Anna’s Story

Anna’s mother is from Russia and has been in the US for 9 years. Besides Anna there are 3 other children, one girl and two boys. These are her mother’s words.

Anna had been very healthy until just before her 4^th birthday. She complained of back pain, so we took her to the doctor. He told us she might have bladder infection. Then, 2 day's later they called us and told us there was no bladder infection, perhaps she had cramps. The pain continued and she started getting night-time nose bleeds. Doctors told me, perhaps her nose was dry. She started turning yellow, more nose bleeds, her appetite disappeared and she drank almost nothing. I went away for a weekend and when I returned her skin was really yellow. The doctor insisted I wait until Monday to be seen but I took her to ER, where they thought she has Leukemia. She was transferred OHSU hospital. It took them 2 days to make a diagnosis. They started blood transfusions and put her on BP medication. They tried to get her to drink lots of water. She was hospitalized for 4 weeks, were released on medication for BP and instructed to monitor her BP everyday. We were home for 3 days, returned for a check up, but with a BP of 150/100 she was admitted. They tried to maintain her BP at safe levels and decided to do a kidney biopsy which caused internal bleeding. They give her FFP which succeeded in stopping the bleeding. We stayed there for another 2-3 weeks in order to control her BP. Then 2 days before her 4th birthday, we went home. She was so excited. We have been on BP medication for 6 month. She still gets back pains; as her mother it is really hard to see her go thru this. To hear her plead for relief from pain and know there nothing that can be done, as unbearable.

Hemostasis & Thrombosis Staff Note

Background: I was asked by Dr. Robert Mak of Nephrology to see this patient on 5/14/02 re: her atypical Hemolytic Uremic Syndrome (HUS) for which she was first hospitalized at OHSU from 4/15/02 - 4/27/02. She was subsequently readmitted (5/4/02 - 5/19/02) due to bleeding post outpatient renal biopsy, which was done for persistent proteinuria, and remained admitted due to a positive blood culture (coagulase negative staph from L arm PICC line 5/13) and difficulties controlling her bp. Dr. Greg Thomas of Peds Hematology, who I believe saw her previously and arranged the Factor B and H testing on her (still pending) was away at the time I saw her. I have reviewed her history, including her transfusion history and lab findings in the LCR and in her chart, and have spoken with her mother. I have also examined her blood smear, reviewed her recent renal biopsy with Dr. Don Houghton, and ordered some blood work (notably a crossed immunoelectropheresis for von Willebrand multimers), which was only completed today as the first sample was unsatisfactory and had to be redrawn.

Basically her history is well documented in the LCR. She is almost 4 years old with minimal past medical history until her recent admission to OHSU for treatment of atypical HUS. There is no known family history of any TTP/HUS syndrome. She has an older brother who is almost 6 and a younger brother who is 18 months old--both well, although the older brother is a bit tired, according to the mother. Her mother says she thinks the patient had been unusually tired for about a year before her admission this April, and had also had occasional nosebleeds but was otherwise well. More specifically there was no history of abnormal bruising or CNS symptoms and her appetite was good until about 2-3 weeks prior to that admission at which point she developed progressive malaise and jaundice. There does not appear to have been a clear diarrheal prodrome, and certainly there was no bloody diarrhea. Stool culture was negative for E coli 0157:H7 infection. On admission on 4/15/02 the Hct was 12.6 with a platelet count of 27 (minimum was 23), an LD of 2002 (maximum was 2881) and a Cr of 1.2 (maximum was 1.7). Abundant schistocytes were present on the peripheral smear, haptoglobin was <15, and the PT and PTT were normal. There was no serological evidence of an underlying immunological (lupus, schleroderma, etc) or infectious etiology and C3 and C4 levels were normal. A bone marrow aspirate done 4/15 was consistent with microangiopathic hemolysis and showed severe anemia and thrombocytopenia with increased schistocytes and polychromasia with increased and left-shifted erythropoiesis and adequate megakaryocytes.

She was treated supportively for her atypical HUS during that hospitalization and received 8 red cell transfusions (total 4 1/2 units) between 4/15 and 4/27. She did not receive plasma apart from the small amounts in the red cells (I calculate this would have been between 112 and 225 cc total). She never required dialysis. At the time of discharge on 4/27 the Hct was 22.8, platelets had increased from their minimum 23 to 135, LD had decreased from a maximum of 2881 to 940, and Cr was 1.1. She received another unit of red cells on 5/4/02 when she bled post renal biopsy. At that time Hct was 17.6, platelets were 93, and LD was 666. Hct rose post transfusion to 27.8 the next day, but had gradually declined to 17.4 by 5/8 at which time she received additional red cells as well as a unit of plasma on 5/9. On this her Hct rose to 28.0 and it has remained in the low-to-mid-20 since. Prior to her receiving the plasma her platelets had risen spontaneously from 95 to 230, and her LD had declined from 666 to 518. Haptos on 5/9 were still < 15, and on examination of her peripheral smear on 5/14 I counted 1-2 schistocytes/hpf. However her platelets were up to 304, and her LD down to 366 at that time.

Assessment/Discussion: Atypical hemolytic uremic syndrome. Of particular concern is the issue of chronicity--both with respect to how long the schistocytic hemolytic process with associated renal damage was going on before it came to medical attention and with respect to whether it is likely to recur. The lack of an acute diarrheal prodrome or of an inciting infectious agent is worrisome in this regard. By history there appears to have been a prodrome of at least 2-3 weeks; the renal biopsy suggests a possible chronicity of weeks to months with evidence of chronic endothelial cell damage. Although she recovered without plasma therapy, I am concerned that she may have a familial form of TTP/HUS overlap syndrome. Certainly her age at presentation, clinical and laboratory findings, failure to find an alternative etiology for her disease, the evidence for a chronic process on her renal biopsy would be consistent with this.

The etiology of the familial relapsing forms of TTP/HUS was recently elucidated (Levy GG et al, Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura, Nature 413: 488, October 2001) by studies on 4 families with this problem. It appears to be lack of a VWF-cleaving protease present in normal plasma and coded for by an ADAMTS 13 metalloproteinase. As a result of a variety of mutations in the gene sequence for this protease, functional protease is not produced, and unusually large vWF multimers, (ul-vWF multimers), probably originating from endothelial cells, circulate uncleaved during convalescent intervals when they are detectable in the plasma. During relapses they are absent and are believed to be the agent agglutinating platelets. Should this patient prove to have this defect it would have both prognostic and therapeutic implications. Prognostic in that the disease would tend to relapse. Therapeutic in that most such cases are plasma responsive, as normal plasma supplies the missing protease. While in Canada I was actually involved in treating a family of 4 brothers with this defect (now diagnosed retrospectively) who had presented between the ages of 2 and 12 with a spectrum of pathologies in the TTP/HUS spectrum ranging from a CVA with no associated renal symptoms to recurrent bouts of renal insufficiency with no CNS symptoms. All were plasma-responsive.

Suggest: The OHSU Hemostasis & Thrombosis Lab has just finished running a crossed immunoelectropheresis (XIE) on Anna's plasma to look for ul-vWF multimers which normally show up as a pointed shoulder on the high molecular weight side of an otherwise symmetrical "hump" of normal VWF multimers of varying sizes. Unhappily, the results were not definitive, for while Anna did appear to have a largely normal vWF multimeric pattern, there appeared to be a bulge on the high-molecular weight side of the curve, and the presence of some ul-VWF multimers could therefore not be excluded with confidence. Due to this, I have sent off a sample of her plasma for vWF multimeric analysis to the Blood Center of SE Wisconsin. They do multimeric analysis by an alternate and more sensitive technology.

The Blood Center of SE Wisconsin also does a new assay for the vWF-cleaving protease, and I have requested that they assay Anna's plasma for this as well. Presence of normal levels of protease activity would weigh against a diagnosis of familial TTP/HUS and low or absent levels would support this diagnosis. However, these findings cannot be considered absolute as this assay is technically difficult and appears to be influenced by a number of other disease states, and a number of investigators have recently raised issues about its sensitivity and specificity regarding diagnosis and treatment of TTP/HUS (Kelton JG, Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: will recent insight into pathogenesis translate into better outcome?, Transfusion 42: 388, April 2002).

I also ordered a Factor V Leiden as there is some recent evidence that this is a genetic risk factor of thrombotic microangiopathy in patients with normal VWF-cleaving protease activity (Raife TJ, Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor-cleaving protease activity, Blood 99: 437, January 15, 2002).

Good luck to all.

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