1. Cara Buskmiller M.D. Faculty Mentor: Cherie LeFevre M.D
Hemoperitoneum after Ovulation in Systemic Lupus Erythematosus and Immune Thrombocytopenia
Cara Buskmiller M.D.
Faculty Mentor: Cherie LeFevre M.D

2. Objectives
List methods of platelet detection available in modern laboratories.
Diagnose hemoperitoneum on computed tomography.
Form a differential diagnosis for hemoperitoneum of gynecologic origin.
Recognize occasions for nonsurgical management of hemoperitoneum.
Discuss management of immune thrombocytopenia from the perspective of a consultant to a multidisciplinary team.

3. Case 34yo African-American G0 Chief Complaint: abdominal pain, emesis
Pertinent positives: fatigue, dizziness, shortness of breath, gingival bleeding, bruising, heavy menses, pica, epistaxis, joint stiffness, headache
Medical history: none
Gynecologic history:
ASC-H
Follicular cyst
Surgical history: laparoscopic ovarian cystectomy
5 weeks before admission: gingival bleeding after a dental appointment
3 weeks before admission: spontaneous bruising and "red spots" on her skin
1-2 weeks before admission:
soaking 1 pad/1-2 hours during her 12-day long menstrual period (very abnormal for her)
epistaxis following minimal trauma or sneezing
craving for ice chips
fatigue and shortness of breath with minimal activity
Day before admission: abdominal bloating
Day of admission: acute abdominal pain described as
“Like someone punched me in the gut”
Waxing and waning
Associated with emesis (x3), last of which was flecked with blood
ROS pos for HA
No h/o travel, toxicology, or ticks/insects
Course at Progress West
AFVSS
Hgb 5.4, plts undetectable
Pelvic CT with hemorrhagic ovarian cyst with free intraabdominal fluid
Given 1 u pRBCs and transferred bc they did not have platelets

4. Case Physical Exam: Vital Signs:
HEENT: petechiae over tongue and oral mucous membranes, conjunctival pallor; no lymphadenopathy
Lungs: clear to auscultation
Heart: tachycardic, no murmur, no JVD, capillary refill < 2 seconds in all four extremities
Abdomen: flat, distant bowel sounds, soft, tender to deep palpation in all quadrants, no organomegaly, no peritoneal signs
Musculoskeletal: no joint deformity
Integument: petechiae on chest, arms, lower legs
Vital Signs:
BP 120/68
Pulse 105
Temp 99 F
Resp 18
SpO2: 100
BMI: 23.5

5. Labs b-hCG negative CBC: WBC 11.7, Hgb 6.3, platelets 0
CMP: bicarb 21, calcium 7.2, albumin 2.8
Coags: PT 10.6, PTT 23.2, fibrinogen 182
Iron panel: Iron 26, iron saturation 9%, transferrin 222, ferritin 10
LDH: 332
Haptoglobin: 8
Smear: no platelets, schistocytes or blasts
Auto-diff on Sysmex XN 3000 detects platelets by two methods
Platelet eye (impedance: interruption in electrical pulse; can be affected by clumping because clumps are too big)
Platelet fluorescence (fluorescent dye binds to nucleic acids in the platelet count and counts the fluorescence) is performed after flag by machine; approximately <5% reflex to platelet F
Look at scattergrams and peripheral smear is final assessment; very few get manually looked at
Immature platelet fraction is used like a reticulocyte count

7. Differential Diagnosis
Infectious Disease
Hepatitides
HIV/AIDS
Erlichiosis
Rocky Mountain Spotted Fever
Hematology/Oncology
Immune thrombocytopenia
Warm microangiopathic hemolytic anemia
Hereditary thrombocytopenias
Hypersplenism or sequestration crisis
Antiphospholipid syndrome
Nutrient deficiency, heavy metal toxicity
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Myelodysplasia, aplastic anemia, leukemias
Endocrine
Thyroid dysfunction
Rheumatology
Secondary ITP (lupus-associated)
Also H Pylori (not formally ruled out as invasive and another cause found), intracellular parasites. Also drug-induced TCP, lab error, DIC, PREGNANCY!!
Less likely in this patient are the rare infections, DIC due to sepsis (she is not acutely ill), HUS (no uremia), splenic etiology (no h/o SCD, no organomegaly), aplastic anemia or myelodysplastic syndrome (no leukopenia), and toxins (no occupational or other unusual exposures).
In this patient, the most likely diagnosis is immune thrombocytopenia. This is not only the most common cause of thrombocytopenia in asymptomatic adults, but this diagnosis is supported by her normal peripheral smear (no schistocytes, no abnormal lymphocytes) and her consumption of platelets between CBCs today. ITP can be primary (autoimmune), secondary (due to another condition, e.g. HIV), or drug-induced. This patient would qualify for severe ITP as she has a platelet count less than 10,000 with spontaneous bleeding. ITP is often incited by infection or immune alteration (e.g. development of SLE or lymphoproliferative disorder). There is no identified inciting event in this patient yet.
9.6% of patients with ITP experience non-ICH severe bleeding. Risk factors for severe bleeding, such as this patient's intraperitoneal bleed, include platelet count below 10,000, previous minor bleeding (such as her gingival bleeding), and diagnosis >12 months ago.
This patient has a six week history of mucosal bleeding, indicating that she was likely thrombocytopenic below 50,000 a month and a half ago. Her intraperitoneal bleed appears to be from a hemorrhagic ovarian cyst, as there is contrast blush around the right ovarian cyst on abdominal CT. Because this cyst likely ruptured at ovulation, the peritoneal bleed likely started approximately two weeks before her LMP, which would have been approximately 5 weeks ago. Symptoms beginning so acutely may be related to diaphragmatic irritation, mass effect, or critical overwhelming peritoneal irritation.
Other congenital TCPs: giant platelets (the size of red blood cells) in May-Hegglin anomaly or Bernard-Soulier syndrome, or an absence of platelet granules in gray platelet syndrome

8. Additional Labs Infectious Disease Endocrine Negative hepatitis panel
Non-reactive HIV
Erlichia PCR negative
RMSF IgG/IgM negative
Hematology/Oncology
Positive direct Coombs
vWF Activity 205 (high)
Beta 2 glycoprotein panel IgG/IgM negative
Lupus anticoagulant negative
Cardiolipin antibody IgG/IgM negative
Folate 22.1, B12 491, Pb negative, Cu 460
Hemosiderin (urine) negative
PNH panel negative
Endocrine
Normal TSH
Rheumatology
ANA 1:640
SS-A 6.6, SS-B <0.2
anti-Smith > 8
anti-RNP > 8
dsDNA 8
Rheumatoid factor <10
Anti-centromere B negative
Low C3 (73), adequate C4
Low IgM 41, normal IgG and IgA
DAT IgG positive
CRP <0.29, ESR 39
Anti Jo-1 <0.2
Retic count 1.7 in 8/2016

9. Systemic Lupus Erythematosus
Requires four or more criteria (at least one from each category)
Clinical criteria
Acute cutaneous lupus
Chronic cutaneous lupus
Oral ulcers
Non-scarring alopecia
Synovitis of two or more joints
Serositis
Renal impairment
Neurologic deficits
Leukopenia or lymphopenia
Thrombocytopenia (<100)
Immunologic Criteria
Positive anti-nuclear antibodies
Positive anti-dsDNA antibodies
Positive anti-Smith antibodies
Positive aPL antibodies
Low complement
Positive direct Coomb’s test
Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum ; 64(8):

10. Immune Thrombocytopenia
Incidence: 1 to 3 per 100,000 adults, 20-30% asymptomatic
Presentation: asymptomatic young woman with an inciting event, a constant, mild TCP ( ) and a normal peripheral smear, managed outpatient with steroids
Classification
Primary: acquired disorder of platelet consumption and decreased production due to anti-platelet IgG antibodies and T-cell mediated platelet destruction
Secondary: acquired thrombocytopenia from another condition or drug
Severe: ITP with bleeding sufficient to require treatment (platelets less than 10-20)
Intracranial hemorrhage: 1.4%
Non ICH severe bleeding: 9.6%
Refractory: persistent or recurrent ITP with bleeding requiring therapy after splenectomy
Mortality: 2-4% ITP-related deaths per 10 years
No described cases of adults with spontaneous hemoperitoneum from ovulation
Primary immune thrombocytopenia (ITP, also called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults.
Major diagnostic concerns in an adult with suspected ITP are distinguishing ITP from other causes of thrombocytopenia, which often have a similar presentation but may require completely different management approaches, and determining whether the ITP is primary or secondary to an underlying condition that might also benefit from treatment.
The lack of a sensitive or specific diagnostic test for ITP, and large number of other potential causes of thrombocytopenia, some of which may be overlooked (eg, drug- induced, congenital platelet disorder), also contribute to the challenges in diagnosing ITP.
Antibodies are from B cells, usually against GPIIb/IIIa and other membrane glycoproteins. Antibody production in ITP appears to be driven by CD4-positive helper T cells reacting to platelet surface glycoproteins, possibly involving CD40:CD40L co- stimulation [32-34]. Splenic macrophages appear to be the major antigen-presenting cells
Most common diagnosis in adults with asymptomatic TCP
The specific inciting events for ITP are not always clear. Genetic and acquired factors probably contribute [7-9]. Two commonly cited acquired events are infections (typically viral) and systemic conditions that disrupt immune homeostasis (eg, autoimmune disease, lymphoid malignancy).
●Infection – Some cases of ITP are associated with a preceding viral infection or, less commonly, bacterial infection. Antibodies against viral antigens may cross- react with normal platelet antigens (a form of molecular mimicry). Infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), cytomegalovirus (CMV), and varicella zoster virus (VZV) have been proposed to cause secondary ITP by this mechanism [10-13]. Bacterial products, such as lipopolysaccharide, may attach to platelet surfaces and can increase platelet phagocytosis [14]. Helicobacter pylori infection may contribute to the development of ITP in some cases by an unknown mechanism that might include molecular mimicry, immune alterations, and activities of bacterial products such as CagA [15].
●Immune alteration – Alterations in immune homeostasis might induce loss of peripheral tolerance and promote the development of self-reactive antibodies. Potential examples include the antiphospholipid syndrome, systemic lupus erythematosus, Evans syndrome, hematopoietic cell transplantation, chronic lymphocytic leukemia (CLL) and other low-grade lymphoproliferative disorders (especially those treated with purine analogs), common variable immunodeficiency, and the autoimmune lymphoproliferative syndrome [7,16,17].
Alternative immunologic mechanisms involving T cells have also been postulated to cause ITP, including T cell-mediated cytotoxicity and defects in the number and/or function of regulatory T cells (Tregs) [18-27]. The latter mechanism is supported by a study showing a reduced number and defective suppressive capacity of Tregs in patients with ITP versus controls, and restored Treg numbers and regulatory function, especially in responders, following treatment with rituximab [25]. (See "T helper subsets: Differentiation and role in disease".)
In contrast to ITP associated with lymphoid malignancies, such as CLL, reports of ITP in association with nonhematologic malignancies, especially breast cancer, are likely due to coincidence rather than a causal relationship [28-31].
Many are asymptomatic at incidental finding of TCP (risk of severe bleeding eg ICH, GIB, hematuria/VB, hemoptysis at presentation is <1%). If you are looking only for those with sx or hospitalizations, incidence is 2.94 per 100,000 person-years with most cases > 60 years old (incidence highest in men > 75 y/o) although this is generally a disease of young women. Peak in winter and the highest incidence in northern France.
PE: if there are purpura, they’re in dependent areas (unlike vasculitic purpura)
Constant TCP, normal peripheral smear, normal remaining hematologic indices, normal coags
Inconstant TCP may be drug related d/t changing serum levels
Large platelets are often noted on the peripheral blood smear. Importantly however, ITP is not characterized by abnormal platelet morphology (eg, lack of granules, uniform populations of large or small platelets). These abnormal platelet morphologies should prompt consideration of an inherited platelet disorder.
Immature white blood cells may suggest infection or leukemia.
Schistocytes may suggest a microangiopathic process such as thrombotic thrombocytopenic purpura (TTP).
Prolonged clotting times may suggest liver disease or disseminated intravascular coagulation (DIC).
BM biopsy not indicated but would be normal (normal or increased megakaryocytes sometimes with less polyploidy (younger), normal cellularity)
Steroids and IVIG are first-line
Treatment is guided by platelets >10 or 20, and no serious bleeding -- -goal is NOT to normalize plts
Mortality — The mortality of ITP is considered to be similar to or only marginally higher than an age-matched population, despite the possibility of fatal hemorrhage from thrombocytopenia or infection in the setting of therapies that cause immunosuppression [5,8-10,55-58]. Patients with ITP are more likely to die of conditions unrelated to ITP than to ITP or its treatment.
The following examples illustrate the mortality rates and causes of death:
●A series of 152 adults followed for slightly over nine years reported 21 deaths (14 percent) [9]. There were six ITP-related deaths (4 percent; two from bleeding and four from infection, which may have been a complication of immunosuppressive treatment), four cases of sudden death (3 percent), and 11 deaths unrelated to ITP (7 percent).
●A series of 245 adults followed for five years reported 27 deaths (11 percent) [10]. Three of these were attributed to hemorrhage, one to sepsis following splenectomy, and the rest to non-ITP causes.
●A series 208 adults reexamined 14 years after their initial ITP diagnosis reported 11 deaths (5 percent) [8]. Five were from bleeding and six from causes unrelated to ITP.
●A series of 310 adults and children followed for 10 years reported a single hemorrhagic death in a 43-year-old with longstanding severe thrombocytopenia [57].

12. Surgical management in ITP
Chang et al, British Journal of Surgery, 2013
Retrospective population-based cohort study of 11,085 patients with ITP and 44,340 controls without ITP, controlling for preoperative co-morbidities by means of multiple logistic regression
ITP patients had a higher risk of
Postoperative death (odds ratio (OR) 1.89, 95% CI )
Overall postoperative complications (OR 1.47, 95% CI )
Increased hospital stay (OR 1.90, 95% CI )
ICU admission (OR 1.73, 95% CI )
Medical costs (OR 1.89, 95% CI )
Risk factors for adverse postoperative outcomes
Preoperative platelet and/or red blood cell transfusion
Emergency visits
Admission to hospital for ITP care

13. Follow Up
August 2016:
Diagnosed with steroid-refractory autoimmune thrombocytopenia
Started azathioprine, stopped due to severe arthralgias
September 2016: Pap test NIL, - HRHPV
October 2016: DEXA scan T-score -2.0, fasting glucose 116, A1C 6.1, TG 385
March 2017: self-discontinued plaquenil and prednisone, platelets 176 and H/H 12.8/42.4
June 2017: Medication-free with resolution of platelets to 216, H/H 15.2/46.3
For patients with severe bleeding (eg, intracranial, gastrointestinal) and a platelet count <30,000/microL, we recommend immediate therapy that includes all of the following:
●Platelet transfusion (see "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Actively bleeding patient')
●Intravenous immune globulin (IVIG, 1g/kg, repeated the following day if the platelet count remains <50,000/microL)
●Glucocorticoids (eg, methylprednisolone, 1 g intravenously, repeated daily for three doses; or dexamethasone, 40 mg orally or intravenously, repeated daily for four days)
●Romiplostim, 500 mcg subcutaneously, which represents approximately 5 to 7 mcg/kg for most patients [20]. This may be repeated in one week for severe bleeding and thrombocytopenia. (See "Immune thrombocytopenia (ITP) in adults: Second-line and subsequent therapies", section on 'Romiplostim' and "Clinical applications of thrombopoietic growth factors", section on 'Romiplostim (Nplate, Romiplate)'.)
Responses to ITP therapy can be defined as follows:
•Response – A response is defined as a platelet count above 30,000/microL and at least doubling of the baseline platelet count.
•Complete response – A complete response is defined as a platelet count ≥100,000/microL.
First line is IVIG and steroids
Second line is rituximab, thrombopoietin receptor agonists, and splenectomy
Monitoring — Monitoring of patients with ITP includes clinical evaluation for bleeding and measurement of the platelet count. The frequency of monitoring depends on disease severity and treatment.
●Patients with mild thrombocytopenia who have been evaluated by a hematologist and who do not require treatment, such as those with platelet counts >30,000/microL, may need only infrequent monitoring once it is determined that the platelet count is stable and bleeding symptoms do not occur. For these patients, evaluations one to three times per year may be appropriate, and these evaluations may be performed by the patient's primary care provider or hematologist.
●Patients who have more severe and symptomatic thrombocytopenia, especially patients who are receiving treatments, require more frequent monitoring, often as frequently as once every one to three weeks.
Patients should be aware of the symptoms of severe bleeding (eg, melena, severe headache) and should be advised to consult their clinician if bleeding occurs.

14. Objectives
List methods of platelet detection available in modern laboratories.
Diagnose hemoperitoneum on computed tomography.
Form a differential diagnosis for hemoperitoneum of gynecologic origin.
Recognize occasions for nonsurgical management of hemoperitoneum.
Discuss management of immune thrombocytopenia from the perspective of a consultant to a multidisciplinary team.