Disseminated Intravascular Coagulation (DIC)

Context

Disseminated intravascular coagulation (DIC) is a haematological disorder which results in a paradoxical tendency to thrombosis and bleeding at the same time.¹

Also referred to as consumptive coagulopathy or defibrination syndrome, it can present as a life-threatening emergency, or as a chronic or subclinical process dictated by the underlying aetiology and associated morbidities.²

DIC occurs in response to an underlying trigger or pathological process. In the early 1980s Spero and colleagues labelled DIC as a sign that “death is coming”.³ Since that time, advances in laboratory testing and our understanding of the underlying pathogenesis have allowed a clearer picture of the process of DIC to develop.⁴

Epidemiology

The incidence and mortality of DIC varies based on several factors such as the underlying disorder, place of treatment and diagnostic criteria used.⁶

Table-1 Epidemiology of DIC

ISTH – International Society on Thrombosis and Haemostasis

The above table highlights that the incidence of DIC is highest in trauma and severe sepsis (8.9% to 28.9 %).^7-10Mortality in these patients is alarmingly over 30% which emphasises the need for early detection and treatment.

Learning bite

DIC is a syndrome and not a specific disease entity.

DIC is associated with high rates of mortality.  

Definition

The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) formally defined DIC in 2001 as

“An acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes. It can both originate from and cause damage to the microvasculature, which, if sufficiently severe, can produce organ dysfunction.”¹³

The British Journal of Haematology states that DIC is

“a clinicopathological syndrome which complicates a range of illnesses. It is characterised by systemic activation of pathways leading to and regulating coagulation, which can result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors that may result in clinical bleeding.”¹⁴

Learning bite

Clinical investigations have shown that DIC is an independent prognosticator of organ dysfunction and death.

In normal haemostasis, vessel injury triggers localised clot formation (coagulation) at the site of injury, followed by clot resolution (fibrinolysis) with tissue repair. This process is tightly controlled by regulatory proteins and feedback mechanisms.

In DIC, there is abnormal systemic activation of the coagulation and fibrinolytic pathways, when blood cells and the endovascular lining are exposed to a procoagulant factor from which they would be protected under normal circumstances. Table 2 below includes the pathological processes that can trigger DIC:

Table 2 Common triggers and procoagulant factors in DIC²

Trigger	Procoagulant factor/ process
Sepsis	Liposaccharides
Meningococcal sepsis	Microparticles containing tissue factors
Trauma	Damage to endothelium results in release of phospholipids
Malignancy	Tissue factors produced by cancer cells
Blood transfusion mismatch	Cytokines including tissue necrosis factor, Interleukin-1

The ISTH definition emphasises three factors that lead to organ dysfunction¹³

Activation of intravascular coagulation and fibrinolysis

• • Activation of the coagulation cascade leads to the formation of thrombi in the microvasculature and large vessels.

• • Fibrinolysis at the site of thrombus formation, and the resulting fibrin degeneration products interfere with platelet aggregation and fibrin clot formation.

• • Consumption of coagulation factors then leads to a haemorrhagic tendency.

Vascular factors

• • Endothelial damage from thrombi or ischaemia result in procoagulant release.

• • Reduced organ perfusion leads to a reduced clearance of coagulation byproducts.

• • Associated hypothermia or acidosis in sepsis and trauma can interfere with normal coagulation processes.

• • Reduced local blood flow hampers the diffusion of procoagulant factors away from site.

Neutrophil activation

• • Neutrophil activation results in the formation of neutrophil extracellular traps (NETs)

• • NET is a procoagulant

• • Under normal conditions NET formation is a well regulated component of innate immunity, but under severe inflammatory conditions NET formation is dysregulated and activates the clotting cascade, causing
    • • Activation of the contact phase of coagulation by cell-free DNA, which is a damage associated pattern molecule released as a response to infection or cell death.
  • • • Induction of platelet aggregation by cell-free DNA

• • Kim JE et al demonstrated elevated plasma levels of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers of NETosis, correlated with the severity of coagulopathy in DIC and were independent prognostic factors^.15

These processes result in simultaneous bleeding and thrombosis resulting in multi organ dysfunction.

Fig.2 Schematic representation of pathogenesis of DIC²

Learning Bite

In DIC abnormal systemic activation of the coagulation and fibrinolytic pathways results in a paradoxical tendency to clotting and bleeding at the same time.

The contributing factors include intravascular activation, dysregulation of fibrinolysis, neutrophil activation, increased tissue factors and endothelial damage.

Prompt identification and treatment of the underlying cause of DIC improves clinical outcomes.

Sepsis	Identify source Identify organ dysfunction
Trauma	Mechanism Injury profile
Obstetrics emergencies	Pregnancy details Foetal movement Symptoms of preeclampsia or eclampsia Symptoms of infection and/or clinical instability
Malignancy	Recent significant weight loss Generalised Symptoms
Immunological	Blood transfusion details Transplant details

Identify the Pattern of DIC

DIC presents as a spectrum of pathological intravascular thrombosis and bleeding, which vary in extent according to the underlying causative disease which triggered the DIC.

When considering the clinical manifestations specific to DIC, features can be divided into two groups; those secondary to bleeding and those secondary to thrombosis.

Manifestations of bleeding

• Dermatological bleeds ranging from minor petechiae to widespread purpura
• Excessive bleeding and purpura around venepuncture sites
• Prolonged external bleeding including epistaxis or menorrhagia
• Occasionally patients may present with catastrophic internal haemorrhage including gastrointestinal or intracranial bleeds

Manifestations of thrombosis

Thrombotic manifestations in DIC can be further classified as macrovascular and microvascular thromboses.

Macrovascular thrombosis

Involves larger vessels and presents in most cases as a venous thromboembolism e.g. DVT or PE.

Microvascular thrombosis

Involves smaller vessels and usually manifests as organ dysfunction.

• Renal involvement presents as oliguria and haematuria which may progress to renal failure
• Pulmonary involvement presents as haemoptysis (pulmonary haemorrhage) and breathlessness which may develop into Acute Respiratory Distress Syndrome (ARDS)
• CNS involvement presents as an altered sensorium ranging from delirium to coma
• Skin involvement presents as necrosis known as purpura fulminans and is mostly seen on the extremities and digits.

General principles

The diagnosis of DIC is made by combining clinical findings with laboratory abnormalities.¹⁹

Laboratory Investigations²⁰

Into the precipitant of DIC: This will be based on the underlying cause, for instance, blood cultures in sepsis.

Into the consequences of DIC: These are aimed at identifying organ dysfunction, for example U&Es, LFTs.

DIC Specific Investigations

Test	Results	Mechanism	Pearls
Platelet count	Thrombocytopenia	Excessive consumption	Seen in up to 98% of DIC cases with a platelet count <50.3
Coagulation screen PT, aPTT	Prolonged	Consumption of coagulation factors Impaired synthesis of factors due to abnormal liver function, vitamin K deficiency, and loss of coagulation proteins.21	PT or aPTT is prolonged in about 50–60% of cases of DIC.21 Normal clotting times do not exclude activation of the haemostatic system.22
Fibrin degradation products and D-dimers	Raised	Degradation of fibrin clots around the body	Non-specific and should not be used as a stand-alone test for DIC, but if raised is supportive of the diagnosis.
Fibrinogen	Typically, low in acute DIC	Fibrinogen is converted to fibrin leading to intravascular thrombosis.	The BCSH guidelines on fibrinogen assays recommend a Clauss test for fibrinogen levels.20 Fibrinogen levels can be normal in as many as 57% of patients.3
Thromboelastography (TEG)	Typically shows hypercoagulability during early DIC or hypocoagulability in fulminant DIC.		TEG is a whole-blood integrative test that may help clarify the overall balance of coagulation.
Blood smear	Schistocytes	RBCs passing through compromised vasculature become fragmented to form schistocytes. If significant this can cause microangiopathic haemolytic anaemia.	The finding of fragments is neither sensitive nor specific to DIC.20

Fig. Schistocytes on peripheral blood smear⁵

The International Society of Thrombosis and Haemostasis has developed a scoring system for patients with an underlying clinical condition associated with DIC utilising laboratory parameters.¹⁴

Parameter	Result	Score
Platelet count	>100 x 109 L <100 x 109 L >50 x 109 L	0 1 2
PT	<3s prolonged <3s but < 6s >6s	0 1 2
Fibrinogen	>1.0g/L <1.0g/L	0 1
FDP/ D dimer	No increase Moderate increase Strong increase	0 2 (2500-5000) 3 (>5000)

A score of > 5 associated with a “trigger” disorder is compatible with overt DIC.

This scoring system has a sensitivity of 93% and a specificity of 98% for DIC but can only be applied to those with clinical evidence of a precipitating cause, not indiscriminately to anyone with bleeding. It should be recalculated daily.

Learning Bite

It is important to assess the whole clinical picture; considering the clinical condition of the patient, the diagnosis, and all available laboratory results.

DIC is a dynamic situation. Blood tests provide a snapshot of this dynamic state and hence will require constant monitoring.

Other conditions which present with hypercoagulability, bleeding or microangiopathic haemolytic anaemia can mimic DIC. These include:

Immune Thrombocytopenia (ITP)

An acquired autoimmune process in which autoantibodies are raised to platelets.

• Primary ITP – Usually a diagnosis of exclusion, in a well patient with isolated thrombocytopenia and a normal peripheral smear.
• Secondary ITP – Occurs due to an underlying disorder that leads to autoantibody formation. Common etiologies include HIV, hepatitis C, leukaemia, SLE and certain drugs.²³

Coagulopathy in acute liver failure

Acute liver failure results in a decreased production of Vitamin K-dependent clotting factors (II, VII, IX, and X).

Moderate reduction of platelets may also occur secondary to splenic sequestration, bone marrow suppression or decreased thrombopoietin production.

Patients may have physical characteristics of liver failure such as clubbing, palmer erythema, spider nevi, gynecomastia, testicular atrophy, small shrunken liver, and anaemia.

Thrombotic Thrombocytopenic Purpura²⁴

Characterised by a decrease in proteolytic activity of the von Willebrand factor (vWF) cleaving enzyme ADAMTS 13, usually as a result of abnormal antibody production. As a result, vWF is released from endothelial cells and not cleaved into its functional form.

Larger vWF multimers deposit in the vasculature causing platelet aggregation, diffuse thrombus formation, decreased platelet counts and eventually ischemia of the affected organs.

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome

The hallmarks of this obstetric condition are hypertension, deranged liver function tests and thrombocytopenia. It is associated with pre-eclampsia.

HELLP syndrome is also a cause of DIC. HELLP syndrome alone will not cause PT/APTT derangements and usually not have evidence of bleeding/thrombosis.

Table 5 – Laboratory derangements of common conditions that may mimic DIC²⁵

Learning Bite

There are a wide number of differentials for DIC but they can usually be differentiated by the patient’s presentation and the specific haematological derangements they cause.

The treatment of DIC can be broadly subdivided into:

• Measures to treat the cause
• Early appropriate expert consultation
• Specific haematological interventions

Treat the cause

The most important step in the treatment of DIC is to initiate specific and vigorous treatment of the underlying disorder.

Multidisciplinary involvement

Patients with DIC will invariably be the sickest patients in the department. Studies have shown mortality rates above 30% once DIC is confirmed.^7-10

Haematology advice should be requested as soon as the diagnosis is suspected.

Critical Care teams should also be involved early in the patient journey. Patients with DIC will usually require admission to an Intensive Care Unit.

Specific treatment

Specific treatment options in DIC can be grouped into

• Blood products and derivatives
• Antithrombotic drugs (anticoagulants)
• Anti-fibrinolytic drugs

These interventions should be discussed with Haematology.

Blood Products & derivatives recommendation

Manifestation	Treatment
Significant anaemia      <800 g/L in non-cardiac patients      <900 g/L in cardiac patients	Blood transfusion depending on clinical status
Active bleeding or high risk of bleeding (pre/post-surgery) + platelet count of <50 x 109 / L Or No active bleeding + platelet count of <30 x 109 / L	Platelet transfusion
Active bleeding + aPPT/PT ratio < 1.5	Give fresh frozen plasma (FFP) at 15 ml/kg Factor concentrates such as prothrombin complex concentrate (PCC) are an alternative but contain fewer clotting factors
Severe hypofibrinogenemia (<1 g/l)	Give fibrinogen concentrate or cryoprecipitate

Anticoagulant / anti-fibrinolytic recommendations

Anticoagulant:

• Therapeutic dosing is only used in thrombosis predominant DIC with severe arterial or venous thrombosis and/or severe purpura fulminans
• Intravenous unfractionated heparin (UFH) infusion is recommended as it has a short half-life and is reversible
• Prophylactic doses of UFH or low molecular weight heparins (LMWH) are recommended in critically unwell and non-bleeding patients

Antifibrinolytics:

• Tranexamic acid is recommended in hyper-fibrinolytic states with severe bleeding

Learning bite

The treatment of DIC should always initially focus on the underlying aetiology.
Involve a haematologist in the decision making for administration of blood products.

Pitfalls

• Not identifying and treating the underlying cause of DIC
• Treating DIC as a uniform static condition. DIC presents with an evolving pattern of thrombosis and bleeding. Treatment should be individualised and modified as needed.
• Failing to involve specialist input from Haematology and Critical Care early.

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