Buku Medicine

Prolonged PT

Quick Tip; The most common causes for a prolonged PT are vitamin K deficiency and sepsis

A prolonged prothrombin time is incredibly common in inpatients as the inpatient population are commonly admitted with infection/sepsis and can be nutritionally deplete, both of which cause prolongation of the PT. Infection and sepsis processes consume clotting factors, commonly affecting both the PT and APTT (although PT usually more so as factor VII has one of the shortest half lives of all clotting factors), and nutritional deficiency or malabsorption of vitamin K inhibits production of vitamin K-dependent clotting factors.

Common causes:

Vitamin K deficiency
Sepsis or infection
Warfarin
NOACs (although not proportional to anticoagulant effect)
Liver disease
Factor deficiency-uncommon
As part of DIC if APTT also prolonged (see DIC module)

Workup;

History;
- Check for undocumented use of anticoagulants
- Review of dietary intake
- Causes for malabsorption - diseases affecting the terminal ileum or bile salts and fat absorption particularly affect vitamin K absorption
- Ask about a bleeding history if unsure about whether the prolongation is acute or chronic. This includes spontaneous bleeding or bruising, prolonged bleeding after surgery or dentistry in the past, and menorrhagia in women
Repeat the test including a 50:50 mix- this will correct a factor deficiency (check local laboratory protocols)
Liver function tests inc. albumin

If on repeat the PT remains prolonged and is felt to be due to factor consumption or nutritional deficiency;

Give 10mg IV/PO vitamin K for 3 days (check allergies) and repeat the test after all doses given
If in community and no bleeding, oral vitamin K (5mg) can be given and the test repeated to check if corrected
If it does not correct refer to haematology (often laboratory will advise sending 3 coagulation tubes to arrive at the lab within 1 hour to look for factor deficiencies)

If urgent correction is needed when prolongation is due to warfarin;

See Warfarin reversal guideline within 'Coagulation' section
In principle the main agents used are IV vitamin K (5mg for full correction if severe bleeding) which has peak action in 6 hours or prothrombin complex concentrates (e.g beriplex) which act immediately. The interventions require a repeat INR at 6 hours and 15 minutes respectively to ensure adequate reversal of anticoagulant effect. See local guidelines.
FFP is not indicated for the reversal of warfarin overdose/INR correction (unless beriplex not available)

If urgent correction is needed when prolongation is not due to warfarin;

Discuss with haematology regarding the use of IV vitamin K versus FFP

Links: Practical Haemostasis

Prolonged APTT

Quick tip; Prolonged APTT is more likely to indicate underlying factor deficiency than a prolonged PT

Prolonged APTT is a more likely to indicate an underlying clotting disorder than a prolonged PT, but certain test anomalies and other clinical conditions need excluding before testing for these conditions is undertaken.

Common causes

Heparin - unfractionated more than low molecular weight heparin (and warfarin to a very minor extent)
Lupus anticoagulant - this is a quirk of the standard APTT test method and is fact clinically procoagulant rather than anticoagulant
Liver disease
Vitamin K deficiency (much lesser effect than on PT)
As part of disseminated intravascular coagulation (DIC)
Factor deficiency (VIII, IX, XI, XII)
High haematocrit can also prolong the APTT

Workup

History;
- Check for undocumented use of anticoagulants
- Ask about a bleeding history if unsure about whether the prolongation is acute or chronic. This includes spontaneous bleeding or bruising, prolonged bleeding after surgery or dentistry in the past, and menorrhagia in women
Check old APTT tests- have they ever/recently had a normal APTT
Repeat sample (peripheral, not central lines) and add a thrombin time. Interpret as on 'Prolonged APTT flowchart'. Note different laboratories may use different tests such as protamine time instead if reptilase time, or may perform a 50:50 mix* as an initial test- please consult local advice to interpret these tests.
Key points;
- If remains prolonged with normal thrombin (and reptilase) times then perform mixing studies for a correction. If no correction, test for lupus anticoagulant (LA). LA actually clinically prothrombotic so a long APTT due to LA does not confer an increased bleeding risk (see 'Lupus anticoagulant' section below)
- If no lupus anticoagulant present, then factor deficiency suspected- request factor levels (usually 3 coagulation bottles to lab within 1 hour)
- If lupus anticoagulant negative and no factor deficiency then likely contact factor deficiency which confers no increased bleeding risk
- Factor XII deficiency has no clinical significance and does not need haematology referral
*In principle a 50:50 mix adds 50% patient plasma to 50% 'normal' plasma and repeats the test. If there is a factor deficiency, the APTT should correct to within 3-4 seconds of the reference range. If it does not, this implies an inhibitor (AKA antibody) such as lupus anticoagulant or an acquired factor inhibitor (uncommon)

Note 'Short APTT'

This result is seen most often due to acute inflammation increasing factor VIII levels or pre-activation of the clotting cascade during the sampling process (see link below).

Lupus anticoagulant

This is somewhat of a misnomer as a lupus anticoagulant confers a higher thrombosis risk than one of bleeding, but due to the way it prolongs the APTT, it has gained the name lupus anticoagulant. These can often be transient (e.g post viral infection) therefore must be repeated at 3 months to see if they are still present. If there is a thrombosis history, thrombophilia testing is indicated only when considering stopping anticoagulation as only at that point will it change management. Also some clotting tests are affected by the presence of acute thrombosis and by anticoagulants e.g DOACS.

Links: Practical-haemostasis

Prolonged APTT flowchart

Prolonged APTT investigations page
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Monitoring LMWH

Quick tip; Low Molecular Weight Heparin (LMWH) monitoring should be performed if suspicious of supratherapeutic or subtherapeutic treatment.

LMWH can be monitored with Anti-Xa levels if suspicion of inadequate treatment/overdosing. This occurs most commonly in these patient groups;

Extremes of weight
Renal impairment
Development of VTE on treatment
High risk of bleeding

To check adequate dosing;

Anti-Xa level taken 3-4 hours after a dose which has been given at that dose and time for at least 2 previous treatments (applies to once daily and split dose LWMH treatment). If there have not been 2 previous regular doses the result of the anti-Xa cannot be interpreted.
Normal target range is 0.5-1 IU/ml, but check local laboratory reference range, in the case of non-complex VTE. In complex cases such as recurrent VTE while on anticoagulant therapy, it may be beneficial to aim for a higher target anti-Xa, such as nearer 1 IU/ml, but these cases should be discussed with haematology
Dose can then be increased or decreased by 10-20% for a level lower than reference range/desired or a level higher than the reference range respectively. Check anti-Xa again after a further 3 doses to assess response

If concerns about accumulation of LMWH due to renal impairment;

Trough levels pre-dose
Aim for level <0.1 IU/ml

Split dosing of LMWH can be used if;

Patients are needing large doses due to increased bodyweight to spread the large anticoagulant effect more evenly over 24 hours
Patients are at high risk of bleeding and there may be benefit in giving the dose twice daily to have a smaller circulating volume of anticoagulant at any one time

DIC

Quick tip; DIC will not resolve without management of the trigger

Disseminated intravascular coagulation is a process of extreme hypercoagulability following a trigger such as sepsis or bleeding. It results in microthrombosis leading to organ injury, and can be followed by a significant bleeding risk from consumption of clotting factors and platelets (although only up to 12% in published studies (see 'How I treat DIC' article link below)). The condition requires urgent intervention with management of the cause and blood product support as indicated clinically, since DIC increases trauma mortality two- to four-fold, and mortality in obstetric sepsis.

Note it is important to use the Clauss fibrinogen rather than the standard (derived) fibrinogen as the derived test can commonly be falsely elevated

Common causes

Sepsis
Obstetric emergency
Malignancy
Severe trauma
Pancreatitis
ABO-incompatible blood transfusion

Laboratory findings

Prolonged PT
Prolonged APTT
Thrombocytopenia
Low fibrinogen
Raised D Dimers
Fragments (schistocytes) on blood film. (Differential is thrombotic microangiopathy e.g TTP but this is usually associated with near-normal clotting screen and D-Dimer)

The likelihood of DIC depends on the number of these features being present, measured in context of a potential trigger. See the Blood 'How I treat DIC' article for more on the DIC scoring system and some case examples of DIC

Workup

Resolution of trigger - the DIC process will continue until the underlying cause is resolved
Empirical blood product use to 'correct' abnormal coagulation parameters in the absence of bleeding is unlikely to help the patient, and may cause harm
Regular repeat full blood count and coagulation screen
Support with red cell transfusions, platelet transfusions or fresh frozen plasma (or rarely Prothrombin complex concentrate if overloaded and not suitable for FFP) may be warranted for bleeding patients under haematology guidance
Read the 'How I treat DIC' section for a useful flowchart on management of DIC which includes advice about heparin (including thromboprophylaxis) as these patients are significantly prothrombotic and prophylactic LWMH can be protective from thrombosis development which would significantly complicate ongoing management of patients with DIC
See 'Haem emergencies' section

Links: BMJ Blood Journal 'How I treat DIC'

HIT

Quick Tip; The 4 T's score for HIT is a validated score to guide management

Heparin induced thrombocytopenia (HIT) is a phenomenon induced by antibodies to platelets which are formed after heparin exposure. This can occur either during the first exposure episode or up to 100 days later, with a quicker onset of thrombocytopenia, once re-exposed. A thorough history is therefore critical to identify any history of exposure to heparin in any form over the previous 100 days.

HIT should be suspected in any patient who develops thrombocytopenia after being being exposed to heparin. Differential diagnosis (in often very unwell patients) include;

Spurious result- always send a second sample if thrombocytopenia is identified
Platelet consumption by sepsis or trauma
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura

Workup

Repeat full blood count with blood film
Coagulation screen to look for DIC
If HIT seems the most likely diagnosis, perform a 4 T's score for HIT (a validated score available from textbooks or online calculators). This calculates the probably of thrombocytopenia being due to HIT, including consideration of alternative causes (Note if exposure to heparin in the previous 100 days, the time to development of thrombocytopenia can be shorter than if no recent exposure)

If the HIT score is intermediate or high this will usually merit a HIT blood test. Depending on laboratory processes, there is usually a high sensitivity, intermediate specificity screening test, and if positive the sample will be sent for further, more specific testing.

If the score is low, it is unlikely to be HIT but if other diagnoses seem very improbable discuss with haematology.

Links; BSH Guideline

VTE risk in travellers

Quick Tip; The greatest risk factor for VTE in travellers is a history of VTE

There is a general increase in venous thromboembolism (VTE) in long-haul travellers (over 4.5 hours) that may be higher in air travel but should be risk-assessed regardless of the mode of travel.

Risk factors and appropriate management are listed below in terms of severity;

Low risk

Factor

No previous DVT / PE
No recent surgery (<4 weeks)
No moderate or high risk factors

Recommended Management

General advice; keeping mobile, drinking good volume of fluids and avoiding alcohol

Medium risk

Risk factors

Previous DVT/PE-not on anticoagulation
Surgery (anaesthesia >30 minutes) in past 4-8 weeks
Pregnant or post-partum
Clinically evident cardiovascular disease (e.g. recent MI or symptomatic CCF)
Recent major acute illness (e.g. pneumonia)
Taking OCP or HRT
Obese (BMI >30 kg/m2 )
Varicose veins with phlebitis
Family history of VTE (1st degree relative)
Polycythaemia
Lower limb fracture in plaster (can it be changed to a split cast to reduce risk?)

Recommended Management

Same advice as per low risk with either proprietary flight socks or grade 1 compression stockings (not available on prescription for this purpose however) so long as ABPI <0.5

High risk

Risk factors

Surgery (anaesthesia >30 minutes) within past 4 weeks
Known thrombophilia
Cancer – awaiting treatment or on active treatment

Recommended Management

As per moderate but consider the benefit of LMWH (would need prophylactic dose for outbound and return flights, instruction on use & storage, sharps bin, and letter for customs / security).

Above adapted from NICE CKS (ref below)

If the patient has had a VTE in the last 2 weeks travel is usually not be recommended while anticoagulation is established. After 2 weeks however if the patient has tolerated the anticoagulation well, the patient could be viewed as being low-risk and should be managed as such.

Aspirin is NOT recommended as a method of prophylaxis.

Links: Guideline

Unprovoked VTE Ix

Quick tip; Certain thrombophilia tests cannot be interpreted during an acute episode of VTE, or whilst on certain anticoagulants

Good management of deep vein thrombosis (DVT) is important to minimise local sequelae of DVT such as post-thrombotic syndrome and the risk of pulmonary embolus (PE). Further management should include investigation for a trigger if indicated. DVT and PE exist as part of the spectrum of venous thromboembolism (VTE) and many of the general investigations for them are similar.

Most VTEs are secondary/provoked. Causes include;

Sepsis
Trauma
Post-operative
Malignancy (either as background increase in risk or direct vascular compression)
Hormonal (combined oral contraceptive pill) or pregnancy

When there is no obvious trigger, in the case of DVT, it is classified as 'unprovoked DVT' which merits a basic screen for underlying cancer (note this has changed in the NICE 2020 update) . This should include;

Review medical history
Blood tests; FBC, renal and hepatic function, coagulation screen
Offer a physical examination
No further investigations should be offered unless there is clinical suspicion of an underlying malignancy from this history or examination
Note that this is a significant change from previous NICE guidance (pre-2020) which had advised that a chest Xray and possibly abdomino-pelvic CT should be considered in those presenting over 40 with unprovoked VTE. This change has likely come from evidence from studies such as the SOME trial which showed no clinically significant benefit of screening with abdomino-pelvic CT for unprokoved VTE.
Please check with local practice to see whether this 2020 guidance has been adopted.

Thrombophilia testing can be considered after a first unprovoked DVT/PE but only at the point of stopping anticoagulation, as thrombophilia screens are not reliable at the time of an acute VTE, and offer no benefit if anticoagulation is to be continued. Inherited thrombophilia is most likely if there is a family history of thrombophilia, or skin necrosis with warfarin (proteins C/S deficiency). These could include;

Antiphospholipid antibody syndrome screening in all patients with a first, unprovoked VTE.
More common in women, and should be considered especially if there is also a history or recurrent pregnancy losses or arterial events.
Note DRVVT/test for Lupus anticoagulant cannot usually be tested if patient on anticoagulation (Check with local laboratory). Anti-cardiolipin and anti-beta-2-glycoprotein can be tested at any time however.
Hereditary thrombophilia screening (performed by haematology) in the cases of first, unprovoked VTE and a first degree relative with a history of VTE

Links: NICE Venous thromboembolic diseases: diagnosis, management and thrombophilia testing 2020

Bleeding on DOACS

Quick Tip; Check when the patient last had a dose of their DOAC, as this may show that the DOAC is unlikely to still be in circulation and therefore no longer a risk factor for bleeding.

DOACs are increasingly chosen for VTE treatment and AF stroke prophylaxis for their ease of use, both by clinicians and patients. Bleeding on DOACS however is still an area with a very limited evidence base. A normal coagulation screen does not necessarily mean no DOAC on board, as different laboratories will have different sensitivities to the drugs. This is especially true for apixaban whereby therapeutic levels frequently result in a normal standard coagulation screen.

Does my patient still have a DOAC 'on-board'?

It is critical to find out, if possible, when the last dose of DOAC was taken, as although DOAC levels can be done, it takes time, and interpretation of results sadly does not have a clear cut-off for those at risk of bleeding or not. It is important to therefore consider drug half lives;

Rivaroxaban 5-13 hours (see SPC)
Apixaban 12 hours (see SPC)
Dabigatran 13-18 hours (see SPC)

Broadly speaking, in the presence of normal renal function, manufacturers advise avoiding low bleeding risk surgical procedures for 24 hours after the last dose, and high bleeding risk procedures for 48 hours after the last dose. This gives an indication of the suspected bleeding risk i.e most or all of the DOAC should be cleared by 24 hours after the last dose, but the manufacturers recommend 48 hours in elective high bleeding risk surgery. Consider this when reviewing a patient with bleeding on a DOAC.

Bleeding on Dabigatran (thrombin inhibitors)

Dabigatran has an antidote-idarucizumab, which is widely available in the UK and works quickly, with an antidote effect for up to 24 hours or more (Pollack et al. NEJM. 2015). Some centres will have protocols so that haematology do not need consulting before use, others require it to be 'released' by a haematologist-check local practice. A thrombin time is useful- this can be added to a standard coagulation screen and if normal, effectively rules out any active dabigatran in circulation (Keeling et al. Br J Haem. 2016).

Bleeding on Apixaban, Rivaroxaban and Edoxaban (Xa inhibitors)

For apixaban and rivaroxaban there is now a licensed reversal agent, andexanet, but this is only approved for a very specific indication (life-threatening/uncontrolled bleeding from the GI tract when there is a plan for procedural (almost always endoscopic) intervention. Data from patients outside this specific indication showed no significant benefit, and in some cases potentially increased harm. Local guidance should be followed if andexanet felt to be appropriate, and cases should be discussed with endoscopists as they will be making decisions regarding endoscopic interventions and thus suitability for the drug.

Andexanet is not licensed for edoxaban reversal.

The following measures are useful general principles for all cases of bleeding on DOACs;

Consider other relevant medications (e.g clopidogrel/other antiplatelets)
Consider any physical measures that can be done to stop bleeding as those inevitably work best (e.g. surgery or endoscopy)
For minor bleeding, local measures such as pressure/sutures etc can be used, and consider IV/oral tranexamic acid or tranexamic acid-soaked gauze. Tranexamic acid is SAFE- there was no increased thrombosis rate identified in the 20000 patients who took it in the CRASH2 and WOMAN studies vs placebo (both very 'prothrombotic' cohorts). Tranexamic acid STABILISES clots, it does not generate them.
- It must also be used early in the bleeding episode (within 3 hours) as this was where the benefits in mortality were seen in the WOMAN and CRASH-2 cohorts, with a trend to increased mortality if used after 3 hours (hypothesised as due to development of DIC in those patients from around 3 hours onwards).
- Caveats to this are haematuria and active arterial/venous thrombosis ('active thrombosis' can be hard to define but most thrombosis has been cleared with 4 weeks of therapeutic anticoagulation, therefore balance of risk/benefit should be considered with this in mind). Evidence is weak for a history of stable 'ischaemic heart disease', but it would be contraindicated if recent MI or PCI.
If the bleeding is severe and something is required to reduce it, most trusts advise regular tranexamic acid IV and to consider prothrombin complex concentrate (e.g beriplex) if andexanet not appropriate. PCCs are a warfarin antidote and contain factors II, IX and X +- VII (warfarin acts by blocking vitamin K dependent factor production- II, VII, IX and X (+proteins C and S)). In DOAC-associated bleeding, PCCs are used as they offer a high concentration of clotting factors. In theory this should allow clot formation by providing more factor X, which has been inhibited by the DOAC, to 'flood' the cascade.
- This is clearly not a true antidote. However a retrospective analysis recently has shown that PCCs seem to be a reasonable choice. Arachchillage et al. (2019 Br J Haem) reviewed outcomes for 344 patients receiving PCC for DOAC-associated and warfarin-associated severe bleeding.
- They found that PCC when used for warfarin- or DOAC-associated severe bleeding, offered equally reduced bleeding rates and equal thrombosis rates (around 4%).
- This is promising as there has been concern about thrombosis risk with PCC use for DOAC-associated bleeding, as patients may end up with more free factors II & IX which could in theory lead to spontaneous thrombosis.
- Overall using PCC for reduction of bleeding is still an evidence-weak area and this should not be used without due consideration of the risks and benefits (including thrombosis).

In summary, follow local guidelines but broadly speaking; check for other bleeding risks, perform local haemostatic measures and use tranexamic acid. PCC can be used for severe bleeds and there is weak evidence it may help if no other options are available, but the risk of thrombosis is not minimal. Discuss with haematology if this is being considered. If the case is complex or elements are unclear (e.g when last dose was taken) discuss with haematology for DOAC levels and advice on PCC use.

References;

Pollack et al. 2015 NEJM https://www.ncbi.nlm.nih.gov/pubmed/26095746

Keeling et al. 2016 Br J Haem https://www.ncbi.nlm.nih.gov/pubmed/27714755

Arachchillage et al 2019 Br J Haem https://www.ncbi.nlm.nih.gov/pubmed/30515764

WOMAN trial collaborators. 2017. The Lancet https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446563/

Roberts I et al. 2013. CRASH-2 study. Health Technology Assessment https://www.ncbi.nlm.nih.gov/pubmed/23477634

Andexanet data - Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors NEJM

NICE andexanet technology appraisal 1 Recommendations Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban Guidance NICE

Bleeding on DOAC guidance

Northumbria Healthcare NHS Foundation Trust guideline for reversal of DOACs. Many thanks to Dr Charlotte Bomken for her permission to exhibit this guideline. This guideline is listed as an example and is for information only. Follow local guidelines when managing individual patients.

DOAC bleeding guidance
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IVC filters

Quick tip; Inferior Vena Cava filters should be avoided unless absolutely needed, as they are often left in situ beyond the recommended period, and are associated with significant patient morbidity if so

Inferior vena cava filters are indicated in patients with deep vein thrombosis (DVT) when anticoagulation is contraindicated. They aim to 'trap' any emboli leaving the DVT and passing to the lungs, which would become a pulmonary embolus (PE). These can be of critical important in patients who have, for example, an ongoing imminent need for surgery, or unstable bleed in a critical area e.g the brain.

The evidence around IVC filters is controversial, but a large systematic review and meta-analysis (Bikdeli et al. 2017) (with 1,986 studies of low to moderate quality) did show a reduction in PE risk with use (OR: 0.50; 95% confidence interval [CI]: 0.33 to 0.75), albeit with an increased DVT incidence (OR: 1.70; 95% CI: 1.17 to 2.48).

The problem with IVC filters is that they are often requested by the team caring for the patient during the acute episode, and inserted by interventional radiology, and it may be that after this episode, neither team has routine follow up with the patient, and the IVC filter is 'forgotten'. 'Forgotten' IVC filters are common, one large retrospective study (Jia et al. 2018) identified 13% of patients who had had the filters inserted were lost to follow up, and a further 4% remained in place due to 'physician oversight'. 2% of patients with IVC filters still in situ had PE, 7.7% had recurrent DVT, 5.4% had vessel wall penetration and almost 10% of patients who had an attempted retrieval, could not have their filter removed.

Prophylactic IVC filters in trauma patients - an NEJM paper from 2019 (Ho K, et al 2019) showed that prophylactic IVC filter placement in patients with severe trauma in whom prophylactic anticoagulation was contraindicated, did not reduce incidence of pulmonary embolism compared to those that had no filter sited. In those who had no anticoagulation of any kind by day 7 after trauma, there were incidences of PE in the control arm, but not the filter arm. This was not statistically significant, but does highlight the importance of starting prophylactic anticoagulation as soon as possible, once haemostasis is stable and considering alternative methods of thrombosis risk reduction such as pneumatic compression where appropriate.

Summary

IVC filters have a proven benefit in reducing PE in those who cannot receive anticoagulation in the context of a known DVT. However they also have a proven risk of increased subsequent DVT, no role as a prophylactic measure in major trauma patients, and can be 'forgotten' with significant morbidity for the patient (DVT, occlusion and leg swelling). Therefore, be sure that they are being placed for the right indication, and that there is a plan for removal with a named individual responsible for that. Use prophylactic anticoagulation as soon as possible and consider alternative thrombosis risk reduction strategies as appropriate.

References

Inferior Vena Cava Filters to Prevent Pulmonary Embolism. Bikdeli et al. Journal of the American College of Cardiology. Volume 70, Issue 13, September 2017. DOI: 10.1016/j.jacc.2017.07.775

Utility of Retrievable Inferior Vena Cava Filters: A Systematic Literature Review and Analysis of the Reasons for Nonretrieval of Filters with Temporary Indications. Jia K, et al. Cardiovasc Intervent Radiol. 2018 May;41(5):675-682. doi: 10.1007/s00270-018-1880-9.

A Multicenter Trial of Vena Cava Filters in Severely Injured Patients. Ho K, et al. N Engl J Med 2019; 381:328-337
DOI: 10.1056/NEJMoa1806515