content
• Red cell fragmentation (MAHA)

HIT Histopathology

• Venous > arterial thrombosis
• "White clot syndrome"
• platelet-rich thrombi
• Limb gangrene if arterial involvement
• Skin necrosis at injection sites
• Adrenal haemorrhage (adrenal vein thrombosis)

---

Australian/New Zealand Context

Massive Transfusion Protocols

Australian Red Cross Lifeblood provides guidelines for MTP implementation:

Standard MTP Pack (typical):

• 6 units pRBC
• 4 units FFP
• 1 adult dose platelets (pooled or apheresis)
• Fibrinogen concentrate (if available) or cryoprecipitate

State-Based Variations:

• NSW: ITIM (Incidence of Trauma-related Massive Blood Transfusion) registry
• Victoria: Better Blood Management project
• Queensland: Clinical Excellence Queensland guidelines

TEG/ROTEM Availability

• Increasingly available in major trauma centres and cardiac surgery units
• Not universally available in smaller hospitals
• NHMRC Blood Management Guidelines recommend viscoelastic testing in trauma

Australian Envenomation and Coagulopathy

Unique to Australia/NZ context (PMID: 23356799):

Brown Snake (Pseudonaja species):

• Venom contains prothrombin activator
• Causes severe consumptive coagulopathy
• "Venom-induced consumption coagulopathy" (VICC)
• Fibrinogen depletion, prolonged PT/APTT, elevated D-dimer
• Treat with antivenom + FFP/cryoprecipitate

Tiger Snake:

• Similar prothrombin activation
• VICC pattern

Taipan:

• Most potent coagulopathy-inducing venom
• Also neurotoxic

---

Indigenous Health Considerations

---

SAQ Practice Questions

---

Viva Scenarios

---

MCQ Practice Questions

---

Z. Factor VII has shortest half-life (4-6 hours) - first to be affected" tags= />

---

References

Landmark Papers

1. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86(5):1327-1330. PMID: 11816725

2. CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23-32. PMID: 20554319

3. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. PMID: 25647203

DIC Pathophysiology

4. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341(8):586-592. PMID: 10451465

5. Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037. PMID: 27250996

6. Iba T, Levy JH, Warkentin TE, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019;17(11):1989-1994. PMID: 31327219

7. Levi M. Pathogenesis and management of perioperative coagulopathy. Br J Surg. 2019;106(2):e95-e101. PMID: 30693517

TTP and HUS

8. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol. 2008;3:249-277. PMID: 18215115

9. Tsai HM. Thrombotic thrombocytopenic purpura: a thrombotic disorder caused by ADAMTS13 deficiency. Hematol Oncol Clin North Am. 2007;21(4):609-632. PMID: 17666280

10. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339(22):1578-1584. PMID: 9828245

11. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654-666. PMID: 25119611

12. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. PMID: 21902819

Heparin-Induced Thrombocytopenia

13. Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373(3):252-261. PMID: 26176382

14. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. Chest. 2004;126(3 Suppl):311S-337S. PMID: 15383477

15. Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. PMID: 30482768

16. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. PMID: 16634744

Trauma-Induced Coagulopathy

17. Brohi K, Cohen MJ, Ganter MT, et al. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg. 2007;245(5):812-818. PMID: 17457176

18. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127-1130. PMID: 12813333

19. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77(6):811-817. PMID: 25423534

20. Dobson GP, Letson HL, Sharma R, Sheppard FR, Cap AP. Mechanisms of early trauma-induced coagulopathy: The clot thickens or not? J Trauma Acute Care Surg. 2015;79(2):301-309. PMID: 26218702

Hypothermia and Acidosis

21. Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56(6):1221-1228. PMID: 15211129

22. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma. 2003;55(5):886-891. PMID: 14608161

23. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58(5):1002-1009. PMID: 15920416

Liver Disease

24. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156. PMID: 21751907

25. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood. 2010;116(6):878-885. PMID: 20400681

26. Caldwell SH, Hoffman M, Lisman T, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44(4):1039-1046. PMID: 17006940

Acquired Haemophilia

27. Franchini M, Mannucci PM. Acquired haemophilia A: a 2013 update. Thromb Haemost. 2013;110(6):1114-1120. PMID: 24008306

28. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870-1877. PMID: 17047148

Vitamin K

29. Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 2014;55(3):345-362. PMID: 24489112

30. Stafford DW. The vitamin K cycle. J Thromb Haemost. 2005;3(8):1873-1878. PMID: 16102054

TEG/ROTEM

31. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol. 2014;89(2):228-232. PMID: 24123050

32. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a Viscoelastic Assay to Conventional Coagulation Assays. Ann Surg. 2016;263(6):1051-1059. PMID: 26720428

33. Hunt H, Stanworth S, Curry N, et al. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev. 2015;2015(2):CD010438. PMID: 25686465

Massive Transfusion

34. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. PMID: 17297317

35. Snyder CW, Weinberg JA, McGwin G Jr, et al. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma. 2009;66(2):358-362. PMID: 19204507

Envenomation

36. Isbister GK. Snakebite doesn't cause disseminated intravascular coagulation: coagulopathy and thrombotic microangiopathy in snake envenoming. Semin Thromb Hemost. 2010;36(4):444-451. PMID: 20614396

37. Maduwage K, Isbister GK. Current treatment for venom-induced consumption coagulopathy resulting from snakebite. PLoS Negl Trop Dis. 2014;8(10):e3220. PMID: 25340339

Guidelines

38. Wada H, Thachil J, Di Nisio M, et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11(4):761-767. PMID: 23379279

39. Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23(1):98. PMID: 30917843

40. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100. PMID: 27072503

Australian/NZ Specific

41. Australian Red Cross Lifeblood. Transfusion Medicine Manual. 2023.

42. Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM, Young PP. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. J Trauma. 2009;66(1):41-48. PMID: 19131804

43. Joseph B, Azim A, Zangbar B, et al. Improving mortality in trauma laparotomy through the evolution of damage control resuscitation: Analysis of 1,030 consecutive trauma laparotomies. J Trauma Acute Care Surg. 2017;82(2):328-333. PMID: 27787437

Histopathology

44. Shimamura K, Oka K, Nakazawa M, Kojima M. Distribution patterns of microthrombi in disseminated intravascular coagulation. Arch Pathol Lab Med. 1983;107(10):543-547. PMID: 6414988

45. Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb Res. 1985;38(5):469-479. PMID: 2990466

Additional References

46. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015;125(9):1387-1393. PMID: 25519752

47. Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018;131(8):845-854. PMID: 29255070

48. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014;370(9):847-859. PMID: 24571757

---

Related Topics

• SIRS and Sepsis Pathology
• Shock Pathology
• Blood Product Transfusion
• Massive Transfusion Protocol
• Anticoagulation in ICU
• Liver Failure