Case 66 – summary

Thanks for all who have been involved in this week’s case.  We reviewed the causes of thrombocytosis in general and also applicable to pregnancy. Causes of thrombocytosis are usually reactive or secondary to another cause:

  • Blood loss
  • Infection/inflammation
  • Malignancy
  • Thrombopoietin agonists e.g. romiplostim, eltromboplag
  • Rebound post chemotherapy
  • Iron deficiency
  • Tissue damage e.g. post surgery
  • Hyposplenism

 

It is important to examine the blood film to ensure there is not a spurious cause – rarely bacteria, microspherocytes/fragments, cryoglobulin etc. can imitate platelets on the analyser.

 

In pregnancy one would expect the platelet count to fall rather than rise – especially in the third trimester. Platelet counts are generally lower in pregnancy and possible mechanisms include:

  • Increased plasma volume/haemodilution
  • Consumption by placenta
  • Hormonal inhibition of megakaryocytes
  • Increased platelet activation and clearance by vWF

 

In our case all causes of secondary thrombocytosis were excluded and thoughts moved to excluding primary causes. Pointers to primary causes include:

  • Previous VTE or other thrombotic episode
  • Recurrent infections or bleeding
  • B symptoms
  • Pregnancy morbidity including trouble conceiving and miscarriage
  • Splenomegaly
  • Abnormalities on blood film: platelet anisocytosis, tear drop cells, nucleated red cells, basophilia

 

Causes of ‘primary’ thrombocytosis include

  • Essential thrombocytosis
  • Polycythaemia vera
  • Myelofibrosis
  • Chronic myeloid leukaemia
  • Chronic myelomonocytic leukaemia
  • Atypical chronic myeloid leukaemia
  • Myelodysplasia (especially with the 5q deletion)
  • Myelodysplasic syndrome/myeloproliferative neoplasm unclassifiable
  • Refractory anaemia with ringed sideroblasts with thrombocytosis

In order to investigate thrombocytosis where a primary bone marrow disorder is deemed likely first line investigation includes sending for various genetics tests:

  • JAK2 V617F
  • MPL exon 10
  • CALR exon 9
  • BCR-ABL

 

In CML BCR-ABL is detected. For essential thrombocytosis JAK2 is present in about 60%, CALR 30% and MPL 5% cases. These mutations can also be present in other myeloproliferative neoplasms and a bone marrow may be needed for exact classification. Some haematologists may omit a marrow if the clinical and laboratory features are most in keeping with essential thrombocytosis (there is no splenomegaly, isolated thrombocytosis with usually no other abnormality in FBC, no nucleated red cells or tear drop cells and frequently no constitutional symptoms).

 

Essential thrombocytosis

This is a clonal/malignant myeloid blood disorder characterised by persistent thrombocytosis.  Patients are often asymptommatic and the finding is usually found on routine bloods.  Some patients may present with bleeding problems or thrombotic complications such as stroke or ischaemic heart disease. Patients usually have a near normal life expectancy but there is a risk of progression to myelofibrosis or acute myeloid leukaemia.  When AML occurs secondary to ET the prognosis is generally poor.

For treatment, patients are divided up into low, medium and high risk depending on platelet count, age and other risk factors. High risk patients are over the age of 60, PLT >1500×10*9/L and previous thrombotic episode. Intermediate risk patients are 40-60 years old and low risk are less than 40. Patients should be offered clinical trials where available.  High risk patients are often treated with cytoreductive therapy such as hydroxycarbamide (interferon if younger due to potential risk of leukaemogeneisis) and aspirin.  Low and medium risk patients should be given aspirin alone.  Other cardiovascular risk factors should be investigated and managed appropriately.  Other second line therapies include anegrelide, busulfan and radioactive phosphorus.  JAK inhibitors are being used in myelofibrosis.

Thrombotic complications are common, however bleeding can occur, especially in high platelet counts.  This may be due to platelet dysfunction, antiplatelet agents or aquired von Willebrand’s disorder.

 

ET in pregnancy

This is a rae event. Many women will have miscarriage due to placental microvascular infarcts. There is also increased risk of intra-uterine growth retardation, pre eclampsia, VTE and haemorrhage. All women should be given aspirin 75mg once a day and six weeks of LMWH prophylaxis post-partum. LMWH antenatally is more controversial but should be considered if there are additional risk factors (see guidance from ROCG). Hydroxycarbamide is contraindicated and therefore if cytoreduction is required then interferon should be used. Patients should have regular scans including uterine artery doppler from 20 weeks gestation.

It is not clear when patients should have cytoreduction and this is often decided on a case by case basis. Some retrospective studies have shown better outcome when interferon is used and that patients with a JAK2 mutation have worse outcomes. Possible reasons for using interferon include:

  • Very high platelet counts
  • Recurrent VTE despite usual measures
  • Pregnancy morbidity despite aspirin/LMWH
  • Bleeding symptoms associated with ET

A useful flow chart is seen here: (taken from BCSH guidance – reference below)

Figure 4.

 

VTE in pregnancy

Patients are generally treated with LMWH using booking weight with no dose reductions for obese patients. Once daily or twice daily dosing are both options and anti-Xa activity should be monitored in those with renal failure and high or low BMI (e.g. <50kg; >90kg). Generally if there are no other risk factors LMWH is continued throughout pregnancy and six months post-partum (or three months; which ever is longer). Patients on anticoagulation are more at risk of thrombosis so need correction of iron status and an up to date group and antibody screen.

 

Our case

The patient had no other risk factors for VTE (except for ET and pregnancy). She was given aspirin and therapeutic LMWH once daily. As her platelet count was not too high and after discussion with the patient interferon was not used but a plan that if there was recurrence or changes in the uterine artery doppler then it would be instigated. Some clinicians may choose to use interferon after the VTE was diagnosed in addition to LMWH. Given her additional risk factors it was decided to continue LMWH for three months post-partum and then stop and carry on aspirin alone. This would be a risk vs benefit decision and as the VTE was provoked by pregnancy the decision was made not to continue long term but for aggressive VTE prophylaxis during at risk periods.

 

As ET in pregnancy is rare these decisions need careful MDT discussion.

 

References

BCSH guidance on ET and thrombocytosis

Update from BCSH guidance

Outcome of 122 pregnancies in ET

Prenancy complications with JAK2 mutation

 

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