DDAVP

CHIEF COMPLAINT:

Abdominal pain, hematuria

HISTORY OF PRESENT ILLNESS

This 66 year old previously healthy man developed symptoms of fatigue, malaise, diffuse myalgias, chills, and cough productive of yellowish-green and occasionally blood-tinged sputum nine days prior to admission. After two days of symptoms, he presented to an outside urgent care center where he was diagnosed with pneumonia and given a prescription for clarithromycin. In the following week, he noted a change in the color of his urine - from orange to black, then red-and noted that it was deep red on the night prior to admission. He did not complain of dysuria. That same night, he developed crampy bilateral lower abdominal and flank pain, intermittent and severe, that persisted through the clay of admission, prompting his visit to TMH Emergency Room. A Foley catheter was placed in the ER, and a 600cc post-void residual (bloody, without clots) was obtained.

REVIEW OF SYSTEMS:

In the three days prior to admission, the patient felt somewhat fatigued and lightheaded. He otherwise denied any constitutional, cardiovascular, pulmonary, gastrointestinal, genitourinary, neurologic, dermatologie, musculoskeletal, endocrine, hematologie, or allergic problems, other than those listed above.

PAST MEDICAL HISTORY:

Tonsillectomy and adenoidectomy performed at age 13, without bleeding or other complications.

MEDICATIONS:

Clarithromycin 500 mg PO BID for one week. Aspirin prn (rarely taken)

ALLERGIES:

No known drug allergies.

SOCIAL HISTORY:

The patient smoked one pack of cigarettes per day for 45 years. He denied alcohol or drug use. The patient is married, and works as an iron worker and welder.

FAMILY HISTORY:

There is a positive family history of malignancy-his father had lung cancer, his mother had bladder cancer, and his brother had an unspecified brain malignancy.

PHYSICAL EXAM: Temp=37.5°C BP=100/49 HR=75(reg.) RR=12 SaO^sub 2^= 98%/RA

General: Well nourished, well developed man, appearing his stated age, in no apparent distress.

HEENT: Anicteric, EOMI/PERRL. Oropharynx clear and without lesions, mucous membranes moist.

Neck: Supple, without JVD or palpable lymphadenopathy.

CV System: Regular rhythm, no audible murmurs, gallops, or rubs.

Lungs: CTA bilaterally, without wheezes or rales.

Abd: Soft, NT/ND, +BS, no organomegaly. Mild left flank tenderness elicited with palpation.

Extr: Warm, well-perfused, no edema.

Neuro: Normal.

Derm: Warm, dry, no rashes. No petechiae or purpura; one ecchymosis present on the back.

LABS:

CBC:

WBC count: 14,200 per mL

Hemoglobin: 8.4 g/dL

Hematocrit: 25%

Platelet count: 367,000 per mL

Differential: 88% Granulocytes/0% band Forms/7 Lymphnocytes/4 Monocytes

Chem 7:

Sodium: 136 mmol/L

Potassium: 4.3 mmol/L

Chloride: 103 mmol/L

Bicarbonate: 36 mmol/L

BUN: 25 mg/dL

Creatinine: 1.7 mg/dL

Glucose: 121 mg/dL

Coagulation panel:

PT: 14.2 seconds

INR: 1.3

PTT 50.0 seconds

Liver chemistry: Within Normal Limits (WNL)

Amylase/lipsae: WNL

Urinalysis showed packed RBC's and 15 WBCs, 500 protein, few bacteria and mucous present.

CXR showed a RML infiltrate

CT of chest, abdomen, and pelvis was performed to evaluate the patient's abdominal pain and urinary obstruction

CT chest: RML consolidation with an air-bronchogram present

CT abdomen/pelvis: Moderate hydrophrosis with obstruction on the left, with associated soft tissue prominence along the renal pelvis/sinus bilaterally (most consistent with either blood or an inflammatory/infectious process; less likely to represent malignancy).

HOSPITAL COURSE:

The patient was admitted to the medical service with the diagnoses of hematuria and RML pneumonia. He was started on ceftriaxone and azithromycin for community-acquired pneumonia, and continuous bladder irrigation for the hematuria. Urology was consulted due to the hydronephrosis and other CT scan findings, but cystoscopy could not be performed at the time due to the coagulopathy seen on initial laboratory testing. The patient was given 2 mg of oral phytonadione (vitamin K) with minimal effect on the partial thromboplastin time (PTT). To determine if the patient had a coagulation factor deficiency or if a factor inhibitor were present, 1:1 mixing studies were done -the pretest mixed PTT was 33.3, and posttest was 39.8 -consistent with factor inhibitor presence. Levels of coagulation factors V, VII, VIII, IX, X, XI, and XII were checked, with the only abnormality being a low factor VIII level of 8%. A factor VIII inhibitor assay was positive (quantitatively reported at 3.4 Bethesda Units, with the normal range of 0.0 to 0.9 BU). Prednisone at 1 mg/kg/day was started, as well as administration of factor VIII concentrate with a 3000 unit bolus followed by continuous infusion at 12 units/kg/hour. The goal of factor VIII therapy was serum factor level of > 50% and a PTT of

His hematuria persisted for several days before resolving as the rate of factor VIII infusion was titrated upwards and ddAVP and IVIG were administered. Renal failure resolved with the continuous bladder irrigation. The patient developed hyponatremia, presumably as a result of the ddAVP therapy, which resolved with free water restriction. When factor VIII infusion was discontinued, factor levels dropped to 15% with a subsequent rise in the PTT to 46.1 and recurrence of hematuria. Factor VIII infusion was restarted with good clinical result, and cyclophosphade therapy was begun. The factor infusion was then successfully tapered completely, and the patient discharged to home on oral immunosuppressant therapy with outpatient urologie followup.

DIAGNOSIS:

Coagulopathy due to presence of factor VIII inhibitor

Acute renal failure from obstruction

Community acquired pneumonia, right middle lobe

DISCUSSION:

1. How does one develop an inhibitor to a coagulation factor (so-called 'acquired hemophilia')? How commonly does this occur?

Acquired hemophilia is very uncommon, with an estimated incidence of one case per million persons per year. Most patients developing the condition are older than age 50. The pathophysiology involves development of an autoantibody to a coagulation factor, with factor VIII being by far the most common antigenic target. Inhibitors to factors V, VII, IX, X, XI, and XIII have also been described. The antibody is generally of the IgG class, and interferes with the normal function of the coagulation factor it is directed at. It may also increase its rate of clearance from the serum causing a deficiency in its concentration.

There is a relatively high frequency (approximately 25%) of development of factor VIII inhibitors among patients born with hemophilia A (inherited factor VIII deficiency) who have received factor VIII infusions. However, the etiology by which autoantibodies to factor VIII are developed in non-hemophiliacs, such as this patient, is not clear. Epidemiologic studies have shown associations between this entity and other illnesses/ conditions in almost half of cases. Most common associations are that of underlying cancer (particularly hematologic malignancy, but also solid tumors), certain medications (e.g. penicillins, sulfa drugs, chloramphenicol, and antiepileptic agents), the early post-partum period (usually in the first 4 months after delivery, although cases during pregnancy have also been seen), and collagen vascular diseases (e.g. rheumatoid arthritis and lupus).

Bossi P, et al. Acquired hemophilia due to factor VIII inhibitors in 34 patients. Amer J Med 1988;105:400-8.

Hay CRM, et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctor's Organization (UKHCDO). Br J Hematol 2000; 111:78-90.

Delgado J, et al. Acquired hemophilia: Review and meta-analysis focused on therapy and prognostic factors. Br J Hematol 2003; 121:21-35.

2. How do disorders of coagulation usually present? How is the diagnosis made?

Deficiencies in platelet number and function generally present with petechiae/non-palpable purpura and superficial skin or mucosal bleeding (e.g. epistaxis, oropharyngeal bleeding) directly following trauma. However, disorders of coagulation generally result in delayed bleeding following trauma, and development of ecchymoses, hematomas, and arthroses; common sites for bleeding include the GI and GU tracts as well as the CNS. Bleeding in patients with acquired hemophilia tends to be severe, with 87% of patients developing "major bleeds" (those requiring transfusion or other intervention), and there is an associated mortality rate between 14 and 22%.

One clue that a patient such as the one presented here may have developed acquired hemophilia is that the bleeding disorder is associated with a normal prothrombin time and a prolonged partial thromboplastin time, as the defect most commonly lies in the intrinsic pathway of the coagulation cascade. It is important to first rule out the presence of heparin in the blood sample as a cause for this lab abnormality. Whereas a patient with an inherited factor deficiency should see correction of the PTT during a 1:1 mixing study with normal serum, a patient with acquired hemophilia will not have such a correction as the inhibitor will affect factor in both serum samples (correction may occur immediately after mixing, but the PTT will rise within 1-2 hours of incubation at body temperature). Factor levels can be checked to see which factor the autoantibody is directed at, with factor VIII being the most common. The Bethesda Assay tests for presence and quantity of factor VIII inhibitor in a serum sample.

Bossi, P et al op. cit.

Hay CRM, et al. op. cit.

Delgado J, et al. op. cit.

3. What are the treatment options in someone who develops an acquired inhibitor of Factor VIII?

Patients with acquired hemophilia infrequently remit spontaneously (about 36% of cases), and treatment is usually initiated since patients may have a major bleeding event before remission occurs. The primary goals in therapy are to stop the patient's bleeding and to stop production of factor inhibitor. Hemostasis can be acutely achieved by administration of factor VIII concentrates and ddAVP (desmopressin; which acts by increasing release of endogenous factor VIII and vWF several-fold). Use of recombinant factor VIIa has also been used effectively, which largely drives coagulation through the extrinsic pathway. Eradication of factor inhibitor is most effectively achieved through use of immunosupprcssion therapy with a combination of prednisone and cyclophosphamidc, which results in a 60100% success rate of eliminating inhibitor production. There is some evidence for the utility of high-dose IVIG and also for plasmapheresis, although immunosuppressants tend to contribute more significantly to clinical improvement and outcome. Recent evidence points to the possibility for rituximab (Rituxan, or anti-CD20 which is directed at B-lymphocytes) as a treatment modality as well.

BOSSI P, et al. op. cit.

Hay CRM, et al. op. cit.

Delgado J, et al. op. cit.

4. Does hematuria in the presence of coagulopathy require further urologic investigation?

There have been no studies evaluating hematuria in the setting of coagulopathy that is not associated with anticoagulation therapy. Consensus opinion from prospective studies investigating hematuria in the setting of therapeutic anticoagulation at recommended levels, is that use of this therapy alone does not predispose patients to microscopic or gross hematuria. Presence of two or more episodes of microscopic hematuria in the patients evaluated, whether or not on anti-coagulation, was associated with underlying genitourinary disease in 81% of cases. Malignancy is present in about 2.4% of patients older than 50 years old presenting with microscopic hematuria; this number is significantly lower in younger patients. Once the patient presented here has completely stabilized from the standpoint of his bleeding disorder and renal failure, an outpatient urologie workup will be undertaken.

Culclasure TF, et al. The significance of hematuria in the anticoagulated patient. Arch Intern Med 1994; 154:649-52.

Van Savage JG, et al. Anticoagulant associated hematuria: A prospective study. J Urol 1995; 153:1594-6.

JOHN E. SNYDER, MS, MD

CORRESPONDENCE:

John E. Snyder, MD, MS

Phone: (401) 350-9556

Email: JSnyder@lifespan.org

Copyright Rhode Island Medical Society Feb 2004
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