Haemostasis

Physiology

Haemostasis is achieved through several main steps:

1. Formation of a platelet plug
2. Coagulation cascade: amplification of the clotting process by sequential enzyme activation
3. Termination of the clotting process
4. Clot breakdown by fibrinolysis

The traditional model of the coagulation cascade contains two converging pathways. This is a good way to interpret coagulation tests (APTT and PT) but is no longer thought to represent in vivo coagulation.

Pathway	Initiated by	Measurement
Intrinsic	Exposure to negatively charged ions activates factor XII	APTT
Extrinsic	Damage to a blood vessel exposes tissue factor, which activates factor VII	PT

Image Source: Wikimedia Commons (2007). Coagulation full., Licensed under a creative commons licence. Available for free at: https://en.m.wikipedia.org/wiki/File:Coagulation_full.svg (Accessed: 16 January 2024)

Anticoagulants and antiplatelets

MRCP Part 2 will not test your ability to recall the exact mechanisms as described in the diagram above, however they may test the clinical application, for example how common anticoagulants affect the clotting cascade.

Warfarin

• Mechanism: inhibits the vitamin K-dependent synthesis of clotting factors II, VII, IX and X
• Monitoring: INR (derived from PT)
• Key indications: prosthetic heart valves requiring anticoagulation; AF and VTE, although DOACs (see below) are increasingly being used for these conditions
• Takes around five days to reach therapeutic effect, and for the first 36 hours is pro-thrombotic due to  decreased protein C and S. Bridging therapy with other anticoagulants may be necessary
• Caution with medications affecting the cytochrome P450 system (Table 2), which metabolises warfarin. Inducers decrease the concentration of warfarin, thus lowering the INR. Inhibitors of the cytochrome P450 system increase the concentration of warfarin

Class	Inducers	Inhibitors
Antimicrobials	Griseofulvin	Ciprofloxacin, ketoconazole, erythromycin, metronidazole, chloramphenicol
Antiepileptics	Carbamazepine, phenobarbitone	Sodium valproate
Anti-tuberculous	Rifampicin	Isoniazid

• Side effects: can include pain and purpura in digits
• Reversal: prothrombin complex concentrate (acts within minutes) and vitamin K (slower)
• Deficiency in vitamin K can mimic effects of taking warfarin with prolonged PT and INR. This can occur in conditions such as malnutrition or malabsorption (terminal ileal resection)

Direct oral anticoagulants (DOAC)

• Mechanism: factor Xa inhibition (rivaroxaban, edoxaban, apixaban) or thrombin inhibition (dabigatran)
• Key indications: non-valvular AF and VTE
• Reversal: andexanet alfa (apixaban and rivaroxaban); idarucizumab (dabigatran)
• Benefits: no need for regular monitoring

Heparin

• Unfractionated heparin (UFH): binds to antithrombin, enhancing inhibition of multiple factors, predominantly thrombin and Xa. Monitoring is with APTT. Benefits include that it can be given in renal failure and that it can be stopped rapidly by stopping the infusion
• Low molecular weight heparin (LMWH): binds to antithrombin, predominantly resulting in increased inhibition of factor Xa (less inhibition of thrombin than with UFH). Monitoring is with factor Xa activity assays. Benefits include that there is no need for IV administration (given subcutaneously) or monitoring
• Indication: VTE prophylaxis or treatment; used in procedures, e.g. angiography
• Reversal: protamine
• Heparin-induced thrombocytopenia is a complication of heparin use
• Special circumstances: heparin may be chosen as long-term anticoagulation in cancer patients who have evidence of liver impairment such as those with liver metastases. In pregnancy, heparin is the anticoagulation of choice

Antiplatelets

It is also worth noting the mechanism of key antiplatelet drugs. These are used predominantly for arterial disease such as in myocardial infarction and acute strokes (anticoagulation may be started after a delay if indicated, e.g. in AF, but antiplatelets are the initial mainstay to reduce the risk of haemorrhagic transformation).

Aspirin	Inhibits COX-1, which generates thromboxane A2, a potent stimulator of platelet aggregation
Clopidogrel, prasugrel	Inhibit P2Y12, a key receptor of the glycoprotein IIb/IIIa complex. Leads to less thromboxane production and thus lower levels of platelet aggregation

Periprocedural antithrombotic medication management

Prior to invasive procedures it is important to review a patient’s drug chart. Antiplatelets and anticoagulation may need to be held before proceeding. The decision to withhold will be a weighing up of risk versus benefit.

Find below a short summary of British Society of Gastroenterology guidelines. Classify procedures as high risk (e.g. ERCP, therapy for varices) or low risk (e.g. diagnostic procedures ± biopsy), and patients as having high thrombotic risk (e.g. recent coronary stent) or low (e.g. ischaemic heart disease but no stents).

• Clopidogrel, prasugrel: for low-risk procedures, continue. For high-risk procedures and low thrombotic risk, discontinue 5 days prior. For high-risk procedures and high thrombotic risk, liaise with a cardiologist
• DOACs: for low-risk procedures omit morning dose. For high risk-procedures hold DOAC for 48 hours
• Warfarin: for low-risk procedures, if INR is within range, continue; if INR is raised, delay until within range. For high-risk procedures and low thrombotic risk (e.g. prosthetic aortic valve), stop warfarin for a week and proceed when INR <1.5, then restart warfarin on the evening of the procedure. For high-risk procedures and high thrombotic risk (e.g. prosthetic mitral valve), omit warfarin for 5 days and cover with LMWH for 48 h prior. Restart warfarin on the evening of procedure

For lumbar punctures, aspirin can be continued, however clopidogrel is commonly held 7 days prior to procedure.

The above provides a rough guide and should be used as a framework which can be applied to other procedures such as intercostal drains. Prior to surgery, a discussion is warranted between surgical and haematology teams.  Please refer to society or local hospital guidelines where applicable for up-to-date guidance.

References

• Damman P, Woudstra P, Kuijt W, de Winter R, James S. P2Y12 platelet inhibition in clinical practice. Journal of Thrombosis and Thrombolysis. 2011;3(2):143-153
• Leung L. Overview of Haemostasis [Internet]. Mannucci P, Tirnauer J, editors. UpToDate Inc. 2021 [cited 28 December 2021]. Available from: https://www.uptodate.com/contents/overview-of-hemostasis
• Veitch, A.M., Vanbiervliet, G., Gershlick, A.H., Boustiere, C., Baglin, T.P., Smith, L.-A., Radaelli, F., Knight, E., Gralnek, I.M., Hassan, C. and Dumonceau, J.-M. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.  Gut. 2016. 65(3): 374–389. doi:10.1136/gutjnl-2015-311110

Bleeding disorders

Von Willebrand disease (vWD)

This is the most common inherited bleeding disorder. It is inherited via an autosomal pattern with variable penetrance.

There is deficiency or poor function of von Willebrand factor (vWF), which is critical for platelet aggregation at sites of vascular injury. It is also bound to factor VIII, a key component of clotting, which degrades when not bound.

Clinical features of vWD

Presentation is often with mucocutaneous bleeding. Females are more likely to present, commonly with menorrhagia or postpartum bleeding.

Investigations include:

• FBC: anaemia may be present; platelet counts are often normal, although can be reduced
• Coagulation studies: PT is normal; APTT is either prolonged or normal
• vWF antigen level: low

Management of vWD

For minor bleeding, antifibrinolytic treatment such as tranexamic acid can be used, as well as desmopressin, which can stimulate the release of vWF and factor VIII. vWF-containing concentrates are given prior to major procedures or in severe bleeding.

Haemophilia A and B

These are X-linked recessive disorders, and therefore affect males. Haemophilia B is also called Christmas disease.

There is a deficiency or absence of factor VIII (haemophilia A) or factor IX (haemophilia B), which are important in the amplification of thrombin and thus fibrin production.

Clinical features of haemophilia

Symptoms include frequent bruising and bleeding into muscles and joints. Patients with complete absence of the factor present at an earlier age than those with milder disease.

Coagulation studies will show a prolonged APTT that normalises on mixing with normal pool plasma, suggesting factor deficiency rather than inhibition. Factor VIII and IX levels confirm the diagnosis.

Management of haemophilia

Factor replacement remains the cornerstone of treatment. It can be used prophylactically to prevent bleeding, both before procedures and in general to prevent major joint bleeds, which can lead to debilitating haemophilic arthropathy.

Repeated doses of factor concentrate can lead to inhibitor formation, reducing the efficacy of treatment. In these cases, bypassing agents are required. Desmopressin may be used for haemophilia A.

References

• Berntop E, Fischer K, Hart D. Haemophilia. Nature Reviews Disease Primers. 7, 45 (2021).[cited 16 December 2021] https://doi.org/10.1038/s41572-021-00278-x
• Laffan M. Von Willebrand disease [Internet]. BMJ Best Practice. BMJ Publishing Group; 2021 [cited 16 December 2021]. Available from: https://bestpractice.bmj.com/topics/en-gb/365
• Poon MC, Lee A. Haemophilia. In: BMJ Best Practice. [Internet]. London: BMJ Publishing Group, 2021 [cited 16 December 2021]. Available from: https://bestpractice.bmj.com/topics/en-gb/468

Venous thromboembolism

Definition of VTE

Venous thromboembolism (VTE) is a common disorder defined as the formation of a clot within vessels which carry deoxygenated blood. VTE can occur anywhere in the venous system but is most often found within the deep veins of the legs (deep vein thrombosis, DVT) and in the pulmonary arteries (pulmonary embolism, PE).

DVT

Clinical features of DVT

Presentation is typically with an acutely swollen, erythematous leg. Differentials include cellulitis or knee bursitis.

Risk factors include: recent immobilisation, recent surgery, dehydration, active malignancy, pro-thrombotic conditions, trauma, intrinsic compression of veins, Covid-19, medications such as the oral contraceptive pill, nephrotic syndrome, obesity and inflammatory bowel disease. A risk factor history must be taken for anyone with suspected VTE.

If there is doubt about the diagnosis, the Well’s score for DVT can be used (see online calculators, e.g. MDCalc.com). With a low score, D-dimer should be performed. If negative, no further investigations are required; if positive, US Doppler should be performed. With a higher Well’s score, US Doppler should be performed directly.

Management of DVT

Management is predominantly with DOACs, but warfarin and LMWH are also used. The duration of treatment is determined by whether the clot was provoked (typically treated for three months) or unprovoked. For VTE with no obvious cause, treatment must be continued for a minimum of 6 months and can be indefinite.

PE

Clinical features of PE

Presentation is typically with dyspnoea, pleuritic chest pain, haemoptysis or collapse. Examination may be normal.

Scoring systems to aid diagnosis and choose investigations include Well’s score for PE and PERC (both can be found online).

Investigations findings may include:

• ECG: the most common finding is sinus tachycardia; there may be evidence of right heart strain such as new onset right bundle branch block; the classical finding of S1Q3T3 can be caused by PE, but is uncommon and not diagnostic
• CXR: unremarkable in the majority of patients, however PEs can cause pleural effusions (normally exudative) or, if severe, can cause pulmonary infarction which can be seen on CXR
• Troponin and BNP: if positive, demonstrate heart strain
• CT pulmonary angiogram (CTPA) is the gold standard test to investigate PE

Management of PE

The vast majority of patients with PE will be anticoagulated, however for those in which this is contraindicated, inferior vena cava (IVC) filters can be considered. Thrombolysis (usually with alteplase) and thrombectomy are considered for patients with haemodynamic compromise.

Aetiology of VTE

Another important consideration when managing VTE is working out the underlying cause. This is important as it will help determine the duration of treatment and change management (e.g. if medication related, the offending agent may have to be stopped). Common causes include: immobility, surgery, combined oral contraceptive pill, malignancy and prothrombotic conditions including inherited. If a VTE is considered to be provoked, then a 3-month duration of anticoagulation is sufficient, however if unprovoked, 6 months of treatment may be indicated.

If a cause is not obvious, further investigations may be warranted. Malignancy is a common cause of VTE, however NICE only recommends investigating for cancer if the history or examination is suggestive.

References

• Bauer K, Lip G. Overview of the causes of thromboembolism [Internet]. Leung L,  Mandel J, editors.  UpToDate; 2021 [cited Dec 17 2021]. Available from: https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis
• NICE Guidelines. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. March 2020 [cited December 17 2021]. Available from: https://www.nice.org.uk/guidance/ng158/chapter/Context

Thrombophilia

Overview of thrombophilia

Thrombophilia is a predisposition to clot formation and manifests clinically as VTE. These causes will be discussed:

• Factor V Leiden (FVL)
• Proteins C and S deficiency
• Antiphospholipid syndrome (APLS)

When the aetiology of a VTE is not known, it may be tempting to investigate whether there is an underlying thrombophilia. However, NICE only recommends screening for these conditions in certain circumstances:

• Consider testing for APLS in patients with unprovoked VTE where there are plans to stop anticoagulation
• Consider testing for hereditary thrombophilia in patients with unprovoked VTE who have a first-degree relative who has had a VTE and where there are plans to stop anticoagulation

These tests should not be offered routinely to family members of patients with a history of VTE. When thrombophilia testing is performed whilst patients are on anticoagulation the results will have to be interpreted with caution as they may be affected by the medication.

Factor V Leiden

FVL is the most commonly inherited thrombophilic condition in caucasian populations and is an autosomal dominant condition. Most patients are heterozygotes. Though many may have the genotype, only around 5-10% develop VTE. Homozygotes have a higher risk of VTE than heterozygotes.

Factor V is a key component of the conversion of fibrinogen to fibrin and, therefore, clot production. Protein C is an endogenous anticoagulant, inhibiting factor V. In FVL a mutation factor V means it cannot be inactivated by protein C and thus, more fibrin can be produced and clots formed.

Screening for FVL is only required in those who present with recurrent VTE, those at a young age with no other obvious risk factor and those with unusual clot location, e.g. cerebral vein. FVL testing includes genetic testing and functional aPC (activated protein C) resistance testing (higher values in FVL). Functional resistance can be affected by DOACs and in these cases genetic testing may be more reliable.

Management of a confirmed VTE is the same in FVL patients as in those without.

Protein C deficiency

Protein C is a vitamin K-dependent anticoagulant whose main role is to inactivate factor V. Low levels can, therefore, lead to a prothrombotic state. Deficiency can either be inherited or acquired – secondary to conditions such as liver disease, use of vitamin K antagonists, infection and uraemia.

The vast majority of patients remain asymptomatic. Skin necrosis as a side effect of warfarin is more prevalent in those with protein C deficiency.

Diagnosis is by demonstrating low protein C levels. Acquired cases tend to have higher levels than inherited forms.

If VTE is confirmed, warfarin is to be avoided if possible, and another anticoagulant used. No other specific management is required.

Protein S deficiency

Protein S works synergistically with protein C to inactivate factor V. As with protein C, a deficiency of protein S leads to a prothrombotic state. It also is dependent on vitamin K. Conditions such as nephrotic syndrome, liver failure, pregnancy and oral contraceptive use lead to lower levels of protein S.

Free protein S levels can aid diagnosis, though can be complicated by the fact that these vary within the population.

If a patient has confirmed VTE and protein S deficiency the choice of anticoagulant does not differ from regular management.

Antiphospholipid syndrome

APLS is an autoimmune condition that presents with both venous and arterial thrombosis as well as obstetric complications such as first trimester miscarriage.

The exact mechanism of thrombus generation in APLS is not known, however it is thought that the presence of antiphospholipid antibodies along with minor vascular injuries or increased inflammation predispose the body to vascular events.

Investigations in APLS

General screening is not recommended. Testing should be aimed at those with a high probability of having APLS, such as patients with clots in unusual locations, unprovoked VTE in under 50s and obstetric complications associated with autoimmune disease.

Diagnosis is made using clinical and serological features:

• Clinical features suggestive of APLS include arterial and venous clots and complications in pregnancy, such as recurrent miscarriage or intrauterine growth restriction
• There must be positive serology in the form of lupus anticoagulant, anti-cardiolipin antibodies or anti-beta2 glycoprotein. The antibodies must be present on at least two occasions, 12 weeks apart. Antiphospholipid antibodies alone do not satisfy the criteria for APLS diagnosis

Management of APLS

Often, anticoagulation is given indefinitely.

In non-pregnant patients, LMWH followed by long-term use of warfarin is the standard treatment. INR targets vary. In those with confirmed APLS and a first venous thrombosis, INR target should be 2-3. However, if there is an arterial thrombosis, the INR target should be >3 or 2-3 with aspirin.

Pregnant women should be treated with LMWH only.

Risk factor modification is vital and patients should be encouraged to modify traditional cardiovascular risk factors such as obesity, smoking and hyperlipidaemia.

References

• Bauer, K. Factor V Leiden and activated protein C resistance [Internet]. Leung L, Tirnaeur J, editors. UpToDate. 2021 [cited 3 January 2022]. Available from: https://www.uptodate.com/contents/factor-v-leiden-and-activated-protein-c-resistance
• Bauer, K. Protein C deficiency [Internet]. Leung L, Tirnaeur J, editors. UpToDate 2021 [cited 3 January 2022]. Available from:https://www.uptodate.com/contents/protein-c-deficiency
• Bauer, K. Protein S deficiency [Internet]. Leung L, Tirnaeur J, editors. UpToDate 2021 [cited 16 June 2022]. Available from:https://www.uptodate.com/contents/protein-s-deficiency
• Breen KA, Hunt B. Antiphospholipid syndrome [Internet]. BMJ Best Practice. BMJ Publishing Group; 2021 [cited 16 December 2021]. Available from: https://bestpractice.bmj.com/topics/en-gb/469
• Schreiber, K., Sciascia, S., de Groot, P. et al. Antiphospholipid syndrome., Nature Reviews Disease Primers. 17103. 2018 [cited 16 December 2021]. https://doi.org/10.1038/nrdp.2017.103
• NICE Guidelines. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. March 2020 [cited June 16 2022]. Available from: https://www.nice.org.uk/guidance/ng158/chapter/Context

Thrombocytopenia

Overview of thrombocytopenia

Key causes of low platelets can be categorised as follows:

Decreased bone marrow production	Bone marrow failure, infiltration or suppression
Increased consumption, destruction and/or sequestration	Immune thrombocytopenic purpura (ITP) Microangiopathic haemolytic anaemia (MAHA, see below) with thrombocytopenia Hypersplenism Heparin-induced thrombocytopenia/with thrombosis (HIT/T)
Dilution	Massive transfusion

Microangiopathic haemolytic anaemia is defined by the destruction of red blood cells within the small arteries of the body. Schistocytes can be seen on blood film. The following causes of MAHA will be discussed in detail:

• Haemolytic uraemic syndrome (HUS)
• Thrombotic thrombocytopenic purpura (TTP)
• Disseminated intravascular coagulopathy (DIC)

Other causes include metallic valve haemolysis, malignant hypertension, paroxysmal nocturnal haemoglobinuria and eclampsia.

Immune thrombocytopenic purpura

The pathophysiology of ITP is not entirely understood, but it is thought that sensitised antibodies destroy platelets.

Clinical features of ITP

ITP typically presents with purpura, bruising and bleeding. Mucocutaneous bleeding is common.

A low platelet count with unaffected haemoglobin and white cell count is suggestive of ITP; a blood film can show that other blood lines are not affected and will demonstrate thrombocytopenia. In difficult cases, bone marrow biopsy may be indicated. ITP is a diagnosis of exclusion and it is important to rule out other causes of thrombocytopenia.

Management of ITP

Most patients are treated conservatively with regular monitoring of platelet count. If bleeding symptoms persist and platelet counts are low (<30 x109), prednisolone can be used. If a quicker increase in platelet count is indicated such as before a procedure or surgery or in active bleeding, then IVIG plus steroids is indicated. Platelet transfusion can also be given in bleeding. Second line treatments involve immunosuppression or novel treatments such as thrombopoietin receptor agonists (e.g. eltrombopag).

ITP can also occur secondary to an underlying condition, for example CLL, HIV, HCV, APLS and H. Pylori infection; the treatment of secondary ITP is that of the underlying disease.

Microangiopathic haemolytic anaemias

Microangiopathic haemolytic anaemia is defined by the destruction of red blood cells within the small arteries of the body. It encompasses all three of DIC, HUS and TTP but also includes conditions such as metallic valve haemolysis, malignant hypertension, paroxysmal nocturnal haemoglobinuria and eclampsia. On blood film, all of the above conditions will demonstrate schistocytes.

Metallic valve haemolysis can be managed medically with folate, iron replacement and EPO injections, however redo surgery may be indicated if the anaemia is poorly controlled.

Haemolytic uraemic syndrome

HUS typically occurs in children and is associated with shiga-producing toxin which causes bloody diarrhoea. Cases presenting without diarrhoea can be labelled atypical HUS.

Clinical features of HUS

HUS is characterised by a triad of findings:

• Microangiopathic haemolytic anaemia
• Thrombocytopenia
• AKI

FBC will show low Hb and low platelet count; U&E will demonstrate renal dysfunction. A blood film is vital, as it will have evidence of haemolysis such as schistocytes. A clotting screen is useful to distinguish HUS from disseminated intravascular coagulation (DIC): PT and APTT are normal in HUS. A haemolysis screen should also be ordered, including haptoglobins (low), LDH (high), Coomb’s test (negative). If diarrhoea is present, a stool test should be ordered.

Management of HUS

Management is supportive, with IV fluids and blood pressure control. Around 50% of patients may need renal replacement therapy.

Thrombotic thrombocytopenic purpura

TTP is defined by reduced activity of the vWF-inactivating protein ADAMTS13. This leads to platelet aggregation within vessels, microangiopathic haemolytic anaemia and organ damage.

Clinical features of TTP

Traditionally, TTP has been thought of as a pentad consisting of:

• Thrombocytopenia
• Microangiopathic haemolytic anaemia
• AKI
• Fever
• Neurological symptoms

However, due to earlier treatment, the complete pentad is much rarer nowadays. Symptoms can vary and typically affect the neurological system (confusion, headache, weakness and stroke), gastrointestinal tract (pain, nausea, vomiting and diarrhoea), kidneys (this may manifest as rises in creatinine that are not necessarily diagnostic for AKI; anuria is rare) and cardiac (arrhythmias, MI). Patients can vary from ambulant to moribund.

Investigations are similar to those in HUS. ADAMTS13 levels should be checked, however results may take some time.

TTP can be secondary to HIV, medications such as clopidogrel and pregnancy.

Management of TTP

Due to the potential rapid deterioration with TTP it is a medical emergency. Plasma exchange is the first line treatment along with steroids, followed by monoclonal antibody infusions such as rituximab.

Disseminated intravascular coagulation

In normal homeostasis, coagulation and fibrinolysis are under control and activated in an ordered fashion. In DIC, these processes are overactive, leading to both increased coagulability and increased bleeding. There is release of large volumes of tissue factor, which activates the clotting cascade. Coagulation factors are used up quicker than they are able to be produced. Fibrin degradation products are produced and interfere with clot formation and platelet aggregation, leading to an increased bleeding state. DIC can present acutely or chronically.

DIC can be caused by infection, cancer (importantly APML), trauma and obstetric complications such as preeclampsia.

Clinical features of DIC

FBC will show low Hb and platelets; schistocytes will be present on blood film; coagulation studies will show prolonged PT and APTT; fibrinogen can be low and d-dimer elevated.

Management of DIC

Treatment of the underlying cause of DIC is paramount. Blood products to correct clotting derangements are indicated when patients are actively bleeding. This includes platelets, FFP and cryoprecipitate.

Heparin-induced thrombocytopenia/with thrombosis

This is a rare complication of heparin therapy, more common with UFH than LMWH.

Antibodies are produced against platelet factor 4 (PF4)-heparin complex. This leads to thrombocytopenia and, conversely, thrombosis.

Clinical features of HIT/T

HIT/T should be suspected with new thrombocytopenia, venous or arterial thrombosis or necrosing skin lesions at the site of heparin injection. There are assays to detect the presence of PF4-heparin antibodies and their ability to bind and activate platelets.

Management of HIT/T

Heparin should be discontinued and a non-heparinoid anticoagulant considered such as argatroban, danaparoid or bivalirudin.

Liver disease

Liver disease is a heterogeneous condition with complex interplay between different bleeding and thrombotic mechanisms. It is no longer thought that patients with liver disease are only more prone to bleeding – there is often both a prothrombotic and concomitant pro-bleeding state.

Common haematological derangements in liver disease include:

Platelets	Low due to splenic sequestration secondary to portal hypertension, reduced thrombopoietin production by the liver, and bone marrow suppression from infection or alcohol.
Factors V, VII, IX, X and XI	Reduced production by the liver, leading to prolonged PT/APTT. Factors VII, IX and X require vitamin K for their production, and in patients who have vitamin K deficiency (e.g. in alcohol dependence or cholestatic liver disease) vitamin K administration may improve levels of some factors. PT/APTT is not necessarily useful in assessing coagulability in the context of liver disease, but it is a key component in the prognostic UK MELD scoring system.
Proteins C and S	Reduced production by the liver, which can contribute to a prothrombotic state.

Platelets are often transfused once below 50 x 10-9 but INR is not routinely corrected.

For common procedures encountered in liver disease such as paracentesis, pre-procedure prophylaxis is not routinely recommended owing to the low bleeding risk. Prior to invasive procedures, a discussion between haematologists and hepatologists is advised to assess the overall bleeding/coagulable state of a given patient.

References

• Andreoli S. Haemolytic uraemic syndrome [Internet]. BMJ Best Practice. 2019 [cited 4 January 2022]. Available from: https://bestpractice.bmj.com/topics/en-gb/470
• George J, Cuker A. Diagnosis of immune TTP [Internet]. Leung L, Mandel J, editors. UpToDate. 2021[cited Jan 4 2022]. Available from: https://www.uptodate.com/contents/diagnosis-of-immune-ttp
• George J, Cuker A. Immune TTP: Initial treatment [Internet]. Leung L, Mandel J, editors. UpToDate. 2021[cited Jan 4 2022]. Available from: https://www.uptodate.com/contents/immune-ttp-initial-treatment
• Intagliata N, Shah N. Hemostatic abnormalities in patients with liver disease [Internet]. Leung L, Tirnauer J, editors. UpToDate. 2021 [cited 26 December 2021]. Available from: https://www.uptodate.com/contents/hemostatic-abnormalities-in-patients-with-liver-disease
• Leung L. Evaluation and management of disseminated intravascular coagulation (DIC) in adults [Internet]. Mannucci P, Tirnauer J, editors. UpToDate. 2021 [cited 5 January 2022]. Available from: https://www.uptodate.com/contents/evaluation-and-management-of-disseminated-intravascular-coagulation-dic-in-adults
• Linkins L. Heparin induced thrombocytopenia. BMJ. 2015;350(jan08 7):g7566-g7566. [cited 5 January 2022] DOI: 10.1136/bmj.g7566
• Scully M. Immune thrombocytopenia [Internet]. BMJ Best Practice. 2019 [cited 4 January 2022]. Available from: https://bestpractice.bmj.com/topics/en-gb/138

Blood products

Types of blood product

The components of blood are separated out and can be used individually to correct isolated parameters or used in conjunction for conditions which affect multiple factors of the haemostatic/bleeding pathways.  Whole blood is rarely used.

Common blood products include:

Blood product	Indication
Packed red blood cells	Low Hb; the trigger for transfusion is often 70 g/l or 80 g/L in patients with ACS
Platelets	Active bleeding; prophylaxis against bleeding either from invasive procedures or spontaneous bleeding (when the platelet count is critically low)
Fresh frozen plasma (FFP)	Contains many pro-coagulant factors; used to correct abnormal clotting parameters during bleeding or prior to procedures
Cryoprecipitate	Produced by thawing FFP, thus producing a low-volume source of fibrinogen. Frequently used to replace fibrinogen in DIC
Human albumin solution (HAS)	Liver disease-related conditions such as hepatorenal syndrome, spontaneous bacterial peritonitis (to prevent AKI) and as fluid replacement in therapeutic paracentesis

Major haemorrhage

The Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee defines major haemorrhage as:

• Loss of more than one blood volume within 24 hours (around 70 mL/kg, i.e. > 5L in a 70 kg adult)
• Half of total blood volume lost in less than 3 hours
• Bleeding in excess of 150 mL/minute.

This is difficult to calculate in an acute setting.  A more pragmatic approach is bleeding which leads to a systolic blood pressure of below 90 mmHg or heart rate above 110 beats per minute.

Management of major haemorrhage

All hospitals in the UK have a major haemorrhage protocol that will include the involvement of the blood products laboratory, haematologists, medical emergency team and porters. Major haemorrhages should be approached in an ABCDE manner with identification of bleeding source and stabilisation of the patient taking priority.

It is important not to forget the other blood products that are required in major bleeding. As well as red cells being lost in bleeding, plasma is also lost, which contains key components of the clotting cascade. If large quantities of only blood and IV fluids are transfused, this will lead to a dilutional coagulopathy. FFP, cryoprecipitate and platelets are therefore also required in major haemorrhage situations.

Anticoagulant therapy is common and it is important to reverse these agents during bleeding.

Certain conditions which cause major haemorrhage also require specific treatments. Terlipressin, a somatostatin analogue, is indicated in variceal bleeding as it acts as a splanchnic vasoconstrictor. In major trauma, immediate tranexamic acid is recommended, however in upper GI bleeds the recent HALT-IT trial has not endorsed its use. The management of bleeding in thrombophilic conditions such as haemophilia are covered elsewhere.

Complications of blood products

It is important to remember that blood transfusions, whilst increasingly safe, can have side effects. Patients must be informed of the risks prior to starting a transfusion. Note also that if a patient receives a blood transfusion, they cannot donate blood in the future.

Common complications include:

• ABO incompatibility: occurs when the blood group of transfused blood is incompatible with the recipient blood group, for example group AB blood being given to a patient who is O group. A serious haemolytic reaction will occur, potentially causing cardiovascular instability.
• Transfusion-associated circulatory overload (TACO): often associated with patients with heart failure who receive a transfusion. The patient presents with dyspnea, oxygen requirement and bilateral infiltrates on chest X-ray. Usually, this occurs within 6 hours of transfusion. As with pulmonary oedema, treat with diuretics.
• Transfusion-related acute lung injury (TRALI): presents with hypoxia (due to non-cardiogenic pulmonary oedema), fever and often hypotension. It is thought to be immune mediated. Typically, symptoms appear around 6 hours post transfusion. Treatment is supportive and discussion with intensive care may be needed. TRALI is rare, with an incidence of 1 in 150,000  units transferred.
• Bacterial contamination can occur, especially with platelet transfusions which are stored at 22-24°C (a temperature compatible with bacterial growth). Symptoms are similar to an acute sepsis response, with hypotension, tachycardia and fever. The transfusion should be stopped and the ‘sepsis 6’ protocol initiated.
• Febrile non-haemolytic transfusion reactions (common): typically, the patient develops a temperature whilst having a transfusion but is otherwise well. Paracetamol, slowing the transfusions and close observation is usually sufficient. However, fever may be the first symptom of a more serious reaction and thus close observation is advised.

References

• NICE Guidelines. Blood Transfusion (NG24). 2015 [cited December 17 2021] Available from: https://www.nice.org.uk/guidance/ng24
• Norfolk D. Handbook of transfusion medicine. 5th ed. London: H.M.S.O.; 2013