You Make the Call: How would you approach diathesis in a 65-year-old woman with newly diagnosed breast cancer?

This month, Barbara Konkle, MD, discusses a bleeding diathesis in a 65-year-old woman with newly diagnosed breast cancer.

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!

I am evaluating a 65-year-old woman with newly diagnosed breast cancer for a possible bleeding diathesis.

Her bleeding history is as follows:

• Epistaxis as a child
• History of heavy menstrual cycles requiring uterine ablation and iron supplementation
• Heavy bleeding with first intercourse requiring vaginal packing and vitamin K administration
• No bleeding after a vaginal delivery in 1973
• Postpartum hemorrhage after a vaginal delivery in 1976
• Long-standing history of easy bruising

She has undergone several procedures including port-a-cath placement, breast biopsy, bilateral breast reduction, knee surgery, tonsillectomy, and routine dental work all without significant or unexpected bleeding.

However, after her breast cancer diagnosis, she underwent a partial mastectomy with sentinel lymph node biopsy in January. During the surgery, her estimated blood loss was 58 mL. A few days later, she reported extensive bruising of the breast and surrounding tissues. During a visit in early February, she had extensive ecchymosis and hematoma over the left breast wound site that extended down the left side of her chest. Her bleeding was so extensive she was anemic, underwent a red blood cell transfusion, and required ventriculoperitoneal drain placement. Similarly, she had a history of extended bleeding for a few days after a laparoscopic hysterectomy in 2011.

Blood work in early February showed a hemoglobin level of 12.6 g/dL, mean corpuscular volume of 89.7 fL, red cell distribution width of 14.1%, and a platelet count of 280 x 109/L. Her prothrombin and partial thromboplastin times were 10.9 and 27 seconds, respectively. She had a fibrinogen level of 169 mg/dL, factor XIII functional level of 82%, factor XI activity of 119%, factor IX activity of 125%, factor VIII activity of 99%, and negative test for factor VIII inhibitor. A von Willebrand panel was normal. Her comprehensive metabolic panel and lactate dehydrogenase were also normal.

A repeat fibrinogen level two weeks later was 157 mg/dL. Additional bloodwork from March showed a thrombin time of 25.9 seconds, fibrinogen activity of 130 mg/dL, fibrinogen antigen of 155 mg/dL, fibrin degradation products of <5 mcg/mL, a reptilase time of 18.2 seconds, and chromogenic factor VIII activity of 106%.

I think she might have a congenital hypofibrinogenemia. Although her fibrinogen levels are not terribly low, challenges such as surgery could have tipped the scale and led to bleeding a few days later. She is currently doing well with CMF chemotherapy (cyclophosphamide, methotrexate, and fluorouracil).

Would you recommend any further testing? How would you treat with surgery? The patients’ parents died when she was a toddler. Would you recommend that her children/grandchildren be tested? If so, with which test?

The first question to address is whether or not the patient has a life-long bleeding disorder. That will affect the differential diagnosis. She does have some symptoms from childhood, but also had multiple surgical procedures without increased bleeding. Whether her recent surgical bleeding complications are from an inherited bleeding disorder will likely stay unresolved unless we find similar abnormalities in one or more of her children (see below). With the extensive testing undertaken, the abnormalities found are a modestly decreased fibrinogen antigen and activity and, I presume, a prolonged thrombin time. The most common reasons for decreased fibrinogen are liver disease – which is an unlikely cause for her as other clotting factors are normal and her factor VIII is not elevated – or disseminated intravascular coagulation (DIC). Although her fibrin degradation products and platelet count are normal, I would also check a D-dimer level to exclude the diagnosis of DIC. Dysfibrinogenemia can be associated with a bleeding tendency, but she does not appear to have this given her normal fibrinogen activity/antigen ratio and normal reptilase time. Thus, I would agree that the most likely diagnosis is mild hypofibrinogenemia. Testing fibrinogen levels in her children may be helpful in determining whether this is an inherited disorder. If it is, then testing for fibrinogen genetic variants is available. It may be uninformative, but if there are other families with the same variant reported, their clinical symptoms could be informative.

If her von Willebrand levels are in the lower normal range (they are not given), it would be worthwhile to repeat the levels. It is unclear whether additional testing to look for very rare disorders associated with increased fibrinolysis (such as PAI-1 [fasting AM], tPA, alpha2-antiplasmin, Quebec platelet disorder) would be useful. Of note, neither von Willebrand disease nor described inherited disorders of fibrinolysis are associated with low plasma fibrinogen levels. In terms of treatment, antifibrinolytic therapy (tranexamic acid or epsilon-aminocaproic acid) could be used for minor procedures. For major procedures I would replace fibrinogen with fresh frozen plasma (alternatively fibrinogen concentrate) and use antifibrinolytic therapy, with the length of treatment depending on the extent of the procedure. This approach should be modified going forward based on her response to treatment and whether additional hemostatic abnormalities are found.

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This case is regarding a patient with T-cell large granular lymphocytic leukemia (T-LGL). A 73-year-old-asymptomatic female was found to have severe neutropenia (absolute neutrophil count <0.3 x 10⁹/L). On exam she did not have splenomegaly. A bone marrow biopsy showed diffuse extensive replacement of the marrow architecture with T-cell large granular lymphocytic leukemia. T-cell receptor gene rearrangement analyses were identified both beta- and gamma-positive clones. A metaphase karyotype done on the bone marrow aspirate was normal, and fluorescence in-situ hybridization testing for del6q was negative. Molecular testing identified a point mutation in STAT3 (Y640F).

Her T-LGL responded briefly (1 week) to prednisone. She was then treated with methotrexate (20 mg/week for 3 months) without improvement in her disease. Likewise, her disease did not respond to oral cyclophosphamide. She has now started cyclosporin. How would you recommend this patient be managed? Is there a role for tofacitinib? Are there any novel or clinical trial options?

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