Disseminated Intravascular Coagulation (DIC)

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Introduction

Disseminated intravascular coagulation (DIC) is a serious disorder occurring in response to an illness or disease process which results in dysregulated blood clotting.1

In health, there is usually a balance between the clotting and fibrinolytic systems. However, in DIC inappropriate activation of one or both systems leads to a paradoxical tendency to both bleeding and thrombosis simultaneously.


Aetiology

Pathophysiology

DIC does not arise by itself but instead develops on a background of some other severe pathology.

Triggers for DIC are varied but in general, may include infectious causes (e.g. sepsis) and non-infectious causes (e.g. malignancy or severe burns).1 

Some trigger conditions such as sepsis and trauma lead to a release of pro-inflammatory cytokines in a so-called systemic inflammatory response. In other conditions, the expression of certain pro-coagulant factors, such as tissue factor, is upregulated.2

Whatever the mechanism, these triggers lead to intravascular activation of the coagulation cascade throughout the body (Figure 1).

Microvascular thrombosis results due to the formation of fibrin webs and the activation and aggregation of platelets within the small blood vessels. These small thrombi can lead to multi-organ failure due to tissue ischaemia.3

Clotting cascade
Figure 1. Inappropriate systemic activation of the coagulation cascade in DIC leads to the production of thrombin, which activates fibrin from its inactive precursor fibrinogen. This leads to the formation of networks of cross-linked fibrin within the blood vessels.

At the same time, widespread activation of coagulation leads to a reduction in the concentration of circulating coagulation factors. This is referred to as a consumptive coagulopathy since clotting factors are being used up (consumed) by intravascular thrombosis.

As the concentration of available clotting factors falls, the risk of bleeding increases. Platelets are also being used up due to activation and aggregation within the circulation, which leads to thrombocytopenia, further increasing the risk of bleeding.

Thus, in severe DIC there is paradoxically simultaneous thrombosis and spontaneous bleeding. A summary of the pathophysiology of DIC can be seen in Figure 2.

Figure 2. DIC results from the activation of the coagulation system via a variety of mechanisms. This leads to thrombosis in the small vessels (microvascular thrombosis) as well as spontaneous bleeding due to consumption of clotting factors and platelets.

Causes of DIC

The causes of DIC include:4

  • Shock
  • Sepsis/severe infection: these lead to the massive release of pro-inflammatory cytokines in a systemic inflammatory response. These cytokines can activate the coagulation system.
  • Major trauma or burns
  • Malignancies: including both solid organ and haematological malignancies. Acute promyelocytic leukaemia (APML) is strongly associated with DIC.
  • Obstetric emergencies: including eclampsia, HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome, placental abruption, intrauterine death and amniotic fluid embolism.
  • Severe immune-mediated reactions: such as acute haemolytic transfusion reactions due to mismatched ABO antigens, organ transplant rejection and bites from certain venomous snakes.
  • Severe organ dysfunction: including acute hepatic failure and severe acute pancreatitis.

DIC can be acute or chronic. Acute DIC is the most common subtype, with rapid-onset conditions such as trauma, sepsis and haemolytic transfusion reactions. Chronic DIC tends to occur with less rapid-onset conditions such as cancer.4


Clinical features

The features of DIC can vary from a mild chronic form with little overt features to an acute and catastrophic event resulting in severe, spontaneous haemorrhage and multi-organ failure.3

Since DIC evolves in association with some other pathology, often the most obvious features from the history and examination are those of the underlying condition itself.

History

For a diagnosis of DIC to be made, there must be some objective evidence of a precipitating factor.

Precipitating factors identified in the history may include:1

  • Acute illness or major trauma
  • Symptoms of infection
  • Symptoms of malignancy: weight loss, anaemia, night sweats, lymphadenopathy or masses
  • Past medical history: underlying organ dysfunction (especially hepatic cirrhosis or pancreatitis)
  • Recent blood transfusion: acute haemolytic transfusion reaction
  • Obstetric history: symptoms of pre-eclampsia (headache, oedema, visual disturbance), fetal movements, abdominal pain or vaginal bleeding

Typical symptoms of DIC may include:

  • Bleeding from unusual sites: ears, nose, gastrointestinal tract, genitourinary tract, respiratory tract or sites of venepuncture or cannulation. Bleeding from three unrelated sites is highly suggestive of DIC.
  • Widespread or unexpected bruising without a history of trauma
  • New confusion or disorientation: a sign of microvascular thrombosis affecting cerebral perfusion

Clinical examination

Clinical examination will typically reveal signs of an underlying cause.

Non-specific clinical examination findings which may point towards DIC include:

  • Signs of haemorrhage: bleeding from cannula sites/venepuncture sites, melaena, haematemesis, rectal bleeding, epistaxis, haemoptysis, haematuria
  • Petechiae or purpura (Figure 3)
  • Livedo reticularis: a mottled lace-like patterning of the skin (Figure 4)
  • Purpura fulminans: widespread skin necrosis
  • Localised infarction and gangrene for instance of the digits (Figure 5)
  • Confusion
  • Oliguria, hypotension and/or tachycardia: signs of circulatory collapse, which is associated with DIC

 


Investigations

There is no single investigation that can ‘prove’ DIC. The diagnosis is made based on both clinical and laboratory features. Tests also need repeating regularly as the condition evolves over time.1

ISTH scoring system

The international society of thrombosis and haemostasis (ISTH) has produced a scoring system, which aims to make the diagnosis of DIC more objective. The score has a sensitivity of 93% and a specificity of 98%.5

This scoring system utilises the platelet count, D-dimer value, prothrombin time and fibrinogen levels to assess the likelihood that a patient has DIC. 

It is important that the scoring system is only used for patients in whom there is clinical evidence of a precipitating cause and isn’t applied indiscriminately to those with unusual bleeding, bruising or thrombosis.

Bedside investigations

There are no specific bedside investigations, but since these patients may be critically unwell an updated set of observations should be obtained and repeated regularly to monitor for signs of acute deterioration.

Laboratory investigations

Important laboratory investigations to consider include:4

  • Full blood count: there is typically thrombocytopenia in DIC due to excessive consumption. 
  • Coagulation screen: including PT and APTT. PT is a measure of the extrinsic and common pathways of coagulation (Figure 1) and is prolonged in 50-70% of patients with DIC. APTT measures the intrinsic and common pathways of coagulation (Figure 1) and is prolonged in 50-60% of DIC patients.
  • Clauss fibrinogen: typically decreased as fibrinogen is converted to fibrin in intravascular thrombosis. Clauss fibrinogen should be requested rather than the derived fibrinogen sometimes included as part of the standard coagulation screen, since this may overestimate the actual levels.
  • D-dimer/fibrin degradation products: are typically raised providing evidence of degradation of fibrin clots around the body. 

Other investigations

All other blood tests and imaging studies will depend on the underlying cause. For instance, in cases of sepsis blood cultures and serum lactate should be requested.


Differential diagnoses

There are several differentials to be aware of when considering a diagnosis of DIC.4

Acute hepatic failure

Acute hepatic failure is the most common differential diagnosis and also a well-recognised cause of DIC, which can make distinguishing the two conditions challenging.

There may be signs of bleeding but no symptoms and signs of thrombosis (e.g. infarction, gangrene, necrosis). There may be peripheral stigmata of liver disease on examination and LFTs are often elevated. D-dimer is likely to be mildly elevated but not markedly so, as seen in DIC.

The platelets may be low but in DIC the platelet count will fall over time whereas the levels are more likely to be stable in acute liver failure.

Vitamin K deficiency

In cases of vitamin K deficiency there will be signs of bleeding but no signs or symptoms of thrombosis. The PT will be prolonged and sometimes the APTT as well. D-dimer will be normal in contrast to DIC.

The best test is to give a dose of intravenous vitamin K. In vitamin K deficiency clotting results will correct within six hours.

HELLP Syndrome

HELLP syndrome usually occurs after 28-weeks’ gestation and is associated with pre-eclampsia. The key features are hypertension, deranged LFTs and thrombocytopenia.

HELLP syndrome is also a recognised cause of DIC. If the diagnosis is HELLP syndrome alone, there will be no symptoms or signs of thrombosis and the PT/APTT will be normal.

D-dimer is often elevated in pregnancy so is not a particularly useful test in this context. The FBC will show low platelets and possibly anaemia (due to haemolysis).

Idiopathic purpura fulminans

Idiopathic purpura fulminans (IPF) is a condition characterised by well-demarcated cutaneous purpuric lesions.

It is usually associated with sepsis. D-dimer levels are often normal, helping to distinguish it from DIC. However, many patients with IPF will go on to develop DIC.

Table 1. Pattern of coagulation screen results in different coagulopathies. Table adapted from the Oxford Handbook of Clinical Medicine. 

Disorder

PT/INR

APTT

Platelets

DIC

Increased

Increased

Decreased

Liver disease

Increased

Increased

Normal/decreased but stable

Heparin use

Normal    

Increased

Normal

Thrombocytopenia

Normal

Normal

Decreased

Platelet defects

Normal

Normal

Normal

Vitamin K deficiency

Increased

Increased

Normal

Von Willebrand’s

Normal

Increased

Normal

Haemophilia

Normal

Increased

Normal

 
Other causes of a prolonged APTT/PT and low fibrinogen (as seen in DIC) include:3
  • Dilutional coagulopathy: which occurs due to massive transfusion when large volumes are infused into the patient, diluting the concentration of coagulation factors. This is now less common with modern major haemorrhage protocols.
  • Post-thrombolysis: treatment with Alteplase for stroke or myocardial infarction can give the same pattern of coagulation abnormalities as seen in DIC.

Management

The treatment of DIC involves two stages: treatment of the underlying disorder, which stops the triggering process, and supportive treatment to restore normal coagulation.

Transfusion protocols for DIC are complicated but in general should be based on whether there is clinical evidence of bleeding or need for an invasive procedure, rather than any specific ‘trigger’ value from laboratory tests.1 It is important to get urgent senior support and input from a haematologist.

Platelet transfusions should be considered if the patient is bleeding. The platelet count should be maintained >50 x 109/L in the presence of bleeding.    

In bleeding patients with a prolonged PT and/or APTT, fresh frozen plasma can be considered.

Concentrated solutions of clotting factors may also be considered such as prothrombin complex concentrate, or specific factor infusions.

If there is severely low fibrinogen then transfusions of cryoprecipitate or fibrinogen concentrate should be considered.

If thrombosis is a prominent feature, then therapeutic doses of heparin should be considered. If there is co-existing high risk of bleeding, then unfractionated heparin can be used since this has a significantly shorter half-life and is more readily reversible than low molecular weight heparin.1

In other patients who are non-bleeding, prophylactic doses of heparin are recommended to protect against VTE. This might seem counter-intuitive since these patients remain at high risk of bleeding, but they are also at risk of venous thromboembolism so will require thromboprophylaxis.


Complications

Complications of DIC include:

  • Multi-organ failure: both DIC and the conditions that cause it can lead to multi-organ failure. For example, acute renal failure, hepatic failure and acute respiratory distress syndrome (ARDS). Patients with evolving multi-organ failure should be escalated to ICU for organ support.
  • Life-threatening haemorrhage: this occurs late in the disease process after coagulation factors and platelets have been severely depleted. Aggressive replacement of coagulation factors and platelets is required to prevent this complication.
  • Cardiac tamponade: can occur when there is bleeding into the pericardial space resulting in Beck’s triad of hypotension, muffled heart sounds and elevated JVP. This can rapidly progress to obstructive shock and death if not urgently managed with pericardiocentesis.6
  • Haemothorax: bleeding into the pleural space can cause a haemothorax. There will be typical signs of fluid in the pleural space (dullness to percussion, absent breath sounds and reduced chest expansion). Chest X-ray will show a homogenous opacification with a meniscal fluid level when in the erect position. If the haemothorax is very large there may be contralateral mediastinal shift.
  • Intracranial haemorrhage: should be suspected in any patient with evolving neurological signs or a falling GCS. A CT head should be urgently requested, and a neurosurgical input sought.
  • Gangrene and loss of digits: microvascular thrombosis leads to ischaemia and infarction of the digits. This can lead to loss of fingers and/or toes.

Key points

  • DIC is a serious condition in which there is a simultaneous tendency to spontaneous bleeding and thrombosis.
  • It occurs when there is systemic activation of the coagulation system and widespread microvascular thrombosis, which also leads to depletion of clotting factors and platelets and an elevated risk of bleeding.
  • The triggers for DIC are diverse and include infectious causes such as sepsis and non-infectious causes such as major trauma, burns or cancer.
  • There will be a history of some precipitating event and often the most prominent findings on examination are of the underlying condition itself rather than the DIC.
  • Specific features in the history and examination pointing to DIC include bleeding from three or more unrelated sites and skin changes such as livedo reticularis, infarction and gangrene of the digits and widespread or evolving purpura.
  • The diagnosis is based on clinical assessment and the ISTH scoring system.
  • Management involves prompt recognition and treatment of the underlying cause.
  • Transfusion support may need to be provided if there is evidence of bleeding or the patient needs to go for an invasive procedure. Seek advice from a haematologist.
  • DIC can rapidly progress to multi-organ failure and death if not aggressively treated.

Reviewer

Dr James Wilson

Haematology SpR

Calderdale & Huddersfield NHS Foundation Trust


Editor

Dr Chris Jefferies


References

  1. Tidy C. Disseminated Intravascular Coagulation. Patient.info. Published in 2020. Available from: [LINK]
  2. Gando S et al., Disseminated Intravascular Coagulation. Nature Reviews Disease Primers. Published in 2016. Available from: [LINK]
  3. Nickson C. Disseminated Intravascular Coagulation. Life in the Fast Lane (LITFL.com). Published in 2020. Available from: [LINK]
  4. Wang H. Disseminated Intravascular Coagulation. BMJ Best Practice. Published in 2020. Available from: [LINK]
  5. Toh CH et al., The Scoring System of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. Journal of Thrombosis and Haemostasis. Published in 2007. Available from: [LINK]
  6. Sharma R & Rezaee A et al., Beck Triad. Radiopedia.com. Published in unknown. Available from: [LINK]
  7. Botz B & Weerakkody Y et al., Haemothorax. Radiopedia.com. Published in unknown. Available from: [LINK]

Image references

  • Figure 1. Jcchem183. The Blood Clotting Cascade. License [CC BY-SA]
  • Figure 2. Manning J. The Pathophysiology of DIC.
  • Figure 3. DrFO.Jr.Tn. Petechial Rash. License [CC BY-SA
  • Figure 4. Nantsupawat T et al., Livedo Reticularis of the Left Leg. License [CC BY-SA]
  • Figure 5. Wellcome Images. Dry Gangrene of the Hand Wellcome L0062224. License [CC BY 4.0]

 

 
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