Disorders of coagulation or thrombosis - disseminated intravascular coagulation
Description
- Systemic intravascular coagulation activation - always secondary, never a primary diagnosis
- Simultaneous thrombosis and bleeding
- Microvascular fibrin deposition -> organ failure
- Consumption of platelets and factors + hyperfibrinolysis -> bleeding
- *Find and treat the trigger. Nothing else works.*
Two phenotypes - they behave differently
| Bleeding-dominant | Thrombotic / organ-failure-dominant | |
|---|---|---|
| Setting | APML, obstetric haemorrhage, trauma, aortic aneurysm, liver disease | Sepsis, malignancy (Trousseau), purpura fulminans |
| Driver | Hyperfibrinolysis predominates | PAI-1 suppresses fibrinolysis |
| Picture | Oozing, mucosal bleeding, low fibrinogen | Acral ischaemia, skin necrosis, AKI, ARDS |
- Chronic/compensated DIC - solid tumours, aortic aneurysm; normal or near-normal counts, high D-dimer, migratory thrombophlebitis
Epidemiology
- Sepsis is the commonest cause overall - DIC in ~30-50% of severe sepsis
- Occurs in ~1% of hospital admissions
- Present in >90% of newly diagnosed APML
- Obstetric: placental abruption, amniotic fluid embolism, retained dead fetus, severe pre-eclampsia/HELLP
- Mortality attributable to DIC roughly doubles the mortality of the underlying condition
Aetiopathogenesis
Core mechanism
- Tissue factor exposure to blood (the initiating event in almost every cause)
- -> FVIIa/TF -> excess thrombin
- -> fibrin deposition in the microvasculature -> microangiopathic haemolysis, ischaemic organ injury
- -> consumption of platelets, fibrinogen, factors V, VIII, and antithrombin, protein C
- -> plasmin activation -> fibrin degradation products, which themselves impair platelet function and fibrin polymerisation
- Impaired anticoagulant pathways - antithrombin consumed, protein C pathway downregulated by inflammatory cytokines, TFPI overwhelmed
- Suppressed fibrinolysis in sepsis (inc PAI-1) -> the thrombotic phenotype
Causes
- Sepsis - Gram negative and Gram positive; meningococcaemia -> purpura fulminans
- Malignancy
- APML - *the highest-risk single cause*
- Mucin-secreting adenocarcinoma (pancreas, stomach, prostate) - chronic DIC/Trousseau
- Obstetric - abruption, amniotic fluid embolism, retained products/dead fetus, pre-eclampsia/HELLP, septic abortion
- Trauma - especially head injury (brain is rich in tissue factor), crush, burns, fat embolism
- Vascular - giant haemangioma (Kasabach-Merritt), large aortic aneurysm, vascular malformation
- Immunological - ABO-incompatible transfusion, severe transfusion or drug reaction, transplant rejection, anaphylaxis
- Toxins - snake envenomation (Australian brown snake -> venom-induced consumption coagulopathy), amphetamines
- Severe liver disease, acute pancreatitis, heat stroke, hyperthermia
APML - why the coagulopathy is uniquely severe
- Tissue factor and cancer procoagulant on the promyelocyte membrane -> unregulated thrombin generation
- Simultaneously, annexin II on the promyelocyte surface accelerates plasminogen -> plasmin -> primary hyperfibrinolysis
- Granule elastase degrades fibrinogen directly
- -> consumptive coagulopathy + hyperfibrinolysis together = catastrophic haemorrhage
- *Intracranial and pulmonary haemorrhage is the commonest cause of early death in APML, and it happens before and during the first days of treatment*
Diagnosis
Recognise the setting first
- DIC is a clinical diagnosis supported by tests. The tests alone are neither sensitive nor specific.
- Bleeding from venepuncture sites, drains, wounds; oozing rather than a discrete bleed
- Acral cyanosis, purpura fulminans, skin necrosis, AKI, delirium, ARDS
Laboratory pattern
| Test | DIC |
|---|---|
| Platelets | Low, and FALLING - the trend matters more than the value |
| PT / INR and APTT | Prolonged (may be normal or short early, from circulating thrombin) |
| Fibrinogen | Low - but it is an acute phase reactant, so a "normal" fibrinogen in sepsis may already represent a large fall |
| D-dimer / FDPs | High - sensitive, very non-specific |
| Film | Schistocytes (~50%, usually few) |
| Antithrombin, protein C | Reduced |
| Factor VIII | Low (distinguishes from liver disease, where FVIII is preserved or high) |
ISTH overt DIC score - >=5 = overt DIC
Requires an underlying condition known to be associated with DIC.
| Points | |
|---|---|
| Platelets >100 = 0; 50-100 = 1; <50 = 2 | |
| D-dimer/FDP no rise = 0; moderate = 2; strong = 3 | |
| PT prolongation <3 s = 0; 3-6 s = 1; >6 s = 2 | |
| Fibrinogen >1 g/L = 0; <1 g/L = 1 |
Key differentials
| Distinguishing feature | |
|---|---|
| Liver disease | Factor VIII normal or high; fibrinogen falls late; splenomegaly, stigmata |
| TTP | Coagulation screen NORMAL, ADAMTS13 <10%, many schistocytes, neurological/renal |
| HUS | Normal coagulation, diarrhoeal prodrome or complement abnormality |
| HIT | Isolated thrombocytopenia, normal fibrinogen, thrombosis not bleeding |
| Vitamin K deficiency / warfarin | PT >> APTT, normal platelets, normal fibrinogen |
| Dilutional coagulopathy | History of massive transfusion/fluid resuscitation |
- *Repeat the panel every 4-8 hours in an unstable patient - the trend is the diagnosis*
Management
A. Treat the cause - the only intervention that changes outcome
- Source control and antibiotics in sepsis (within 1 hour)
- Deliver the fetus/evacuate the uterus in obstetric DIC
- Start ATRA immediately on clinical suspicion of APML - do not wait for cytogenetic confirmation
- Antivenom for envenomation; chemotherapy for the malignancy; surgical control of trauma
B. Blood product support - only for bleeding, or before an invasive procedure, or at very high bleeding risk
*Do not transfuse to correct numbers in a patient who is not bleeding.*
| Product | Trigger | Target |
|---|---|---|
| Platelets | Bleeding, or pre-procedure | >50 x10^9/L (>20-30 if not bleeding and at high risk; >=50 in APML regardless of bleeding**) |
| FFP 15-25 mL/kg (~4+ units) | Prolonged PT/APTT (>1.5x normal) with bleeding | Correct PT/APTT |
| Cryoprecipitate (~10 units) or fibrinogen concentrate | Fibrinogen <1.5 g/L (many protocols use <1.0; *obstetric haemorrhage target >2.0 g/L*) | Fibrinogen >1.5-2.0 |
| Prothrombin complex concentrate | Volume-restricted patients | Second line - lacks factor V and can worsen thrombosis |
- Vitamin K and folate replacement where deficient
C. Anticoagulation - narrow indication
- Therapeutic heparin only for the thrombotic phenotype: purpura fulminans, acral ischaemia, macrovascular thrombosis, Trousseau syndrome
- Prophylactic-dose heparin/LMWH in non-bleeding critically ill patients - VTE prophylaxis
- Antithrombin and activated protein C concentrates are not standard - no consistent mortality benefit
- *Protein C concentrate is used in purpura fulminans, especially meningococcal and congenital protein C deficiency*
D. Antifibrinolytics
- *Generally contraindicated in DIC* - blocking fibrinolysis with ongoing fibrin deposition worsens organ failure
- Exceptions: primary hyperfibrinolytic states - APML, obstetric haemorrhage (as part of a major haemorrhage protocol), prostatic surgery, snake envenomation
E. APML-specific
- ATRA on suspicion; ATRA + arsenic trioxide is standard for non-high-risk disease
- Aggressive product support - platelets >=50, fibrinogen >=1.5 g/L, INR near normal, *continued daily until the coagulopathy resolves (usually 7-14 days)*
- Avoid central lines, lumbar punctures and any non-essential procedure during the coagulopathic phase
- Watch for differentiation syndrome - fever, dyspnoea, infiltrates, weight gain, hypotension -> dexamethasone
Associations
- Sepsis, especially meningococcaemia (purpura fulminans) and Gram-negative shock
- Acute promyelocytic leukaemia and other acute leukaemias
- Mucin-secreting adenocarcinoma - Trousseau syndrome, migratory thrombophlebitis, non-bacterial thrombotic endocarditis
- Obstetric: abruption, amniotic fluid embolism, HELLP, retained dead fetus, septic abortion
- Major trauma, head injury, burns, fat embolism, crush injury, rhabdomyolysis
- ABO-incompatible transfusion, acute haemolytic transfusion reaction
- Kasabach-Merritt phenomenon; large aortic aneurysm
- Snake envenomation (Australian elapids), heat stroke, severe pancreatitis, acute liver failure
- Adrenal haemorrhage - Waterhouse-Friderichsen syndrome
Natural history & complications
- Prognosis is that of the underlying disease, worsened by the DIC
- Resolves within days once the trigger is controlled; persistence means the trigger is not controlled
- DIC roughly doubles mortality in sepsis; overt DIC in sepsis carries ~40-60% mortality
- APML: early haemorrhagic death ~5-10% even in modern practice, and almost all of it occurs in the first 2 weeks
- Otherwise APML is the most curable acute leukaemia (>90% long-term survival)
Complications
- Intracranial and pulmonary haemorrhage (the killer in APML)
- Acute kidney injury, ARDS, hepatic dysfunction - microvascular fibrin deposition
- Purpura fulminans and digital/limb gangrene requiring amputation
- Waterhouse-Friderichsen syndrome - bilateral adrenal haemorrhage -> adrenal crisis
- Sheehan syndrome after obstetric DIC
- Transfusion-associated complications - TACO, TRALI, alloimmunisation
Monitoring
- Serial platelets, PT/APTT, fibrinogen, D-dimer 4-12 hourly while unstable
- A rising fibrinogen and platelet count is the earliest sign the trigger is under control
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