Pathophysiology
Haemostasis does not only involve clot formation, but equally it requires dissolution of this clot (fibrinolysis). As we have discussed other aspects of the coagulation cascade in other CCCs such as in haemophilia and patient on anti-platelet therapy, let’s review the physiology of fibrinolysis briefly as this is the final component to consider in haemostasis:
Prostacyclin and nitrous oxide are constantly being released by intact endothelium to inhibit any unwanted coagulation. Endothelium also produces tissue plasminogen activator (tPA) as well as thrombomodulin which confine haemostasis to the site of injury.
tPA activates plasminogen → plasmin. Plasmin is the important proteolytic enzyme that breaks down fibrin into fibrin degradation products such as D-dimers, for example.
In DIC, there is dysregulation of fibrinolysis and clotting resulting in widespread coagulation and depletion of the clotting factors and platelets.
Tissue factor (TF) is released in response to pro-inflammatory cytokines which then promotes coagulation in inflammatory states (such as sepsis). It is also highly prevalent in the lungs, brain and placenta, hence it is readily released and activates coagulation in traumatic states as well.
⚠️ Risk factors and causes
- Sepsis
- Major trauma/burns
- Malignancies - such as AML.
- Obstetric complications - eclampsia/HELPP syndrome, abruptio placental, amniotic fluid embolism.
- Organ failure - such as severe pancreatitis or acute liver failure.
We will discuss some of these in a little more detail at the end of this page.
- Causes of DIC in paediatric patients:
- Protein C deficiency
- Protein S deficiency
- Kasabach-Merritt syndrome - this is a rare syndrome that occurs when there is a haemangioma results in thrombocytopenia and DIC. It occurs due to clotting factors being used up within the tumour.
- Causes of DIC in neonates:
- Sepsis - due to:
- Bacterial sepsis - especially with group B streptococcus and gram-negative organisms.
- Congenital infections (TORCH infections).
- Systemic candidiasis
- Neonatal viral infections (such as rubella, HSV, CMV, enterovirus)
- Perinatal asphyxia - secondary to eclampsia, pre-eclampsia, placental abruption, foetal distress during labour.
- Necrotising enterocolitis - ischaemic bowel tissue releases tissue factor which activates the clotting cascade.
- Respiratory distress syndrome - presumably due to the tissue damage acquired from the hypoxia
Newborn infants, especially preterm infants are susceptible to DIC because the endogenous anticoagulants (antithrombin and protein C) are normally low at this age.
The main causes of DIC in neonates are:
🔢 Classification
We can classify DIC as either acute or chronic
- Acute DIC - rapid-onset widespread bleeding and thrombosis → hypoperfusion, infarction and end-organ failure. It occurs with major trauma, sepsis, massive blood transfusion.
- Chronic DIC - subacute bleeding and diffuse thrombosis. More prevalent in malignancies, and less acute disorders.
😷 Presentation
- ⭐️ Excessive bleeding - such as epistaxis, gingival bleeding, haematuria, ecchymosis, or oozing.
- ⭐️ Petechiae - another sign of widespread bleeding.
- Confusion or coma - signs of microvascular/macrovascular thrombosis.
- Fever - as it often occurs due to severe infection.
- Hypotension, tachycardia, oliguria - signs of circulatory collapse, for example within the context of sepsis.
- Purpura fulminans or gangrene - rapid bleeding of the skin followed by sudden death due to microvascular thrombosis.
If there are signs of bleeding at 3 unrelated sites, this is highly suggestive of DIC. It is also vital to consider the systemic disease or trauma that could be causing the DIC of course.
🔍 Investigations
- Platelet count - thrombocytopenia.
- Prothrombin time - often prolonged.
- Fibrinogen - decreased as it is excessively used up.
- D-dimer - elevated as fibrin is continuously being broken down, producing more degradation products.
💯 Criteria and scoring
The International Society of Thrombosis and Haemostasis (ISTH) provides a scoring system to help with diagnosis of DIC.
A score of >5 is suggestive of overt DIC, while a score of <5 does not rule out DIC, but is suggestive of non-overt DIC and so tests should be repeated in the next 1-2 days.
There are 4 parameters that are considered:
- Platelet count
>100 - 0
<100 - 1
<50 - 2
- Fibrin degradation products (D-dimer)
No increase - 0
Moderate increase - 1
Strong increase - 2
- Prolonged prothrombin time
<3 seconds - 0
3-6 seconds - 1
>6 seconds - 2
- Fibrinogen level
>1 - 0
<1 - 1
🧰 Management
- Treatment of underlying disorder
- If the patient is actively bleeding or at high-risk of bleeding:
- Platelet transfusion + fresh frozen plasma (for replacement of coagulation factors) + anti-coagulants
- Treatment of underlying disorder
Protein C and protein S are both vitamin K dependent anticoagulatory proteins. Once activated they inhibit factors Va and VIIIa selectively. They do this by binding to the thrombin-thrombomodulin complex and cleaves factor Va and factor VIII to turn them into their inactive forms. Factor Va is involved in the common pathway and factor VIIIa is a part of the intrinsic pathway.
Inhibition of these molecules results in reduced fibrin production and reduced clot formation. This prevents excessive coagulation in secondary haemostasis.
Therefore a deficiency in one or both of these proteins predisposes an individual to hypercoagulability and thrombosis. This means that individuals with protein C or S deficiencies are likely to develop DVT and DIC.
🔢 Classification
The congenital protein C and S deficiencies can be classified into 2 types (both of which are autosomal dominant):
- Type 1 - this is when there is not enough protein C or S (a quantitative deficiency).
- Type 2 - this is when there is a defective protein C or S (a qualitative deficiency).
There also may be acquired deficiencies due to impaired synthesis (occurring with liver failure) or excessive protein losses in urine (nephrotic syndrome).
After birth, levels of protein C take time to reach normal adult levels. Preterm infants have only 7-18% of normal adult levels. Full term infants have 20-40% of normal adult levels. For this reason, prematurity and infancy are risk factors for DIC.