Case 81 – summary

Thank you for all the contributions to the case this week.

The case

We looked at a case of a 58 year gentleman who had an incidental finding of thrombocytopenia, whilst on apixaban therapy.

Immediate intervention was required to stop the apixaban in order to limit the risk of bleeding.  We looked into the management of bleeding in the case of thrombocytopenia, as well as how to determine whether the apixaban could be contributing to the bleeding.

Our followers came up with a very extensive list of investigations/initial management plans.  These included:

  • stopping apixaban.
  • Checking Fbc ? Any other abnormalities/previous FBC/ clot in sample
  •  coagulation.  Prolonged PT, normal aptt and fibrinogen
  • renal and liver function
  • HIV, hepatitis serology, helicobacter pylori
  • autoimune screen
  • blood film to check for platelet clumps, primitive cells, size of platelets, red cell fragments
  • haematinics
  • Review medications ? Any that cause thrombocytopenia.  Thrombocytopenia is listed as an uncommon potential side effect of apixaban therapy.
  • history  ? Any red flags for malignancy
  • examination for lymphadenopathy, hepatosplenomegaly
  • Bleeding history/alcohol history/transfusion history

 

Patients presenting with thrombocytopenia can have numerous precipitating factors which may be reversible, such as infections and medications, or it may be a presenting feature of an underlying malignancy.  Primary ITP was defined by the international working group as a platelet count less than 100 × 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. Treatment should be administered for newly diagnosed patients with a platelet count < 30 × 109/L.

 

Apixaban

Apixaban in this case complicated the matter once the patient was bleeding.  With no bleeding symptoms the patient could have simply discontinued the apixaban and its effects would have resolved within 48hours, in a patient with normal renal function.   A key role of the haematologists in this case is trying to determine what is contributing to bleeding, in order to provide an appropriate management plan.  In this case, with normal renal function we can be relatively confident that the apixaban is playing very little role in bleeding.  However the PT was marginally prolonged.  If further confirmation was required then anti-xa assay could be used.  This then allows the clinician to focus improving the platelet count, as well as encouraging surgical intervention to help stem the bleeding.

Antedotes to apixaban were mentioned by our followers.  Currently, andexanet alfa is still in trial and therefore not available for use.  Consideration would still be needed in this case to determine the contributing factors for the bleeding as using the antidote inappropriately would be costly, as well as exposing the patient to potential side effects of the drug unnecessarily.  Options to support a patient with active bleeding secondary to apixaban include supportive measures and consideration for tranexamic acid, PCC, FEIBA and novoseven.  All treatments should be discussed with the haematologist oncall.

 

Steroid treatment and response

The platelet count responds following treatment with IVIG, and dexamethasone 40mg given for four days. Options for steroid treatment include dexamethasone, or prednisolone.  Kindly, one of our follower tweeted a link to a study that had previously compared these two options. This study concluded that high-dose dexamthasone for 4 days produced a higher incidence of overall initial response and complete response compared to prednisolone, as well as time to response being shorter in the dexamethasone group.  Although the overall sustained response was not significantly different between the two groups, dexamethasone was better tolerated and therefore could be the preferred method of treatment.

 
Complete response (CR) A platelet count ≥ 100 × 109/L measured on 2 occasions > 7 days apart and the absence of bleeding.
Response (R) A platelet count ≥ 30 × 109/L and a greater than 2-fold increase in platelet count from baseline measured on 2 occasions > 7 days apart and the absence of bleeding.
No response (NR) A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.
Loss of complete response A platelet count < 100 × 109/L measured on 2 occasions more than a day apart and/or the presence of bleeding.
Loss of response A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.

2 weeks following commencement of steroids the platelet count has fallen to 17.  There is value in repeat the course of dexamethsone, however if there are bleeding concerns, an alternative therapy would need to be considered.  Guidelines suggest that >60 year old presenting with ITP, require bone marrow biopsy at diagnosis.  Failure to response to steroids at any age would also be an indicator for biopsy.

When considering possible management options it is important to appreciate the expected time to response.  This is important for example when trying to assess a patients response to steroids in the initial phase, or when using second line therapy such as rituximab when response can be seen up to 4 months later

Time to response From start of treatment until either complete response or response
Duration of response Time from complete response or response until loss of complete response or response Measured as the proportion of the cumulative time spent in complete response or response during the period under examination as well as the total time observed from which the proportion is derived
Expected time to response Treatment type Initial response, days Peak response, days
Anti-D 1-3 3-7
Azathioprine 30-90 30-180
Danazol 14-90 28-180
Dexamethasone 2-14 4-28
Eltrombopag 7-28 14-90
IVIg 1-3 2-7
Prednisone 4-14 7-28
Rituximab 7-56 14-180
Romiplostim 5-14 14-60
Splenectomy 1-56 7-56
Vinblastine 7-14 7-42
Vincristine 7-14

TPO agonists

Romiplostim and elthrombopag may be used.  The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes.  Choice of TPO is based on the individual patient and clinican preferences.  Elthrombopag is an oral agent taken once daily, compared to romiplostin which is a once weekly subcutaneous injection.  Although the oral agent may be preferred there are numerous dietary restrictions pre and post ingestion of the drug which may be difficult for some patients to comply with.  Both can be incremented in dosage depending on platelet response.  Both have potential to increase bone marrow reticulin formation, however the relevance of this is still to be determined.  The fibrosis is reversible after short term treatment.  Currently it is recommended to perform bone marrow biopsy on an annual basis and discontinue treatment if grade2/3 marrow fibrosis is identified.

Splenectomy

Guidelines still recommend splenectomy if patients have failed steroid treatment. However current practice in the UK does not represent this.  Advise currently would be to exhaust medical treatment for thrombocytopenia, and only if the patient persistently has plt cout <25, and is having haemorrhagic complications, would splenectomy be considered.  This is due to risks associated with major surgery, risk of infections post operatively, and the inability to accurately predict patients response to splenectomy.

 

 

References

  1. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.  Cindy NeunertWendy LimMark CrowtherAlan CohenLawrence Solberg Jr and Mark A. Crowther.   
  2. High-dose dexamethasone versus prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial.   Yu WeiXue-bin JiYa-wen WangJing-xia WangEn-qin YangZheng-cheng WangYuqi SangZuo-mu BiCui-ai RenFang ZhouGuo-qiang LiuJun Peng and Ming Hou.  
  3. TPO-mimetics and myelofibrosis? A reticulin question!  Michele P. Lambert. 

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