Case 142: summary

Pregnancy-associated TTP

Definition:

  • Rare but life-threatening thrombotic microangiopathy characterised by thrombocytopenia, MAHA and end organ damage due to microvascular thrombosis

Pathogenesis:

  • Severe ADAMTS13 deficiency (acquired or congenital)
    • ULVWF multimers lead to platelet adhesion resulting in platelet-rich microthrombi, red cell fragmentation (MAHA) and end organ damage
  • Acquired – autoantibody-mediated, more common
  • Congenital – genetic, less common
  • Pregnancy provoking factor for both acquired and congenital acute TTP episodes
    • Haemostatic changes: rising VWF levels, falling ADAMTS13 levels
    • Immunologic: changes in immune tolerance both during pregnancy and postpartum leading to autoimmunity
    • Often first provoking event in adult-onset congenital TTP

Presentation:

  • More common third trimester and postpartum
  • Microangiopathic haemolytic anaemia
    • Red cell fragments on blood smear
    • Features of non-immune haemolysis: raised LDH, raised reticulocytes, raised bilirubin, low haptoglobin, DAT negative
  • Severe thrombocytopenia can lead to bleeding complications although not usually severe/life-threatening
  • Usually normal coagulation
  • End organ damage
    • Gastrointestinal: abdominal pain and vomiting
    • Cardiac: chest pain, dyspnoea, raised troponin
    • Neurological: confusion, lethargy, seizures, focal deficits, coma
    • Renal: acute kidney injury (usually only mild-moderate)

Differential diagnosis (with differentiating features):

  • Pregnancy-specific
    • Pre-eclampsia with severe features (hypertension, proteinuria, peripheral oedema)
    • HELLP syndrome (LFTs more deranged than in TTP, often overlaps with pre-eclampsia)
  • Not pregnancy-specific
    • Acute DIC (deranged coagulation)
    • ST-HUS (acute diarrhoea from Shiga toxin, renal failure)
    • cHUS (renal failure)
    • Systemic vasculitis (acute nephritis, hypertension, positive ANCA)
    • CAPS (multiorgan failure with positive antiphospholipid antibodies)

Diagnosis:

  • Clinical diagnosis – MAHA and thrombocytopenia in the absence of other alternative cause (see differential diagnosis above)
  • Investigations
    • Haematology panel, including haemolysis screen and peripheral blood smear
      • Confirms MAHA and thrombocytopenia
    • LFTs, U/Es, coagulation, urinalysis, ANA, ANCA, anti-phospholipid antibodies, stool culture (if diarrhoea present), blood pressure measurement
      • Excludes differentials
    • Fetal ultrasound
      • Assess for intrauterine growth restriction
    • ADAMTS13 activity and anti-ADAMTS13 IgG
      • Confirms diagnosis and differentiates between acquired and congenital TTP
    • Troponins, CT brain (if neuro symptoms)
      • To assess for cardiac and neuro involvement

 Management (acute episode)

  • MDT approach: haematologists, obstetricians, nephrologists and intensivists
  • PEX and steroids as soon as clinical diagnosis is made (send ADAMTS13 assay off first)
  • Regular fetal monitoring for growth restriction
  • Confirmed aTTP = ADAMTS13 activity <10%, positive anti-ADAMTS13 IgG
    • Daily PEX and corticosteroids
    • Monitor response with platelet count, LDH, serial blood smears, clinical status
    • Stop PEX when platelets > 150 x 10^9/L for at least two days and monitor for recurrence
    • Gradual wean of steroids when in remission
    • Consider thromboprophylaxis and aspirin when platelets > 50 x 10^9/L
    • Normal obstetric indications for delivery of foetus
  • Confirmed cTTP = ADAMTS13 activity <10%, negative anti-ADAMTS13 IgG
    • Switch to plasma infusions – daily until remission
    • Ongoing management outside scope of this case but requires specialist tertiary care service with experience in managing this rare condition

Management (subsequent pregnancies)

  • Counselling re: risk of recurrence
  • Previous aTTP with persistently low ADAMTS13 activity
    • Pre-emptive treatment with rituximab to normalise ADAMTS13 activity
    • Avoid conception for at least 6 months after rituximab
  • Clinical and laboratory monitoring during pregnancy for relapse
    • ADAMTS13 activity normal – watchful waiting
    • ADAMTS13 activity borderline (10-20%) – low dose steroids
    • ADAMTS13 activity <10% – prophylactic PEX and low dose steroids
    • Overt acute TTP – see above management for acute episode

References

BSH guidelines: https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-management-of-thrombocytopenic-purpura-and-other-thrombotic-microangiopathies/

ISTH guidelines: https://www.isth.org/page/TTPGuidelines

Blood – “How I treat thrombotic thrombocytopenic purpura in pregnancy”: https://doi.org/10.1182/blood.2019000962

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Case 142: update 3

ADAMTS13 activity level subsequently comes back at <5% with positive anti-ADAMTS13 IgG antibodies, consistent with a diagnosis of acquired, immune TTP. The patient continues on daily PEX and 1 mg/kg prednisolone for immunosuppression. The patient responds well with resolution of neurologic symptoms and resolution of thrombocytopenia after 13 PEX sessions. PEX is continued for a further 3 days then discontinued. Steroids are continued and she is commenced on LMWH thromboprophylaxis and aspirin.

The patient remains in hospital for the remainder of her pregnancy for strict monitoring. ADAMTS13 activity recovers to 43% and she is successfully weaned off steroids. She goes into labour at 38 weeks gestation with an uncomplicated vaginal delivery of a healthy baby boy. She enters of period of surveillance for clinical, biochemical and serological relapse but after 6 months is lost to follow up.

Two years later, she is re-referred to haematology by her GP as she has expressed a desire to become pregnant again. On review in clinic, her blood counts are completely normal and she is asymptomatic. ADAMTS13 activity level is checked, which demonstrates an activity level of 11%.

How would you counsel the patient on the potential risks of further pregnancy?

How would you manage the patient to reduce the risk of TTP relapse?

How would you monitor the patient during the pregnancy? Is there a role for prophylactic PEX during pregnancy?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning

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Case 142: update 2

Due to concerns regarding possible TTP, you make your way back to hospital immediately. You request a slew of investigations to be arranged urgently. LDH and reticulocytes are markedly elevated and DAT is negative, consistent with non-immune haemolysis.  Cardiac troponin is elevated indicating cardiac involvement. Urinalysis excludes significant proteinuria. An ADAMTS13 assay is requested and sent to the reference lab for urgent processing.

On arrival to the ward, the patient is being assessed by the obstetrics registrar. Fetal ultrasound demonstrates that the foetus is growing normally with no immediate concerns. After liaising with the renal consultant on-call, you arrange admission to the renal ward for emergency plasma exchange with S/D-plasma (1.5 plasma volumes per day). Joint care is agreed between haematology, obstetrics and renal medicine.

How would you differentiate between acquired and congenital TTP? Would it change how you manage the patient?

Given the degree of the thrombocytopenia, would you give a platelet transfusion prior to Vascath insertion?

What clinical and laboratory parameters would you use to assess response to PEX?

What role (if any) do glucocorticoids, rituximab and caplacizumab have in this patient’s management?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning

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Case 142: update 1

Many thanks for all your suggestions. We have some more information about the patient.

She is a normally fit and well and is currently pregnant (23 weeks gestation). This is her first ever pregnancy and has been, until now, uncomplicated. Her anomaly scan done at 20 weeks gestation was unremarkable – the foetus is growing normally and there were no concerns.

She was brought in earlier on in the afternoon by her partner as she has been behaving oddly and has been disorientated for the last 24 hours. Her GCS is currently 14/15 (confused speech) and she is not orientated to time or place. She is also reporting a throbbing headache and some abdominal pain. Other than some petechiae on her lower limbs, she has no bleeding symptoms.

Her observations are normal except for a heart rate of 105 bpm and a temperature of 38.1 degrees Celsius. Blood pressure is 119/70. She has some mild photophobia but no nuchal rigidity. A CT brain was done, which is reported as normal. Admission blood tests are seen below. The working diagnosis from the medical team is viral encephalitis.

While the medical SHO is relaying this history, you get another call from the haematology laboratory about an urgent blood film (see image below).

Full blood count
Hb 71              (115-165)
MCV 92           (80-100)
Platelets 13     (150-450)
WCC 7.0         (4.0-11.0)
Neut 5.2          (2.0-8.0)

Coagulation
PT 15              (11-15)
APTT 31          (25-35)
Fibrinogen 6.7 (1.5-5.0)

Biochemistry
Na 142            (133-146)
K 4.9               (3.5-5.3)
Creat 101        (45-85)
Bili 72              (0-21)
ALT 49            (0-40)
ALP 102          (30-130)
CRP 23           (0-5)



What is the differential diagnosis and how would you differentiate between the possibilities?

What are the next steps you would take, including further investigation and management?

Who else would you want to involve in the patient’s care?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning






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Case 142: the beginning

You are the haematology registrar on call (non-resident in the evening). It’s 6:15 pm and as you’re walking into your home, you get called by the medical SHO on the Acute Medical Unit for advice on pre-procedure platelet transfusion. They would like to perform a diagnostic lumbar puncture to exclude encephalitis in a 31-year-old woman who presents with fevers, confusion and a headache. Her platelet count has come back as 13 x 10^9/L.

Would you be happy to advise on platelet transfusion with the information provided here?

If not, what further information would be helpful and what steps would you take to help guide your decision making in this situation?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning

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Case 141: Mini case 4

You are the urology FY2, and you have been asked to clerk a patient who has been electively admitted for transurethral resection of bladder tumour (TURBT) in the morning. You look through his pre-assessment bloods from 2 weeks ago and note:

Hb 124, WCC 6.2, Plt 210

PT 12, APTT 64, Fibr 2.2

Can the surgery proceed tomorrow? What blood products could you order to ensure a safe procedure?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning

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Case 141: mini case 3

A 41 year old female patient is an inpatient on the haematology ward progressing through her first cycle of the UKALL14 protocol for a new diagnosis of ALL. She complains of a swollen and painful left arm, and US confirms a DVT at the sight of her PICC line.

FBC: Hb 81, WCC 2.1, Plt 21

How would you manage her anticoagulation?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 141: Mini case 2

You are the IMT2 doctor on a gastroenterology ward. A 54 year old man has been admitted with decompensated alcoholic liver disease and has fevers with high CRP. As part of the ward round plan you have been asked to perform an ‘ascitic tap’ to determine whether he has spontaneous bacterial peritonitis (SBP). You review his admission blood tests from yesterday:

Hb 84, WCC 12.2, Plt 67

PT 22, APTT 45, Fibr 1.9

Does the patient require any blood product support before the procedure?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 141: Short case 1

You are an interventional radiology trainee (ST5) and are running a procedure list tomorrow morning, with support from a consultant. You look through the cases and one of the request forms states:

‘New AML. For CPX. Requires Hickman line for chemo etc.’

You review this 68 year old, female patient’s recent bloods:

Hb 80, WCC 2.1, Plt 23

PT 13, APTT 30, Fib 4.5

Does the patient require any blood product support pre-procedure?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 140: Summary

Thanks for your valuable input this week!

This case was about a patient who develops cold haemagglutinin disease secondary to
lymphoplasmacytic lymphoma.

Cold haemagglutinin disease is a type of cold auto-immune haemolytic anaemia associated with IgM antibodies. It can be primary or secondary to infection (e.g. Mycoplasma, EBV, CMV), auto-immune disease (e.g. SLE), and lymphoproliferative disorders.

Lymphoplasmacytic lymphoma (LPL, also known as Waldenström macroglobulinaemia) is a rare low
grade B-cell non-Hodgkin lymphoma which is typically associated with an IgM paraprotein and a
MYD88 mutation.

It is more common in males over 60 years old, and a familial component has been suggested.

Several complications can arise from LPL, including cold haemagglutinin disease, cryoglobulinaemia,
hyperviscosity syndrome, and peripheral neuropathy.

Diagnostic work-up includes blood tests (full blood count, renal/liver function testing, serum protein
electrophoresis, beta 2 microglobulin, LDH), imaging (CT chest/abdomen/pelvis) and bone marrow examination (immunophenotype, immunohistochemistry, molecular studies).

Prognostication can be established using the International Prognostic Scoring System for Waldenström Macroglobulinaemia (IPSSWM) which includes age, haemoglobin, platelet count, beta2-microglobulin, and serum monoclonal protein concentration.

Management for asymptomatic patients should be based on watchful waiting as there is no evidence to support treatment based on laboratory or radiological features alone. Nevertheless, patients with significant marrow infiltration, significant splenomegaly/lymphadenopathy, and high
IgM paraprotein levels are more likely to require treatment sooner and this should be taken into
consideration.

For symptomatic patients, first line treatment options should be based on patients’ overall fitness
and performance status, treatment toxicities and patient wishes. First line therapy recommendations involve rituximab-based regiments, including DRC (dexamethasone, rituximab, cyclophosphamide), BR (bendamustine, rituximab), and FCR (fludarabine, cyclophosphamide,
rituximab). For patients unfit for these therapies, chlorambucil might be an appropriate option.

At relapse, watchful waiting is again an option if the patient is asymptomatic. In the event of
symptoms, second line chemotherapy with rituximab containing regiments should be considered along with stem cell transplantation.
High grade transformation should follow standard management options as for diffuse large B-cell
lymphoma.

Patients are often hypogammaglobulinaemic and antimicrobial prophylaxis should be considered e.g. aciclovir, co-trimoxazole.

References:

Owen RG, et al; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of Waldenström macroglobulinaemia. Br J Haematol. 2014 May;165(3):316-33.

Kastritis E, et al; ESMO Guidelines Committee. Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv41-iv50.

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Case 140: Update 5

Given this lady’s CHAD and heavy marrow infiltration, a decision is agreed to offer treatment. She is
commenced on DRC chemotherapy (dexamethasone, rituximab, cyclophosphamide) with good
response.


Good job, team!

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Case 140: Update 4

We now have a report on the bone marrow.

Immunophenotype:
Lambda restricted B cell population = 8.9% of total nucleated cells.
CD19+, CD5 negative, FMC7 variable (+/neg), CD23 variable (neg/+), CD200 variable (weak/neg),
CD20+, CD22+, CD103 negative, CD10 negative, CD45+, CD79b weak, CD38 variable (neg/+),
CD11c negative, CD2 negative, sIg++

Immunohistochemistry:
Trilineage haematopoiesis is reduced and the normal bone marrow architecture is disrupted by
mixed diffuse, nodular and paratrabecular infiltrates of small mononuclear cells. The infiltrate
comprises CD20+/CD79a+/BCL2++small B cells that are negative for BCL6, cyclinD1, CD3, CD5 and
CD10. The heavy, abnormal B cell population represents 80% of the total specimen.

Molecular studies:
Variant MYD88 L265P detected.

You think this lady has CHAD secondary to lymphoplasmacytic lymphoma.
How would you manage her at this point?

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Case 140: Update 3

This lady has been diagnosed with CHAD and we are trying to establish whether it is primary or secondary.

Her viral serology and auto-immune screen are unremarkable. Given her full blood count and splenomegaly, you are concerned about an underlying malignancy.


Her serum protein electrophoresis reveals an IgM paraprotein of 12g/L.
A bone marrow biopsy is performed and you can see the images below:

Aspirate
Trephine
Trephine (close up)

Based on her bone marrow morphology, what do you think is the most likely diagnosis?
Which one diagnostic test do you think would be of benefit to help confirm the diagnosis?

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Case 140: Update 2

This lady’s blood film shows red cell agglutination at room temperature which resolves with sample
warming to 37 degrees Celsius. There is also polychromasia with spherocytosis. Her
thrombocytopenia is mild but genuine with no platelets clumps.


You suspect this lady has haemolytic anaemia secondary to cold haemagglutinin disease (CHAD) and
arrange for her to be admitted to your hospital’s urgent care centre. You arrange further tests which
support your diagnosis, including:

Direct antiglobulin (Coombs) test: positive (anti-C3d +++)
Bilirubin: 26 umol/L
LDH: 740 U/L
Haptoglobin: undetectable
Reticulocytes: 188 x109/L (5.8%)


A CT chest/abdomen/pelvis is only significant for moderate splenomegaly (17cm) with no associated
lymphadenopathy.


What do you think could be the cause of this lady’s CHAD, and how would you investigate?

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Case 140: Update 1

This lady has a new macrocytic anaemia and is symptomatic. She is also mildly thrombocytopenic.


Her B12 and folate are normal, unfortunately the rest of her biochemistry has haemolysed. Her reticulocyte count is raised at 188 ×109/L. She has no B-symptoms or palpable lymphadenopathy/organomegaly.

She takes no medications, does not drink alcohol, and has a balanced diet.


Given how troubled she is by her symptoms, her GP arranges for this lady to receive a red cell
transfusion. Unfortunately her FBC sample is now a couple of days old so you are unable to obtain a
blood film. You ask the GP to repeat her FBC after a few days with a request for a blood
film. At that point, her FBC and blood film are as follows:


Hb 78 g/L
MCV 104 fL
Plt 135 x109/L
WCC 12.7 x109/L
Neut 5.8 x109/L
Lymph 5.6 x109/L
Mono 1.1 x109/L
Eosino 0.2 x109/L
Baso 0.01 x109/L

What is your main differential at this point and how would you further investigate?

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Case 140: The beginning

You are the on call haematologist and are asked by one of the secretaries to speak to a worried GP
on the phone.


It is regarding a 52 year old lady who saw her GP with a 2 week history of worsening fatigue and
shortness of breath on minimal exertion. Her full blood count is as follows:


Hb 81 g/L
MCV 103 fL
Plt 138 x109/L
WCC 11.2 x109/L
Neut 4.8 x109/L
Lymph 5.1 x109/L
Mono 1.0 x109/L
Eosino 0.3 x109/L
Baso 0.01 x109/L


Her GP is concerned because this lady has no bleeding symptoms and her last haemoglobin done 2
months previously was in the normal range.


What advice would you give her GP?

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Case 139 – Summary

The cases this week were designed to consider the complexities of VTE management in cancer patients. 

VTE is four to seven times as common in the cancer population compared to the general population.

Cancer associated thrombosis is the second commonest cause of death in cancer patients after disease progression.

It is the source of a huge amount of morbidity for patients with associated anxiety regarding treatment delays, bleeding issues or further thrombosis.  It is often a challenging situation to manage as patients may well have bleeding and thrombosis risk factors and may even have this present simultaneously (as seen in short case 2). 

Importantly a good haematologist will consider patient choice, prognosis of the disease and practical considerations such as drug interactions, abnormalities in blood tests, surgery and biopsies.

Role of thromboprophylaxis in cancer patients: (Case 1)

There is no benefit in unselected thromboprophylaxis in ambulatory cancer patients. The number needed to treat for the population as a whole is which is felt to be too high to warrant unselected intervention (NNT 60) from Cochraine review of 3538 patients. The review found no difference in mortality at 12 and 24 months despite reductions in symptomatic VTE rates but it did show possible increased bleeding rates while on prophylaxis.

In 2008 Khorana et al. Devised a validated score to evaluate the risk of thrombosis in a cancer patients. This score suggested if patients scored 3 or more had a high risk of VTE (7.8% over 2.5 months, compared to 0.8% for low risk individuals). The use of this tool is recommended by ASCO, ESMO and BSH guidelines. 

It should be stressed that NICE guidance suggests that all patients with active cancer therapy should be considered for thromboprophylaxis on admission to hospital unless there are contraindications.

NICE also suggest that consideration is given to thromboprophylaxis for ambulatory cancer patients with other thrombotic risk factors. It also advocates  consideration of prophylaxis in pancreatic cancer patients while on chemotherapy and myeloma patients on Thalidomide, Lenolidamide or Pomalidamide.

In our short case one the patients Khorana score is 1 (score for bladder cancer 1-8 -2% risk over 2.5 months of VTE). He had some bleeding risk factors to consider such as his history of active haematuria and iron deficiency at present. He was also planned to start chemotherapy which cause thrombocytopenia.  It was decided no thromboprophylaxis was indicated.

Management of Cancer associated thrombosis: (Case 1)

It is important to have a sound understanding of the literature with regards to anticoagulation to be able to apply the principles to practice. 

Here is a quick summary of the important trials in this area:

CLOT trial 2003: Dalteparin Vs VKA  –  Recurrent thrombosis reduced in Dalteparin group (9% Vs 17%) and similar bleeding risk (4% Dalteparin Vs 6% VKA). Minor criticism of this trial is in VKA arm 50% of recruited patients in VKA arm had poor time in INR range.

CATCH trial 2015: Tinzaparin Vs VKA  – Reduced recurrence rates in Tinzaparin group with major bleeding rates the same (2%) but lower clinically relevant non major bleeds in Tinzaparin group.

This established LMWH is superior to VKA in management of cancer associated thrombosis.

HOKUSAI VTE 2018: Edoxaban 60mg OD (After 5 days LMWH) Vs LMWH. No difference VTE recurrence rates (12.8% Edoxaban Vs 13.5% LMWH). Increased major bleeding rates in trial (6.9% Edoxaban Vs 4% LMWH) when analysed these were particularly GI bleeds and convincingly on subgroup analysis were linked to urothelial and GI malignancy patients. ICH rates in both groups were the same.

SELECT-D 2018: Rivaroxaban (15mg BD for 21 days then 20mg OD) Vs LMWH. Reduced VTE recurrence rates (4% Rivaroxaban Vs 11% LMWH). Increased major bleeding on Rivaroxaban (6% Rivaroxaban vs 4% LMWH) and clinically relevant non major bleeding. This finding lead to stopping recruitment for upper GI malignancy cancer patients early. In this trial again ICH rates were not increased with Rivaroxaban.

ADAM VTE 2019: Apixaban (10mg BD 7 days to 5mg BD) Vs LMWH. Primary outcome in this trial was Major bleeds with 0% in Apixaban group compared to 1.4% in LMWH group. These rates were low compared to other DOAC Vs LMWH trials and this may be due to selection of patients and small study population of 287 patients. This trial also confirmed statistically significant lower VTE recurrence rates of (0.7% Apixiban Vs 6.3%).

CARVAGGIO 2020: Apixiban (10mg BD for 7 days to 5mg BD) Vs LMWH. Recurrent VTE rates 5.6% Apixaban Vs 7.9% LMWH) statistically significant for non inferiority of Apixaban in this setting. Major bleeding rates same (3.8% Apixaban Vs 4% LMWH) this included Major GI bleeds. It did find an increase in clinically significant non major bleeding rates in Apixiban group and these were mainly in genitourinary and upper airway bleeds. Older patients >75 years appeared to have more major bleeding on Apixiban on subgroup analysis. 

These trials have established DOACs are non inferior to LMWH in terms of recurrent VTE. DOACs may be associated with increased clinically relevant minor bleeding and it seems that patients with GI malignancy are at increased risk of major bleeding on these drugs. 

Recent ESMO guidelines sensibly suggest particular patient groups where care should be taken with DOACS:

Frail patients – None of the DOAC trials included patients with ECOG <2.

Luminal GI cancers, Genitourinary cancers, nephrostomy tubes or those with known Gastritis, Oesophagitis or Colitis – Increased bleeding risk on DOACs.

Thrombocytopenia – Patients will require interruption of DOAC if plt <50. 

Pharmacokinetic considerations – CYP3A4 pathway used for metabolism of DOACS. Many anti cancer drugs can interact with this pathway including Biclutamide, TKI, Paclitaxel  plus supportive medications such as Azol anti fungals.

Poorly controlled vomiting and patients with GI resection – May affect absorption of DOACs 

The patients choices and values may also need to be considered and often a patient has a clear idea of which anticoagulant they would prefer and the decision making and the risk/ benefit need to be shared with the patient.

IVC Filters in cancer associated thrombosis: (Case 2)

BSH guidelines suggest these can be considered as an option for patients with an acute VTE and an absolute contraindication to anticoagulation. These are not a permanent substitute to anticoagulation and need to be inserted with clear plan for removal.

IVC filters that are left in situ can lead to serious complications due to stent migration, perforation of IVC and occlusion can occur in up to 20% of patients who have stents left in for 5 years.

In short case 2 the patient had a PE and DVT in the context of haemorrhagic cerebral metastasis with neurological deficit. It was unlikely that she would ever be considered suitable for anticoagulation and hence an IVC filter was unlikely ever to be able to be removed. The patient also had a poor prognosis from her metatstatic malignancy and hence this intervention was felt to be inappropriate in her case.

BSH guidelines also support the use of IVC filters when need for urgent surgery and VTE within last 4 weeks due to high recurrence rates during interruption of anticoagulation. This would clearly be important to consider for any cancer surgery in patients with recent thrombosis. 

Many thanks for your help this week I hope it was interesting and that you feel more confident in the recent literature surrounding this area of practice.

References:

Akl  EA, Kahale  LA, Hakoum  MB, Matar  CF, Sperati  F, Barba  M, Yosuico  VED, Terrenato  I, Synnot  A, Schünemann  H. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD006652. 

Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE guideline [NG89] Published date: 21 March 2018.

Khorana AA et Al. Development and validation of a predictive model for chemotherapy associated thrombosis. Blood, 111, 4902-4907.

Watson, H.G., Keeling, D.M., Laffan, M., Tait, R.C., Makris, M. and (2015), Guideline on aspects of cancer‐related venous thrombosis. Br J Haematol, 170: 640-648.

Moik F, Pabinger I, Ay C. How I treat cancer-associated thrombosis. ESMO Open 2020;4:e000610. doi:10.1136/ esmoopen-2019-000610

Key N et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update Journal of Clinical Oncology 38, no. 5 (February 10, 2020) 496-520.

Guidelines on use of Vena cava filters. Br J Haematol, 136 :90-595.

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Case 139 – short case 2 update 2

Thanks for your input with regards to IVC filter decision making.

You ask a few more questions and establish that the patient has declined any further investigation for her likely metatataic malignancy and the oncology team advise her prognosis is weeks to months.

Knowing the patients wishes for no further intervention and her poor prognosis it isn’t felt she is an appropriate candidate for an IVC filter.

She has also developed right arm weakness presumably secondary to her haemorrhaging brain metastasis. You agree to stop anticoagulation given her neurology. The patient is informed of the difficult situation with regards to PE and brain haemorrhage and is also in agreement with this plan.

Many Thanks for your help with the two short cases this week. A summary of important issues to consider in cancer associated thrombosis will follow this weekend.

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Case 139 – short case 2

You are the haematologist on call and phoned at 5pm on a Friday about a 75 year old lady who presented to the acute admissions unit with confusion. She was diagnosed with Hypercalcaemia and a subsequent CT is suggestive of metastatic Lung Adenocarcinoma. She has a past medical history of Type two diabetes, AF on Apixiban, Gallstones, Diverticular disease and has an elevated BMI with a weight of 130kg.

The medical team contact you as she has had a staging CT that shows a segmental PE in right lung and a CT Brain that shows probable cerebellar metastasis with one metastasis showing possible small haemorrhage. Her right leg is swollen and clinically there is suspicion of a DVT.

They are concerned about the new VTE while she is “on Apixiban” and had planned to change her to treatment dose LMWH but wanted your approval for this before starting this given the possible bleed on CT Head.

They tell you her FBC is normal and her coagulation screen is normal apart from an elevated fibrinogen and D-Dimer. Her renal function is Normal.

What are your initial thoughts regarding anticoagulation?

Are there any other investigations that may help in this case?

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Case 139 – short case 1 update 3

After careful consideration you opted for weight based LMWH due to concerns about Thrombocytopenia and he has a bladder cancer with history of haematuria.

A month later his platelet count has recovered but he has developed new dyspnoea. He is found to have a new segmental PE on CTPA. He has been on LMWH weight based with normal renal function eGFR >90. He has no active bleeding and his Hb has improved to 111 following Iron replacement.

What would you do now?

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