Disseminated Intravascular Coagulation

Quick Answer

Disseminated Intravascular Coagulation (DIC) is an acquired syndrome characterised by systemic activation of coagulation, leading to widespread intravascular fibrin deposition causing microvascular thrombosis and multi-organ dysfunction, with concurrent consumption of platelets and clotting factors resulting in hemorrhage. [1,2]

Key diagnostic criteria (ISTH Overt DIC Score):

• Platelet count (below 50 = 2 points, 50-100 = 1 point)
• D-dimer/FDP elevation (strong increase = 3 points, moderate = 2 points)
• Prolonged PT (greater than 6 sec = 2 points, 3-6 sec = 1 point)
• Fibrinogen below 1.0 g/L (= 1 point)
• Score ≥5 = Overt DIC [3]

Core principles of management:

1. Treat the underlying cause (definitive treatment - sepsis source control, delivery in obstetric DIC)
2. Blood product support (if bleeding or high-risk for procedures):
   • Platelets: Target greater than 50 x 10^9/L (or greater than 20 x 10^9/L if not bleeding)
   • FFP: If PT/APTT ratio greater than 1.5
   • Cryoprecipitate/fibrinogen concentrate: If fibrinogen below 1.5 g/L
3. Anticoagulation: Consider prophylactic heparin when thrombosis predominates; therapeutic heparin for overt thromboembolism [2,4]
4. Avoid antifibrinolytics (tranexamic acid) in most DIC - exception: overt hyperfibrinolysis (APL, specific hemorrhage) [5]

Major causes:

• Sepsis (30-50% of cases)
• Trauma (major tissue injury)
• Obstetric emergencies (amniotic fluid embolism, placental abruption, HELLP)
• Malignancy (acute promyelocytic leukaemia, mucin-secreting adenocarcinomas)
• Transfusion reactions (ABO incompatibility)
• Vascular abnormalities (aortic aneurysm, giant haemangioma) [1,6]

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CICM Exam Focus

Key High-Yield Points

1. ISTH Overt DIC Score: ≥5 points diagnostic; requires underlying disorder PLUS platelet count, D-dimer, PT, fibrinogen [3]
2. Sepsis-Induced Coagulopathy (SIC) Score: Earlier phase detection (≥4 points) using platelets, PT-INR, and SOFA score [7]
3. Pathophysiology triad: Tissue factor → thrombin generation → fibrinolysis inhibition (PAI-1) [8]
4. Consumption vs bleeding: DIC causes BOTH microvascular thrombosis (organ failure) AND hemorrhage (factor consumption) [1]
5. Fibrinogen threshold: below 1.0-1.5 g/L indicates severe consumption; target greater than 1.5 g/L with cryoprecipitate/fibrinogen concentrate [2,4]
6. Tranexamic acid: Generally CONTRAINDICATED in DIC (risk of microvascular thrombosis) - exception is hyperfibrinolytic phenotype (APL, trauma) [5,9]
7. APL-DIC: Life-threatening hyperfibrinolysis; ATRA (all-trans retinoic acid) is disease-modifying therapy [10,11]
8. KyberSept trial: Antithrombin failed to reduce mortality in sepsis; increased bleeding with concomitant heparin [12]

Common Viva Themes

• Pathophysiology of DIC (tissue factor pathway, thrombin generation, natural anticoagulant consumption)
• Distinguish DIC from TTP/HUS (ADAMTS13 deficiency, microangiopathic hemolysis, renal/neurological features)
• Blood product replacement strategy and targets in bleeding DIC
• Role of anticoagulation in thrombotic vs hemorrhagic DIC phenotypes
• Evidence base for antithrombin, recombinant thrombomodulin, protein C (negative trials)
• Obstetric DIC (amniotic fluid embolism pathophysiology, management priorities)
• APL-associated DIC and the role of ATRA

Common Pitfalls

• Forgetting to treat the underlying cause (source control in sepsis, delivery in obstetric DIC)
• Using tranexamic acid inappropriately in thrombotic DIC (worsens microvascular thrombosis)
• Over-transfusing platelets without addressing underlying process (consumed rapidly)
• Missing the diagnosis due to reliance on single laboratory values (use scoring system)
• Failing to distinguish DIC from other thrombotic microangiopathies (TTP, HUS, CAPS)
• Using antithrombin concentrate empirically (no mortality benefit, increased bleeding)
• Not recognising that schistocytes on film suggest microangiopathic process (DIC, TTP, HUS)

---

Key Points

• DIC is a secondary syndrome; always identify and treat the underlying cause [1,2]
• ISTH Overt DIC Score ≥5 is diagnostic; requires platelet count, D-dimer, PT, fibrinogen [3]
• Pathophysiology: Tissue factor release → thrombin generation → microvascular thrombosis + factor consumption [8]
• Sepsis accounts for 30-50% of DIC cases; trauma and obstetric causes also common [1,6]
• Blood products: Target platelets greater than 50 x 10^9/L, fibrinogen greater than 1.5 g/L in bleeding patients [2,4]
• FFP/cryoprecipitate: PT/APTT greater than 1.5x normal or fibrinogen below 1.5 g/L [4]
• Heparin: Consider prophylactic dose when thrombosis predominates; therapeutic for overt VTE [2]
• Tranexamic acid: CONTRAINDICATED in DIC except hyperfibrinolytic phenotype [5,9]
• Natural anticoagulants (antithrombin, rhsTM): No proven mortality benefit in large RCTs [12,13]
• APL-DIC: Unique hyperfibrinolytic mechanism; ATRA reverses coagulopathy [10,11]

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Definition and Classification

Definition

Disseminated Intravascular Coagulation (DIC) is defined by the International Society on Thrombosis and Haemostasis (ISTH) as:

"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 microvasculature, which if sufficiently severe, can produce organ dysfunction." [3]

This definition emphasises several key concepts:

• Acquired (not inherited coagulation disorder)
• Systemic activation of coagulation (not localised thrombosis)
• Secondary to an underlying cause (DIC is never a primary diagnosis)
• Bidirectional pathology (both thrombosis AND hemorrhage)

Classification

DIC exists on a clinical spectrum from early, compensated states to overt, decompensated coagulopathy:

Overt (Decompensated) DIC:

• Coagulation system overwhelmed; consumption exceeds synthesis
• Manifest as bleeding AND/OR organ failure from microvascular thrombosis
• ISTH Overt DIC Score ≥5 [3]

Non-Overt (Compensated) DIC:

• Early activation of coagulation without clinical bleeding
• Hemostatic system maintains compensation
• ISTH Score below 5; requires serial monitoring
• May progress to overt DIC if underlying cause persists [3,14]

Sepsis-Induced Coagulopathy (SIC):

• Intermediate state between normal coagulation and overt DIC
• Specifically designed for sepsis patients
• SIC Score ≥4 (platelets, PT-INR, SOFA components) [7]
• May identify patients who benefit from anticoagulant therapy

Phenotypic Classification (increasingly recognised):

This phenotypic classification has therapeutic implications, particularly regarding the use of antifibrinolytic agents. [5,9]

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Epidemiology

Incidence in ICU

DIC is common in critically ill patients, with incidence varying by underlying condition:

Overall ICU incidence: 9-19% of ICU admissions meet criteria for overt DIC when systematically screened using ISTH criteria. [1,14]

Condition-specific incidence:

[1,6,15,16]

Mortality Impact

DIC is independently associated with increased mortality even after adjustment for underlying disease severity:

• Sepsis with DIC: Mortality 40-80% vs 20-40% without DIC [1,17]
• Trauma with DIC: 3-4x increased mortality [18]
• Obstetric DIC: Maternal mortality 20-40% if untreated [19]
• APL with DIC: Early mortality 5-10% (improved with ATRA/ATO) [10]

The presence of DIC serves as both a marker of disease severity and an independent contributor to poor outcomes through:

• Multi-organ dysfunction from microvascular thrombosis
• Hemorrhagic complications from factor consumption
• Delayed diagnosis and treatment of underlying cause [1,2]

---

Aetiology

Major Causes of DIC

DIC is always secondary to an underlying disorder. The major categories are:

Infection/Sepsis (30-50% of cases):

• Gram-negative bacteria (endotoxin/LPS)
• Gram-positive bacteria (peptidoglycan, lipoteichoic acid)
• Fungi (invasive aspergillosis, candidiasis)
• Parasites (severe malaria)
• Viral hemorrhagic fevers (Ebola, dengue)
• COVID-19 (immunothrombosis phenotype)

[1,17,20]

Trauma and Tissue Injury:

• Major trauma (especially with shock)
• Burns (greater than 40% TBSA)
• Major surgery (cardiac surgery, orthopedic)
• Rhabdomyolysis
• Crush syndrome

[18,21,22]

Obstetric Emergencies:

• Placental abruption (most common obstetric cause)
• Amniotic fluid embolism
• HELLP syndrome (variant of pre-eclampsia)
• Acute fatty liver of pregnancy
• Retained dead fetus (greater than 4 weeks)
• Septic abortion

[19,23,24]

Malignancy:

• Acute promyelocytic leukaemia (APL) - most severe
• Acute myeloid leukaemia (other subtypes)
• Mucin-secreting adenocarcinomas (pancreatic, gastric, prostatic)
• Metastatic solid tumours
• Trousseau syndrome (migratory thrombophlebitis)

[10,11,25]

Vascular Disorders:

• Aortic aneurysm (especially dissecting)
• Giant haemangioma (Kasabach-Merritt syndrome)
• Large vessel malformations

Toxic/Immunologic:

• ABO-incompatible blood transfusion
• Acute haemolytic transfusion reactions
• Transplant rejection (hyperacute)
• Snake envenomation (viper, brown snake)
• Drug reactions

Other:

• Acute pancreatitis
• Fulminant hepatic failure
• Heat stroke
• Fat embolism syndrome
• Drowning

[1,6]

Pathophysiological Mechanisms by Cause

[8,22,24,25]

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Pathophysiology

Normal Haemostasis

Normal coagulation involves a delicate balance between:

1. Procoagulant factors (coagulation cascade)
2. Anticoagulant mechanisms (antithrombin, protein C/S, TFPI)
3. Fibrinolytic system (plasmin, tPA, PAI-1)

In DIC, this balance is catastrophically disrupted. [8,26]

Central Mechanism: Tissue Factor Pathway

The pathophysiology of DIC centres on uncontrolled activation of coagulation via the tissue factor (TF) pathway:

Step 1: Tissue Factor Expression

• Under pathological conditions, TF is expressed on:
  • Monocytes (activated by LPS, cytokines in sepsis)
  • Endothelial cells (damaged by trauma, sepsis)
  • Cancer cells (APL promyelocytes, adenocarcinoma)
  • Decidual cells (obstetric emergencies)
• Circulating microparticles bearing TF also contribute [8,27]

Step 2: Massive Thrombin Generation

• TF binds Factor VIIa, forming TF-VIIa complex
• This activates Factor X → Xa
• Factor Xa converts prothrombin → thrombin (Factor IIa)
• Positive feedback amplification through Factors V, VIII, XI
• Result: Explosive, systemic thrombin generation [8,26]

Step 3: Widespread Fibrin Deposition

• Thrombin converts fibrinogen → fibrin
• Fibrin is deposited in the microvasculature
• Causes organ ischemia and dysfunction (kidney, lung, liver, brain)
• Mechanical destruction of red cells → schistocytes (microangiopathic haemolysis) [1,8]

Step 4: Consumption Coagulopathy

• Platelets consumed in forming microthrombi → thrombocytopenia
• Clotting factors depleted → prolonged PT/APTT
• Fibrinogen consumed → hypofibrinogenaemia
• Natural anticoagulants exhausted (antithrombin, protein C) [2,8]

Impairment of Natural Anticoagulants

Three major anticoagulant systems are overwhelmed in DIC:

Antithrombin (AT):

• Normally inhibits thrombin and Factor Xa
• Consumed by excessive thrombin generation
• Degraded by neutrophil elastase (sepsis)
• Reduced hepatic synthesis (liver dysfunction)
• AT levels below 50% associated with worse outcomes [12,28]

Protein C/Protein S System:

• Protein C activated by thrombomodulin-thrombin complex
• Activated protein C (aPC) inactivates Factors Va and VIIIa
• In DIC: Thrombomodulin downregulated on damaged endothelium
• Protein C consumed and synthesis reduced
• Results in impaired anticoagulant response [29,30]

Tissue Factor Pathway Inhibitor (TFPI):

• Normally inhibits TF-VIIa complex
• Overwhelmed by massive TF exposure
• Expression may be reduced on damaged endothelium [8]

Fibrinolysis Dysregulation

The fibrinolytic response in DIC varies by aetiology, creating different clinical phenotypes:

Fibrinolysis Suppression (Sepsis):

• Massive release of Plasminogen Activator Inhibitor-1 (PAI-1)
• Driven by inflammatory cytokines (TNF-α, IL-1)
• tPA activity inhibited → fibrin clots persist
• Contributes to organ failure from persistent microthrombi
• This is the thrombotic phenotype [8,17]

Hyperfibrinolysis (Trauma, APL, Obstetric):

• Excessive tPA release from damaged endothelium
• In APL: Annexin II on promyelocytes accelerates plasmin generation
• Plasmin activity exceeds clot formation
• Results in severe bleeding despite clot attempts
• This is the hemorrhagic phenotype [10,21,22]

Endotheliopathy

The vascular endothelium is both target and amplifier in DIC:

Glycocalyx Shedding:

• The glycocalyx (protective carbohydrate layer on endothelium) is shed during shock and inflammation
• Measured by elevated syndecan-1 levels
• Causes: Catecholamine surge, direct injury, ischemia-reperfusion
• Results in: "Auto-heparinization," capillary leak, loss of anticoagulant properties [31]

Endothelial Activation:

• Expresses adhesion molecules (ICAM-1, VCAM-1, E-selectin)
• Produces pro-inflammatory cytokines
• Secretes von Willebrand factor (VWF) multimers
• Converts from anticoagulant to procoagulant phenotype [27,31]

Pathophysiology by Clinical Phenotype

[8,10,22,24,25]

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Clinical Presentation

Hemorrhagic Manifestations

Bleeding in DIC results from consumption of platelets and clotting factors:

Cutaneous:

• Petechiae and purpura
• Ecchymoses (often large, irregular)
• Bleeding from venipuncture sites and surgical wounds
• Oozing from IV cannulae and arterial lines

Mucosal:

• Epistaxis (often bilateral)
• Gingival bleeding
• Gastrointestinal hemorrhage (melena, haematemesis)
• Genitourinary bleeding (haematuria, menorrhagia)

Organ-Specific:

• Intracranial hemorrhage (especially in APL)
• Pulmonary hemorrhage
• Retroperitoneal hemorrhage
• Intra-abdominal bleeding

Characteristic Features:

• Bleeding from multiple unrelated sites simultaneously
• Oozing from sites of minor trauma (venipuncture, catheter sites)
• Bleeding disproportionate to apparent injury [1,2]

Thrombotic Manifestations

Microvascular thrombosis causes organ dysfunction:

Renal:

• Acute kidney injury (oliguria, rising creatinine)
• Cortical necrosis (severe cases)
• Prerenal component from hypoperfusion

Pulmonary:

• Hypoxemia from microvascular occlusion
• ARDS overlap (inflammation + coagulopathy)
• Pulmonary hemorrhage (hemorrhagic phenotype)

Hepatic:

• Elevated transaminases
• Synthetic dysfunction (worsening coagulopathy)
• Hepatic ischemia

Neurological:

• Altered consciousness (multi-organ dysfunction)
• Focal deficits (microinfarcts or hemorrhage)
• Delirium

Cutaneous:

• Purpura fulminans: Symmetric, rapidly progressive purpura with skin necrosis
• Acral cyanosis (fingers, toes, ears, nose)
• Digital ischemia and gangrene
• Associated with protein C deficiency, meningococcal sepsis [1,2,32]

Presentation by Aetiology

Sepsis-Associated DIC:

• Organ dysfunction predominates (thrombotic phenotype)
• Often subtle bleeding initially
• Progressive multi-organ failure
• Purpura fulminans in severe cases (especially meningococcemia)

Trauma-Induced Coagulopathy:

• Early: Severe hemorrhage (hyperfibrinolysis)
• Late: May transition to thrombotic phenotype
• Coagulopathy present on arrival in 25% of major trauma

Obstetric DIC:

• Placental abruption: Vaginal bleeding, uterine tenderness, fetal distress
• Amniotic fluid embolism: Sudden cardiovascular collapse, hypoxemia, DIC
• HELLP: Hemolysis, elevated liver enzymes, low platelets
• Typically hemorrhagic phenotype

APL-Associated DIC:

• Severe hemorrhage (including intracranial) despite only moderate thrombocytopenia
• Hyperfibrinolysis is dominant mechanism
• May present before leukaemia diagnosed
• Life-threatening until ATRA initiated

Malignancy-Associated DIC:

• Often chronic, compensated DIC
• Trousseau syndrome: Migratory superficial thrombophlebitis
• Arterial thrombosis (stroke) may be presenting feature
• Thrombotic predominates over hemorrhagic [1,10,24,25]

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Investigations

Laboratory Diagnosis

No single test diagnoses DIC. Diagnosis relies on clinical context plus a combination of tests:

Essential Tests:

Ancillary Tests:

[1,2,3]

ISTH Scoring Systems

ISTH Overt DIC Score (2001) [3]:

Prerequisite: Patient must have an underlying disorder known to cause DIC.

Interpretation:

• Score ≥5: Compatible with overt DIC (repeat daily)
• Score below 5: Suggestive of non-overt DIC (repeat in 1-2 days)

Sepsis-Induced Coagulopathy (SIC) Score (2017) [7]:

*Sum of respiratory, cardiovascular, hepatic, and renal SOFA components

Interpretation:

• Score ≥4: SIC present
• Identifies earlier coagulation activation than overt DIC score
• May identify patients who benefit from anticoagulant therapy

Viscoelastic Testing (ROTEM/TEG)

Point-of-care viscoelastic tests provide functional assessment of coagulation and fibrinolysis:

ROTEM (Rotational Thromboelastometry):

Advantages:

• Rapid results (15-30 minutes for key parameters)
• Detects hyperfibrinolysis
• Guides targeted blood product therapy
• Can distinguish clot strength vs lysis problems

Limitations:

• Operator-dependent
• Less standardised than standard coagulation tests
• May not correlate with clinical bleeding
• Not validated for DIC diagnosis [33,34]

Differential Diagnosis

DIC must be distinguished from other thrombotic microangiopathies (TMAs):

[35,36]

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Management

Principles of DIC Management

Fundamental principle: DIC is always secondary. Treatment of the underlying cause is the only definitive therapy.

Management priorities:

1. Identify and aggressively treat the underlying cause
2. Provide supportive care (hemodynamic, respiratory)
3. Blood product replacement for bleeding or high-risk patients
4. Consider anticoagulation in appropriate phenotypes
5. Avoid interventions that may worsen the condition

[2,4]

Treatment of Underlying Cause

This is the most important intervention:

The coagulopathy typically resolves once the underlying trigger is controlled. [2,4]

Blood Product Replacement

Blood products are indicated for bleeding patients or those at high risk for bleeding (e.g., requiring invasive procedures). Transfusion should not be guided by laboratory values alone.

Platelets:

• Standard dose: 1 pooled platelet unit (4-6 single donor units)
• Expect rise of ~20-40 x 10^9/L per pooled unit (often less in DIC due to consumption)
• May require repeated transfusions [2,4]

Fresh Frozen Plasma (FFP):

• Contains all coagulation factors
• Volume load may be limiting factor
• Monitor PT/APTT response [4,37]

Cryoprecipitate/Fibrinogen Concentrate:

• Each pool of cryoprecipitate (10 units) raises fibrinogen by ~0.5-1.0 g/L
• Target fibrinogen greater than 1.5 g/L in bleeding patients
• Fibrinogen concentrate allows more precise dosing, faster reconstitution [4,38]

Anticoagulation

The role of anticoagulation in DIC is controversial and depends on phenotype:

When to Consider Anticoagulation:

Unfractionated Heparin (UFH):

• Prophylactic: 5,000-7,500 units SC BD
• Therapeutic: Weight-based infusion (target APTT 1.5-2.5x)
• Requires adequate antithrombin for activity
• May be ineffective if AT below 50-60%

Low Molecular Weight Heparin (LMWH):

• Enoxaparin 40 mg SC daily (prophylactic)
• More predictable pharmacokinetics
• Preferred in chronic/malignancy-associated DIC

Practical approach:

• Most ICU patients with acute DIC: Avoid therapeutic anticoagulation
• VTE prophylaxis: Once bleeding controlled, resume standard prophylaxis
• Thrombotic phenotype with organ failure: Consider therapeutic heparin after blood product support [2,4]

Antifibrinolytic Therapy

Tranexamic acid (TXA) is generally CONTRAINDICATED in DIC

Rationale:

• DIC involves both thrombosis and fibrinolysis
• Inhibiting fibrinolysis may worsen microvascular thrombosis
• Risk of organ failure from persistent microthrombi [5,9]

Exceptions (hyperfibrinolytic phenotype):

• APL with documented hyperfibrinolysis
• Trauma with viscoelastic evidence of hyperfibrinolysis (ML greater than 15%)
• Obstetric hemorrhage (WOMAN trial included DIC patients)
• Snake envenomation with hyperfibrinolysis

If used in DIC:

• Must have documented hyperfibrinolysis (viscoelastic testing, clinical context)
• TXA 1 g IV over 10 minutes, then 1 g over 8 hours
• Monitor for thrombotic complications [5,9,39]

Specific Therapies (Limited Evidence)

Antithrombin Concentrate:

The KyberSept trial (2001) was the definitive study:

• 2,114 patients with severe sepsis randomised to high-dose AT vs placebo
• No mortality benefit (38.9% vs 38.7%, p=0.94)
• Increased bleeding when given with concomitant heparin
• Subgroup analyses suggested possible benefit in DIC without heparin (not definitive) [12]

Current recommendations:

• NOT recommended for routine sepsis/DIC (Surviving Sepsis Campaign)
• May be considered in selected patients in Japan (different guidelines)
• Not routinely available or used in Australia/UK

Recombinant Thrombomodulin (ART-123):

The SCARLET trial (2019) was the key study:

• 800+ patients with sepsis-associated coagulopathy
• No significant mortality benefit (26.8% vs 29.4%, p=0.32)
• Well tolerated with low bleeding risk [13]

STARDUST trial (2024): Also failed to show mortality benefit [40]

Current status:

• Approved in Japan for DIC treatment
• NOT recommended internationally (SSC guidelines suggest against)

Recombinant Activated Protein C (drotrecogin alfa):

• PROWESS trial (2001): Initial promise in severe sepsis
• PROWESS-SHOCK trial (2012): No benefit, increased bleeding
• Withdrawn from market - no longer available [29]

Algorithm for DIC Management

Step 1: Recognize DIC

• Calculate ISTH score (requires underlying disorder + lab criteria)
• Consider SIC score in sepsis patients

Step 2: Treat Underlying Cause

• This is the only definitive treatment
• Aggressive source control, antibiotics, delivery, chemotherapy as appropriate

Step 3: Supportive Care

• Hemodynamic resuscitation
• Respiratory support
• Organ support (RRT if needed)

Step 4: Blood Product Support (if bleeding)

• Platelets: Target greater than 50 x 10^9/L
• FFP: If PT/APTT greater than 1.5x normal
• Cryoprecipitate/fibrinogen: If fibrinogen below 1.5 g/L

Step 5: Consider Anticoagulation

• Thrombotic phenotype: May benefit from heparin
• Hemorrhagic phenotype: AVOID anticoagulation
• Once bleeding controlled: Resume VTE prophylaxis

Step 6: Avoid Harmful Interventions

• TXA contraindicated (except hyperfibrinolytic phenotype)
• Routine antithrombin not recommended

Step 7: Monitor and Repeat

• Serial ISTH scores daily
• Monitor clinical bleeding/thrombosis
• Adjust therapy based on phenotype evolution

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Special Populations

Sepsis-Associated DIC

Pathophysiology:

• LPS/endotoxin → Monocyte TF expression
• Inflammatory cytokines (TNF-α, IL-1) amplify coagulation
• PAI-1 surge → Fibrinolysis suppression (thrombotic phenotype)
• Consumption of AT, Protein C [17,20]

Key Features:

• Thrombotic phenotype predominates
• Organ dysfunction often more prominent than bleeding
• Purpura fulminans in severe cases (especially meningococcemia)
• DIC present in 30-50% of severe sepsis [1,17]

Management Priorities:

• Sepsis bundle: Early antibiotics, source control, fluid resuscitation
• Blood products for bleeding
• VTE prophylaxis once stable
• Avoid antifibrinolytics

Trauma-Induced Coagulopathy (TIC)

TIC represents a distinct but overlapping entity with DIC:

Pathophysiology:

• Tissue factor release from damaged tissue
• Shock → Activated Protein C → Factor Va/VIIIa inactivation
• Glycocalyx shedding → "Auto-heparinisation"
• Early hyperfibrinolysis may transition to "fibrinolysis shutdown" [21,22]

Key Features:

• Present on arrival in 25-35% of major trauma
• Early hemorrhagic phenotype
• May transition to thrombotic phenotype later
• Worse outcomes than trauma without coagulopathy [18]

Management:

• Damage control resuscitation
• 1:1:1 ratio transfusion (PROPPR trial)
• Tranexamic acid within 3 hours (CRASH-2)
• Fibrinogen replacement (target greater than 1.5-2.0 g/L)
• Avoid crystalloid overload [39,41]

Obstetric DIC

Placental Abruption:

• Most common obstetric cause of DIC
• Decidual tissue factor release
• Hemorrhagic phenotype
• Treatment: Urgent delivery (source control), MTP, fibrinogen replacement [23,24]

Amniotic Fluid Embolism (AFE):

• Rare (1:15,000-40,000 deliveries) but catastrophic
• Anaphylactoid reaction to amniotic fluid
• Sudden cardiovascular collapse + DIC
• Management: ABC resuscitation, MTP, supportive care
• No specific treatment; high mortality (20-40%) [19,42]

HELLP Syndrome:

• Hemolysis, Elevated Liver enzymes, Low Platelets
• Microangiopathic process (overlap with DIC/TTP/HUS)
• Treatment: Delivery if severe; may use steroids, supportive care
• Usually resolves within 72 hours of delivery [43]

Acute Promyelocytic Leukaemia (APL)

APL represents the most severe form of DIC-associated hemorrhage:

Pathophysiology:

• Promyelocytes express tissue factor and cancer procoagulant
• Annexin II overexpression accelerates plasmin generation
• Severe hyperfibrinolysis → Life-threatening bleeding
• Intracranial hemorrhage is leading cause of early death [10,11]

Key Features:

• DIC present in 80-90% at diagnosis
• Bleeding severity disproportionate to platelet count
• Hypofibrinogenemia is hallmark
• Responds rapidly to ATRA

Management:

• ATRA (all-trans retinoic acid): Start immediately upon suspicion
  • Differentiates promyelocytes, reduces TF/Annexin II expression
  • DIC typically improves within 24-72 hours
• Aggressive platelet transfusion (target greater than 30-50 x 10^9/L)
• Fibrinogen replacement (target greater than 1.5 g/L)
• Antifibrinolytics (TXA) may be considered for severe hyperfibrinolysis
• Avoid therapeutic heparin initially [10,11,44]

Malignancy-Associated DIC (Chronic)

Trousseau Syndrome:

• Migratory superficial thrombophlebitis
• Associated with mucin-secreting adenocarcinomas (pancreatic, gastric, lung, ovarian)
• Mucins interact with selectins → Platelet-rich microthrombi
• May be first presentation of occult malignancy [25]

Management:

• Anticoagulation (LMWH preferred over warfarin)
• Treat underlying malignancy
• Chronic, low-grade DIC may not require specific intervention
• Arterial thrombosis may occur (non-bacterial thrombotic endocarditis)

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Evidence Summary

Key Trials

[12,13,39,40,41]

Guidelines

ISTH Guidelines (2013):

• Use ISTH scoring system for diagnosis
• Treat underlying cause
• Blood products for bleeding patients
• Anticoagulation in selected thrombotic phenotypes [4]

British Society for Haematology (2022):

• Updated guidance on DIC management
• Emphasis on phenotype-directed therapy
• Fibrinogen replacement highlighted
• Antifibrinolytics contraindicated except hyperfibrinolytic states [37]

Surviving Sepsis Campaign (2021):

• Suggests against antithrombin for sepsis
• Suggests against recombinant thrombomodulin
• Standard VTE prophylaxis once stable [45]

Japanese Guidelines:

• More permissive use of AT and rhsTM
• Different diagnostic criteria and thresholds
• Not directly applicable to Australian practice [7]

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Prognosis

Mortality

DIC is associated with substantial mortality, largely reflecting the severity of underlying conditions:

[1,10,17]

Prognostic Factors

Poor prognostic indicators:

• Higher ISTH DIC score
• Antithrombin below 50%
• Protein C below 40%
• Fibrinogen below 1.0 g/L
• Platelet count below 50 x 10^9/L
• Multi-organ dysfunction
• Delayed treatment of underlying cause
• Intracranial hemorrhage (in APL)

ISTH score for prognosis:

• Score correlates with 28-day mortality
• Each point increase associated with higher mortality risk
• Serial scoring tracks response to treatment [3,14]

Resolution

Timeframe for resolution:

• Depends on control of underlying cause
• Sepsis: May resolve within 24-72 hours of effective treatment
• Trauma: Typically resolves once hemorrhage controlled
• APL: DIC improves within 24-72 hours of ATRA
• Obstetric: Usually resolves within 24-48 hours post-delivery

Monitoring for resolution:

• Serial ISTH scores (declining indicates improvement)
• Rising fibrinogen is good prognostic sign
• Normalisation of PT/platelet count
• Reduced transfusion requirements [2,4]

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CICM Exam Practice

SAQ 1: DIC Diagnosis and Management

Question: A 58-year-old male with community-acquired pneumonia develops septic shock. Day 3 investigations show: Platelets 42 x 10^9/L (admission 180), PT 22 seconds (control 12), APTT 52 seconds (control 32), Fibrinogen 0.8 g/L, D-dimer greater than 20,000 ng/mL.

(a) Calculate the ISTH DIC score and interpret. (3 marks) (b) Describe the pathophysiology of DIC in sepsis. (4 marks) (c) Outline your management priorities for this patient. (5 marks)

Model Answer:

(a) ISTH DIC Score (3 marks):

Prerequisites: Underlying disorder present (sepsis) - YES

Interpretation: Score ≥5 = Overt DIC confirmed. This patient has severe overt DIC requiring active management and daily score monitoring.

(b) Pathophysiology of sepsis-associated DIC (4 marks):

Tissue factor activation:

• Bacterial products (LPS/endotoxin) and inflammatory cytokines (TNF-α, IL-1, IL-6) activate monocytes and endothelial cells
• These cells express tissue factor (TF) on their surface
• TF binds Factor VIIa, initiating the extrinsic coagulation pathway

Thrombin generation:

• Massive, systemic thrombin generation occurs
• Thrombin converts fibrinogen to fibrin
• Widespread fibrin deposition in the microvasculature
• Results in microvascular thrombosis and organ dysfunction

Natural anticoagulant consumption:

• Antithrombin consumed by excessive thrombin
• Protein C depleted (also thrombomodulin downregulated on damaged endothelium)
• TFPI overwhelmed by massive TF exposure
• Loss of normal hemostatic regulation

Fibrinolysis suppression:

• Inflammatory cytokines cause massive release of PAI-1 (plasminogen activator inhibitor-1)
• This inhibits fibrinolysis, preventing breakdown of microthrombi
• Results in persistent microvascular occlusion and organ failure
• This is the "thrombotic phenotype" characteristic of sepsis-DIC

Consumption coagulopathy:

• Platelets and clotting factors consumed in forming microthrombi
• Results in thrombocytopenia, prolonged PT/APTT, hypofibrinogenemia
• Creates paradox of simultaneous thrombosis AND hemorrhage risk

(c) Management priorities (5 marks):

Priority 1: Treat underlying cause

• This is definitive treatment
• Optimise sepsis management: appropriate antibiotics, source control
• Complete sepsis bundle: fluid resuscitation, vasopressors to target MAP ≥65 mmHg
• Assess for source requiring intervention (e.g., drainage of abscess, debridement)

Priority 2: Blood product support (patient is at high bleeding risk)

• Platelets: Transfuse pooled platelets; target greater than 50 x 10^9/L given active DIC
• Fresh frozen plasma: PT prolonged greater than 1.5x normal; give 15-20 mL/kg FFP
• Cryoprecipitate: Fibrinogen 0.8 g/L; give 2 pools (10 units) targeting greater than 1.5 g/L
• Check response 30-60 minutes post-transfusion

Priority 3: General supportive care

• ICU admission with invasive monitoring
• Respiratory support (intubation if required)
• Renal replacement therapy if AKI develops
• Temperature management
• Avoid invasive procedures unless essential

Priority 4: Avoid harmful interventions

• Do NOT give tranexamic acid (thrombotic phenotype - would worsen microvascular thrombosis)
• Do NOT give antithrombin concentrate routinely (no mortality benefit, increased bleeding - KyberSept trial)
• Do NOT give recombinant thrombomodulin (no benefit - SCARLET trial)

Priority 5: Monitor and reassess

• Serial ISTH DIC score daily
• Monitor for bleeding and organ dysfunction
• Once bleeding controlled and stable, resume VTE prophylaxis
• Adjust blood product therapy based on clinical response and laboratory trends

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SAQ 2: Obstetric DIC

Question: A 32-year-old primigravida at 36 weeks gestation presents with sudden-onset abdominal pain, vaginal bleeding, and fetal distress. She becomes hypotensive (BP 75/40 mmHg) and is taken for emergency caesarean section. Intraoperatively, she develops profuse bleeding from surgical sites and her uterus fails to contract.

(a) What is the most likely diagnosis and underlying cause of coagulopathy? (2 marks) (b) Explain the pathophysiology of DIC in this condition. (4 marks) (c) Describe your approach to managing the coagulopathy in this patient. (6 marks)

Model Answer:

(a) Diagnosis (2 marks):

Most likely diagnosis: Placental abruption with DIC and uterine atony

Underlying cause of coagulopathy: Disseminated intravascular coagulation secondary to placental abruption

Placental abruption is the most common obstetric cause of DIC. The coagulopathy results from release of tissue factor from the damaged decidua and placenta into the maternal circulation.

(b) Pathophysiology (4 marks):

Tissue factor release:

• Separation of the placenta from the uterine wall exposes the maternal circulation to large amounts of tissue factor (TF) from decidual and placental tissue
• The retroplacental hematoma contains high concentrations of TF and procoagulant phospholipids
• These enter the maternal venous system at the site of placental separation

Coagulation cascade activation:

• TF binds Factor VIIa, initiating massive activation of the extrinsic pathway
• This triggers explosive thrombin generation throughout the maternal circulation
• Widespread fibrin deposition occurs in the microvasculature

Consumption coagulopathy:

• Rapid consumption of clotting factors and platelets
• Fibrinogen is particularly affected (often below 1.0-1.5 g/L)
• Low fibrinogen is highly predictive of severe hemorrhage in obstetric DIC

Hyperfibrinolysis:

• Unlike sepsis-DIC, obstetric DIC typically shows a hyperfibrinolytic phenotype
• Excessive plasmin generation leads to rapid clot breakdown
• This manifests as severe hemorrhage (hemorrhagic phenotype)
• Bleeding is often more prominent than organ failure

Uterine contribution:

• Uterine atony may result from myometrial infiltration by blood (Couvelaire uterus)
• This prevents effective uterine contraction and perpetuates bleeding
• Creates a vicious cycle of hemorrhage and coagulopathy

(c) Management approach (6 marks):

Immediate resuscitation:

• Call for help: obstetric, anaesthetic, haematology, transfusion services
• Large-bore IV access (minimum 2x 16G)
• Activate massive transfusion protocol (MTP)
• Cross-match blood urgently; use O-negative/group-specific until available
• Invasive monitoring (arterial line, central line if time permits)

Source control (surgical):

• Delivery has occurred (caesarean section complete) - this removes the source of TF
• Address uterine atony:
  • "Uterotonic drugs: Oxytocin infusion (40 units in 1L over 4 hours), ergometrine 250 mcg IM (if no contraindications), carboprost (Hemabate) 250 mcg IM"
  • Bimanual uterine compression
  • Bakri balloon tamponade
  • Consider B-Lynch suture, uterine artery ligation, or hysterectomy if medical management fails

Blood product replacement:

• 1:1:1 ratio transfusion (approximating whole blood):
  • 1 unit PRBCs : 1 unit FFP : 1 pooled platelet unit
• Fibrinogen is critical:
  • Target fibrinogen greater than 2.0 g/L in obstetric hemorrhage (higher threshold than non-obstetric DIC)
  • "Cryoprecipitate: 2 pools (10 units) = raises fibrinogen ~0.5-1.0 g/L"
  • OR Fibrinogen concentrate 2-4 g IV (more rapid)
• Monitor ionised calcium (citrate toxicity from massive transfusion):
  • Calcium gluconate 1 g IV per 4 units blood products
  • Target iCa2+ greater than 1.1 mmol/L

Tranexamic acid:

• TXA 1 g IV over 10 minutes
• WOMAN trial showed mortality benefit in postpartum hemorrhage
• Obstetric DIC has hyperfibrinolytic phenotype (unlike sepsis) - TXA is indicated
• Give within 3 hours of delivery for maximum benefit

Point-of-care testing (if available):

• ROTEM/TEG to guide therapy:
  • "FIBTEM MCF below 10 mm: Give fibrinogen"
  • "Low MCF on EXTEM: Give platelets"
  • "Hyperfibrinolysis (ML greater than 15%): Consider additional TXA"

Monitoring and targets:

• Hb greater than 70-80 g/L (higher target in ongoing hemorrhage)
• Platelets greater than 50 x 10^9/L
• Fibrinogen greater than 2.0 g/L
• PT/APTT below 1.5x normal
• iCa2+ greater than 1.1 mmol/L
• Temperature greater than 35°C (avoid hypothermia)
• pH greater than 7.2, lactate clearing

Post-stabilisation:

• ICU admission for ongoing monitoring
• VTE prophylaxis once bleeding controlled
• Serial coagulation studies
• DIC typically resolves within 24-48 hours once source controlled

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Viva Scenarios

Viva 1: Pathophysiology of DIC

Examiner: Describe the pathophysiology of DIC. What is the central mechanism?

Candidate response:

DIC is an acquired syndrome of systemic coagulation activation. The central mechanism is uncontrolled activation of coagulation via the tissue factor pathway.

Step 1 - Tissue factor exposure: Under pathological conditions, tissue factor (TF) is expressed on cells that don't normally express it:

• Monocytes activated by bacterial products (LPS) and inflammatory cytokines in sepsis
• Damaged endothelium in trauma and sepsis
• Cancer cells, particularly APL promyelocytes
• Decidual tissue in obstetric emergencies
• Circulating microparticles bearing TF

Step 2 - Thrombin generation:

• TF binds Factor VIIa, forming the TF-VIIa complex
• This activates Factors IX and X
• Factor Xa converts prothrombin to thrombin
• Positive feedback amplification occurs through Factors V, VIII, and XI
• The result is massive, systemic thrombin generation

Examiner: What happens to the natural anticoagulant systems?

Candidate response:

All three major anticoagulant systems are overwhelmed or consumed:

Antithrombin (AT):

• Normally inhibits thrombin and Factor Xa
• Consumed by excessive thrombin generation
• Also degraded by neutrophil elastase released in sepsis
• Reduced hepatic synthesis if liver dysfunction present
• Levels below 50% associated with worse outcomes

Protein C/Protein S system:

• Protein C is activated when thrombin binds thrombomodulin on endothelial cells
• Activated protein C (aPC) normally inactivates Factors Va and VIIIa
• In DIC, thrombomodulin is downregulated on damaged endothelium
• Protein C is also consumed, and synthesis is reduced

Tissue Factor Pathway Inhibitor (TFPI):

• Normally inhibits the TF-VIIa complex
• Simply overwhelmed by massive TF exposure

Examiner: How does fibrinolysis differ between sepsis-DIC and trauma-DIC?

Candidate response:

This is a crucial distinction that affects management:

Sepsis-DIC (Thrombotic phenotype):

• Inflammatory cytokines cause massive release of PAI-1 (plasminogen activator inhibitor-1)
• PAI-1 inhibits tissue plasminogen activator (tPA)
• Result: Fibrinolysis is SUPPRESSED
• Fibrin clots persist in the microvasculature
• Leads to organ dysfunction from persistent microthrombi
• Bleeding may occur but organ failure often predominates
• Tranexamic acid is CONTRAINDICATED as fibrinolysis is already impaired

Trauma-DIC (Initially hyperfibrinolytic):

• Shock induces activation of Protein C
• Activated Protein C inhibits PAI-1, allowing unrestricted fibrinolysis
• Damaged endothelium releases excessive tPA
• Result: HYPERFIBRINOLYSIS (clots break down too quickly)
• Manifests as severe hemorrhage
• May later transition to "fibrinolysis shutdown"
• Tranexamic acid is indicated (within 3 hours) - CRASH-2 trial

This phenotypic distinction guides the use of antifibrinolytic therapy.

---

Viva 2: DIC Scoring and Diagnosis

Examiner: How do you diagnose DIC? Tell me about the ISTH scoring system.

Candidate response:

DIC is diagnosed using a combination of clinical context and laboratory testing. No single test is diagnostic. The ISTH (International Society on Thrombosis and Haemostasis) developed a validated scoring system for overt DIC.

Prerequisites: The patient MUST have an underlying disorder known to cause DIC. Without this, the scoring system should not be applied.

ISTH Overt DIC Score: There are four parameters:

Interpretation:

• Score ≥5 = Compatible with overt DIC
• Score below 5 = Suggestive of non-overt (compensated) DIC

Examiner: What about the SIC score? When would you use that?

Candidate response:

The Sepsis-Induced Coagulopathy (SIC) Score was developed in 2017 to identify an earlier phase of coagulation activation specifically in sepsis patients.

SIC Score components:

• Platelet count: ≥150 = 0, 100-149 = 1, below 100 = 2
• PT-INR: ≤1.2 = 0, 1.21-1.4 = 1, greater than 1.4 = 2
• SOFA score (respiratory + cardiovascular + hepatic + renal): 0 = 0, 1 = 1, ≥2 = 2

Score ≥4 indicates SIC.

Differences from overt DIC score:

• Designed specifically for sepsis (includes SOFA)
• Does not require fibrinogen or D-dimer
• Identifies earlier coagulopathy before meeting overt DIC criteria
• May identify patients who benefit from anticoagulant therapy

Clinical use:

• In sepsis patients, the SIC score can detect coagulopathy earlier
• Japanese data suggest SIC-positive patients may benefit from antithrombin or thrombomodulin
• However, large international trials (SCARLET, STARDUST) did not confirm treatment benefit
• In Australian/UK practice, we use overt DIC score more commonly

Examiner: What differential diagnoses would you consider for a patient with thrombocytopenia and schistocytes on blood film?

Candidate response:

Schistocytes with thrombocytopenia indicate a microangiopathic haemolytic anaemia (MAHA). The differential includes:

DIC:

• PT/APTT prolonged
• Fibrinogen LOW
• D-dimer very HIGH
• Underlying trigger present (sepsis, trauma, etc.)

Thrombotic Thrombocytopenic Purpura (TTP):

• ADAMTS13 activity below 10%
• PT/APTT NORMAL
• Fibrinogen NORMAL
• Neurological features, fever
• Treatment: Plasma exchange

Haemolytic Uraemic Syndrome (HUS):

• Renal failure predominates
• Typical HUS: E. coli O157:H7, Shiga toxin
• Atypical HUS: Complement dysregulation
• PT/APTT normal
• Treatment: Supportive (Eculizumab for aHUS)

Catastrophic Antiphospholipid Syndrome (CAPS):

• Multi-organ failure
• Antiphospholipid antibodies positive
• May have prolonged APTT (lupus anticoagulant)
• D-dimer elevated
• Treatment: Anticoagulation + plasma exchange + steroids

The key distinguishing features are the coagulation tests (PT, APTT, fibrinogen) and ADAMTS13 activity. In DIC, coagulation tests are abnormal; in TTP/HUS, they are typically normal.

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Viva 3: Management of Bleeding DIC

Examiner: A patient with septic shock develops profuse bleeding from venipuncture sites and surgical wounds. Labs show platelets 25 x 10^9/L, PT 28 seconds (control 12), fibrinogen 0.6 g/L. How would you manage this?

Candidate response:

This patient has overt DIC with hemorrhagic manifestations. My management priorities are:

Priority 1: Resuscitation

• Ensure adequate IV access for transfusion
• Activate massive transfusion protocol
• Consider permissive hypotension is NOT appropriate here - we need adequate MAP for organ perfusion

Priority 2: Treat the underlying cause

• This is definitive treatment - the coagulopathy will not resolve without addressing sepsis
• Ensure appropriate antibiotics
• Identify and control source (imaging, surgical consultation if needed)

Priority 3: Blood product replacement I would give:

Platelets:

• Currently 25 x 10^9/L with active bleeding - needs urgent transfusion
• Target greater than 50 x 10^9/L
• Give 1 pooled unit (expect rise of 20-40 x 10^9/L, often less in DIC due to consumption)

Fresh frozen plasma:

• PT 28 seconds (16 seconds prolonged, greater than 1.5x control)
• Give 15-20 mL/kg (approximately 4 units for 70 kg patient)
• Contains all coagulation factors

Cryoprecipitate/fibrinogen:

• Fibrinogen 0.6 g/L - critically low
• Give 2 pools of cryoprecipitate (10 units) - expect rise of ~0.5-1.0 g/L
• OR fibrinogen concentrate 4 g IV
• Target fibrinogen greater than 1.5 g/L

Examiner: Would you give tranexamic acid?

Candidate response:

No, tranexamic acid is CONTRAINDICATED in this patient.

This is sepsis-associated DIC, which has a thrombotic phenotype:

• PAI-1 is elevated, fibrinolysis is already suppressed
• Microthrombi are forming throughout the microvasculature
• Adding an antifibrinolytic would prevent breakdown of these clots
• This could worsen organ failure from persistent microvascular thrombosis

Tranexamic acid is only indicated in DIC with documented hyperfibrinolysis:

• APL-associated DIC
• Trauma with hyperfibrinolysis on viscoelastic testing
• Obstetric hemorrhage (WOMAN trial - different mechanism)

Examiner: What about antithrombin concentrate?

Candidate response:

I would NOT routinely give antithrombin despite low levels being likely in this patient.

Evidence against:

• The KyberSept trial (2001) randomised 2,114 patients with severe sepsis to high-dose antithrombin vs placebo
• Primary finding: No mortality benefit (38.9% vs 38.7%)
• Safety concern: Increased bleeding when given with concomitant heparin
• Subgroup analysis suggested possible benefit in DIC without heparin, but this was post-hoc and not definitive

Current recommendations:

• Surviving Sepsis Campaign guidelines recommend AGAINST antithrombin for sepsis
• Not used routinely in Australian/UK practice
• Japanese guidelines are more permissive, but these are based on different evidence

Similarly, recombinant thrombomodulin (SCARLET trial, STARDUST trial) showed no mortality benefit and is not recommended.

The only effective treatment for DIC is treating the underlying cause.

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Viva 4: APL-Associated DIC

Examiner: A 28-year-old presents with pancytopenia and gum bleeding. Blood film shows promyelocytes with Auer rods. Coagulation shows PT 18 seconds, fibrinogen 0.8 g/L, D-dimer greater than 20,000. What is the diagnosis and how would you manage the coagulopathy?

Candidate response:

This is acute promyelocytic leukaemia (APL) with DIC.

APL (FAB M3) is characterised by the t(15;17) translocation producing the PML-RARA fusion. It has a unique and severe coagulopathy requiring specific management.

Pathophysiology of APL-DIC:

• Promyelocytes express high levels of tissue factor - triggering coagulation
• Additionally express cancer procoagulant - directly activates Factor X
• Critically, they overexpress Annexin II - a receptor for plasminogen and tPA
• Annexin II accelerates plasmin generation → severe hyperfibrinolysis
• This causes life-threatening bleeding disproportionate to platelet count
• Intracranial hemorrhage is the leading cause of early death

Management priorities:

1. Start ATRA immediately:

• All-trans retinoic acid (ATRA) 45 mg/m²/day in divided doses
• Do NOT wait for molecular confirmation if APL is clinically suspected
• ATRA differentiates promyelocytes, reducing TF and Annexin II expression
• DIC typically improves within 24-72 hours
• This is disease-modifying therapy

2. Aggressive blood product support:

• Platelet target: greater than 30-50 x 10^9/L (higher than standard DIC)
• Fibrinogen target: greater than 1.5-2.0 g/L
• Cryoprecipitate or fibrinogen concentrate as needed
• FFP if PT significantly prolonged

3. Consider antifibrinolytics:

• Unlike sepsis-DIC, APL has hyperfibrinolysis
• Tranexamic acid may be considered for severe hemorrhage
• Some centres use TXA prophylactically until ATRA takes effect
• This is one of the few situations where antifibrinolytics may be appropriate in DIC

4. Avoid therapeutic heparin initially:

• Not indicated in hemorrhagic phenotype
• May worsen bleeding

5. Close monitoring:

• Coagulation tests twice daily initially
• Watching for DIC resolution (rising fibrinogen, normalising PT)
• Monitor for differentiation syndrome with ATRA (fever, dyspnea, weight gain)

Prognosis:

• With ATRA and arsenic trioxide, APL has excellent cure rates (greater than 90%)
• Early mortality from DIC-related hemorrhage is now below 10%
• Key is early recognition and immediate ATRA initiation

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