SYMPTOMS TO DIAGNOSIS GREGORY W. RUTECKI, MD, Section Editor TAHANI ATIEH, DO ALAN LICHTIN, MD Department of Internal Medicine, Cleveland Department of Hematologic Oncology and Blood Clinic; Clinical Instructor, Cleveland Clinic Lerner Disorders, Cleveland Clinic; Associate Professor, College of Medicine of Case Western Reserve Cleveland Clinic Lerner College of Medicine of Case University, Cleveland, OH Western Reserve University, Cleveland, OH

An unusual cause of bruising

61-year-old woman presented to our can prolong the aPTT but is usually associated A hematology clinic for evaluation of mul- with thrombosis rather than bleeding.1 The tiple episodes of bruising. The fi rst episode oc- differential diagnoses for this and other pat- curred 8 months earlier, when she developed a terns of assay abnormalities are large bruise after water skiing. Two months be- listed in Table 3. fore coming to us, she went to her local emer- gency room because of new bruising and was ■ EVALUATION FOR AN ISOLATED found to have a prolonged activated partial PROLONGED aPTT thromboplastin time (aPTT) of 60 seconds (reference range 23.3–34.9), but she under- What is the appropriate next test to evalu- went no further testing at that time. 1ate this patient’s prolonged aPTT? At presentation to our clinic, she reported □ panel having no fevers, night sweats, unintentional □ Coagulation factor levels weight loss, swollen lymph nodes, joint pain, □ Mixing studies rashes, mouth sores, nosebleeds, or blood in □ Bethesda assay the urine or stool. Her history was notable only for hypothyroidism, which was diagnosed Mixing studies in the previous year. Her medications includ- Once a prolonged aPTT is confi rmed, the ap- Factor VIII ed levothyroxine, vitamin D , and vitamin C. 3 propriate next step is a mixing study. This in- inhibitor She had been taking a baby aspirin daily for volves mixing the patient’s plasma with pooled the past 10 years but had stopped 1 month ear- normal plasma in a 1-to-1 ratio, then repeat- is the most lier because of the bruising. ing the aPTT test immediately, and again after common On examination, she had a single small 1 hour of incubation at 37°C. If the patient factor inhibitor hematoma on her right thigh. She had no ec- does not have enough of one of the coagula- chymoses, petechiae, or adenopathy, and her tion factors, the aPTT immediately returns to spleen was nonpalpable. the normal range when plasma is mixed with Ten years earlier she had been evaluated the pooled plasma because the pooled plasma for a possible transient ischemic attack; labo- contains the factor that is lacking. If this hap- ratory results at that time included a normal pens, then factor assays should be performed aPTT of 25.1 seconds and a normal factor VIII to identify the defi cient factor.1 level of 153% (reference range 50%–173%). Various that inhibit coagulation Laboratory testing at our clinic showed a factors can also affect the aPTT. There are 2 normal complete blood cell count (Table 1); general types: immediate-acting and delayed. the coagulation factor assay confi rmed that With an immediate-acting inhibitor, the her aPTT was elevated (prolonged), but other aPTT does not correct into the normal range values were normal (Table 2). with initial mixing. Immediate-acting inhibi- Causes of an isolated prolonged aPTT in- tors are often seen together with lupus antico- clude medications (eg, ), inherited agulants, which are nonspecifi c phospholipid factor defi ciencies, acquired inhibitors of co- antibodies. If an immediate-acting inhibitor agulation factors, and inherited or acquired is detected, further testing should focus on von Willebrand disease. evaluation for lupus anticoagulant, including doi:10.3949/ccjm.86a.18119 phospholipid-dependency studies.

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the case of a factor VIII inhibitor, serial dilu- TABLE 1 tions of patient plasma are incubated at 37°C Our patient’s complete blood cell count results with pooled normal plasma for 2 hours, then factor VIII activity is measured. The recipro- Test Valuea Reference range cal dilution of patient plasma that results in White blood cell count 8.91 × 109/L 3.70–11.00 50% of factor VIII activity in the control plas- ma is 1 Bethesda unit (BU). The stronger the Red blood cell count 5.16 × 1012/L 3.90–5.20 inhibitor in the patient’s sample, the more di- Hemoglobin 14.6 g/dL 11.5–15.5 lutions are required to measure factor VIII ac- tivity, and thus the higher the Bethesda titer.3 Hematocrit 44.5% 36.0%–46.0% Case continued: count 251 × 109/L 150–400 Results of mixing and Bethesda studies Neutrophils 60.6% 40%–60% Results of the mixing study (Table 4) showed an initial correction of the aPTT in a 1-to-1 Lymphocytes 34.1% 20%–40% mix, but after 1 hour of incubation, the aPTT Monocytes 4.7% 2%–8% was again prolonged at 42 seconds (reference range < 37.3). Further testing revealed very Eosinophils 0.4% 1%–4% low levels of factor VIII (< 1%), and the pres- ence of a factor VIII inhibitor, quantifi ed at Basophils 0.2% 0.5%–1% 5.8 BU (reference range < 0.5) (Table 5). Ad- a Abnormal results are shown in bold. ditional coagulation tests, including von Wil- lebrand factor testing and a lupus anticoagula- tion panel, were negative. TABLE 2 Our patient’s coagulation test results ■ FACTOR VIII INHIBITOR EVALUATION Test Valuea Reference range What is the most likely underlying condi- 2tion associated with this patient’s factor 11.0 seconds 8.4–13.0 VIII inhibitor? International normalized 1.0 0.8–1.2 □ Autoimmune disease ratio □ Malignancy Activated partial thrombo- 46.7 seconds 23.0–32.4 □ A medication plastin time □ Unknown (idiopathic) a Abnormal results are shown in bold. Acquired hemophilia A (AHA) is a rare disor- der caused by autoantibodies against factor VIII. Its estimated incidence is about 1 person per mil- With a delayed inhibitor, the aPTT ini- lion per year.4 It usually presents as unexplained tially comes down, but subsequently goes back bruising or bleeding and is only rarely diagnosed up after incubation. Acquired factor VIII in- by an incidentally noted prolonged aPTT. The hibitor is a classic delayed-type inhibitor and severity of bleeding is variable and can include is also the most common factor inhibitor.1 If a subcutaneous, soft-tissue, retroperitoneal, gas- delayed-acting inhibitor is found, specifi c in- trointestinal, and intracranial hemorrhage.5 trinsic factor levels should be measured (fac- tors VIII, IX, XI, and XII),2 and testing should AHA is considered idiopathic in more than half of cases. A study based on a European regis- also be done for lupus anticoagulant, as these 5 6 inhibitors may occur together. try of 501 patients with AHA and a UK study of 172 patients found no underlying disease in Bethesda assay 52% and 65% of patients, respectively. For pa- If factor levels are decreased, a Bethesda assay tients with an identifi ed cause, the most com- should be performed to differentiate a specifi c mon causes were malignancy (12%5 and 15%6) factor inhibitor from a lupus anticoagulant. In and autoimmune disease (12%5 and 17%6).

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Drugs have rarely been associated with TABLE 3 factor VIII inhibitors. Such occurrences have been reported with interferon, blood thinners, Differential diagnoses antibiotics, and psychiatric medications, but associated with coagulation assay results no study yet has indicated causation. How- ever, patients with congenital hemophilia A Prolonged prothrombin time (PT), normal activated partial thromboplastin time (aPTT) treated with factor VIII preparations have about a 15% chance of developing factor VIII Factor VII defi ciency or factor VII inhibitor inhibitors. In this setting, inhibitors develop in response to recombinant factor VIII expo- defi ciency sure, unlike the autoimmune phenomena seen use in AHA. Disseminated intravascular coagulation ■ TREATMENT OF ACQUIRED HEMOPHILIA A Normal PT, prolonged aPTT What is the most appropriate treatment Defi ciency of intrinsic pathway factors (VIII, IX, XI, XII) or inhibitors 3for AHA? of these clotting factors □ Desmopressin and prednisone von Willebrand disease (if factor VIII is very low) □ Recombinant porcine factor VIII and Heparin use prednisone plus cyclophosphamide Lupus anticoagulant (usually associated with thrombosis instead □ Recombinant factor VIIa and of bleeding) rituximab □ Any of the above Prolonged PT and aPTT Any of the above regimens can be used. In gen- Defi ciency of common pathway factors (II, V, X, or fi brinogen) eral, treatment of AHA has two purposes: to Severe liver disease stop acute hemorrhage, and to reduce the level of factor VIII inhibitor. No standard treatment Vitamin K defi ciency guidelines are available; evidence of the effec- Warfarin use tiveness of different drugs is based largely on Disseminated intravascular coagulation 3 data on congenital hemophilia A. Heparin overdose Acute treatment to stop bleeding Initial treatment of AHA often focuses on Normal PT and aPTT with bleeding stopping an acute hemorrhage by either rais- Platelet dysfunction (acquired or congenital) ing circulating levels of factor VIII or bypass- von Willebrand disease (if factor VIII is mildly decreased) ing it in the coagulation cascade. Scurvy Desmopressin can temporarily raise factor VIII levels, but it is often ineffective in AHA Ehlers-Danlos syndrome unless the patient has very low inhibitor titers.3 Hereditary hemorrhagic telangiectasia Factor VIII concentrate (human or recom- Factor XIII defi ciency binant porcine factor VIII) may be effective Hyperfi brinolysis in patients with low inhibitor titers (< 5 BU). Higher doses are often required than those used in congenital hemophilia A. Factor VIII passing activity), or recombinant factor VIIa concentrate is usually combined with immu- is available. These agents bypass factor VIII in nosuppressive treatment to lower the factor the clotting cascade. VIII inhibitor level (described below).3 If these methods are ineffective or the pa- Immunosuppression tient has high inhibitor titers (> 5 BU), ac- to reduce factor VIII inhibitor tivated prothrombin complex concentrates, Immunosuppressive agents are the mainstay of known as FEIBA (factor eight inhibitor by- AHA treatment to lower the inhibitor level.

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TABLE 4 bleeding, 16 died of causes related to immu- nosuppression, and 45 died of causes related to Our patient’s mixing study results the underlying condition.5 In the UK registry of 172 patients, 13 patients died of bleeding, Reference and 12 died of sepsis related to immunosup- Test Valuea range pression.6 Activated partial thromboplastin 61.2 seconds 24.4–33.4 The factor VIII level and inhibitor titer time (aPTT) screen are not necessarily useful in stratifying bleed- ing risk, as severe and fatal bleeding can occur Immediate aPTT 1:1 mix 33.1 seconds < 33.5 at variable levels and patients remain at risk of Incubated aPTT 1:1 mix 42.2 seconds < 37.3 bleeding as long as the inhibitor persists.6,7

a Abnormal results are shown in bold. ■ CASE CONTINUED: TREATMENT, LYMPHOCYTOSIS TABLE 5 The patient was started on 60 mg daily of prednisone, resulting in a decrease in her Further studies aPTT, increase in factor VIII level, and lower Reference Bethesda titer. On a return visit, her absolute Test Valuea range lymphocyte count was 7.04 × 109/L (reference Factor VIII:C assay 1% 50%–173% range 1.0–4.0). She reported no fevers, chills, or recent infections. Bethesada assay 5.8 Bethesda < 0.5 units ■ EVALUATING LYMPHOCYTOSIS a Abnormal results are shown in bold. Lymphocytosis is defi ned in most laborato- ries as an absolute lymphocyte count greater Regimens vary. A 2003 meta-analysis4 in- than 4.0 × 109/L for adults. Normally, T cells The stronger cluding 249 patients found that prednisone (CD3+) make up 60% to 80% of lymphocytes, alone resulted in complete response in about B cells (CD20+) 10% to 20%, and natural the inhibitor 30% of patients, and the addition of cyclo- killer (NK) cells (CD3–, CD56+) 5% to 10%. in the patient’s phosphamide increased the response rate to Lymphocytosis is usually caused by infection, sample, 60% to 100%. High-dose intravenous immu- but it can have other causes, including malig- noglobulin led to confl icting results. Conclu- nancy. the higher sions were limited by the variability of dosing Peripheral blood smear. If there is no clear the Bethesda and duration in treatment regimens among cause of lymphocytosis, a peripheral blood smear can be used to assess lymphocyte mor- titer the 20 different studies included. An analysis of 331 patients in the European phology, providing clues to the underlying eti- Acquired Hemophilia Registry (EACH2)7 ology. For example, atypical lymphocytes are found that steroids alone produced remission often seen in infectious mononucleosis, while in 48% of patients, while steroids combined “smudge” lymphocytes are characteristic of with cyclophosphamide raised the rate to chronic lymphocytic leukemia. If a peripheral smear shows abnormal morphology, further 70%. Rituximab-based regimens were suc- workup should include establishing whether cessful in 59% but required twice as long to the lymphocytes are polyclonal or clonal.8 achieve remission as steroid or cyclophospha- mide-based regimens. No benefi t was noted ■ CASE CONTINUED: from intravenous immunoglobulin. LARGE GRANULAR LYMPHOCYTES Risks of disease and treatment On the patient’s peripheral smear, 54% of lym- AHA is associated with signifi cant risk of mor- phocytes were large lymphocytes with mod- bidity and death related to bleeding, compli- erate amounts of pale cytoplasm fi lled with cations of treatment, and underlying disease. azurophilic granules, consistent with large In EACH2, 16 of the 331 patients died of granular lymphocytes (LGLs) (Figure 1).

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What is the next step to evaluate the pa- 4tient’s lymphocytosis? □ Bone marrow biopsy □ Karyotype analysis □ Flow cytometry □ Fluorescence in situ hybridization Flow cytometry with V-beta analysis is the best fi rst test to determine the cause of lym- phocytosis after review of the peripheral smear. For persistent lymphocytosis, fl ow cy- tometry should be done even if a peripheral smear shows normal lymphocyte morphology. Most T cells possess receptors composed of alpha and beta chains, each encoded by variable (V), diversity (D), joining (J), and constant (C) gene segments. The V, D, and J segments un- Figure 1. A large granular lymphocyte. dergo rearrangement during T-cell development Image provided by Karl Theil, MD, Clinical Pathology, Cleveland Clinic. in the thymus based on antigen exposure, pro- ducing a diverse T-cell receptor population. creased CD7 expression. T-cell V-beta analysis In a polyclonal population of lymphocytes, demonstrated an expansion of the V-beta 17 the T-cell receptors have a variety of gene seg- family, and T-cell receptor gene analysis with ment arrangements, indicating normal T-cell polymerase chain reaction confi rmed the pres- development. But in a clonal population of ence of a clonal rearrangement. lymphocytes, the T-cell receptors have a sin- gle identical gene segment arrangement, indi- ■ LGL LEUKEMIA: cating they all originated from a single clone.9 CLASSIFICATION AND MANAGEMENT Lymphocytosis in response to an infection is AHA usually LGLs normally account for 10% to 15% of typically polyclonal, while malignant lympho- peripheral mononuclear cells.11 LGL leukemia presents cytosis is clonal. is caused by a clonal population of cytotoxic Monoclonal antibodies against many of as unexplained T cells or NK cells and involves an increased the variable regions of the beta chain (V-beta) bruising number of LGLs (usually > 2 × 109/L).10 of T-cell receptors have been developed, en- LGL leukemia is divided into 3 categories or bleeding abling fl ow cytometry to establish clonality. according to the most recent World Health T-cell receptor gene rearrangement studies Organization classifi cation10,12: can also be performed using polymerase chain T-cell LGL leukemia (about 85% of cases) reaction and Southern blot techniques.9 is considered indolent but can cause signifi - Karyotype analysis is usually not performed cant cytopenias and is often associated with for the fi nding of LGLs, because most leuke- 13 mias (eg, T-cell and NK-cell leukemias) have autoimmune disease. Cells usually express a cells with a normal karyotype. CD3+, CD8+, CD16+, and CD57+ pheno- Bone marrow biopsy is invasive and usu- type. Survival is about 70% at 10 years. ally not required to evaluate LGLs. It can be Chronic NK-cell lymphocytosis (about especially risky for a patient with a bleeding 10%) also tends to have an indolent course disorder such as a factor VIII inhibitor.10 with cytopenia and an autoimmune associa- tion, and with a similar prognosis to T-cell Case continued: LGL leukemia. Cells express a CD3–, CD16+, Flow cytometry confi rms clonality and CD56+ phenotype. Subsequent fl ow cytometry found that more Aggressive NK-cell LGL leukemia (about than 50% of the patient’s lymphocytes were 5%) is associated with Epstein-Barr virus infec- LGLs that co-expressed CD3+, CD8+, tion and occurs in younger patients. It is char- CD56+, and CD57+, with aberrantly de- acterized by severe cytopenias, “B symptoms”

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Factor VIII inhibitor response to treatment

Figure 2. The patient’s clinical course: factor VIII inhibitor response to treatment.

(ie, fever, night sweats, weight loss), and has a for 4 weekly doses, resulting in normalization very poor prognosis. Like chronic NK-cell lym- of aPTT and factor VIII level with undetect- phocytosis, cells express a CD3–, CD16+, and able Bethesda titers (Figure 2). Immuno- CD56+ phenotype. Fas (CD95) and Fas-ligand 10,13 ■ suppressive (CD178) are strongly expressed. LGL LEUKEMIA Most cases of LGL leukemia can be diag- AND AUTOIMMUNE DISEASE agents are nosed on the basis of classic morphology on Patients with LGL leukemia commonly have the mainstay peripheral blood smear and evidence of clon- or develop autoimmune conditions. Immune- of treatment ality on fl ow cytometry or gene rearrangement mediated cytopenias including pure red cell studies. T-cell receptor gene studies cannot be aplasia, aplastic anemia, and autoimmune he- for AHA used to establish clonality in the NK subtypes, molytic anemias can occur. Neutropenia, the as NK cells do not express T-cell receptors.11 most common cytopenia in LGL leukemia, is Case continued: thought to be at least partly autoimmune, as Diagnosis, continued course the degree of neutropenia is often worse than In our patient, T-cell LGL leukemia was di- would be expected solely from bone-marrow infi ltration of LGL cells.10,14,15 agnosed on the basis of the peripheral smear, Rheumatoid arthritis is the most common fl ow cytometry results, and positive T-cell re- autoimmune condition associated with LGL ceptor gene studies for clonal rearrangement leukemia, with a reported incidence between in the T-cell receptor beta region. 11% and 36%.13–15 While her corticosteroid therapy was be- Felty syndrome (rheumatoid arthritis, ing tapered, her factor III inhibitor level in- splenomegaly, and neutropenia) is often asso- creased, and she had a small episode of bleed- ciated with LGL leukemia and is thought by ing, prompting the start of cyclophosphamide some to be part of the same disease process.15 50 mg daily with lower doses of prednisone. She then developed elevated liver , Treat with immunosuppressives if needed prompting discontinuation of cyclophospha- Indications for treating LGL leukemia include mide. Rituximab was started and continued the development of cytopenias and associ-

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ated autoimmune diseases. Immunosuppres- factor VIII inhibitor levels could be detected. sive agents, such as methotrexate, cyclophos- Given the strong association of LGL leu- phamide, and cyclosporine, are commonly kemia with autoimmune disease, it is tempting used.10,11,14 Most evidence of treatment effi cacy to believe that her factor VIII inhibitor was is from retrospective studies and case reports, somehow related to her malignancy, although with widely variable response rates that overall the exact mechanism remained unclear. The are around 50%.10 average age at diagnosis is 60 for LGL leuke- mia11 and over 70 for AHA,5,6 so advanced age ■ ACQUIRED HEMOPHILIA A may be the common denominator. Whether AND HEMATOLOGIC MALIGNANCY or not our patient will have recurrence of her A systematic review found 30 cases of AHA as- factor VIII inhibitor or the development of sociated with hematologic malignancies.16 The other autoimmune diseases with the persis- largest case series17 in this analysis had 8 patients, tence of her LGL leukemia remains to be seen. and included diagnoses of chronic lymphocytic At last follow-up, our patient was off all leukemia, erythroleukemia, myelofi brosis, mul- therapy and continued to have normal aPTT tiple myeloma, and myelodysplastic syndrome. and factor VIII levels. Repeat fl ow cytometry In 3 of these patients, the appearance of the in- after treatment of her factor VIII inhibitor hibitor preceded the diagnosis of the underlying showed persistence of a clonal T-cell popu- malignancy by an average of 3.5 months. In 1 lation, although reduced from 72% to 60%. patient with erythroleukemia and another with It may be that the 2 entities were unrelated, multiple myeloma, the activity of the inhibitor and the clonal T-cell population was simply could be clearly correlated with the underlying fl uctuating over time. This can be determined malignancy. In the other 6 patients, no associa- only with further observation. As the patient tion between the two could be made. had no symptoms from her LGL leukemia, she In the same series, complete resolution of continued to be observed without treatment. the inhibitor was related only to the level of ■ TAKE-HOME POINTS Bethesda titer present at diagnosis, with those AHA causes who achieved resolution having lower mean • The coagulation assay is key to initially as- 17 Bethesda titers. Similarly, in EACH2, lower sessing a bleeding abnormality; whether the signifi cant inhibitor Bethesda titers and higher factor prothrombin time and aPTT are normal or morbidity VIII levels at presentation were associated prolonged narrows the differential diagnosis and mortality with faster inhibitor eradication and normal- and determines next steps in evaluation. ization of factor VIII levels.7 from bleeding, 18 • Mixing studies can help pinpoint the re- Murphy et al described a 62-year-old sponsible defi cient factor. complications woman with Felty syndrome who developed • Acquired factor VIII defi ciency, also known a factor VIII inhibitor and was subsequently as AHA, may be caused by autoimmune of treatment, given a diagnosis of LGL leukemia. Treatment disease, malignancy, or medications, but it and underlying with immunosuppressive agents, including cy- is usually idiopathic. clophosphamide, azathioprine, and rituximab, disease • AHA treatment is focused on achieving he- successfully eradicated her factor VIII inhibi- mostasis and reducing factor VIII inhibitor. tor, although the LGL leukemia persisted. • Lymphocytosis should be evaluated with a Case conclusion: peripheral blood smear and fl ow cytometry Eradication of factor VIII inhibitor to determine if the population is polyclonal Our patient, similar to the patient described (associated with infection) or clonal (asso- by Murphy et al18 above, had eradication of ciated with malignancy). the factor VIII inhibitor despite persistence of • LGL leukemia is usually a chronic, indo- LGL leukemia. Between the time of diagnosis lent disease, although an uncommon sub- at our clinic, when she had 54% LGLs, and type has an aggressive course. eradication of the inhibitor 3 months later, • The association between AHA and LGL the LGL percentage ranged from 45% to 89%. leukemia is unclear, and both conditions No clear direct correlation between LGL and must be monitored and managed. ■

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■ REFERENCES 10. Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogen- esis to treatment. Blood 2017; 129(9):1082–1094. 1. Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an doi:10.1182/blood-2016-08-692590 abnormal prothrombin time, activated partial thromboplastin time, 11. Zhang D, Loughran TP Jr. Large granular lymphocytic leukemia: and bleeding time in adults. Mayo Clin Proc 2007; 82(7):864–873. molecular pathogenesis, clinical manifestations, and treatment. doi:10.4065/82.7.864 Hematology Am Soc Hematol Educ Program 2012; 2012:652–659. 2. Tcherniantchouk O, Laposata M, Marques MB. The isolated pro- doi:10.1182/asheducation-2012.1.652 longed PTT. Am J Hematol 2013; 88(1):82–85. doi:10.1002/ajh.23285 12. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the 3. Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiol- World Health Organization classifi cation of lymphoid neoplasms. ogy and treatment. Hematology Am Soc Hematol Educ Program Blood 2016; 127(20):2375–2390. doi:10.1182/blood-2016-01-643569 2006:432–437. doi:10.1182/asheducation-2006.1.432 13. Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and 4. Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. related disorders. Oncologist 2004; 9(3):247–258. pmid:15169980 Acquired : review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121(1):21–35. 14. Bockorny B, Dasanu CA. Autoimmune manifestations in large pmid:12670328 granular lymphocyte leukemia. Clin Lymphoma Myeloma Leuk 2012; 5. Knoebl P, Marco P, Baudo F, et al; EACH2 Registry Contributors. De- 12(6):400–405. doi:10.1016/j.clml.2012.06.006 mographic and clinical data in acquired hemophilia A: results from 15. Liu X, Loughran TP Jr. The spectrum of LGL and Felty’s syndrome. the European Acquired Haemophilia Registry (EACH2). J Thromb Curr Opin Hematol 2011; 18(4):254–259. Haemost 2012; 10(4):622–631. doi:10.1111/j.1538-7836.2012.04654.x doi:10.1097/MOH.0b013e32834760fb 6. Collins PW, Hirsch S, Baglin TP, et al; UK Haemophilia Centre Doc- 16. Franchini M, Lippi G. Acquired factor VIII inhibitors: a systematic tors’ Organisation. Acquired hemophilia A in the United Kingdom: review. J Thromb Thrombolysis 2011; 31(4):449–457. a 2-year national surveillance study by the United Kingdom Haemo- doi:10.1007/s11239-010-0529-6 philia Centre Doctors’ Organisation. Blood 2007; 109(5):1870–1877. 17. Sallah S, Nguyen NP, Abdallah JM, Hanrahan LR. Acquired hemo- doi:10.1182/blood-2006-06-029850 philia in patients with hematologic malignancies. Arch Pathol Lab 7. Collins P, Baudo F, Knoebl P, et al; EACH2 Registry Collaborators. Med 2000; 124(5):730–734. Immunosuppression for acquired hemophilia A: results from the 18. Murphy PW, Brett LK, Verla-Tebit E, Macik BG, Loughran TP Jr. European Acquired Haemophilia Registry (EACH2). Blood 2012; Acquired inhibitors to factor VIII and fi brinogen in the setting of 120(1):47–55. doi:10.1182/blood-2012-02-409185 T-cell large granular lymphocyte leukemia: a case report and review 8. George TI. Malignant or benign leukocytosis. Hematology Am Soc of the literature. Blood Coagul Fibrinolysis 2015; 26(2):211–213. Hematol Educ Program 2012; 2012:475–484. doi:10.1097/MBC.0000000000000209 doi:10.1182/asheducation-2012.1.475 9. Watters RJ, Liu X, Loughran TP Jr. T-cell and natural killer-cell large ADDRESS: Alan Lichtin, MD, Department of Hematology and Medical granular lymphocyte leukemia neoplasias. Leuk Lymphoma 2011; Oncology, CA-60, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 52(12):2217–2225. doi:10.3109/10428194.2011.593276 44195; [email protected]

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