Disseminated Intravascular Coagulopathy (DIC)

DIC is a life-threatening complication of several conditions, including sepsis and malignancy, major trauma, pancreatitis, and dissection aortic aneurysm. Inflammatory conditions and damage to blood vessels trigger the formation of platelet plugs, and the coagulation cascade. This results in excessive fibrin deposition, faster than it can be removed by natural anti-coagulants. Additionally, the coagulation cascade consumes clotting factors faster than it can be replaced, resulting in an increased risk of haemorrhage. 1,2

​

Other causes of DIC include when pro-coagulant materials enter the blood, for example in amnitoic fluid embolism, acute promyelocytic leukemia, and in liver disease. 

​

Clinical Features

Bleeding from multiple sites, including ears, nose, GI tract, and venepuncture sites is common. The patient may also have signs of gangrene due to thrombosis obstructing blood flow. Signs and symptoms of the underlying causes will be evident. 2

​

Investigations

The purpose of ordering investigations is to diagnose DIC, and find out the underlying cause. 

The platelet count will be low, with a low fibrinogen concentration. 

There will be a raised D-dimer as this is a fibrin degradation product. 

PT and APTT will be prolonged due to lower levels of clotting factors. 

Blood Film examination may show schistocytes (fragmented Red blood cells) - this is because the fibrin strands shear the red blood cells as they pass through circulation. 1

​

Management

1) Treat the underlying cause.

2) If the patient is bleeding - Fresh Frozen Plasma to replace clotting factors (FFP), platelet transfusion, red cell transfusion, cryoprecipitate (high concentration of fibrinogen, to replace that being used up to make fibrin)

3) If thrombotic - heparin or anti-platelet drugs2

​

Immune Thrombocytopenia (ITP)

​ITP occurs when autoantibodies attack platelets. This can be primary (idiopathic), or secondary to other diseases such as Systemic Lupus Erythematosus (SLE), antiphospholipid syndrome, malignancy, medication, and viral infections (ex. HIV). ITP can also be classified as either acute or chronic.3

​

Clinical Features

Patients with ITP present with cutaneous bleeding (petechiae and purpura) and bruising, epistaxis, and menorrhagia. Some children with ITP are completely asymptomatic. Life threatening presentations such as intracerebral hemorrhage can also occur. 3

 

Investigations

• Full blood count: low platelet count

• Peripheral blood film: to distinguish between pseudothrombocytopenia and true thrombocytopenia, and rule out other causes of low platelet count such as myelodysplasia or other bone marrow pathology

• Bone marrow examination: only if abnormal features on peripheral blood film/other features suggesting serious bone marrow pathology 

• HIV/Hepatitis Serology: if features or history suggest risk factors

​

Management

Treatment for ITP depends on the severity. Some patients may not require any treatment. In these cases, advice such as avoiding contact sports and medications such as NSAIDs and aspirin is helpful. If the platelet count is very low and causing significant clinical symptoms, then the following treatments can be used:

• First line: steroids (prednisolone), IV Immunoglobulins

• Second line: Rituximab (anti-CD20), dexamethasone1,3

​

Haemolytic Uraemic Syndrome (HUS)

HUS is comprised of a triad of features: 1) microangiopathic haemolytic anaemia, 2) acute kidney injury, and 3) thrombocytopenia. It is the commonest cause of acute kidney injury in children. 4

​

Pathophysiology

HUS is due to bacterial toxins, most commonly verotoxin-producing E.coli (E.Coli O157:H7). This toxin enters the gastrointestinal tract after eating contaminated food containing E.coli, or salmonella. The toxin causes mucosal inflammation and enters the blood stream and travels to other organs in the body where it causes damage to endothelial cells, especially in the kidney. The resulting inflammation in response to endothelial injury resulting in increased platelet production, and platelet thrombi formation. This subsequently causes microangiopathic haemolysis. 1,4

​

Clinical Features

The toxin's affect on the gastrointestinal system results in bloody diarrhea and abndominal pain. The affect on the kidneys means the kidney is not able to clear urea as well, resulting in ureamia. This presents with a general feeling of being unwell, nausea and vomiting. A low urine output can also be a consequence of poor renal function. The haemolytic anaemia will present with fatigue and pallor. Damage to the kidney and other small blood vessels can also result in hypertension due to fluid overload. 4

​

Investigations

A full blood count will show anaemia and thrombocytopenia. A peripheral blood film can show faetures of microangiopathic haemolysis (schistocytes). A stool culture needs to be performed to identify the toxin. Renal function tests help determine the extent of kidney damage.4 

 

Management

Severe cases may need dialysis to clear out the urea and replace other functions of the kidney. Diarrhea from HUS will cause significant fluid and electrolyte disturbances - replacement of these will be guided on the fluid status of the patient - if their kidneys are failing and causing retention of fluid, then this will have to be given cautiously. Hypertension can be treated with calcium channel blockers such as Nifedipine.4 

​

Thrombotic Thrombocytopenic Purpura (TTP)

TTP is a haematological emergency. 

 

Pathophysiology

It is due to an acquired or inherited deficiency of ADAMTS13, which is an enzyme that cleaves von Willebrand factor (vWF) polymers into multimers. In hereditary cases, mutations are responsible for this deficiency. In acquired cases, an IgG autoantibody is produced which blocks the enzyme activity of ADAMTs13.When this enzyme is deficient, the uncleaved long strands of vWF provide an a place for passing platelets to stick on. These platelet-rich strings of vWF can then break off and form emboli and block blood vessels in the body, resulting in organ ischemia, and haemolytic anaemia as these thrombi can shear passing blood cells - this is called microangiopathic haemolysis.1, 5,6 

​

Investigations and Diagnosis

A Full Blood Count will show thrombocytopenia, as the platelets are consumed when they bind to the VWF strands. A peripheral blood film will show schistocytes (fragmented red blood cells) due to the microangiopathic haemolysis. Clotting tests (PT and APTT) are normal - this is in contrast to DIC. 6

​

Management 

DO NOT GIVE PLATELETS to a TTP patient, as their blood already has platelet-rich thrombi! Plasma exchange  is the treatment for TTP. It works by removing the vWF proteins and the antibodies against ADAMTS13.6

​

​Aplastic Anaemia

Aplastic anaemia is a condition where the bone marrow is hypoplastic, or empty. It results in pancytopenia. 1

 

Pathophysiology

Aplastic anaemia is due to an immune attack against the bone marrow, resulting in decreased production of haematopoietic cells. 1

​

Causes

Primary: congenital or idiopathic acquired AA

Secondary: post-radiation, drugs (chemotherapy - busulfan, cyclophosphamide), some anti-thyroid and anti-psychotic medications, viruses (viral hepatitis, EBV), autoimmune disease (SLE)1

 

Clinical Features 

The clinical features are a result of loss of red blood cells, which will cause anaemia, loss of white blood cells which will result in infection, and loss of platelets which will predispose to bleeding and present with menorrhagia/epistaxis/gum bleeding. 7

​

Investigations

Full blood count  will show pancytopenia, with a normocytic normochromic anaemia. 

A reticulocyte count will show a low number of reticulocytes as the bone marrow is unable to produce new immature red blood cells. 

Vitamin B12 and folate levels are necessary as these are essential for haematopoiesis, and therefore deficiency can lead to the bone marrow's inability to produce any blood cells. 

LFTs and hepatitis and EBV serology if hepatitis is a suspected underlying cause. 

Bone marrow biopsy will show a hypoplastic bone marrow replaced with fatty tissue, with no abnormal cells. 

Cytogenetics must be performed to exclude other diseases which can cause pancytopenia.

Anti-DsDNA and anti-nuclear antibodies should be investigated for systemic erythematous lupus, as a possible cause of aplastic anaemia. 7

​

Management

If an underlying cause is determined, then this should be treated. Supportive care including platelet and red blood cell transfusions are used to replace what the bone marrow does not contain.  In some cases, prophylactic antibiotics and antifungals are given to prevent the risk of infection.7

 

The first line of treatment includes cyclosporine and Anti-thymocyte globulin (ATG). ATG works by blocking the T-cells which attack the bone marrow. Alemtuzumab is an anti-CD52 antibody. CD52 is found on mature T cells, so this drug works by blocking T cells as well. 7

 

Allogeneic Stem cell transplantation are a curative option. This works by replacing the empty bone marrow with new healthy donor cells. 

​

​Human Immunodeficiency Virus (HIV)

HIV can cause a destruction of platelets peripherally, or decreased production of platelets by affecting the megakaryocytes in the bone marrow. Management is with anti-retroviral therapy, which can improve platelet counts.8

​

B12 and Folate Deficiency

B12 and foalte are necessary for the production of cells, including platelets. When these are deficient, the marrow will produce less platelets. Read more about B12 and folate deficiency on our Megaloblastic anaemias page. 

​

​

Clotting Factor Disorders

​

HEREDITARY

Haemophilia A and B are the most common hereditary clotting factor disorders. Haemophilia A is a deficiency of Factor 8, and Haemophilia B is a deficiency of Factor 9. Haemophilia A is much more common than Haemophilia B. 

​

These disorders are X-linked recessive. This makes it much more common in males, and females can inherit another X chromosome from a parent which will not have the recessive gene. Females who inherit one normal gene and one defective gene are carriers of Haemophilia.1 

​

Clinical Features

Patients with low clotting factors often present with joint bleeding (in contrast to patients with platelet disorders who often present with soft tissue bleeding such as epistaxis and menorrhagia). This can cause painful joint bleeds. 1

​

Investigations

A full blood count and peripheral blood film will be normal. Clotting tests will show a prolonged APTT which measures the instrinsic athway of the clotting cascade. Factor 8 and 9 are both part of the intrinsic pathway. The PT will be normal. 

​

Factor 8 and 9 levels can be measured using assays. These will be low.1 

​

Management

Recombinant factor 8 or 9  or plasma-derived clotting factors can be given to patients with haemophilia to replace what is missing. These are given as prophylaxis and management of acute bleeds. If a patient has a joint bleed, this needs to be managed with analgesia, and clotting factor replacement at higher doses (depending on the severity of the bleed).

 

Patients need advice about refraining from contact sports or other activities where the risk of injury and subsequent bleeding is high. Newer therapies which are currently being explored include gene therapy, where a viral vector is used to introduce genes that can encode for production of the missing factor. These trials are mostly conducted for Haemophilia A.1

​

​

ACQUIRED 

Liver disease

The liver produces clotting factors. Therefore any form of liver failure will result in decreased clotting factor production, an abnormal clotting tests. Liver failure patients are at increased risk of bleeding. Examples of causes of liver failure include:

• alcoholic liver disease

• non-alcoholic fatty liver disease

• Wilsons disease

• Viral Hepatitis

• Autoimmune hepatitis 

• alpha 1 antitrypsin deficiency

• Drug induced - paracetamol overdose 9

 

Warfarin 

Warfarin is an anticoagulant, which works as a vitamin K antagonist. Vitamin K is required to make factors 2, 7, 9, and 10. It is used to prevent ischaemic events in patients with mechanical heart valves, and in patients with atrial fibrillation. it can also be used for patients with inherited conditions that predispose them to having clots. It is also used as treatment and prophylaxis for patients who have had a provoked or unprovoked venous thromboembolism. 10

​

​

References

1. Hoffbrand V, Moss P. Hoffbrand's essential haematology. Oxford: John Wiley & Sons, Ltd; 2016.​

2. Harding M. Disseminated Intravascular Coagulation [Internet]. Patient.info. 2019 [cited 10 April 2020]. Available from: https://patient.info/doctor/disseminated-intravascular-coagulation 

3. Harding M. Idiopathic Thombocytopenic Purpura. 2015; Available at: https://patient.info/doctor/immune-thrombocytopenia-pro.

4. Henderson R. Haemolytic Uraemic Syndrome [Internet]. Patient UK. 2016 [cited 7 March 2020]. Available from: https://patient.info/doctor/haemolytic-uraemic-syndrome-pro

5. Tsai H. Pathophysiology of thrombotic thrombocytopenic purpura. International Journal of Hematology. 2010;91(1):1-19.

6. Tidy C. Thrombotic Thrombocytopenic Purpura [Internet]. Patient.info. 2016 [cited 10 April 2020]. Available from: https://patient.info/doctor/thrombotic-thrombocytopenic-purpura-pro

7. Killick S, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A et al. Guidelines for the diagnosis and management of adult aplastic anaemia. British Journal of Haematology. 2015;172(2):187-207.

8. Chu C, Selwyn P. Complications of HIV Infection: A Systems-Based Approach. Am Fam Physician. 2011;83(4):395-406.

9. Willacy H. Liver Failure [Internet]. Patient.info. 2019 [cited 10 April 2020]. Available from: https://patient.info/doctor/liver-failure

10. WARFARIN SODIUM [Internet]. Bnf.nice.org.uk. [cited 10 April 2020]. Available from: https://bnf.nice.org.uk/drug/warfarin-sodium.html

​