Key facts:
Authors: Suzanne Hall
Top Tip: 60% have underlying sepsis; treat it aggressively
Key Differential Diagnoses
- Idiopathic thrombocytopenic purpura (ITP)
- Heparin-induced thrombocytopenia (HIT)
- Thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome (TTP/HUS) (clotting typically normal)
- Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP)
Key Investigations
- FBC (platelets ± Hb low) and blood film
- PT, APTT (high)
- Fibrinogen (low)
- U+E, LFT, Bone, CRP, Glucose
- D-dimer, FDPs (high)
- CXR, E CG
Key Treatments
- Of underlying condition (e.g. antibiotics and fluid resuscitation for infection; or obstetric surgery)
- Consider FFP, platelets, cryoprecipitate (all senior decisions)
- Prophylactic LMWH in all patients unless active bleeding
Key Management Decision
- ITU
- Investigation of underlying cause
- Management of obstetric causes when relevant
Background
DIC = widespread intravascular activation of the coagulation system
Introduction
- Usually there is a balance between the clotting and lysis systems, however, in DIC, the coagulation cascade is activated inappropriately and diffusely
- DIC occurs in response to another pathology rather than as a primary event
- In one study the mortality of sepsis associated with DIC was 43%, compared to 27% for sepsis alone
- A combination of bleeding and thrombosis occurs simultaneously. Fibrin deposition leads to microvascular thrombosis leading to multi-organ failure, whilst consumption of clotting factors and platelets leads to bleeding
- Deposition of intravascular fibrin strands leads to microangiopathic haemolysis. Red cell fragments are thus usually seen on blood films, though not as prominently as in TTP/HUS
- DIC that evolves slowly (over weeks or months) primarily causes thrombotic and embolic manifestations; DIC that evolves rapidly (over hours or days) primarily causes bleeding
- The following haematological abnormalities are characteristic:
- Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged
- Platelet count (± Hb) and fibrinogen decrease
- Fibrin degradation products (FDP), such as D-dimers, are elevated - Clinical features are mainly of the underlying disease along with bleeding and/or thrombosis
- DIC strictly cannot be diagnosed in the absence of an underlying diagnosis known to be associated with DIC
- The complete set of clotting abnormalities with low platelet count will not always be present and there is no single confirmatory test; however a scoring system (see below) has been developed to aid diagnosis
- Treatment of DIC remains the optimal management of the underlying disorder, with appropriate blood product support
Pathophysiology
Bleeding
- Depletion of clotting factors causes prolongation of PT and aPTT
- Widespread thrombin activation consumes plasma fibrinogen leading to an increased thrombin time
- Activation of fibrinolysis (indicated by raised FDPs such as D-dimers)
- Thrombocytopenia (platelets consumed in microthrombi)
Thrombosis
- Formation of microthrombi (clots) from circulating activated clotting factors, within small blood vessels leads to end-organ damage e.g. kidney and liver
- Formation of larger thrombi in significant vessels also contributes towards morbidity and mortality
Anaemia
- Destruction of red cells causes a microangiopathic haemolytic anaemia
Definition
"An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction" (Subcommittee on DIC, International Society on Thrombosis and Haemostasis)
Epidemiology
- DIC is more common than you might think
- A degree of DIC may occur in 30-50% of patients with sepsis
- And in 1% of all hospitalised patients
- There are no predisposing factors in terms of age, sex or race
Causes
- Infections (60%): particularly gram-ve septicaemia, E. coli O157, Staphylococcus aureus, meningococcal septicaemia, typhoid fever, malaria (especially Falciparum),
- Malignancy, especially disseminated adenocarcinoma e.g. pancreas or prostate, and acute promyelocytic leukaemia
- Obstetric emergencies: placental abruption, amniotic fluid embolism, severe pre-eclampsia, retained dead fetus
- Major trauma, including crush syndrome/burns
- Aortic aneurysm and cavernous haemangiomas (Kasabach-Merritt syndrome)
- Liver failure
- Recreational drug use e.g. ‘ecstasy’
- Some connective tissue disorders including antiphospholipid syndrome
- ABO incompatible blood transfusion
- Anaphylaxis
- Snake bites
- Transplant rejection
Symptoms
- Non-specific (patient often very unwell)
- Bleeding (typically dominant in acute DIC)
- Of thrombosis (typically dominant in chronic DIC)
- Rash (purpura)
- Of underlying cause
Key questions
- “When did the bleeding start?"
- “What other medical problems do you have?”
Signs
- Bleeding from at least three unrelated sites is typical and likely sites include:
- Ears, nose and throat
- Gastrointestinal tract
- Respiratory tract
- Site of arterial (eg ABG) or venepuncture/cannulation - Signs of adult respiratory distress syndrome (ARDS)
- Skin may show various signs including:
- Petechiae
- Purpura
- Haemorrhagic bullae
- Acral cyanosis
- Skin necrosis of lower limbs (purpura fulminans; secondary to protein C deficiency as part of the generalised consumption of clotting and anticoagulant factors)
- Signs of venous thrombosis (i.e. warmth, dilated superficial veins)
- Signs of arterial thrombosis (localised infarction and gangrene) - Confusion secondary to intracerebral microthrombi
- Signs of underlying condition
- Fever, septic shock
- Pregnancy with absence of fetal signs of life or sudden onset shock and hypoxia (i.e. amniotic fluid embolus)
- Clubbing, spider naevi, palmar erythema etc. in chronic liver disease
Clinical features (Siegal et al, 1978)
- Bleeding 64%
- Renal dysfunction 25%
- Hepatic dysfunction 19%
- Respiratory dysfunction 16%
- Shock 14%
- Central nervous system dysfunction 2%
Investigation
No single laboratory assay is pathognomonic of DIC
Blood
- FBC (platelets ± Hb low), blood film (red cell fragments; NB if very prominent, consider other causes f MAHA such as TTP)
- Prothrombin time (PT), Activated partial thromboplastin time (aPTT) (high)
- Fibrinogen (low)
- Fibrin degradation products (FDP) e.g. D-dimer (high, but not specific for DIC)
- U+E, LFT, Bone profile, Glucose, CRP
- Blood cultures
Notes:
- Liver disease and renal impairment can raise the level of FDPs, as can recent trauma, surgery, infection or thrombosis
- PT/aPTT may be shortened or normal in DIC, especially in chronic cases or in the early phase of acute DIC
- In DIC, abnormalities in haemostasis in decreasing order of frequency are: thrombocytopenia, increased FDPs, prolonged PT, prolonged aPTT, low fibrinogen
Other
Radiology
- CXR
- Ultrasound with Dopplers, CTPA etc. if clinical features of thrombosis or pulmonary embolism
Other - Urinalysis, ECG
- Cardiotocograph (CTG) in pregnancy, plus further investigations as guided by obstetricians if relevant
- Consider investigations for underlying malignancy (e.g. CXR, CT scan, PSA) if cause of DIC uncertain, or if there are suspicious symptoms and signs
ISTH scoring system (Fletcher, 2001)
Parameter Score 0 1 2 3
Platelet count (x109/L) >100 50-100 <50
Elevated fibrin marker* (inc) No Mod Strong
PT (seconds) <3 3-6 >6
Fibrinogen (g/L) >1 <1
*multiple measures of FDP available; specific parameters to be determined locally
Calculate score:
- Greater than or equal to 5 = compatible with ‘Overt DIC’; repeat scoring at least daily
- Less than 5 = possible non-overt DIC or alternative diagnosis needs to be considered
Notes: mortality increases with higher scores; score should only be utilised in the presence of a disorder known to be associated with DIC (usually sepsis or malignancy). Can be used in both chronic and acute DIC
Key investigations
- Clotting ‘screen’ with D-dimer and fibrinogen (D-dimer is non-specific and may be more useful for monitoring than diagnosis, but a normal value would rule out the diagnosis)
- No single test can diagnose DIC
Specialist investigation
- Blood film
Differential diagnoses
Thrombocytopenia (other causes):
- Idiopathic thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome (TTP/HUS)
- Heparin-induced thrombocytopenia (HIT)
- Haemolysis, Elevated Liver enzymes and Low Platelet count (HELLP)
- Marrow infiltration e.g. in patients with malignancy
- Drug causes
- Disorders of haematopoiesis
- Artefact (e.g. EDTA-induced platelet aggregation)
Deranged clotting - Artefactual e.g. sample contaminated with heparin, delayed processing of sample
- Liver disease
- Massive haemorrhage/transfusion
Microangiopathic haemolytic anaemia (MAHA) - Severe sepsis
- TTP/HUS
- HELLP
- Renal disease e.g. acute glomerulonephritis
Other - Vasculitis
- Burns
- Drugs
- Prosthetic cardiac valves
Treatment
The only definitive therapy for DIC is control of the initiating disease process
Treatment (principles)
- Of underlying disease, e.g. broad spectrum (empirical in the presence of focal symptoms and signs) antibiotics and aggressive fluid resuscitation for infection; or,
- Of obstetric cause (e.g. surgery; involve obstetric team urgently)
- Following treatment of the underlying cause, DIC should resolve, however it is often necessary to support deranged clotting in the intervening period
- Clotting tests should be repeated following administration of blood products
- If blood products are required in DIC, clotting tests should be repeated twice daily as a minimum; products will often need to be given many times during the course of the illness
- Always discuss with senior haematologist
Treatment
(first line)
- FRESH FROZEN PLASMA (FFP)* (15-30 ml/kg, usually 4-5 units), if PT or APTT >1.5x control
- 1 adult therapeutic dose (ATD) PLATELETS, if platelet count
<10-20x109/L in the absence of bleeding or risk factors for bleeding (e.g. postoperatively)
<50x109/L in the presence of bleeding or planned invasive procedure
<100x109/L and rapidly falling - CRYOPRECIPITATE (2 pools), if fibrinogen <1 g/L
- Prophylactic dose low molecular weight heparin, e.g. SC ENOXAPARIN 40mg should be given to patients with DIC except those who are actively bleeding
Notes:
- Consider therapeutic doses of heparin in patients with arterial or venous thromboembolism, or severe purpura fulminans
- Consider recombinant activated protein C only if not at high risk of bleeding, and platelets >30x109/L (specialist only)
- Recombinant Factor VIIa has been used in patients with DIC and life-threatening bleeding but the efficacy and safety of this is unknown and it should be used by experts only
- In patients in whom the volume of FFP is not able to be administered because of volume overload, consider using prothrombin complex concentrates (seek specialist advice); these will only partially correct the deficit (only contain factors II, VII, IX and X)
Supportive measures (nursing)
- Bleeding sites e.g. venepuncture sites
- Monitoring for signs of bleeding and new skin changes
Stop
- Drug causes
- Heparin if bleeding develops
Treatment
(second line)
- Supportive measures such as correction of hypoxia, acidosis, renal failure (?dialysis), and shock
Prescribing issues
- Senior staff only; discuss need for blood product support with senior haematologist
Admit?
- Always. Will usually be admitted anyway (often on ITU)
Bed plan
- ITU, often
- Obstetric ward if relevant
Referrals
- Team responsible for underlying condition,i.e. oncology, obstetrics
- ITU
- Haematology
- Microbiology (if infection is or may be the cause)
The Rest
Maxim
- "If you see a low platelet count, think DIC, think action"
Complications
- Organs can be destroyed by infarction, and limb ischaemia can lead to loss of digits or more
- Bleeding can be fatal
Risk stratification
- See scoring system in Investigations
Follow-up
- With team responsible for underlying condition
Prognosis
- The mortality of DIC is unknown, but probably high; it mainly relates to the severity of the underlying disease
- In the setting of major trauma, the presence of DIC approximately doubles the mortality rate
- In one study, septic patients with DIC had higher mortality than trauma patients with DIC (34.7% vs 10.5%)
2° Prevention
+ Health promotion
- Treat infection aggressively, especially if organism known to cause DIC
Don't forget
- It is more common that you might think
- The 'full house' of haematological abnormalities is rare
- There is no single laboratory test
- Clinical features are mainly of the underlying disease
- Treatment involves optimal management of the underlying disorder
- Treat infection aggressively
Red flags
- Shock
- System failure
- Neurological involvement
- Uncontrolled bleeding
Synonyms: DIC, consumptive coagulopathy, consumptive thrombo-hemorrhagic disease, defibrination syndrome