Haematological Emergencies

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Neutropenic Sepsis

Neutrophils are a type of white blood cells which help in the immune system's defence against bacteria. When neutrophils are insufficient, the body is very susceptible to life-threatening infections leading to sepsis, which is why this is an emergency. 

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Definition

• Neutrophil count < 0.5 x 10^9/L

• Temperature > 38oC and/or Signs and symptoms of sepsis1

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Clinical Features

Patients present generally unwell, with shakes and rigors, with or without a temperature. Some neutropenic patients are unable to mount a febrile response, and may have a temperature <36oC. There may be evidence of a source for the infection. It is vital to do a septic screen to look for a source1:

• Meningitis/Encephalitis - headache, neck stiffness, drowsiness

• Chest - crackles on auscultation, low oxygen saturation, dyspnea and tachypnea, productive cough

• Cardiac - murmur, features of endocarditis

• GI - diarrhoea, abdominal pain

• GU - suprapubic pain/tenderness, dysuria

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Causes/Risk Factors

Chemotherapy

Chemotherapy can damage the bone marrow, and therefore interfere with the bone marrow's ability to produce neutrophils. The lowest neutrophil count after chemotherapy (called the "nadir") typically occurs 7-10 days post-chemotherapy, which is when patients are at greatest risk.1 ​

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Haematological Malignancies and other causes of Bone Marrow Failure

In patients haematological malignancies or aplastic anaemia, the bone marrow is unable to produce sufficient neutrophils.1 

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Immunosuppressive Medications 

Drugs such as anti-TNF agents used for rheumatological diseases or inflammatory bowel disease, azathioprine, methotrexate and others all work by reducing the body's immune response.1 

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Haematopoietic Stem Cell Transplant

The transplant process involves delivering bone-marrow killing chemotherapy, followed by infusions of the new stem cells. From the time that chemotherapy is given till engraftment occurs (where the infused stem cells start to make mature stem cells in the peripheral blood), the patient is profoundly neutropenic and therefore at risk of neutropenic sepsis. 

 

Investigations

Any patient at risk should be investigated along the Sepsis 6 pathway, which would involve taking blood cultures, measuring urine output by inserting a catheter, and a VBG for lactate levels. A Full blood count will show low neutrophil count. A full septic screen is required to find the source of the infection, This can include a urine dip and culture, stool culture, sputum culture, chest x-ray, ECHO, lumbar puncture (depending on clinical findings). 

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Management

Initial approach to management is the same for any acute emergency - ABCDE.

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Give intravenous broad spectrum antibiotics according to trust guidelines for neutropenic sepsis (ex. Tazocin or Meropenem)1

• It is vital to remember that in at-risk patients, treat before you get the results of blood tests. Waiting for a neutrophil count before treating causes unnecessary delay. Studies show that with each hour of delay in administering antibiotics, there is a 18% increase in 28-day mortality.2 

• Many trusts have adopted a 1-hour door to needle target, which is the time from patient presentation to the time antibiotics is administered. 

 

The patient will need to be reviewed by the oncology/haematology team.

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Tumor Lysis Syndrome

Tumor lysis syndrome is a group of clinical features/consequences of rapid cell breakdown. It usually occurs after the administration of chemotherapy for high grade malignancies. Most commonly, it occurs in Burkitt's lymphoma and acute lymphoblastic leukaemias. The cell breakdown results in release of intracellular products such as potassium, uric acid, calcium and phosphate.3

 

This is an emergency for several reasons. The high potassium levels can result in life-threatening arrhythmias and seizures. Calcium binds to phosphate and precipitates in the kidney, which can lead to acute kidney injury. High uric acid levels can lead to symptoms of gout, and can also cause acute kidney injury by forming uric acid crystals.3

 

Clinical Features

Patients present feeling generally very unwell. This occurs within 3 to 7 days after chemotherapy. Features can include:

• Hyperkalemia - palpitations, seizures, loss of consciousness

• Hypocalcemia - seizures, tetany, numbness and tingling, arrhythmias, muscle spasms/cramps, confusion

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Investigations

• Full blood count, Urea and Electrolytes, Liver Function Tests, Clotting screen

• Measure urine output

• ECG - check of life threatening arrhythmias as a result of hyperkalemia

• VBG - faster way of obtaining electrolyte information3

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Diagnostic Criteria

Laboratory TLS is defined as having 2 or more of:

• Hyperkalemia

• High uric acid

• Hyperphosphatemia

• Hypocalcemia (this is because there is more phosphate released than calcium, and the calcium gets bound to phosphate to form calcium phosphate)3

 

Clinical TLS is define as having laboratory TLS with any 1 of the following:

• Arrhythmia

• Seizure

• Acute Kidney Injury 

• Sudden death3

 

Management

Management involves preventing TLS from occurring, and treating it once it occurs. To prevent TLS from occurring, patients are risk assessed. Those at high risk are put on cardiac monitoring with regular ECG monitoring, they are given IV fluids and Allopurinol (if intermediate risk) or Rasburicase (if high risk). Rasburicase is a drug that converts uric acid to allantoin, a product that is easier to excrete than uric acid itself. Rigorous IV fluids helps o wash out and prevent precipitation of crystals in the kidneys.3

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Once established TLS occurs, management involves treating the electrolyte disturbances:

• Hyperkalemia - 10% calcium gluconate, IV insulin and glucose, salbutamol nebulisers, calcium resonium 

• Hyperurecemia - allopurinol/rasburicase

• Hyperphosphatemia - phosphate binders (not routinely as it takes time to work)

• Dialysis may be required to get rid off these waste products if hydration and other medical therapies do not work.3

 

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. 

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Other causes of DIC include when pro-coagulant materials enter the blood, for example in amniotic fluid embolism, acute promyelocytic leukemia, and in liver disease.4

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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.4 

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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.4

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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 drugs4

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Thrombotic Thrombocytopenic Purpura (TTP)

TTP is a haematological emergency. 

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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.5 

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Clinical Presentation

Patients can present with:

• features of haemolytic anaemia, including jaundice

• features of thrombocytopenia such as bleeding and purpura

• neurological symptoms (ex. focal neurological signs, seizures, coma, confusion, headache

• acute kidney injury

• fever6

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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, where PT and APTT are both prolonged. LDH levels are raised due to haemolysis and tissue ishcemia as a result of the platelet thrombi. Plasma ADAMTS13 level is reduced.6

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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 ADAMTS13.5,6

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References

1. Cks.nice.org.uk. 2020. Neutropenic sepsis NICE CKS. [online] Available at: <https://cks.nice.org.uk/neutropenic-sepsis?_escaped_fragment_=diagnosisbasis> [Accessed 28 March 2021].

2. Rosa, R. and Goldani, L., 2014. Cohort Study of the Impact of Time to Antibiotic Administration on Mortality in Patients with Febrile Neutropenia. Antimicrobial Agents and Chemotherapy, 58(7), pp.3799-3803.

3. Jones G, Will A, Jackson G, Webb N, Rule S. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. British Journal of Haematology. 2015;169(5):661-671.

4. Levi M, Toh C, Thachil J, Watson H. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Journal of Haematology. 2009;145(1):24-33.

5. Hoffbrand V, Moss P. Hoffbrand's Essential Haematology. Oxford: John Wiley & Sons, Ltd; 2016.​

6. Scully M, Hunt B, Benjamin S, Liesner R, Rose P, Peyvandi F et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. British Journal of Haematology. 2012;158(3):323-335.