6
Jo ur nal o f Ca se s in Ob st et ri cs &G yn ec olog y J Cases Obstet Gynecol, 2015;2(4):69-74 Case Report Acquired postpartum hemophilia: Clinico-pathological correlation through autopsy of a case and review of the literature Rig Vardhan 1 , TS Sachin 1 , Jyoti Kotwal 2,* , Bhushan Asthana 1 , Shakti Vardhan 3 , Jasjit Singh 4 1 Department of Pathology, Army Hospital, Delhi Cantt, India 2 Department of Hematology, Sir Gangaram Hospital, New Delhi, India 3 Department of Obstetrics and Gynecology, Army Hospital, Delhi Cantt, India 4 Department of Hematology, Army Hospital, Delhi Cantt, India Abstract Acquired hemophilia A is a rare bleeding disorder with estimated incidence of 1.5 cases/million/year with only 7% of these being post partum. To the best of our knowledge, there has been no case in the literature of acquired post partum hemophilia where an autopsy has been conducted. We present a case of 33-year-old lady who underwent elective caesarean after an uneventful ante partum period and developed fatal complications arising due to post partum hemophilia A characterized by hemorrhage, septicemia, consumptive coagulopathy and multiorgan dysfunction syndrome leading to death. Key words: Acquired postpartum hemophilia, autopsy Introduction Acquired hemophilia A is a potentially life-threatening but uncommon hemorrhagic disorder which is caused by the development of autoantibodies directed against coagulation factor VIII (FVIII) [1, 2]. The incidence of acquired hemo- philia A has been estimated to be 0.2–1.0 cases per 1 million per year. Only 7% of these cases occur in the postpartum peri- od but this figure may be an underestimate given the difficul- ty in establishing the diagnosis [3]. The condition is known to be associated with pregnancy, where it typically presents in women with no personal or family history of abnormal bleeding [3]. The clinical profile is dominated by severe hem- orrhage in the majority of patients, with an inhibitor related mortality rate of up to 22% [1]. Acquired hemophilia A may Journal of Cases in Obstetrics & Gynecology 69 Article history: Received 11 03 2015 Accepted 18 06 2015 *Correspondence: Prof. Jyoti Kotwal Department of Hematology, Sir Gangaram Hospital, New Delhi, 110060, India, Phone: 91 8826313337 (Mobile), 91 11 26151617 (R) Email: [email protected] also develop in patients with dermatological or respiratory diseases, autoimmune disorders, drug allergy and cancers (hematologic and solid) [4]. In approximately half of the diagnosed cases no underlying disease state can be detected [1].the cyanotic unrepaired heart diseases in class III. Pregnancy in unrepaired TOF carries major risks of maternal morbidity (60%), including heart failure, ar- rhythmia and endocarditis, and even maternal mortality (10%) [5,6]. Women with uncorrected TOF and cyano- sis, oxygen saturation < 80%, have an increased risk of miscarriage, fetal growth restriction, fetal loss and thromboembolism, secondary to the reactive polycy- thaemia. Their chance of a live birth has been quoted to be less than 20% [7]. In these patients, as a re- sult of the fall in peripheral vascular resistance that occurs during a normal pregnancy, there may be an increase in right to left shunt, with subsequent wors- ening of the cyanosis. Delivery is indeed problemat- ic since the blood loss associated with the process may induce hypotension and eventually exacerbate the shunt [7]. Risks are particularly high when the average systemic oxygen saturation falls below 80-85% [2].

Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

  • Upload
    others

  • View
    1

  • Download
    0

Embed Size (px)

Citation preview

Page 1: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

Jo ur nal o f Ca se s inOb st et ri cs &G ynec olog y

J Cases Obstet Gynecol, 2015;2(4):69-74

Case Report

Acquired postpartum hemophilia: Clinico-pathological correlation through autopsy of a case and review of the literature

Rig Vardhan1, TS Sachin1, Jyoti Kotwal2,*, Bhushan Asthana1, Shakti Vardhan3, Jasjit Singh4

1 Department of Pathology, Army Hospital, Delhi Cantt, India2 Department of Hematology, Sir Gangaram Hospital, New Delhi, India 3 Department of Obstetrics and Gynecology, Army Hospital, Delhi Cantt, India4 Department of Hematology, Army Hospital, Delhi Cantt, India

AbstractAcquired hemophilia A is a rare bleeding disorder with estimated incidence of 1.5 cases/million/year with only 7% of these being post partum. To the best of our knowledge, there has been no case in the literature of acquired post partum hemophilia where an autopsy has been conducted. We present a case of 33-year-old lady who underwent elective caesarean after an uneventful ante partum period and developed fatal complications arising due to post partum hemophilia A characterized by hemorrhage, septicemia, consumptive coagulopathy and multiorgan dysfunction syndrome leading to death.

Key words:Acquired postpartum hemophilia, autopsy

Introduction

Acquired hemophilia A is a potentially life-threatening but uncommon hemorrhagic disorder which is caused by the development of autoantibodies directed against coagulation factor VIII (FVIII) [1, 2]. The incidence of acquired hemo-philia A has been estimated to be 0.2–1.0 cases per 1 million per year. Only 7% of these cases occur in the postpartum peri-od but this figure may be an underestimate given the difficul-ty in establishing the diagnosis [3]. The condition is known to be associated with pregnancy, where it typically presents in women with no personal or family history of abnormal bleeding [3]. The clinical profile is dominated by severe hem-orrhage in the majority of patients, with an inhibitor related mortality rate of up to 22% [1]. Acquired hemophilia A may

Journal of Cases in Obstetrics & Gynecology69

Article history:Received 11 03 2015Accepted 18 06 2015

*Correspondence: Prof. Jyoti Kotwal Department of Hematology, Sir Gangaram Hospital, New Delhi, 110060, India,

Phone: 91 8826313337 (Mobile), 91 11 26151617 (R)Email: [email protected]

also develop in patients with dermatological or respiratory diseases, autoimmune disorders, drug allergy and cancers (hematologic and solid) [4]. In approximately half of the diagnosed cases no underlying disease state can be detected [1].the cyanotic unrepaired heart diseases in class III. Pregnancy in unrepaired TOF carries major risks of maternal morbidity (60%), including heart failure, ar-rhythmia and endocarditis, and even maternal mortality (10%) [5,6]. Women with uncorrected TOF and cyano-sis, oxygen saturation < 80%, have an increased risk of miscarriage, fetal growth restriction, fetal loss and thromboembolism, secondary to the reactive polycy-thaemia. Their chance of a live birth has been quoted to be less than 20% [7]. In these patients, as a re-sult of the fall in peripheral vascular resistance that occurs during a normal pregnancy, there may be an increase in right to left shunt, with subsequent wors-ening of the cyanosis. Delivery is indeed problemat-ic since the blood loss associated with the process may induce hypotension and eventually exacerbate the shunt [7]. Risks are particularly high when the average systemic oxygen saturation falls below 80-85% [2].

Page 2: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

October 2015www.jcasesobstetgynecol.com70

Case presentation

A 33-year-old lady with previous cesarean delivery un-derwent an elective cesarean at a peripheral hospital and delivered a healthy live male baby. She had no immediate intra- or post-operative complications, however next eve-ning (day 1) she complained of headache and body ache and was found to have hypotension (80/60 mmHg) with tachycardia (154/min), fever (99.20F) and reduced urine

output. There was no evidence of bleeding per vaginum but per abdominal examination showed distension. Emer-gency laparotomy was carried out with suspicion of in-traabdominal bleeding which revealed approximately 500 ml of clotted blood in the peritoneal cavity with no active bleeding sites. As uterus was flabby, hysterectomy was per-formed and intraperitoneal drain was put. She received 3 packed red cells (PC), 3 fresh frozen plasma (FFP) and 3 random donor platelets (RDP). However, she continued to be hypotensive with tachycardia, tachypnea and oliguria.

Jo ur nal o f Ca se s inOb st et ri cs &G ynec olog y

Patient was then transferred to this hospital on day 3, for fur-ther management for acute kidney injury and azotemia (urea: 42 mg/dl, creatinine: 1.7 mg/dl, K+: 4.8 meq/dl and Na+: 135 meq/dl). Her coagulation profile was deranged with

prothrombin time (PT) of 16.9 seconds, prolonged activated partial thromboplastin (APTT) of 54.4 seconds and interna-tional normalized ratio (INR) of 1.64. As she had deranged renal and hepatic parameters (investigation profile as per ta-ble no. 1) and coagulopathy (profile as per table 2) suggest-ing multiorgan dysfunction, a provisional clinical diagnosis of HELLP syndrome with disseminated intravascular hem-orrhage (DIC) and acute kidney injury or hemorrhagic shock

D+ 1; First postoperative day, D+3; she came to this hospitalHb, hemoglobin; TLC, total leucocyte count; DLC, dif-ferential leucocyte count; BUN, blood urea nitrogen; Na, sodium; K, potassium; Ca, calcium; AST, aspartate amino-transferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase

Table 2. Coagulation profile

Table 1. Laboratory findings of the case

Table 3. Mixing Studies and factor profile

Page 3: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

Journal of Cases in Obstetrics & Gynecology71

with ischemic acute tubular necrosis (ATN) and hepatopa-thy was considered. Her coagulation work up was repeated on day 4 which showed prolonged PT and APTT. Keeping in mind her clinical profile mixing and inhibitor screen were performed which revealed time dependent inhibitor. This led us to perform factor assay which revealed diminished FVIII activity and presence of FVIII inhibitor (Table 3). Subsequently she developed bilateral pleural effusion with inability to maintain oxygen saturation with falling hemo-globin and platelets and was intubated. Tracheal aspirates and intra-abdominal drain continued to be blood mixed. She also received multiple, different blood components through-out her course of illness and also two injections of recom

binant activated factor VIIa (rFVIIa) (120 ug/kg) on day 6. Terminally, she had sudden hypotension followed by brady-cardia and suffered cardiac arrest to which she succumbed. Autopsy was performed and external examination re-

vealed icterus, subconjunctival hemorrhage, pallor, nasal bleeding and multiple ecchymosis around nose, mouth, hands, elbow and upper trunk and edema (Fig. 1a-d)The right and left lungs were boggy and heavy with subcrepi-tant feel and exuded serosanguinous fluid on cut section (Fig. 2a). Bilateral pleural and pericardial effusions were present.

Multiple petechial hemorrhages were seen on the epicardi-al surface (Fig. 2b). Liver was soft, friable, congested with intracapsular hemorrhage (Fig. 2c). Both kidneys showed multiple varying sized petechiae with cut surface showing soft and friable cortical region with hemorrhagic areas (Fig. 2d). Approximately 800 ml of clotted blood was found in the pelvic cavity. Adhesions between intestines, omentum and abdominal wall were also noted (Fig. 3a). Large 8.5x7.5x4.5 cm hematoma was seen in left peritoneal wall with multiple petechiae on abdominal wall and organs (Fig. 3b). Menin-ges were markedly congested with adhesion at places with cerebral edema. A small hematoma (1.5 cm) on the surface

Kotwal et al.

Figure 1.

Bleeding from nose and ecchymosis, icterus (inset) (a), Petechiae and ecchymosis on hand (b), Peripheral oede-ma (c), Site of intraabdominal drain (d)

Figure 2.

Heavy and boggy lungs; right lung 750gm and left lung 650 gm (a), Pericardial effusion and petechiae on epicar-dium (b), Soft friable liver with intracapsular hemorrhage (arrow) (c), Cut surface of both kidneys showing conges-tion and cortical hemorrhage (d)

Page 4: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

of right temporal lobe and subdural hematoma under right occipital region was also noted (Fig. 3c). Serial cut sections of brain showed intracerebral hemorrhage in right tempo-ral (0.8cm) and right occipital (2.5cm) regions (Fig. 3d). On microscopy, sections from lungs showed pulmonary edema with hyaline membrane formation (arrow Fig. 4a) with foci of pneumonitis and focal gram-negative bacte-rial colonies (circle Fig. 4b). Sections from liver revealed severe centrilobular necrosis with scattered inflammatory cells and vascular congestion (Fig. 4c). Sections from the meninges and brain parenchyma showed vascular conges-tion. Sections from hemorrhagic areas in the brain showed blood clots and scattered inflammatory cells with evidence of necrosis in the adjoining regions (Fig. 4d). Sections from kidneys showed widespread cortical necrosis with necrosed glomeruli and tubules (Fig. 5a). Viable glomer-uli showed extensive deposition of fibrin thrombi within the glomerular capillaries (Fig. 5b) confirmed by Period-ic acid Schiff and Masson Trichome stain (Fig. 5c-d). Tu-bules showed features of acute tubular necrosis (Fig. 5a).

Jo ur nal o f Ca se s inOb st et ri cs &G ynec olog y

October 2015www.jcasesobstetgynecol.com72

There was splenomegaly and cut surface revealed con-gestive spleen. Gross and microscopy of other organs were essentially unremarkable. Culture of pleural flu-id & pericardial fluid isolated Acinetobactor baumannii.Clinico-pathological correlation as to cause of death: A 33-year-old lady had severe internal bleeding at multiple sites due to consumptive coagulopathy and acquired post-partum hemophilia after postpartum hysterectomy. As she was not treated or investigated for the same in peripheral hospital, thereby delaying definitive treatment she devel-oped multiorgan failure manifesting as widespread corti-cal necrosis with fibrin thrombi in kidneys, centrilobular hepatic necrosis, ARDS, consumptive coagulopathy and intracerebral hemorrhage along with septicemia caus-ing multiorgan dysfunction eventually leading to death.

Discussion

The postpartum development of an inhibitor against FVIII is a rare but severe complication of pregnancy. First case was described by Rosenthal and colleagues, there-after several studies have reported cases of postpartum acquired hemophilia A [1]. The pattern of bleeding var-ies between mild superficial bruising to severe bleeding

Figure 3.

Intraabdominal hemorrhage (a), hematoma left abdomi-nal wall with adhesions between omentum and intestines (b), subdural hematoma in occipital region (c), intrace-rebral hemorrhage in right temporal and occipital region (arrows) (d)

Figure 4.

Lungs showing hyaline membrane (arrow) (a), bacterial colonies (circle) in lungs (b), centrilobular necrosis of liver (c), necrosis of brain parenchyma in areas adjoining the hemorrhage (d)

Page 5: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours of delivery [3]. This was seen in our case.Diagnosis is based on a high level of suspicion from the patient’s history and physical findings. In our case, her di-agnosis was delayed as she was in peripheral hospital and multiple components were transfused which was like add-ing fuel to the fire as antibodies to FVIII was consuming the factor resulting in excessive activation of other clot-ting factors causing consumptive coagulopathy. Howev-er, clinical and laboratory evidence of continuing bleed-ing in spite of adequate blood components as well as persistently elevated APTT led to the diagnosis on day 4 but possibly irreversible damage had already occurred.

Laboratory diagnosis is based on the demonstration of an isolated prolonged APTT that fails to correct during mixing studies [5]. The PT, INR, fibrinogen and platelet levels are typically normal. In our case due to concomitant septice-mia possibly nosocomial (ventilator associated pneumonia) and consumptive coagulopathy platelets were also low. It is necessary to rule out a lupus anticoagulant, which can cause similar picture. Other criteria include a reduced factor VIII level and evidence of factor VIII inhibitor (as determined

by means of the Bethesda method). One Bethesda unit is the quantity of antibody that will inactivate 50% of normal factor VIII activity in a mixture of normal plasma and plas-ma from the patient after incubation at 37°C for 2 hours [1].Recombinant Factor VIIa was used in this case as a life saving measure to salvage the patient but it itself can cause thrombosis which could have caused renal corti-cal thrombosis in our patient. Medical practitioners have expanded the application of rFVIIa toward the control of postoperative bleeding. The efficacy of rFVIIa has been shown in many patients. However, safety concerns have arisen, particularly concerning the risk of thrombotic ad-verse events, when rFVIIa has been used in this manner [6]. In patients with congenital or acquired hemophilia with an inhibitor, adverse events have occurred with the use of rFVIIa with few documented serious adverse events involving clinically significant thrombotic events. [7].The pathophysiology is due to autoantibodies that are di-rected against FVIII that develop in patients with acquired hemophilia A. They are predominantly a mixture of poly-clonal IgG1 and IgG4 immunoglobulins commonly against the C2 and A2 domains. [1]. Both alloantibody and auto-antibody inhibitors appear to recognize the same epitopes on each domain [8]. Anti-C2 antibodies inhibit the binding of FVIII to phospholipids, whereas anti-A2 antibodies im-pede the binding of factor VIII to activated factors of the intrinsic pathway. The inactivation of FVIII resulting from this interaction, however, differs between autoantibodies and alloantibodies. Where alloantibodies inactivate FVIII activity completely (type I kinetics), autoantibodies usual-ly have more complex, exponential kinetics (type II kinet-ics), wherein there is an initial rapid inactivation followed by a slower inactivation or a period of equilibrium [9]. The pathogenesis of pregnancy-related FVIII autoantibodies re-mains unclear. As these antibodies develop more frequent-ly during the postpartum period, it has been hypothesized that the mother is exposed to fetal FVIII during the de-livery. However, this theory does not explain the absence of an anamnestic response in subsequent pregnancies [1].

Management includes supportive care, treatment of acute hemorrhage and eradication of the factor VIII inhibitors and treating underlying cause if any [2]. Hemorrhage can be treated with human factor VIII infusions; however, this may not be effective, particularly in patients with a high inhibitor titre (> 5 Bethesda units). For severe hemorrhage or high titres, it is best to reduce inhibitor levels with plas-mapheresis or to use agents that circumvent factor VIII [5].

Journal of Cases in Obstetrics & Gynecology73

Kotwal et al.

Figure 5.

Kidney showing widespread cortical necrosis (a), viable glomeruli showing fibrin thrombi (b), fibrin thrombi con-firmed on PAS stain (c), fibrin thrombi confirmed on MT stain (d)

Page 6: Acquired postpartum hemophilia: Clinico-pathological ... · such as intracranial, intraabdominal and gastrointestinal hemorrhage. Abnormal bleeding has been reported with-in 24 hours

References1. Franchini M. Postpartum acquired factor VIII inhibitors. Am J Hematol.2006; 81:768-773.2. Mytopher K, Card R, Gilliland B, Dude-bout J. Acquired hemophilia: A present-ing post partum. CMAJ. 2007; 177: 339-340.3. Tengborn L, Baudo F, huth-kuhne A, Knoebl P, Levesque H, Marco P. Pregnan-cy associated acquired hemophilia A: re-sults from European acquired hemophilia (EACH2) registry. BJOG. 2012; 119:1529-1537.4. Franchini M, Gandini G, Di Paolantonio

T, Mariani G. Acquired hemophilia A: a con-cise review. Am J Hematol. 2005; 80:55–63.5. Ma AD, Carrizosa D. Acquired factor VIII inhib-itors: pathophysiology and treatment. Hematol Am Soc Hematol Educ Program 2006; 432-437.6. Mahmoud A, Al-Ruzzeh S, McKeague H, Cross M. Systemic Venous Thrombosis after Recombi-nant Factor VIIa in the Control of Bleeding after Cardiac Surgery. Tex Heart Inst J. 2007; 34: 485–488.7. Abshire T, Kenet G. Recombinant factor VIIa: re-view of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899–909.

8. Prescott R, Nakai H, Saenko EL, et al. The inhibitor antibody response is more complex in hemophil-ia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Ko-genate Study Groups. Blood 1997; 89:3663–3671.9. Green D, Blanc J, Foiles N. Spontaneous inhibitors of factor VIII: kinetics of inactivation of human and porcine factor VIII. J Lab Clin Med. 1999; 133:260–264.10. Tiede A, Klamroth R, Scharf RE, Trappe RU, Holstein K, Huth-Kühne A et al. Prognostic fac-tors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood. 2015; 125:1091-1097.

October 2015www.jcasesobstetgynecol.com74

These include activated prothrombin complex concentrates or recombinant activated factor VIIa. No supporting data is available on which of these agents may be more effec-tive; the choice is at the discretion of the treating physician. Eradication of these inhibitors is more challenging and com-plex and often requires immunosuppressive agents. The use of rituximab after initial therapies have failed has shown promising results. Recently, it has been recommended as a first-line agent [1, 5, 10]. In majority of the cases the inhib-itors disappear spontaneously after a median of 30 months and usually do not recur with subsequent pregnancies [3]. In his literature review, Franchini et al showed that low in-hibitor titres (< 5 Bethesda units) tend to disappear within months, whereas higher titres may persist for years despite treatment. Rarely, such persistence can cause life-threaten-ing hemorrhage in a subsequent fetus because of transpla-cental transfer of IgG autoantibodies [1]. The overall rate of death from all causes of acquired hemophilia is 22%. In conclusion, acquired postpartum hemophilia must al-

Jo ur nal o f Ca se s inOb st et ri cs &G ynec olog y

ways be considered in the differential diagnosis of postpar-tum hemorrhage especially in the setting of an otherwise uncomplicated delivery with an intact perineum and placen-ta, as was seen in our case. An isolated prolonged activated partial prothrombin time should prompt systematic investi-gation for other unusual causes. Although rare, factor VIII inhibitors, if not diagnosed, may result in life-threatening hemorrhage in otherwise healthy young women. Diagno-sis is easily confirmed with the use of mixing studies, in which the activated partial thromboplastin time will fail to correct despite incubation with normal plasma. Treatment options to control hemorrhage and eradicate inhibitors are available. As our case had other significant comorbidities arising due to septicemia and DIC causing multiorgan dys-function, multidisciplinary care of these patients is essential.

Conflict of InterestAll authors have none to declare.