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Haematological emergencies 

Haematological emergencies
Chapter:
Haematological emergencies
Author(s):

Punit S. Ramrakha

, Kevin P. Moore

, and Amir H. Sam

DOI:
10.1093/med/9780198797425.003.0010
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date: 04 August 2020

Blood transfusion reactions

Assessment

See Table 10.1.

Table 10.1 Blood transfusion reactions: assessment

Presentation

Causes

Timing

Shock (major haemolysis)

Lumbar or loin pain, headache

Chest pain, shortness of breath

Rigors, pyrexia

Urticaria, flushing

Hypotension

Oliguria

Haemoglobinuria

Jaundice

DIC

Red cell antibodies

ABO incompatibility

Other antibodies

Immediate

(min/h)

Shock (septic)

Rigors, pyrexia

Hypotension

Oliguria

DIC

Bacterial contamination

Immediate

(min/h)

Fever

Isolated pyrexia

Rigors

White cell antibodies

Recipient cytokines

Early

(30–90 min)

Allergic reactions

Urticaria

Pyrexia

Rigors

Facial oedema

Dyspnoea

Donor plasma proteins (more common with plasma or platelets)

Early

(min/h)

Transfusion-associated circulatory overload (TACO)

Breathlessness

Cough

Oedema

Rapid/over-transfusion in low-weight patient: aim for 4mL/kg

Early

(h)

Transfusion-related acute lung injury (TRALI)

Non-cardiogenic pulmonary oedema

Pyrexia

Cough

Breathlessness

CXR changes

Donor white cell antibodies (rare)

Early

(min/h)

Delayed haemolysis

Pyrexia

Anaemia

Jaundice

Minor red cell antibodies

Late

(7–10 days)

Delayed thrombocytopenia

Purpura

Mucosal bleeding

Platelet antibody (commonly anti-PlA1)

Late

(2–10 days)

Infection

Hepatitis B/C, non-A/B/C, CMV, EBV, HIV, HTLV, toxoplasmosis, malaria, syphilis

Late

(days/months)

Management

The main problem encountered in practice is differentiating a (common) rise in temperature during a blood transfusion from (the rare, but potentially lethal) major transfusion reactions. The common patterns of reactions are outlined in Table 10.1.

Pointers to a severe reaction include:

  • Symptoms: does the patient feel unwell?

  • Pattern of temperature: a rapid rise in temperature to >38°C is common in minor reactions.

  • Hypotension or tachycardia.

(See Table 10.2 for the management of blood transfusion reactions.)

Table 10.2 Management of blood transfusion reactions

Reaction

Management

Isolated pyrexia

Slow transfusion

Give paracetamol

Finish transfusion if no progression of symptoms

Urticarial reaction

Slow transfusion

Give chlorphenamine 10mg IV

Complete transfusion if no progression of symptoms

Sometimes patients need hydrocortisone 100mg IV

Shock

Anaphylaxis

ABO incompatibility

Septic shock

Stop transfusion and give O2

Give adrenaline 0.5–1mg SC, and consider repeating every 10min until improvement. Contact duty anaesthetist and ITU for haemofiltration if AKI

Give chlorphenamine 10mg IV (and crystalloid; consider inotropes)

Monitor fluid balance. Take blood: FBC, U&Es; full coagulation screen (for DIC); repeat cross-match and direct antigen test (DAT); return donor blood

Urine: bilirubin, free Hb

Circulatory overload (Haematological emergencies Pulmonary oedema: assessment, pp. [link][link])

O2, furosemide IV (40–120mg)

Nitrate infusion (0–10mg/h)

TRALI

Life-threatening. Treat as ARDS (Haematological emergencies Adult respiratory distress syndrome 1, p. [link])

Delayed haemolysis

Report to blood bank

Repeat cross-match and DAT

Transfuse with freshly cross-matched blood

Thrombocytopenia

Immune-mediated: treat with PlA1-negative transfusions, high-dose IV IgG, steroids, and plasmapheresis (dilutional Haematological emergencies platelets seen if >5U transfused)

Report any serious or haemolytic reaction to a haematologist.

Sickle-cell crisis: presentation

A small percentage of sufferers with sickle-cell disease have recurrent crises and repeated hospital admissions. There is an unwarranted tendency to attribute this to a low pain threshold or to ‘dependence’ on opiates, rather than to the severity of disease. Analgesia should never be denied to patients. This group of patients has the highest rate of serious complications and mortality as a result of their severe disease. Sudden death is still a major problem.

Painful (vaso-occlusive) crisis

  • This is the most common presentation in adults and children.

  • Severe/excruciating pain is felt at one or more sites, especially long bones (small bones in children), back, ribs, and sternum.

  • There may be associated pyrexia (usually <38.5°C), tenderness, local warmth, and swelling, or there may be no objective features.

  • Haemolysis may be Haematological emergencies (Haematological emergencies bilirubin, Haematological emergencies LDH, fall in Hb) but is not a good correlate.

  • There are no reliable clinical markers for the severity of a crisis.

Chest crisis

  • The most commont cause of mortality.

  • Vaso-occlusion of the pulmonary microvasculature results in reduced perfusion and local infarction.

  • May be heralded by rib/sternal pain and/or falling SpO2.

  • May be precipitated by a chest infection, pregnancy, surgery, and in smokers.

  • Prevented by: increasing HbF, with hydroxycarbamide, and incentive spirometry.

  • Symptoms (which may be minor initially) include pleuritic chest pain and breathlessness.

  • Signs are variable (often minimal) but can progress rapidly; usually reduced air entry at lung bases.

  • CXR is variable: uni-/bilateral consolidation, usually basal; ‘white-out’; minimal changes.

  • PaO2 is often markedly reduced. NB O2 delivery is low, given anaemia.

Cerebral infarction

  • Usually in children <5 years, rare in adults.

  • Presents as acute stroke.

  • High risk of recurrence.

Splenic/hepatic sequestration

  • Usually in children <5 years.

  • RBCs trapped in the spleen and/or liver, usually causing organomegaly.

  • Causes severe anaemia; circulatory collapse.

Aplastic crisis

  • Usually in children, young adults.

  • Mainly caused by parvovirus infection, exacerbated by folate deficiency.

  • Occasionally when hydroxycarbamide dose has Haematological emergencies.

  • Sudden fall in Hb, inappropriately reduced/normal reticulocyte count.

Haemolytic crisis

  • Often accompanies painful crises.

  • Exacerbated by medications, including in those with G6PD (even in ♀).

  • Fall in Hb; Haematological emergencies reticulocyte count.

Cholecystitis/cholangitis/biliary colic

  • Pigment stones common due to haemolytic anaemia and genetic predisposing polymorphism associated with Gilbert’s syndrome.

  • Can be misinterpreted as vaso-occlusive crisis.

Priapism

  • Prolonged, painful erections due to local vaso-occlusion (1–24h long).

  • Major crisis often preceded by ‘stuttering’ priapism episodes.

  • May result in permanent impotence.

  • This is a urological emergency. On-call urologists should be informed on the patient’s arrival in casualty.

Infections/septic shock

  • Any age group.

  • Fever may not be prominent, and hypotension is a late sign in children.

  • Osteomyelitis may not be apparent and may mimic veno-occlusive crises and complicate leg ulcers.

  • Patients receiving iron chelation therapy are at risk of Yersinia spp.

  • Patients with long-term venous access devices (e.g. Portacath) are at risk of Gram +ve infections.

Sickle-cell crisis: management

General measures

See NICE guidelines CG1431.

See Box 10.1 for management key points in sickle-cell crises.

Control pain

  • This should be individualized; seek expert haematology input.

  • Assess pain objectively with a score to assess treatment response.

  • Have a low threshold to investigate for causes of pain not attributable to veno-occlusive disease, especially if atypical for the patient.

  • Usually parenteral opiates are necessary, often in high doses (depending on previous opiate exposure). Start low and review in 0.5h, titrating to response, e.g.

    • Morphine 5–40mg IM every 2h.

    • Diamorphine 5–25mg SC every 2h.

  • Failure to control pain using these regimens usually indicates the need for a continuous opiate infusion or a patient-controlled analgesia (PCA) pump. Some patients prefer pethidine, but there is a risk of seizures as the drug metabolites accumulate.

  • Oral analgesia (dihydrocodeine/NSAIDs) may be sufficient for minor crises, with regular paracetamol (IV preferred initially).

  • Supplementary analgesics, such as diclofenac 50mg tds PO, may have a small additional benefit.

Ensure hydration

  • IV crystalloids are preferred, but venous access may be a problem.

  • Aim for an input of 3–4L/day, with close monitoring of balance.

  • Fluids can be oral where venous access is problematic.

Give oxygen

  • Not of proven benefit (except in chest crises), but often provides symptomatic relief.

  • Incentive spirometry prevents chest crises.

  • Monitor O2 saturations on air and O2; falling sats may be an early indication of a chest crisis.

  • In a severe chest crisis, CPAP/full ventilation may become necessary. Transfer to ITU early.

Give folic acid

Give 5mg PO od (continue long term in all patients).

Review sources of sepsis

  • Infections are frequent (at least partly due to hyposplenism).

  • Penicillin prophylaxis and vaccination [pneumococcal, Haemophilus influenzae b (Hib), meningococcal, influenza] do reduce the incidence, but some penicillin-resistant organisms are emerging.

  • If an infective precipitant, or component, of the crisis is suspected, start ‘blind’ antibiotics (e.g. cefuroxime 750mg IV tds) after an infection screen.

  • Consider less common sources of sepsis (e.g. osteomyelitis, Mycobacterium, etc.).

Give thromboprophylaxis

LMWH prophylaxis should be used routinely.

Give other supportive therapy

Laxatives, antiemetics, and anti-pruritics with opiates.

Investigations

(See Table 10.3.)

Table 10.3 Investigations in sickle-cell crisis

Investigation

Comment

FBC

Hb (? fall from steady state), WCC (neutrophilia common)

Reticulocytes

Raised in haemolysis, reduced in aplastic crisis

HbS and HbF %

Can guide red cell exchange and hydroxycarbamide

Blood cultures

Even if not pyrexial, especially if hypoxic

Stool cultures

If diarrhoea (? Salmonella or Yersinia spp., osteomyelitis)

CXR

Regardless of symptoms

Pulse oximetry

All patients. ABG if hypoxic, otherwise venous blood gas

Bone X-ray

? osteomyelitis (persisting pain, pyrexia, or bacteraemia). ? avascular necrosis (chronic hip/shoulder pain). May need MRI if strong suspicion

Viral PCR

If aplastic crisis (? parvovirus)

Cross-match

If transfusion/exchange indicated (see Haematological emergencies Exchange transfusion, p. [link]). Extended red cell phenotyped transfusion

Exchange transfusion

The exchange can be performed on a cell separator. Aim for Hb of between 70 and 90g/L (end haematocrit of 0.34) in either case; a higher Hb can increase blood viscosity and precipitate further sickling. In severe crises, red cell exchange should be repeated until the HbS % is <30%. If a larger exchange is not required or fluid balance is not precarious, manual venesection of 1–2U can be performed. Fluid replacement (normal saline 1L over 2–4h), followed by transfusion of extended phenotype cross-matched blood.

Indications for urgent exchange transfusion

  • Chest crisis.

  • Cerebral infarction.

  • Severe, persisting painful crisis.

  • Priapism.

  • Organ failure.

  • Refractory ulceration.

  • Preoperative.

References

1. National Institute for Health and Care Excellence (2012). Sickle cell disease: managing acute painful episodes in hospital. Clinical guideline [CG143]. Haematological emergencies https://www.nice.org.uk/guidance/CG143Find this resource:

Bleeding disorders: general approach

Presentation

  • Normal haemostasis requires the interaction of platelets, fibrin from the clotting cascade, and the microvasculature. An abnormality of any of these components may present as easy bruising, purpura, or spontaneous or excessive bleeding.

  • Muscle haematomas or haemarthroses suggest clotting factor deficiencies (e.g. haemophilia) whereas purpura, minor bruising, or epithelial bleeding suggest abnormalities of platelet function, collagen, or primary haemostasis.

  • Mucosal haemorrhage (acute GI bleed) may occur without any haemostatic abnormalities, e.g. due to peptic ulcer disease.

  • If a coagulation or platelet abnormality is uncovered on ‘routine’ testing, examine the patient for occult bleeding (e.g. iron-deficient anaemia, fundal haemorrhages).

  • A personal or family history of excess bleeding may suggest a congenital haemostatic problem—expert haematology input is essential.

Causes

These can be divided into:

  • Coagulation abnormalities.

  • Platelet abnormalities (too few or dysfunctional).

  • Microvascular/collagen abnormalities.

Investigations

All patients should have

  • Coagulation screen [PT, APTT, thrombin time (TT), fibrinogen].

  • von Willebrand factor (vWF) Ag, factor XIII, ristocetin cofactor (RiCof).

  • FBC and film.

  • U&Es.

  • LFTs.

  • Cross-match.

Where appropriate, consider

  • Platelet function tests.

  • 50:50 or 80:20 plasma mixing assays.

  • Specific coagulation factor levels.

  • Acquired factor inhibitors.

  • vWF multimer gels.

  • PFA-100.

  • Thromboelastography (TEG®)/ROTEM®.

  • Genetic tests/gene sequencing.

  • Bone marrow aspirate and trephine.

  • Bleeding time (only for collagen defects).

Management

General measures

  • Avoid non-steroidal medications, especially aspirin.

  • Do not give IM injections.

  • Avoid arterial or lumbar punctures.

  • Enlist expert help with invasive procedures. Use the internal jugular, rather than the subclavian, route for central line insertion with US.

  • Examine the skin, oral mucosa, and fundi for evidence of fresh bleeding.

  • Restore circulatory volume with IV crystalloid (colloids exacerbate bleeding) if there is haemodynamic compromise, and consider blood component transfusion.

Specific therapy

  • Look for any local cause for the bleeding (e.g. oesophageal varices, vascular damage causing epistaxis, chest infection causing haemoptysis) that may be amenable to treatment.

  • Stop any drug that may be exacerbating the bleeding (see Box 10.2).

  • Correct coagulation abnormalities, if appropriate (Haematological emergencies Abnormal coagulation 1, p. [link]).

  • Correct platelet abnormalities, if appropriate (Haematological emergencies Abnormal platelets, pp. [link][link]).

Abnormal coagulation 1

Common causes

  • Anticoagulants.

  • Liver disease.

  • DIC.

  • Massive transfusion.

Rarer causes

  • Haemophilia A (acquired or congenital) and B.

  • von Willebrand’s disease (vWD) (acquired or congenital).

  • Amyloid (acquired factor X or IX deficiency with vasculopathy).

  • α‎2-antiplasmin deficiency.

  • Vitamin K deficiency:

    • Obstructive jaundice.

    • Small bowel disease.

Diagnosis

(See Table 10.4.)

Table 10.4 Diagnosis of abnormal coagulation*

Defect

Interpretation

Consider

Haematological emergencies PT

Extrinsic pathway defect

Warfarin, liver disease, vitamin K deficiency, factor VII deficiency

Haematological emergencies APTT

Intrinsic pathway defect

Heparin, haemophilia A or B, vWD, lupus anticoagulant (antiphospholipid syndrome)

Haematological emergencies PT and APTT

Multiple defects (usually acquired)

Liver disease, DIC, warfarin, factor V and/or X deficiencies, factor Xa inhibitor anticoagulation

Haematological emergencies TT

Abnormal fibrin production

Heparin effect, fibrinogen defect, excess fibrin degradation products (FDPs) (which interfere with reaction). Reptilase time* will be normal if due to heparin

Haematological emergencies PT, APTT, TT

Multiple (acquired) defects

Deficient or abnormal fibrinogen or heparin. Factor IIa inhibitor anticoagulation

Haematological emergencies fibrinogen

Excess consumption of clotting factors and fibrinogen

Consumptive coagulopathy (but not necessarily full DIC), hyperfibrinolysis, severe liver disease

Haematological emergencies FDPs

Haematological emergencies fibrin(ogen) degradation

The exact interpretation depends on the lab test used. Some do not distinguish between fibrin and FDPs. Some are more specific to fibrin degradation (e.g. D-dimers) and are therefore suggestive of widespread clot formation and breakdown (i.e. DIC)

PFA-100

Abnormal platelet function

Congenital or acquired platelet dysfunction. Consider further platelet function studies (aggregation; electron microscopy), vWD (Haematological emergencies APTT)

The lupus anticoagulant usually confers a prothrombotic, rather than a bleeding, tendency.

* Reptilase is a snake venom not inhibited by heparin. It converts fibrinogen to fibrin.

Abnormal coagulation 2

Management

Options are:

  • FFP: indicated for treatment of acute DIC with bleeding, improving haemostasis in decompensated liver failure if bleeding or prior to a procedure, and emergency reversal of warfarin therapy if no PCC available. Give 15mL/kg, i.e. 4–5U (~200mL/U). Watch for signs of fluid overload, and give IV furosemide, if necessary.

  • Vitamin K: phytomenadione 5–10mg IV slowly (daily for 3 days) if deficiency is suspected; 2–5mg IV/PO will improve over-warfarinization in 6–12h if no bleeding with low INR; 0.5–1mg for minor adjustment.

  • Protamine sulfate (1mg IV neutralizes 100IU of heparin): is rarely used in practice. Stopping a heparin infusion will normalize the APTT in 2–4h.

  • Cryoprecipitate or fibrinogen concentrate: should be considered if fibrinogen level is below 1–1.2g/L.

  • Factor concentrates: can be used in the treatment of isolated factor deficiencies, e.g. haemophilia A. Concentrates of factors II, VII, IX, and X are also available in some centres for specific reversal of warfarin effects (PCC).

  • Antifibrinolytics: are used for the treatment of life-threatening bleeds following thrombolytic therapy or major surgery (e.g. cardiac surgery or prostatectomy), and in certain conditions associated with hyperplasminaemia (e.g. acute promyelocytic leukaemia, certain malignancies). Give tranexamic acid 0.5–1g slow IV injection tds.

  • Miscellaneous: desmopressin and oestrogens are occasionally used for haemophilia and renal failure.

Circulating inhibitors of coagulation

Lupus anticoagulant

  • Causes prolonged APTT but predisposes to thrombosis, not bleeding (antiphospholipid syndrome); 50:50 mixing studies do not correct the prolonged APTT.

Acquired haemophilia A/vWF

  • Elderly patients presenting with severe bruising and prolonged APTT.

  • Pregnancy.

  • Patients with aortic stenosis.

  • Discuss with haematologists.

  • 50:50 or 80:20 mixing studies do not fully correct the prolonged APTT.

Abnormal platelets

Causes

Thrombocytopenia

(See Table 10.5.)

Table 10.5 Thrombocytopenia

Increased platelet consumption

Reduced platelet production

  • Immune:

    • Idiopathic (ITP)

    • Drug-induced

    • SLE

    • HIV-related

  • Myelosuppressant:

    • Drugs, alcohol

    • Viral infections

  • Marrow infiltration/failure

  • B12 or folate deficiency

  • ITP (one-third of cases)

  • Inherited disorders (rare)

  • Non-immune:

    • Massive transfusion

    • Hypersplenism

    • DIC, TTP

Abnormal platelet function

  • Drugs (e.g. aspirin, clopidogrel).

  • Uraemia.

  • Liver disease.

  • Myeloproliferative disorders.

  • Myelodysplasia.

  • Dysproteinaemia (e.g. myeloma).

  • Inherited disorders (rare):

    • Glanzman’s disease (GP IIb/IIIa deficiency).

    • Bernard–Soulier (GP deficiency).

    • Chediak–Higashi syndrome (abnormal platelet granules).

    • Grey platelet syndrome (α‎ granule deficiency).

    • Storage pool disease.

    • Secretion defect.

Investigations

  • Peripheral blood film: evidence of haemolysis (? DIC, ? TTP) or marrow infiltration. Abnormal platelet size. Grey platelets.

  • Coagulation screen: ? DIC.

  • Autoantibody screen: associated autoimmune diseases.

  • Bone marrow aspirate: Haematological emergencies megakaryocytes generally indicate peripheral consumption; Haematological emergencies or abnormal megakaryocytes suggest a marrow problem. Dysplasia. Micromegakaryocytes.

  • Antiplatelet antibodies: rarely indicated or useful.

  • Platelet function tests: for bleeding in the presence of adequate platelet numbers on the blood film.

  • Low platelets (<10 × 109/L) may cause spontaneous bleeding and require platelet transfusion ± treatment for the underlying cause; <20 if sepsis present.

  • Moderately low counts (20–140 × 109/L) will rarely cause spontaneous bleeding, unless there is an associated clotting abnormality (e.g. DIC) or a primary marrow defect, with production of defective platelets (e.g. myelodysplasia). Transfuse only if there is continued bleeding or in preparation for major surgery.

  • High counts (500–1000 × 109/L) may also indicate a primary production problem, with abnormal platelets (e.g. myeloproliferative disorders). (NB A moderately raised platelet count is a normal response to bleeding and iron deficiency, and is also seen in chronic inflammation.)

Management

This depends on the platelet count and severity of bleeding.

Immune-mediated thrombocytopenia

  • Platelet transfusions are usually ineffective as sole therapy and rarely indicated, unless severe bleeding or urgent surgery required.

  • Ig 0.4g/kg/day IVI for 5 days (or 2g/kg/day for 1–2 days): this usually works quicker than steroids, but the effect only lasts 2–4 weeks. Start the infusion very slowly, as anaphylactic reactions (fever, urticaria, bronchospasm, and hypotension) are not uncommon.

  • Prednisolone (1mg/kg od) is the standard first-line treatment for adult ITP.

  • Dexamethasone.

Acute DIC/massive transfusion

  • Give platelet transfusions to maintain platelet count >30–50 × 109/L (for chronic DIC, transfuse only for active bleeding).

Surgery

  • Depends on the surgery, but generally aim for platelet count >50 × 109/L.

  • For CNS surgery or multiple trauma, aim for count >100 × 109/L.

Reduced platelet production (chronic, stable)

  • If no bleeding, transfuse if count <10 × 109/L.

TTP/heparin-induced thrombocytopenia

  • Platelet transfusions are contraindicated. Discuss all cases with the haematologists.

Platelet transfusion

  • A single unit is either a pool of four buffy coats or platelets from a single ♂ donor from apheresis.

  • The number of platelets in a unit is <240 × 109 which is sufficient for most indications, unless there is ongoing consumption (e.g. severe DIC).

  • If no consumption, platelets survive 2–5 days in circulation.

Anticoagulant therapy

(See Table 10.6.)

Table 10.6 Anticoagulant therapy, targets, and monitoring

Routes

Anticoagulant drug

Inhibitory targets

Potential assays

PO

Warfarin

Factor II, factor VII, factor IX, factor X, protein S, protein C

INR, PT

PO

Dabigatran

Factor IIa

Anti-IIa, TT, ecarin clotting time (ECT)

PO

Rivaroxaban

Factor Xa

Anti-Xa

PO

Apixaban

Factor Xa

Anti-Xa

IV or SC

Heparin (UF)

Factor IIa and Xa

APTT, anti-Xa, anti-IIa

IV or SC

Enoxaparin (LMWH)

Factor Xa > factor IIa

Anti-Xa

IV or SC

Danaparoid

Factor Xa

Anti-Xa

IV

Argatroban

Factor IIa

APTT, activated clotting time (ACT), ECT, anti-IIa

IV

Bivalirudin

Factor IIa

APTT, ACT, ECT, anti-IIa

SC

Other heparins (LMWH)

Factor Xa > factor IIa

Anti-Xa

SC

Fondaparinux

Factor Xa

Anti-Xa

Vitamin K antagonist oral anticoagulants: warfarin

  • Warfarin overdose (accidental or deliberate self-harm) results in a prolonged PT (and thus INR), and sometimes lesser prolongation of APTT.

  • Risk factors for significant bleeding include poor control, local lesion (e.g. peptic ulcer, angiodysplasia of the colon), high INR, coexisting haematological abnormality (e.g. thrombocytopenia, myelodysplasia, etc.).

Management

(Adapted from British Society for Haematology guidelines.)

  • Major bleeding requires urgent correction of coagulation and drug cessation, regardless of the vitamin K antagonist: warfarin, phenprocoumon, acenocoumarol, phenindione. Discuss with a haematologist. PCC (purified factors II, VII, IX, and X) 25–50U/kg IV with 5mg of vitamin K IV. FFP 15mL/kg should only be used if prothrombin complex not available.

  • Non-major bleeding requires 1–3mg of vitamin K IV.

  • Moderate warfarin overdose (INR 5–8) without overt bleeding does not usually require specific treatment, and the patient may be managed as an outpatient. Withhold warfarin until the INR falls to the therapeutic range. Try to identify the cause (incorrect tablets, alcohol binge, etc.).

  • Asymptomatic patients with INR >8 are given vitamin K 1–5mg PO (phytomenadione), with a repeat INR check the next day in case further vitamin K is needed. Reintroduce warfarin when INR <5.

  • Asymptomatic patients with INR >5 should have warfarin withheld for 1–2 doses, and the maintenance dose should be reduced. The cause for the elevated INR should be addressed.

Non-vitamin K antagonist oral anticoagulants

Renal impairment and drug interaction may exacerbate bleeding. Actively look for occult GI bleeding in the presence of bleeding elsewhere due to a NOAC. See Table 10.7 for possible coagulation screen results with NOACs.

  • Stop the NOAC; activated charcoal can be used if ingested within 1–2h.

  • PCC 50U/kg can be used, with variable success, with other haemostatic measures and agents for major bleeding.

  • In addition, dialysis and/or idarucizumab can be used for the direct thrombin inhibitor dabigatran reversal, and andexanet for factor Xa inhibitor reversal.

  • A normal PT for factor Xa inhibitors (rivaroxaban or apixaban) or a normal TT (or APTT) for the direct thrombin inhibitor dabigatran usually indicates a low drug activity level with most reagents.

  • A normal dilute TT (or ECT) in the presence of a direct thrombin inhibitor (dabigatran), or a normal anti-Xa activity in the presence of a factor Xa inhibitor (rivaroxaban or apixaban), usually indicates subclinical levels that do not require specific reversal therapy.

  • Half-lives in descending order from up to 17h to 9h: dabigatran, rivaroxaban, apixaban.

  • NOACs are contraindicated when the creatinine clearance is <15mL/min (or <30mL/min for dabigatran), for metal cardiac valves, and during pregnancy and lactation.

Table 10.7 Possible coagulation screen results with NOACs

Assay

Dabigatran

Rivaroxaban or apixaban

PT

Haematological emergencies/Haematological emergencies

Haematological emergencies/Haematological emergencies

APTT

Haematological emergencies

Haematological emergencies/Haematological emergencies

TT

Haematological emergencies

Haematological emergencies

Anti-Xa

Haematological emergencies

ECT

Haematological emergencies

Heparin

Risk factors for bleeding include age, recent surgery or trauma, renal or liver failure, malignancy, APTT ratio >3, and a coexisting haematological abnormality.

Management

  • Stop heparin: the APTT usually normalizes in 2–4h.

  • Protamine sulfate (1mg IV neutralizes 100U of heparin): may be used; halve the dose if heparin has been turned off 1h previously.

  • LMWHs: are thought to have fewer bleeding complications. However, their plasma half-life is longer and they are less effectively reversed with protamine. Treatment of OD is as described earlier, but note that the APTT is usually normal on LMWH.

  • Heparin-associated thrombocytopenia (Haematological emergencies Abnormal platelets, pp. [link][link]).

Bleeding with fibrinolytic therapy

Risk factors for bleeding with fibrinolytic therapy are given under Haematological emergencies STEMI: thrombolysis 2, pp. [link][link]. Severe haemorrhage should be managed with:

  • Supportive measures (blood transfusion).

  • Cryoprecipitate or fibrinogen concentrate transfusion as a source of fibrinogen.

  • Tranexamic acid (0.5–1g slow IV injection, tds) should also be given.

Bleeding in liver disease

The liver is involved in the synthesis of factors II, VII, IX, and X (the vitamin K-dependent factors) and the non-vitamin K-dependent factors (e.g. factor V), as well as in the clearance of ‘activated’ coagulation factors, fibrin molecules, and tissue plasminogen activator (tPA). The abnormalities most commonly found are:

  • Obstructive jaundice: prolonged PT (vitamin K deficiency).

  • Acute liver failure: prolonged PT and later prolonged APTT and TT (DIC).

  • Cirrhosis: prolonged PT, APTT, and TT; low fibrinogen and/or dysfibrinogenaemia; raised FDPs, Haematological emergencies clearance of tPA; low platelets (hypersplenism, DIC, and marrow dysfunction).

Management

Treatment is required for active GI bleeding or as prophylaxis for surgery or liver biopsy.

  • Give vitamin K 10mg IV slowly.

  • FFP transfusion is more effective, but short-lived.

  • Consider PCC (purified factors II, VII, IX, and X) for life-threatening bleeding, if fluid-overloaded. Liaise with haematology.

Bleeding in severe uraemia

Uraemia (usually >35–50mmol/L) results in both platelet dysfunction (impaired aggregation, adhesion, and activation) and endothelial dysfunction (exacerbated in the presence of amyloidosis).

Management

  • The treatment of choice is haemodialysis.

  • Other measures that have been shown to be effective include:

    • Cryoprecipitate infusion.

    • Desmopressin (Haematological emergencies Haemophilia and related disorders 1, pp. [link][link]).

    • Conjugated oestrogens.

    • Blood transfusion or erythropoietin to raise the haematocrit to >0.25.

Massive transfusion/cardiopulmonary bypass

  • Dilutional thrombocytopenia and coagulopathy usually occur once red cell concentrates equivalent to ~2 blood volumes have been transfused. With cardiopulmonary bypass, the extracorporeal circuit further damages the native platelets and depletes coagulation factors. Furthermore, cold temperature also inactivates platelets.

  • Abnormalities include Haematological emergencies PT, Haematological emergencies APTT, Haematological emergencies FDPs, and Haematological emergencies fibrinogen.

  • Post-transfusion thrombocytopenia is a distinct disorder seen 8–10 days following a transfusion and is due to a platelet-specific antibody (Haematological emergencies Blood transfusion reactions, pp. [link][link]).

Management

Treatment should be discussed with the haematology team and involves platelet transfusion to keep the platelet count >50–75 × 109/L (or >100 × 109/L for CNS lesions/multiple trauma), FFP (4–5U) if PT or APTT >1.5 × control, and cryoprecipitate (10–15U) if fibrinogen <500g/L.

Haemophilia and related disorders 1

Haemophilia A

X-linked recessive (or acquired) deficiency of factor VIII (Haematological emergencies APTT; Haematological emergencies factor VIII activity).

Haemophilia B

X-linked recessive (or acquired) deficiency of factor IX (Haematological emergencies APTT; Haematological emergencies factor IX activity).

Clinical presentation depends upon the degree of factor deficiency and whether inherited or acquired. If inherited:

  • Patients with <1% activity (= severe disease) have a serious bleeding diathesis. Most are on home therapy.

  • Patients with 1–5% activity are moderately affected; spontaneous bleeding is rare but should be treated as severe haemophiliacs when they do.

  • Patients with 5–40% factor activity rarely bleed, unless there is trauma or surgery; mild disease.

Acute presentations

  • Acute haemarthroses: often occur at sites of previous bleeding, particularly if this has led to degenerative joint disease. Ankles, knees, hips, and elbows are the most common sites. Symptoms include local tenderness, warmth, and swelling, and may take days or weeks to resolve.

  • Intramuscular bleeds: can cause a compartment-type syndrome, leading to ischaemic necrosis and contracture. Iliopsoas bleed causes entrapment of the femoral nerve and produces the triad of groin pain, hip flexion, and sensory loss over the femoral nerve distribution. The pain may radiate to the abdomen and mimic appendicitis.

  • Intracranial bleeding: is infrequent but is still a common cause of mortality. It often follows a minor head injury. Prognosis of intracerebral haemorrhage is generally poor. Extradural and subdural haemorrhage have a better prognosis.

  • Bleeding post-trauma: classically, there may be an initial period of haemostasis; bleeding then becomes persistent or intermittent over days/weeks.

  • Haematuria/ureteric clot colic: is rare in haemophilia. Usually there is no detectable underlying abnormality of the renal tracts.

  • Problems relating to coexisting HIV or hepatitis B/C infection: are now the most common cause of mortality, due to infected factor VIII administered during the 1980s.

Investigations

Generally, acute investigations are not necessary for simple joint and muscle bleeds in a known haemophiliac. Consider:

  • USS: for muscle haematomas (e.g. iliopsoas bleed).

  • CT scan: history of head trauma, headache, abnormal neurology.

  • Factor VIII levels: if bleed is severe and treatment is necessary.

  • Factor VIII inhibitor titre: if refractory bleeds/history of inhibitor development.

von Willebrand’s disease

  • Autosomal dominant type 1 (quantitatively low levels), with varying expression, and type 2 (qualitatively low levels), or recessive (type 3).

  • Reduced levels or abnormal function of vWF, which normally promotes platelet adhesion and protects factor VIII from destruction (hence Haematological emergencies factor VIII activity in severe disease).

  • Less severe than the haemophilias, with haemarthroses and muscle bleeds being rare. Mucocutaneous bleeding (e.g. epistaxis, prolonged bleeding from cuts, heavy menstrual bleeding) and post-traumatic bleeding are the main problems.

Haemophilia and related disorders 2

Most patients contact their haematologist directly, unless they bleed when away from home. Be guided by your local haematologist.

General measures

  • Rest: of the affected part and ice packs may be of benefit.

  • Analgesia: avoid IM injections. Oral analgesia (e.g. dihydrocodeine) for minor bleeds; IV injections or infusions of high-dose opiates may be necessary. Use of NSAIDs is controversial.

Moderate or severe haemophilia

  • Treat with IV factor VIII concentrate.

Mild haemophilia

  • Factor VIII deficiency only: mild or moderate bleeds should be treated with desmopressin. Severe bleeds or those not responding to desmopressin: treat with IV factor VIII concentrate.

  • Factor IX deficiency only: treat with factor IX.

von Willebrand’s disease

  • Mild and moderate bleeds: type 1—treat with desmopressin (except type 1C) + tranexamic acid. Type 2—usually requires vWF concentrate (typically an intermediate-purity factor VIII preparation).

  • Severe bleeds: treat with vWF concentrate, and for type 3 vWD, consider platelet transfusions.

NB All CNS and perispinal bleeds are regarded as severe.

Factor VIII replacement

(See Table 10.8.)

  • Minor bleeds may respond to a single slow IV bolus of factor VIII.

  • Major bleeds: 12-hourly treatments (8-hourly in severe bleeding), with frequent monitoring of factor VIII levels, pre- and post-treatment.

  • Patients with factor VIII inhibitors present a particular problem. This can sometimes be circumvented by the use of other products [e.g. factor VIII inhibitor bypassing activity (FEIBA) or recombinant activated factor VIIa].

Table 10.8 A rough guide for factor VIII and IX replacement

Condition

Desired factor level (IU/dL)

Dose of factor VIII (IU/kg)

Dose of factor IX (IU/kg)

Mild/moderate bleeds

50

25

65 = BeneFix®

40 = Replenine®

Major/life-threatening bleeds

100

50

130 = BeneFix®

80 = Replenine®

For example, a 70kg man with a minor bleed who is known to have haemophilia B and usually receives BeneFix® should receive 65 × 70 = 4550U (round to the nearest vial = 4500U).

Factor IX replacement

(See Table 10.8.)

  • Plasma half-life is longer than factor VIII, and once-daily administration is sufficient (twice daily in severe bleeds).

  • Avoid overdosage of factor IX, as it is highly thrombogenic.

Desmopressin

  • Indications: mild to moderate haemophilia A, especially in children, vWD type 1 and some type 2. Most have previously responded to a challenge test dose.

  • Dosage: 0.3 micrograms/kg in 100mL of normal saline IV over 30min; may be repeated 8–12h later. Alternatively, can be given SC at the same dose or intranasally (300 micrograms for an adult). Peak haemostatic effect in 60–90min.

  • Monitor pulse and BP closely. Side effects include flushing, hypotension, tachycardia, headache, and nausea; rare reports of MI (caution in patients >60 years or with cardiac history). Temporary fluid restriction may be necessary (especially in children) due to ADH effects and risk of hyponatraemia.

Tranexamic acid

  • Give with desmopressin in vWD or mild haemophilia A. Most useful in mucosal bleeds. Avoid in renal tract bleeding (may cause clots).

  • Dosage: 1g PO qds (adults). Mouthwash 4.8% q10min for oral bleeding.

Cryoprecipitate

  • Give for severe bleeding in vWD if vWF concentrate is not available and bleeding not responding to desmopressin and tranexamic acid.

  • Dosage: 10–20U (bags) for 70kg adult.

Combined thrombotic and haemorrhagic disorders

A group of disorders in which the pathways of haemostasis become deregulated, leading to microthrombus formation, platelet consumption, and, to a variable extent, clotting factor consumption. The exact pathogenesis varies, but in each case microthrombi cause organ damage, and thrombocytopenia and depleted clotting factors result in bleeding. This coexistence of thrombosis and bleeding makes management very difficult.

Disseminated intravascular coagulation

An inappropriate activation of coagulation, leading to:

  • Depletion of clotting factors, causing prolongation of PT and APTT.

  • Widespread thrombin activation, causing Haematological emergencies TT and Haematological emergencies fibrinogen.

  • Formation of microthrombi, leading to end-organ damage.

  • Destruction of RBCs in fibrin mesh, causing microangiopathic haemolysis.

  • Consumption of platelets: thrombocytopenia increasing the bleeding tendency.

  • Activation of thrombolysis (raised FDPs) and further bleeding.

The ‘full house’ of abnormalities does not need to be present initially, as the process is a progressive one. For causes, see Box 10.3.

Management

  • Treat the underlying cause (60% have underlying sepsis).

  • Supportive measures, such as correction of shock, acidosis, and hypoxia, may lead to an improvement in coagulopathy.

  • Transfuse blood to correct anaemia. Massive transfusion may exacerbate coagulopathy by dilution of coagulation factors and platelets.

Product replacement

In acute DIC with bleeding, consider:

  • FFP (15mL/kg, i.e. 4–5U) if PT or APTT >1.5 × control.

  • 1U of platelets if platelet count <50 × 109/L or <100 × 109/L and rapidly falling.

  • Cryoprecipitate (10–15U) or fibrinogen concentrate if fibrinogen <500g/L.

  • Occasionally, IV heparin can stabilize severe DIC.

  • Plasma exchange may rarely be considered.

Prognosis

In severe acute DIC, overall mortality is high. Obstetric complications have the best prognosis, if managed expediently. There is little evidence that measures to prevent thrombosis (heparin, antithrombin) or to prevent thrombolysis improve the general prognosis.

Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome

Patients with classic TTP have been found to have an antibody against a metalloproteinase (ADAMTS-13) which cleaves very large multimers of vWF. These then accumulate and cause microthrombi and thrombocytopenia. The clinical picture tends to vary with age, with renal abnormalities being more common in children and neurological problems in adults, but with considerable overlap. In other similar thrombotic microangiopathies and HUS, the primary event appears to be endothelial damage causing microthrombus formation and end-organ damage. For causes, see Box 10.4.

Presentation

  • TTP commonly occurs suddenly in a young or middle-aged woman, or following a viral infection.

  • Fever.

  • Anaemia (microangiopathic picture: associated with jaundice and haemoglobinuria).

  • Thrombocytopenia with purpura; significant bleeding is rare.

  • CNS (confusion, headache, meningitic symptoms, aphasia, visual disturbance, fits, coma, paralysis, psychoses—often fluctuating).

  • Renal involvement (oliguria, anuria, haematuria), often mild initially.

  • HUS is often preceded by gastroenteritis or URTI.

  • Normal coagulation screen initially.

Investigations

(See Table 10.9 and Box 10.4.)

Table 10.9 Investigations in TTP and HUS

Investigation

Further comments

FBC

Anaemia with thrombocytopenia. Moderate leucocytosis with left shift

Blood film

Fragmented RBCs, polychromasia, thrombocytopenia

Clotting

Usually normal

U&Es

In adults, creatinine slow to rise over a few days; rapid deterioration more common in children

LFTs

Haematological emergencies bilirubin (unconjugated). Haematological emergencies LDH (from haemolysis)

Haptoglobins

Haematological emergencies

Urinalysis

Proteinuria frequent; haematuria, haemoglobinuria

Stool

Culture, especially for Escherichia coli strains

ADAMTS-13 activity assay

Low activity

Microangiopathic haemolytic anaemia

Management of HUS and TTP

  • Refer to a specialist unit (haematology and/or renal).

  • Plasma infusion with FFP while transferring to a centre for urgent plasma exchange.

  • Urgent plasma exchange: solvent detergent-treated pooled plasma is currently recommended for TTP in the UK.

  • Plasma exchange: aggressive regimen (40mL/kg/day) with FFP results in improvement of TTP in many patients (except post-BMT). Tail only after remission obtained. Start HAART if HIV-positive.

  • Given 3 days of IV methylprednisolone.

  • Most centres also give rituximab to reduce later recurrence.

  • Dialysis (haemodialysis) is used for AKI (usually children).

  • Broad-spectrum antibiotics: unproven benefit but seem sensible, given an infectious aetiology in some patients.

  • Blood transfusion to correct anaemia.

  • Platelet transfusion contraindicated; exacerbates thrombosis and may worsen the situation.

  • Aspirin may be used once platelet count is >50 × 109/L.

  • Prophylactic LMWH is recommended when platelet count >50 × 109/L and solvent detergent-treated pooled plasma product is being used.

  • Refractory TTP may respond to high-dose steroids, vincristine, or ciclosporin. Rituximab is increasingly being used.

Prognosis

  • Children/predominant HUS picture: 5–30% mortality. Renal impairment and hypertension are common in survivors. Most adults require long-term haemodialysis.

  • Adults/predominant TTP picture: 90% mortality if untreated; most die in first few days. With aggressive and early plasma exchange, mortality is now <15%, but relapses are frequent and reduced with rituximab.

Heparin-induced thrombocytopenia and thrombosis (HITT)

  • An idiosyncratic reaction seen in 1–5%. Much less common with LMWHs (<1%).

  • Type I: mild and transient seen in the first week, often resolving spontaneously with continued therapy.

  • Type II: late-onset thrombocytopenia seen 5 days to 2 weeks after starting therapy and is caused by an IgG autoantibody that results in platelet activation, and thromboembolic events in 40% if untreated.

  • Bleeding is rare at presentation but will be Haematological emergencies because of the need for alternative anticoagulant therapy.

  • Consider the diagnosis if the problem demanding heparinization does not resolve or worsens while the patient is on heparin (e.g. propagation of DVT) or a new thrombotic event takes place in a heparinized patient, in association with a >50% fall in platelet count.

  • Diagnosis is based on the 4T scoring system (see Table 10.10).

Table 10.10 The 4T scoring system*

4T category

2 points

1 point

0 points

Thrombocytopenia

Platelet count fall >50% and platelet nadir ≥20

Platelet count 30–50% or platelet nadir 10–19

Platelet count fall <30% or platelet nadir <10

Timing of platelet count fall

Clear onset days 5–10 or platelet fall ≤1 day (prior heparin exposure within 30 days)

Consistent with days 5–10 fall, but not clear (e.g. missing platelet counts); onset after day 10; or fall ≤1 day (prior heparin exposure 30–100 days ago)

Platelet count ≤4 days without recent exposure

Thrombosis or other sequelae

New thrombosis (confirmed); skin necrosis; acute systemic reaction post-IV UFH bolus

Progressive or recurrent thrombosis; non-necrotizing (erythematous) skin lesions; suspected thrombosis (not proven)

None

Other causes of thrombocytopenia

None apparent

Possible

Definite

* Reproduced from Lo GK, et al. ‘Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings’, Journal of Thrombosis and Haemostasis, 2006; 4: 759–65, with permission from John Wiley and Sons.

The 4T score is the sum of the values for each of the four categories. Scores of 0–3, 4–5, and 6–8 are considered to correspond to a low, intermediate, and high probability of HIT, respectively.

Management

  • HIT can be excluded by a low pretest probability score, without the need for laboratory investigation.

  • If the pretest probability of HIT is not low, heparin should be stopped and an alternative anticoagulant started in full dosage, while laboratory tests are performed. Do not wait to see what happens to the platelet count.

  • An alternative anticoagulant [e.g. danaparoid, argatroban, fondaparinux (pregnancy), bivalirudin (urgent PCI or surgery)] is usually indicated for 3 months in the presence of thrombosis and 1 month without thrombosis.

  • LMWHs can have a crossover effect and perpetuate the problem.

  • Do not start a coumarin (e.g. warfarin) until an alternative anticoagulant has been instated and the platelet count has normalized.

  • Do not give platelets to treat thrombocytopenia, as this can lead to further platelet activation and thrombosis.

  • Heparin re-exposure can occur after >3 months if the patient is IgG antibody-negative.

Acute leukaemias: presentation

Types of acute leukaemia

Acute leukaemia

  • Acute leukaemia is defined using the World Health Organization (WHO) classification, which includes cytogenetic data and provides useful clinical and prognostic information.

  • Acute myeloid leukaemia (AML).

  • Traditional French-American-British (FAB) classification (M0–M7).

  • Acute promyelocytic leukaemia (APL; M3) is often associated with DIC and a relatively low WCC.

  • Monocytic differentiation often manifests with organ infiltration.

  • WHO classification includes AML with characteristic genetic abnormalities, AML with multilineage dysplasia, and AML with myelodysplastic syndrome (MDS), therapy-related.

  • Mainly adults, including the elderly.

  • Acute leukaemias may occur de novo or may transform from chronic myeloid leukaemia [to 70% AML, 30% acute lymphoblastic leukaemia (ALL)]. MDS can also evolve into AML.

  • ALL, usually precursor B-cell, and occasionally precursor T-cell, in origin (FAB L1-2). Burkitt’s lymphoma (L3) is now separately classified.

  • Acute biphenotypic leukaemia.

Poor prognostic factors

  • Increasing age.

  • High WCC at presentation.

  • Prior MDS.

  • Philadelphia chromosome-positive acute leukaemia (20% in adult ALL, 5% in children).

  • Depends upon subclassification of leukaemia on the basis of morphology, chromosomal abnormalities, and cell surface markers.

Presentation

Red cell problems

  • Anaemia: caused by replacement of normal erythropoiesis by leukaemia cells; also by bleeding due to low platelets or deranged clotting (APL). The MCV is usually normal or high (MDS), unless blood loss is predominant.

White cell problems

  • High blast count: may cause ‘leucostasis’ (crudely, sludging of white cells in small vessels), causing respiratory impairment, myocardial ischaemia/MI, renal impairment, acute confusion, stroke, fits, and migraine.

  • Leukaemia-related phenomena: pyrexia, malaise, muscle and joint pains.

  • Neutropenia: secondary to marrow infiltration by leukaemic cells.

Platelet problems

  • Thrombocytopenia due to myelosuppression by leukaemic infiltrate.

  • Existing platelets may have sub-normal function. Risk of bleeding increases if platelets are <10 × 109/L or <20 × 109/L if there is concomitant sepsis or coagulation abnormality.

Coagulation problems

  • Range from a prolongation of PT to DIC: may be due to sepsis or the effects of leukaemia itself, especially APL.

Priorities

  1. 1 Stabilize the patient.

  2. 2 Treat immediate problems, e.g. bleeding, sepsis.

  3. 3 Confirm diagnosis (morphology, cytogenetics, and flow cytometry).

  4. 4 Define the treatment strategy, often urgently.

Acute leukaemias: management

Stabilize the patient

  • Airway: stridor may be secondary to mediastinal obstruction in certain cases of leukaemia, mainly T-ALL. If present, call the anaesthetist immediately and arrange transfer to ITU to start treatment.

  • Breathing: breathlessness may be due to infection (including atypical organisms), leucostasis (high WCC), severe anaemia, cardiac failure (leucostasis, severe sepsis), and pulmonary haemorrhage. Give O2: where possible, use a pulse oximeter to monitor O2 saturation, avoiding arterial puncture with thrombocytopenia. Leukapheresis may be indicated (consider if WBC >100 with AML, >50 with ALL).

  • Circulation: shock is usually secondary to sepsis, but consider the possibility of blood loss if low platelets/clotting abnormalities or cardiac failure from leucostasis.

  • Restore circulatory volume with crystalloid and blood components.

  • Give broad-spectrum antibiotics immediately (after blood cultures) if sepsis suspected (Haematological emergencies The febrile neutropenic patient 1, p. [link]).

  • Refer to a haematologist urgently.

Treat immediate problems

  • Infection: until the blood film has been reviewed by a haematologist, assume the patient is neutropenic and treat all infections aggressively (Haematological emergencies The febrile neutropenic patient 1, p. [link]).

  • Bleeding:

    • Transfuse cross-matched blood components. Caution if high WCCs.

    • If platelets <10 × 109/L, give one pool of platelets. If there is active bleeding and platelet count <50 × 109/L, give platelets.

    • If PT prolonged (>1.5 × control), give 4–5U of FFP.

    • If fibrinogen <1–1.2g/L, consider cryoprecipitate in addition.

Transfusion in the presence of a high WCC is dangerous and can precipitate the complications of leucostasis.

  • High WCC: discuss with haematologists. May require urgent leukapheresis, preferably in an ITU setting.

Confirmation of diagnosis

  • Take a full history, looking for possible aetiological factors. Length of illness (was there a preceding chronic condition, e.g. ? myelodysplasia). Past medical history (? Down’s syndrome, radiation/chemotherapy exposure). Occupation (? exposure to irradiation, benzenes, other mutagens). Family history (rare familial syndromes, e.g. Fanconi’s anaemia).

  • Examine the patient, looking for accessory clues to diagnosis (? lymphadenopathy in ALL, hepatosplenomegaly, gum hyperplasia in M5 monocytic leukaemias), splenomegaly in CML/non-Hodgkin’s lymphoma (NHL)/myelofibrosis, and identifying potential sites for infection (dental caries, skin lesions, etc.)

  • Final confirmation then rests upon a bone marrow aspirate, with samples being sent for morphology, chromosome analysis, and cell surface markers.

Acute leukaemias: treatment

The treatment of acute leukaemia depends upon the type of leukaemia and involves several courses of chemotherapy, taking months or even years to complete. The prognosis has improved in recent years and depends upon the exact diagnosis. Eighty per cent of children with ALL are now cured, whereas only around 30–50% of adults with AML are cured, depending on age. Most patients with APL survive long term if they do not succumb to acute bleeding. The impact of the diagnosis on often young patients and their families is devastating, and extensive time is needed in discussion; this should be done by a haematologist. Before embarking on chemotherapy, the following must be considered.

Sperm banking

Most forms of chemotherapy carry a risk of subsequent infertility. When desired by the patient, every attempt must be made to provide for banking of sperm collection prior to starting chemotherapy. Only 5–10% of men subsequently utilize their banked sperm for assisted fertility. Unfortunately, in practice, the presence of leukaemia itself often makes sperm non-viable, and the need to start treatment precludes repeated collections.

Discussion about side effects

Patients need to be warned about hair loss, sterility, emesis (less of a problem with current antiemetics but varies with individual), infections, bleeding, mucositis, secondary cancers, etc. Patient-orientated literature is available on acute leukaemia and chemotherapy, and may be helpful.

Other considerations

  • LP (? CNS involvement). Indicated in:

    • ALL (because of high risk of CNS relapse).

    • AML if high WCC at presentation.

    • Any neurological symptoms/signs.

  • Human leucocyte antigen (HLA) typing of patient/siblings may be considered, with a view to possible BMT in the future.

  • CMV status should be determined, especially if BMT is an option, along with a viral screen, e.g. HIV, etc.

Prior to commencement of chemotherapy

  • Commence allopurinol 24h in advance. Rasburicase is used if there is a high risk of tumour lysis syndrome (200 micrograms/kg IV od for 5–7 days); no G6PD.

  • Prescribe regular antiseptic mouthwashes, to be used 4–5 times/day in conjunction with antimicrobial prophylaxis (oral fluconazole, ciprofloxacin, aciclovir).

  • Ensure adequate hydration, aiming for 3L/day input.

  • Give antiemetics before chemotherapy, and at regular intervals during treatment with chemotherapy. Appropriate regimens include:

    • Ondansetron 4–8mg IV/PO bd

    • Metoclopramide 10–20mg IV/PO plus dexamethasone 2–4mg IV/PO 4- to 8-hourly.

Early complications of bone marrow transplantation

Always urgently contact and refer the patient back to their BMT centre. Close contact with the ICU for supportive care.

Morbidity and mortality following BMT (especially allogeneic BMT) is high, particularly within the first 100 days. The patients are very reliant on close medical and nursing surveillance to ensure that they do not perish from preventable/treatable causes. Patients may occasionally present outside of their transplant unit overnight or at weekends. They will be vulnerable to infections—bacterial, viral, fungal, and protozoal. Even if the neutrophil count is normal, treat the patients as being neutropenic, as they will have poorly functioning lymphocytes and low antibody production. This section is a guide to some of the problems encountered.

Acute graft-versus-host disease

This causes skin rashes, either localized (e.g. to palms) or widespread. There may be upper and/or lower GI symptoms (severe watery diarrhoea) and liver dysfunction (deranged LFTs). Consider early treatment (usually high-dose methylprednisolone) for graft-versus-host disease (GVHD), with budesonide for diarrhoea. Always discuss with the transplant centre.

Fever

See Haematological emergencies The febrile neutropenic patient 1, p. [link].

Upper GI symptoms (mucositis, vomiting)

Symptomatic management, including adequate analgesia (e.g. opiates) and H2-antagonists or PPIs. Search for an infectious cause (mouthwash and swabs for HSV and Candida). Antiemetics usually required: lorazepam 1–2mg q8–12h; metoclopramide 10–20mg q6–8h; or ondansetron 4–8mg q12h.

Diarrhoea

Rehydrate. Monitor strict fluid balance. Stool culture (green watery diarrhoea suggests GVHD). May require early biopsy and steroids if large-volume diarrhoea. Malabsorption is also a problem. Discuss with the transplant centre.

Abnormal LFTs (drugs, GVHD, veno-occlusive disease)

Supportive measures: monitor fluid balance, coagulation tests, renal function; adjust drug doses accordingly. Search for an infectious aetiology. Veno-occlusive disease presents as hepatomegaly, jaundice, and weight gain in the early post-transplant period. Liver USS with Doppler of the hepatic and portal veins (reversed hepatic portal flow seen in veno-occlusive disease). Discuss with the transplant centre.

Interstitial shadowing on CXR

These may be diffuse or localized and associated with varying degrees of fever, breathlessness, and hypoxia.

Causes

Pulmonary oedema [fluid overload, cardiac failure due to chemo-/radiotherapy, non-cardiac (ARDS)—related to sepsis or drug toxicity]; infection [bacterial, viral (especially CMV), fungal, Pneumocystis]; thromboembolic; GVHD; pulmonary haemorrhage; idiopathic.

Management

Supportive treatment: O2, diuretics (if pulmonary oedema), and ventilatory support. CXR changes often minor if neutropenic, and so consider HRCT early. Cover for infectious causes with broad-spectrum antibiotics, antifungal agents, or occasionally antiviral agents (if viral respiratory tract infection is suspected). PCP is unusual if the patient is on co-trimoxazole prophylaxis. Consider bronchoscopy.

Early complications of BMT

  • Skin rash.

  • GI complications:

    • Nausea and vomiting.

    • Mucositis.

    • Diarrhoea.

  • Abnormal LFTs.

  • Haemorrhagic cystitis.

  • Interstitial shadowing on CXR.

  • Cardiovascular complications:

    • Cardiac failure.

    • Hypertension.

  • Deteriorating renal function.

  • CNS complications.

  • Sepsis.

  • Drug toxicity.

Complications of BMT

Cardiac failure

  • Cardiac toxicity may be secondary to high-dose cyclophosphamide, total body irradiation, and/or previous anthracycline exposure.

  • Transient ST- and T-wave abnormalities and LV dysfunction on Echo are seen in up to 30%, following conditioning prior to BMT.

  • Overt cardiac failure may be seen with repeated high-dose steroid therapy that is required for episodes of GVHD.

Management

  • Standard therapy with diuretics and ACEI.

Hypertension

  • Very common in the early days post-BMT and due to ciclosporin therapy ± renal impairment.

Treatment

  • Calcium antagonists [e.g. nifedipine slow release (SR) 10–20mg PO bd].

Deteriorating renal function

Causes

  • Drug therapy (ciclosporin, amphotericin, aminoglycosides, chemotherapy, aciclovir, allopurinol).

  • Pre-renal (dehydration, shock, bleeding).

  • Tumour lysis syndrome (Haematological emergencies Tumour lysis syndrome, p. [link]).

  • TTP (Haematological emergencies Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, p. [link]).

Haemorrhagic cystitis

Frequency, dysuria, and haematuria; commonly related to cyclophosphamide (caused by acreolin, a metabolite), but also seen with anthracyclines, cytosine arabinoside, etoposide, adenovirus, and BK virus infection. Prevent with mesna (see data sheet for dose).

Management

Supportive therapy with blood and platelet transfusion and hydration is usually sufficient. Discuss with urologists if severe, as more specialist intervention, such as bladder irrigation, may be required.

CNS complications

Symptoms

  • May include seizures, drowsiness/confusion, focal neurological signs, stroke, and visual loss (cortical).

Causes

  • Metabolic (Haematological emergencies Mg2+, Haematological emergencies Ca2+, hypoxia, liver failure, renal failure).

  • Infection: bacterial, viral (e.g. HSV), fungal (especially Aspergillus), Toxoplasma, Cryptococcus.

  • Drug toxicity; ciclosporin can cause tremor, confusion, and seizures.

  • Intracranial haemorrhage.

  • Cerebral infarction (embolic).

  • Relapse of disease.

  • TTP (Haematological emergencies Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, p. [link]).

  • Steroid psychosis.

  • PRES.

Investigations

  • FBC and film, LDH, CT scan, LP (after correcting clotting and platelets), blood cultures, serology, Mg2+ and Ca2+ levels, Echo, drug level, chimerism studies, bone marrow assessment.

Management

  • Specific therapy for the underlying cause.

The febrile neutropenic patient 1

  • Neutropenia (in this context) may be defined as a total neutrophil count of <1.5 × 109/L, regardless of total WCC.

  • Significant infections are usually associated with a fever of ≥38°C. Severely ill patients and those on steroids may not be able to mount a fever; signs such as tachypnoea, tachycardia, or hypotension should be considered serious.

  • The site of infection is not usually obvious; potential sites include the chest, Hickman line, or other central line (or inflammation around the exit site of the line), mouth, perianal area/perineum, urine, or skin.

Organisms

(See Box 10.5.)

  • A microbiological diagnosis is reached in up to two-thirds of cases.

  • Coagulase –ve staphylococci: Hickman or other IV lines.

  • Viridans streptococci: mucositis ± previous exposure to quinolones.

  • Fungal infections: occur after prolonged and profound neutropenia, previous antibiotic therapy, underlying lung disease (pulmonary aspergillosis), stem cell transplantation, or prolonged immunosuppression (steroids for >1 week).

Basic microbiological investigations

  • Blood cultures: taken from Hickman line and by venepuncture. This allows line infections to be differentiated from bacteraemias.

  • Culture of urine and faeces, including stool for Clostridium difficile. C. difficile toxin, adeno viral and rota viral antigens.

  • Cultures from other suspected sites: e.g. line exit sites, sputum, skin lesions, throat. Consider TB cultures.

  • Viral serology: less useful, as a rising titre is often necessary to diagnose infection. Viral detection (e.g. viral PCR-CMV, EBV and adenovirus PCR, respiratory viruses such as RSV, influenza, and parainfluenza), where possible, may be more helpful in an acute situation.

  • Line tips: rush to the laboratory. Do not allow to dry out on the ward bench or insert into a throat swab medium.

Important points

  • Antibiotic therapy should never be delayed to await further assessment of clinical progress or laboratory results.

  • Neutropenic patients may not show a localized response to infection. The most common presentation is that of a fever of unknown origin.

  • Pyrexia lasting >48h, despite IV antibiotics, usually requires some alteration to the antimicrobial regimen. Consider polymicrobial and/or fungal infection.

  • Platelet requirements increase with sepsis: neutropenic patients are commonly also thrombocytopenic—keep platelet count above 20 × 109/L.

  • Thrombocytopenia also demands care with invasive procedures. Central lines and urinary catheters should be inserted with platelet cover, and arterial puncture is best avoided (use pulse oximetry).

The febrile neutropenic patient 2

Immediate management

Given the caveats described under Haematological emergencies The febrile neutropenic patient 1, p. [link], stabilization of a septic neutropenic patient is similar to that of any other septic patient.

  • O2, IV crystalloid, and vasopressors should be administered, as is appropriate to the patient’s clinical condition.

Antimicrobial regimen

When in doubt, take haematological advice; use the hospital policy. Regimens for empirical therapy are based on broad-spectrum bactericidal antibiotics. Monotherapy is usually inappropriate, even when an organism has been isolated; the patient may well have >1 infection. A typical policy is shown in Table 10.11. See Box 10.6 for causes of failure to respond to empirical antibiotics.

Table 10.11 Empirical antibiotic therapy for febrile neutropenia

First line

  • Piperacillin with tazobactam 4.5g IV tds (or meropenem 1g IV tds if penicillin-allergic or renal impairment) plus

  • Amikacin 15mg/kg IV od (guided by levels)

Second line

Add:

  • Vancomycin 1g IV bd (guided by levels) or

  • Teicoplanin 400mg IV od (bd for first 24h) if line infection is suspected

Third line

Consider AmBisome® 3–5mg/kg if fever not settling after 72h, especially in patients with long periods of neutropenia (e.g. AML or BMT patients). Discuss with the local haematologist. Urgent HRCT thorax

Notes

  • Doses of vancomycin and gentamicin will need to be adjusted, according to serum levels.

  • Add metronidazole 500mg IV q8h to first- or second-line regimens if fever persists and anaerobic infection possible (e.g. perineal sepsis or mucositis).

  • Add amphotericin: most units use the lipid formulations Abelcet® or AmBisome® for proven (or possible) fungal infection. Voriconazole is used first line if Aspergillus is likely. Caspofungin or micafungin for Candida. Posaconazole is an oral alternative.

  • The change from first- to second-line therapy should be considered under the following circumstances:

    • Persistent pyrexia >48h (or less if the patient’s condition markedly deteriorates).

    • A new spike of temperature once the fever has settled on first-line antibiotics (suggesting emergence of another resistant organism).

    • Rising CRP in the face of apparently appropriate antibiotics.

  • Choice of third-line antibiotics is often more arbitrary, and combinations should again be discussed with haematology and microbiology. Duration of neutropenia is an important factor, as fungal infections become more likely the longer the period of neutropenia.

Particular situations

  • Infections of the mouth, perianal area, or elsewhere in the GIT: consider adding metronidazole for Bacteroides spp. and others.

  • Suspected line infections: ensure good Gram +ve cover (vancomycin or teicoplanin). Consider linezolid if vancomycin-resistant enterococci (VRE) are present.

  • Diarrhoea after prolonged antibiotic therapy: suspect C. difficile; consider empirical oral vancomycin and/or metronidazole, while awaiting stool toxin detection/culture results.

  • Oropharyngeal mucositis due to reactivation of HSV is common. It is effectively prevented and treated with aciclovir; the main complication is bacterial super-infection.

  • Pyrexia associated with a normal CRP virtually excludes bacterial or fungal infection as a cause of the fever.

  • Deteriorating renal function: avoid nephrotoxic agents, particularly in combination (e.g. vancomycin, liposomal formulation of amphotericin, gentamicin).

  • Systemic candidiasis may be manifest only as fever unresponsive to antibiotics: blood cultures are rarely positive; signs of local invasion (e.g. endophthalmitis) are seen in a minority. Have a high index of suspicion and treat aggressively with amphotericin or fluconazole. Hepatosplenic disease is often diagnosed with imaging.

  • Invasive aspergillosis presents with fever, abnormal CXR/HRCT, and dyspnoea or sinusitis (invasive disease of the sinuses). There is extensive local tissue destruction with cavitating lung lesions or bone destruction of sinuses. Thoracic HRCT should be performed urgently. Treat aggressively with IV AmBisome® or voriconazole/micafungin/caspofungin/posaconazole.

  • Granulocyte colony-stimulating factor (GCSF) may shorten a period of neutropenia and may be used for certain patients. Discuss with haematology.

When selecting an antimicrobial regimen, it is worthwhile reviewing all recent microbiology results, including skin swabs (axilla, groin, perineal). Review past microbiology for resistant organisms that may need to be covered (e.g. MRSA, VRE, resistant Pseudomonas, E. coli, or Klebsiella).

Infections in the transplant patient

Infectious diseases are a major cause of mortality and morbidity following both solid organ and bone marrow transplantation, related to immunosuppression (and in the case of BMT, the innate immuno-incompetence in the neutropenic and early engraftment phases).

Different pathogens are typically implicated in infections, depending on the degree of immunocompetence of the patient:

  • The neutropenic patient (Haematological emergencies The febrile neutropenic patient 1, p. [link]).

  • The non-neutropenic transplant patient.

Cell-mediated immunity may be impaired for several months after bone marrow (and solid organ) transplantation. This predisposes to viral (CMV, HSV, adenovirus, EBV) and protozoal (Pneumocystis jiroveci, toxoplasmosis) infections.

  • CMV infections: see Haematological emergencies Cytomegalovirus infections in transplant patients, p. [link].

  • Suspected Pneumocystis pneumonia: treat with high-dose co-trimoxazole (0.96–1.44g q12h IV) and corticosteroids; consider urgent bronchoscopy/BAL if patient fit enough.

  • Toxoplasmosis: usually due to reactivation of latent infection. Presents as intracranial SOL, meningoencephalitis, or diffuse encephalopathy. Seizures and focal neurological signs are common. Treatment is with pyrimethamine and sulfonamides. Give co-trimoxazole prophylaxis.

  • Other viral infections:

    • HSV commonly produces localized infection and dissemination is rare, but recognized, to produce encephalitis and pneumonia. Treat with high-dose aciclovir IV.

    • VZV reactivation is frequently seen and most infections are mild; encephalitis and pneumonitis are usually fatal. Treat with high-dose aciclovir (10mg/kg IV q8h). Disseminated VZV can present as central abdominal pain, with little or no obvious rash.

    • Adenovirus infection produces interstitial pneumonitis, similar to CMV, and may disseminate.

Cytomegalovirus infections in transplant patients

(Also see Table 8.2.)

  • May be acquired from the reactivation of previous CMV infection in the recipient, due to immunosuppression.

  • May be acquired from the bone marrow from a CMV-positive donor or CMV-positive blood products (less likely due to universal leucodepletion. (All BMT recipients should receive irradiated blood products.)

  • Occur more commonly in allogeneic and unrelated donor transplants, due to greater immunosuppression.

Presentation of acute CMV infections

  • Fever of unknown origin.

  • Positive CMV PCR (detected by routine blood testing).

  • Graft failure/myelosuppression (anaemia, thrombocytopenia, leucopenia).

  • Interstitial pneumonitis: deteriorating O2 saturation, with widespread bilateral interstitial opacities on CXR.

  • Enteritis (oesophagitis, gastritis, colitis): pyrexia, diarrhoea.

  • Hepatitis.

  • Retinitis.

Immediate management

  • Ensure adequate respiration; consult the anaesthetist and consider CPAP/invasive ventilation early if O2 requirements are increasing or the patient is becoming exhausted.

  • Inform the haematologist responsible for the patient’s care.

  • Take blood for CMV PCR.

  • If CMV is strongly suspected, commence ganciclovir/valganciclovir/foscarnet/cidofovir treatment immediately. Otherwise, consider:

    • Bronchoscopy/BAL if pulmonary infiltrate.

    • Upper or lower GI endoscopy and biopsy.

Treatment

  • Valganciclovir 900mg bd or ganciclovir 5mg/kg bd should be commenced.

  • Side effects include nephrotoxicity and myelosuppression/graft failure, which may be difficult to distinguish from the effects of CMV itself.

Hyperviscosity syndrome

Causes

Increased cellularity

  • Polycythaemia (primary or secondary):

    • Haematocrit 50–60%.

  • Leucocytosis (acute leukaemias):

    • WCC >50–100 × 109/L.

    • CML (>300 × 109/L).

Raised plasma proteins

  • Waldenström’s macroglobulinaemia:

    • IgM paraprotein level >30g/L.

  • Myeloma, usually IgA subtype:

    • Paraprotein level >80g/L.

Presentation

Most patients develop symptoms when serum viscosity reached 5–6 centipoises (normal <1.8).

General features

  • Muscle weakness.

  • Lethargy, headache.

  • Mental confusion, proceeding to coma.

  • Visual disturbance.

  • CCF.

  • Fundoscopy:

    • Engorgement and sludging in the veins.

    • Haemorrhage, exudates.

    • Papilloedema.

Specific features

The predominant symptoms vary with the underlying cause.

  • Raised paraprotein:

    • Bleeding/purpura: platelet dysfunction and factor deficiency.

    • Neuropathies.

    • Renal impairment.

    • Cardiac conduction abnormalities.

  • Leucostasis:

    • Myocardial ischaemia/MI.

    • Pulmonary infiltrates.

  • Polycythaemia:

    • Peripheral ischaemia.

    • TIAs/strokes.

    • MI.

Management

Arrange urgent intervention (same day), depending on the cause:

  • Polycythaemia:

    • Venesect 1–2U.

    • Replace with normal saline.

  • Leukaemia: leukapheresis or chemotherapy.

  • High paraprotein: plasmapheresis.

Tumour lysis syndrome

A syndrome of metabolic abnormalities and renal impairment that can occur within hours or days of commencing chemotherapy, due to rapid lysis of tumour cells. It is most likely to occur with bulky, highly chemosensitive lymphoproliferative disease (e.g. T-ALL and Burkitt’s lymphoma). Seen less commonly in other lymphomas, high-blast count leukaemias, and some germ cell tumours.

Features

  • Uric acid ≥476 micromol/L or 25% increase from baseline ± urate nephropathy and oliguric renal failure.

  • Hyperkalaemia (K+ 6mmol/L or 25% increase from baseline), especially with progressive renal impairment.

  • Hyperphosphataemia (≥1.45mmol/L or 25% increase from baseline).

  • Hypocalcaemia (≤1.75mmol/L or 25% decrease from baseline) and hypomagnesaemia (due to rising PO43–).

  • Creatinine ≥1·5 times upper limit of normal (age >12 years or age-adjusted).

  • Cardiac arrhythmias (secondary to Haematological emergencies K+, Haematological emergencies Ca2+, and Haematological emergencies Mg2+).

  • Weakness, twitching, tetany (hypocalcaemia).

  • Severe metabolic acidosis (renal failure).

  • Seizures.

  • Sudden death.

Prevention

  • Start allopurinol 300mg od (or bd) 48h prior to chemotherapy if renal function is normal.

  • Rasburicase should be considered for high-risk patients (non-G6PD-deficient), such as Burkitt’s lymphoma, high WCC ALL, and patients with LDH >2 times normal. Standard dose is 0.2mg/kg IV od for 5–7 days. A starting dose of 3mg is often effective.

  • Hyperhydrate: vigorous hydration is important, and a fluid load of 3L/m2/day should be given to those patients who can tolerate it. A urinary catheter should be used to monitor output.

  • Leukapheresis if high peripheral blast count.

  • Continue IV fluids during therapy, giving furosemide to maintain diuresis (>100mL/m2/h).

  • Urine alkalinization no longer recommended (with sodium bicarbonate to keep urinary pH >7.0).

Management

  • Emergency treatment of hyperkalaemia.

  • Exclude bilateral ureteric obstruction by US.

  • Avoid Ca2+ supplements, except if there is neuromuscular irritability.

  • Monitor U&Es, PO43–, Ca2+, and urate at least twice daily for the first few days of treatment.

  • Strict fluid balance measurements, with a urinary catheter if necessary.

  • Indications for haemodialysis/intensive care:

    • Rising K+, creatinine, or PO43– in spite of measures discussed earlier.

    • Metabolic acidosis.

    • Fluid overload or oliguria in spite of diuretics.

Hypercalcaemia of malignancy

(See Haematological emergencies Hypercalcaemia, pp. [link][link].)

  • Urgent intervention required if Ca2+ >3mmol/L.

NB True Ca2+ = measured Ca2+ + [(40 − albumin) × 0.02].

Causes

  • Bony metastases: probable local cytokine effect.

  • Myeloma: secretion of an osteoclast-activating factor.

  • Secretion of PTHrP (non-small cell lung cancer).

  • T-ALL; NHL.

Presentation

  • Nausea, vomiting, drowsiness, confusion, nocturia, polyuria, bone and abdominal pains, constipation.

Management

  • Hydration: 3–6L over 24h, continuing for 4–5 days. In the past, loop diuretics (e.g. furosemide) were given routinely once fluid repletion had been achieved, to further increase urinary Ca2+ excretion. This has fallen out of favour due to the availability of drugs, such as bisphosphonates, and the potential fluid and electrolyte complications resulting from excessive diuresis, such as hypokalaemia, hypomagnesaemia, and even volume depletion if the diuretic-induced losses are not replaced. However, patients who are unable to excrete the administered salt because of renal insufficiency are at risk of fluid overload and should receive furosemide.

  • Following overnight hydration, recheck Ca2+ and albumin. If symptoms persist and/or Ca2+ remains >3mmol/L, give pamidronate disodium IV—a maximum of 90mg over 4h. It can be given as an infusion of 60mg/h. Suspected or established renal failure—maximum rate 20mg/h. Pamidronate is well tolerated; however, there is a small incidence of transient fever and flu-like symptoms.

  • For myeloma, consider prednisolone 30–60mg PO daily. Start chemotherapy if relapse.

Superior vena cava obstruction

Presentation

Awareness of fullness of the head and tightness of the collar, symptoms exacerbated by bending down, syncope, breathlessness, facial suffusion and oedema, engorgement of veins in the neck, arms, and upper thorax.

Causes

  • Usually bronchogenic carcinoma (± secondary thrombosis of the SVC).

  • Other tumours, including lymphoma, more rarely.

Management

  • FBC and film, U&Es, Ca2+, albumin.

  • CXR, Doppler USS of neck veins if diagnosis uncertain.

  • Heparin, providing platelet count and clotting function are normal.

  • Arrange urgent radiotherapy (within 24h).

  • May require stenting.

  • Avoid Pemberton’s sign.

Massive mediastinal mass

Presentation

  • Dry cough, stridor, and dyspnoea, especially on lying flat.

Causes

  • ALL (especially T-ALL with high WCC).

  • High-grade NHL.

  • Hodgkin’s disease.

  • Germ cell tumour.

Management

Histological diagnosis (or cytological from pleural effusion if present):

  • General anaesthetic carries considerable risk.

  • Definitive treatment (radiotherapy or chemotherapy).

  • Consider prednisolone 1mg/kg/day if urgent treatment is required.