Unexplained hemorrhagic syndrome? Consider acquired hemophilia A or B


There is a dire need to develop an algorithm to improve the recognition of acquired hemophilia A and B (AHA and AHB) in clinical practice. Initial and intensive care unit (ICU) management of the disorder is particular and represents a challenge for the internist/hematologist and the ICU physician. A delay in the proper treatment of bleeding episodes can lead to a life-threatening event. Expert advice should be sought as soon as possible. Succesful resolution involves accurate diagnosis, bleeding control with hemostatic and immunotherapy, and eradication of the autoantibodies to improve overall survival. Current treatment guidelines are based on the literature in the form of cases and observational studies due to a lack of randomized controlled trials. AH can be triggered by many pathologies, presenting as a paraneoplastic syndrome in case of malignancies or as surgical associated acquired hemophilia (SAHA). We have reviewed the literature from 2015 to 2021 regarding the new case reports to further assess if there is an improvement in the clinical approach.

1. Background on diagnosis and underlying causes

Acquired hemophilia (AH) is an autoimmune disorder of a rare entity, which consists of the onset of abnormal spontaneous bleeding in patients without a medical record of a bleeding disorder, in consequence, it can be suspected by the clinical manifestations [1]. Coagulation tests can confirm the disease by revealing an isolated prolongation of the activated partial thromboplastin time (aPTT – factors VIII, IX, XI, XII) both in acquired hemophilia A (AHA) and B (AHB), with normal prothrombin time (PT- factors I, II, V, VII, and X). When the factor VIII activity is less than 50%, a measurement of anti-factor VIII titers should be determined to check whether an inhibitor is present. The patient is potentially diagnosed with AH if the inhibitor levels are over 0.6 Bethesda Units/mL (BU/mL) [2,3]. This disease affects both of the sexes with the same percentage and it is most often found in the elderly (60–80 years old) and peri/postpartum women, with rare encountering in children population [4,5].

The mechanism by which this disorder develops is based on immunoglobulins (IgG) autoantibodies (also known as inhibitors due to inhibition of clotting factors), produced by a triggered immune system, that target the following clotting factors: clotting factor VIII – AHA; clotting factor IX –AHB. Still, some case reports are linking AH to other clotting factors as well [6]. To exclude the genetic factor deficiencies, a mixing study is proposed in which a sample of blood can be withdrawn from the patient and mixed with blood from the control. The lack of resolution of prolonged aPTT confirms the presence of an inhibitor [7]. Inhibitors to factor VIII can be time and temperature-dependent and may correct immediately but prolong with two hours of incubation, and also show second-order nonlinear inactivation pattern with detectable residual FVIII activity – usually less than 15% [8]. Other reasons for prolonged aPTT, such as heparin therapy or lupus anticoagulant, should be excluded because differentiating between a lupus anticoagulant and a true inhibitor to FVIII or FIX is very important since it is possible to have both [2,9]. If an inhibitor is suspected then we order an inhibitor assay and specific factor activity levels (Fig. 1).

Presumably, the pathophysiology is different from congenital hemophilia [7]. For example, the levels of FVIII at diagnosis cannot be used to predict the severity of bleeding in AHA. Life-threatening bleeding can occur with FVIII plasma levels that would otherwise be considered of mild severity in the case of congenital hemophilia. A recent study by Holstein et al reported that FVIII plasma levels and the inhibitor titer at baseline do not predict the incidence of bleeding after day 1 of starting immunosuppressive treatment (IST), but afterward, weekly FVIII levels are statistically associated with bleeding episodes for 12 weeks after IST. This emphasizes the importance of further targeting FVIII levels of 50% and above to prevent rebleeding. In addition, they point out that there is a decrease in the risk of new bleeding after 4 to 6 weeks of IST, regardless of the FVIII activity [10].

Noteworthy, in 50% of patients there is no underlying cause established (idiopathic form), and the remaining 50% have coexisting disease included in Table 1 below [11]. Differential diagnosis is presented in Table 2. Signs and symptoms of the AH are presented in Table 3. Even though the lack of clotting factor activity is come across in both acquired and congenital, the bleeding pattern is different. In 30% of patients, treatment is not required to stop the bleeding but, at the same time, over 30% of patients experience manifold bleeding events. Life-threatening bleeding can occur spontaneously or due to trauma [2,12].

Tabla 1. Different conditions associated with AH.

1. Infections – Mycoplasma pneumoniae, hepatitis type B6. Hematological; solid tumors (malignancy) – prostate, lung, colon, stomach, pancreas, breast, kidney; as paraneoplastic syndrome
2. Diabetes7. Inflammatory bowel disease or ulcerative colitis
3. Hepatitis8. Autoimmune disorders (lupus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, temporal arteritis, Goodpasture’s syndrome, myasthenia gravis)
4. Respiratory (asthma/COPD) or dermatological diseases (pemphigus)9. Drugs (penicillin, sulfonamides, phenytoin, interferon-alpha); anti-TNF-α (adalimumab)
5. Pregnancy10. Idiopathic


Table 2. Differential diagnosis of AH.

Inherited blood clotting disorders (inactive/deficient clotting factors)
Hemophilia A (FVIII deficiency) – X linked
Hemophilia B (FIX deficiency) – X linked
Hemophilia C (FXI deficiency) – autosomal recessive
von Willebrand disease (VWD)
Lupus anticoagulant and heparines


Table 3. Signs and symptoms of hemorrhagic syndrome of AH.

Bleeding into muscles, skin, and soft tissue (bruising and ecchymoses)/(beware of compartment syndrome development)Intracranial hemorrhage
EpistaxisGastrointestinal bleeding
HematomasGenitourinary (hematuria)
Pregnancy – postpartum genital bleedingRetroperitoneal
Surgery with postoperative bleeding 
Hemarthrosis (rare) 

2. Clinical management and treatment

Treatment therapies are individualized, and expert advice should be sought as soon as possible. Spontaneous remission is reported, especially in patients with low titer inhibitors [12].

To successfully manage the AH one should concentrate on the following steps:

1) Suspect and diagnose the disorder
2) Prevention and controlling the bleeding – obtain hemostasis as soon as possible
3) Eliminating the autoantibodies
4) Treat the underlying disease if one exists

The anti-hemorrhagic treatment uses replacement therapy as first-line hemostatic agents. Recombinant porcine factor VIII (rpFVIII) – Obizur®, is used for the treatment of bleeding episodes in adults with acquired hemophilia A with high efficacy [13]. It is considered the first-line treatment when there is life-threatening/limb-threatening bleeding. It works as a co-factor for factor IXa in the coagulation cascade. Together with calcium and phospholipid, it leads to factor X activation contributing to the formation of the clot. It can be used in patients with associated cardiovascular diseases because it is less thrombotic compared to rFVIIa. If there are no anti-porcine FVIII inhibitors available, the dose is 50–100 U/kg initially then continue to monitor every 2–3 h with FVIII activity and dose as needed. If detectable, for anti-porcine FVIII inhibitor the dose is 200 U/kg initially for severe bleeding/50–100 U/kg for less severe bleeding. Further, monitoring of FVIII levels is necessary to guide redosing [14].

Bypassing agents are concentrates of factors that bypass the acquired deficiency and have around 90% efficacy [[15][16][17]]. The recombinant activated factor VII (rFVIIa) eptacog alfa is linked with thrombotic tendencies, as 7% of patients treated with bypassing agents develop a thrombotic-related incident according to a review but bleeding severity outweighs the danger of clotting in most cases [18]. The dose is 70–90 μg/kg every 2–3 h until hemostasis is achieved. Afterward, the dosing interval is prolonged [19]. Activated prothrombin complex concentrate (aPCC or FEIBA®) contains factors II, VII, IX, X (vitamin K dependent factors). The clinical indication is 50–100 U/kg every 8–12 h, but should not exceed 200 U/kg/day [12]. The prophylactic use of bypassing agents is controversial because it can be associated with a risk of arterial and thrombotic events [2].

Strategies to increase FVIII levels are appropriate when the inhibitor titer is very low (i.e. < 5 Bethesda units [BU]) and if bypassing agents are not available. Such therapeutic options include recombinant and plasma-derived FVIII concentrates and desmopressin (DDAVP 1-deamino-8-D-arginine vasopressin). Desmopressin is used at a dose of 0.3 μg/kg intravenously and induces the release of FVIII by endothelial cells. Still, it should be avoided in the elderly population because there is a risk of fluid overload with severe hyponatremia leading to heart failure [20,21].

Antifibrinolytic agents include epsilon-aminocaproic acid and tranexamic acid, which may also be used as an adjunct to manage mucosal bleeding, but caution should be exerted when combining tranexamic acid with bypassing agents [22].

Inhibitor eradication refers to immunosuppression therapy started after the diagnosis of AH. As first-line therapy, this option uses either corticosteroid alone (prednisone 1 mg/kg p.o. daily/alternative being dexamethasone 40 mg p.o. daily) for 3–4 weeks, either corticosteroid plus cyclophosphamide (1–2 mg/kg p.o.), with a faster response than steroids alone, but higher adverse event profile. The median time of corticosteroid treatment for the remission of inhibitors is usually about 5 weeks (FVIII activity level restored to >50 IU/dL) [23]. Rituximab (375 mg/m2 i.v. for 4 weeks), an anti-CD20 monoclonal antibody used against the autoantibodies, is indicated for patients resistant to first-line therapy, with reports of 90–100% complete remission [24].

Still, immunosuppressive therapy increases the risk for infection and therefore sepsis screening should be done on a regular basis. Other available drugs include cyclosporine A, azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine [25,26].

High-dose intravenous immunoglobulin has been explored as a means to eradicate inhibitors in AH, used as an adjunct treatment. However, most reports with IgG added to immunosuppressive agents proved no benefit. Patients with lower inhibitor titers showed better response with a dosage of 2 g/kg over 2–5 days, but overall did not improve the outcome [27].

Plasmapheresis or immunoadsorption is used in patients with very high titers of inhibitors and life-threatening bleeding which have failed to respond to bypassing agents. The Modified Bonn-Malmö Protocol (MBMP) implies a sequence of therapeutic measures such as: immunoadsorption that links FVIII inhibitors, FVIII replacement in high-dose, immunosuppression therapy, and immunoglobulin G administration. A number of 35 patients with AH meeting the above criteria have been successfully treated with MBMP [28].

Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial the authors assessed once-weekly subcutaneous emicizumab for bleeding prophylaxis in patients with hemophilia A with factor VIII inhibitors. The conclusion was that the use of emicizumab prophylaxis for bleeding is associated with a significantly lower rate of bleeding events than no prophylaxis [29]. Despite this, further investigation is warranted to confirm the safety and efficacy of emicizumab in AHA. Concomitant administration of activated prothrombin complex concentrate can increase the thrombotic risk, therefore rFVIIa should be used for the treatment of bleeding episodes in those receiving emicizumab [30].

3. ICU standpoint for the management of emergency hemorrhagic syndrome

It is important to acknowledge that often the emergency room doctor or internist are the first ones who evaluate these patients. As such, there is a need to raise awareness of the existence of this disorder and to encourage referral to hematologists specialized in the management of AH. Furthermore, understanding the underdiagnosed surgery-associated acquired hemophilia A (SAHA) can haste in diagnosis. Patients may have bleeding at the surgical sites, that may occur within a few hours to several days after surgery. Reported case reports have concluded that SAHA can be triggered after minor and major surgery, most of them performed on the digestive tract, especially hepatopancreatobiliary surgery [31].

Often, such clinical scenarios cannot be further managed on the surgery wards and may require admission into an ICU for continuous and more advanced monitoring. The issues that often contribute to the death of the patient are the ones regarding differential diagnosis, difficulty in achieving hemostasis, multiple organ dysfunction syndrome, and development of treatment-related complications (infections or thrombosis). There should be a straightforward approach using the CABC protocol: finding the bleeding source and achieving hemostasis if possible (C-circulation), assessing the airway (A-airway), and breathing (B-breathing). Make sure the airway is always patent and give oxygen if the SpO2 is <94% in atmospheric air to maximize the oxygen-carrying capacity of hemoglobin. Delivering the optimal oxygen concentration (DO2) to the tissues is mandatory in severe anemia situations. By returning to the (C)-circulation step, make sure adequate intravenous access is established (at least two 18 gauge intravenous catheters should be inserted) and initiate parenteral fluid infusion, starting with crystalloid or colloid and continue with blood-derived products once available [32].

In case there is a need for central venous line insertion, the femoral vein should be the first choice because of its anatomical position and access for hemostasis in case of bleeding. The cannulation of the vein should be performed by the most experienced physician and guided by an ultrasound machine. Before and after invasive minor or major procedures bypassing agents or rpFVIII should be used as prophylaxis [12]. During bleeding episodes, the patient must be permanently connected to a monitor with a constant evaluation of clinical parameters, such as ECG, heart rate, blood pressure measured at 3–5 min intervals, SpO2, respiratory frequency, and hourly urine output measurement. Routine clinical evaluation and laboratory studies are mandatory, as well as avoiding therapies that may cause further bleeding. Where intramuscular bleeds develop, fasciotomy can end in severe hemorrhage. In order to prevent compartment syndrome, early hemostatic therapy should be administered [33].

Clinical evaluation, bleeding control with stationary hemoglobin values and imaging studies are the primary mains of monitoring the response after the therapy [34]. Coagulation parameters, such as aPTT, are not good markers to guide therapy, because they will normalize when the levels of FVIII are over 30–50%. The response to human and porcine FVIII replacement therapies can be assessed by FVIII activity assays. There are no laboratory tests for evaluation of the response to bypass agents. Still, the severity of bleeding does not correlate well with residual FVIII activity levels or the titers of inhibitor [12]. Patients who received bypass agents should be clinically assessed for arterial and venous thromboembolism, especially those at high risk. It is important to inform the patients to avoid activities that predispose them to trauma. Relapse can occur after remission, so the patients should be referred to specialist hemophilia hospitals [27].

We have searched the literature for English-written case reports on AH and have gathered information regarding 24 case reports from around the world from 2015 to 2021 (Fig. 2 and Table 4) [15,31,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]]. SAHA is reported after both minor, like tooth extraction [53], and major surgery on the digestive tract due to triggering inhibitors formation [31]. An insight into the literature regarding surgery as a precipitating cause of AH concluded that there is late recognition of the disease among practitioners leading to a high mortality rate. It is characterized by abrupt onset within hours or days of surgery. Hemostasis and eradication of inhibitors are mandatory for the successful treatment of SAHA [31,56]. As to the pathogenesis and mechanism involved, there is probably immune dysregulation triggered by trauma and tissue injury together with associated diseases and different drugs administered [56].

Fig. 2

Fig 2. Information regarding cases published between 2015-2021.

Table 4. Acquired hemophilia cases with countries of origin.

Case with reference and countryAge/sexSigns and symptoms at presentationAPTT at presentation (seconds)Surgical operationBleeding siteAPTT after hemorrhage (seconds)Time from surgery to bleeding (days)FVIII activityFVIII inhibitor titer (Bethesda units)Overall transfuion requirementTime to dissaparance of inhibitorOutcome/follow-up
82/Mhematuria; disuria42cystoscopykidney hematoma491lowelevated (NS)APTT normalized after 4 days/factor VIII levels returned to normal after 2
stable at 6 months
78/Frecurrent GI bleeding,multiple ecchymoses
over her chest and upper extremities,oral mucosal ecchymoses
48<1%59.71PRBCafter 4 doses of Rituximab – inhibitor – > 2stable at 6 months
74/Mright upper shoulder dermatofibrosarcoma and inguinal hernia repairhematoma in the anterior soft tissues of the lower mid abdomen and a moderate to large hemoperitoneum56.81low4.27 PRBC +1FFP + 1 cryoprecipitate+1 unit of plateletAPTT normalized after 10 days
94/MTIA + spontaneous hematoma of upper arm81.4<0.01 UI/ml8.2at 36 months uneventful
75/Mcervical lymphadenopathies (benign follicular hyperplasia with IgG4+ lymphoplasmacytic infiltration)721%27Remission at last follow-up (36 months from AHA diagnosis)
 AHA relapse at 18 moths652%12 
81/Mecchymosis and edema of the right shin and the right and left forearms80Whipple’s operation for carcinoma of the ampulla of Vater2 months (tumor relapse)NANAAPTT normalized after 6 weeksdischargerd after 6 weeks
66/Mspontaneous severe cutaneous and muscle bleeding70<1%25remission achieved on day +21
75/Mtrunk hematoma + SARS-COV2 infection (reappearance of AHA after 9 years)66trunk hematoma<1%19remission achieved on day +20
75/Fspontaneous bruising of the upper extremities (after levofloxacin)spontaneous bruising of the upper extremitieslow30.4remission achieved on day +52
87/Fspontaneous hematomas on the right leg and both feet since 5 weeks and spontaneous large muscular
bleeding in the gluteal region
87.3spontaneous hematomas on the right leg and both feet since 5 weeks and spontaneous large muscular
bleeding in the gluteal region
1%1504PRBCday +55alive at 6 months
 a year later – melena73.9gastrointestinal2%4.6day +14alive at 6 months
66/Mmyelofibrosis evolving in acute myeloid leukemia43.8splenectomy + phrenic artery hemorrhagehematoma in his pancreatic loge5235 days<1%17.3day +50remission achieved on day +50
77/Mcompartment syndrome of left calf following a minor trauma + myeloma119compartment syndrome of left calf2%102APTT normalized after 1 monthalive
65/Mruptured aneurysmal subarachnoid hemorrhage and hydrocephalus55percutaneous gastrostomyPEG insertion site796 days4%10PRBCremission achieved on day +62
64/Fswelling of the left face and neck.106routine dental extraction of toothleft submandibular edema2 days<0.7%2174FFPremission achieved on day +10
46/Mbuccal mucosal squamous cell carcinoma31Radical oral tumor resectionmassive subcutaneous neck hemorrhage1101 day4%2massive transfusioninhibitor still present at 8 months – 1BUday 35/dead from cancer relapse at 1 year
59/Msudden-onset headache followed by coma and left hemiparesis; aneurysmal subarachnoid
22.6surgical clipping of saccular aneurysm of the right middle cerebral artery and after 30 days cranioplastyintracranial hematoma51.76 h27%1.54FFPinhibitor levels normal after 2 weeks and APTT normalized after 5 weeks 
61/Mcompartment syndrome of the posterior compartment44fasciotomy followed by seven debridements and amputationright lower extremity posterior compartment1 day5.60%14.610PRBC and 7FFP dead after 11 weeks
84/Mgastric adenocarcinoma27.5distal gastrectomy followed by peritonitis and aspiration pneumonia12140 days<1%7day +280alive
93/Fgingival hemorrhage recession after tooth extraction followed by subdural hemorrhage from falling in hospital70.7tooth extractiontooth socket followed by subdural hematoma from falling8 days9%7FFPdead day+13
55/FPemphigus foliaceus + acute pain in the left lower limb, in the lumbosacral region
and the left groin
64laparotomy for hematoma evacuationabdominal cavity hematomas + left iliac muscle and left obturator
muscle hematomas
20UI/dl (low)1.8FFP6 weeksalive
65/Mulcer of oral mucosa84.8removal of oral hematomastwo hematomas in the oral cavity from oral ulcer of mucosa>50 <1%165 days +35alive
78/Mperiampullary carcinoma105biposymelena2.50%34multiple transfusions11 daysalive
67/Mmalignant stenosis of the distal bile duct – adenocarcinoma of the distal bile duct+ swelling and large
hematoma on his left thigh + hemoperitoneum
92endoscopic retrograde cholangiopancreatography with stent placement 1%303PRBC + FFP + plateletsdead at +30 day
  total pancreatectomy with splenectomyhemoperitoneum with anastomotic leakage55multiple transfusions 
12/Fcongenital choledochal cyst45resection of common bile duct cyst and gallbladder, Roux-en-Y anastomosis followed by 3 laparotomiesanastomosis site78.17 days5%massive transfusionsdead
18/Mcholedochal cyst45resection of choledochal cyst and gallbladder followed by Roux-en-Y anastomosis followed by 3 laparotomiesanastomosis site1051 day11.20%16massive transfusion2 monthsalive at 6 months/dead at 3 years

Out of the 24 cases, 17 were considered SAHA (triggered before and after surgery), one was associated with follicular hyperplasia with IgG4 and lymphoplasmacytic infiltration, with further similar cases reported earlier in the literature [38], and most of them appeared spontaneous, some of them after minor trauma or linked to cancer. There is also one case in a patient with a history of AHA which reappeared after suffering SARS-COV2 infection [40]. The median age of the patients was 67 (range 12–94). Further information is available in Fig. 2 and Table 4.

There is also important to yield the existence of treatment-resistant AHA, notably due to untreated/associated undiagnosed malignancy because the parallel treatment of cancer can help improve the response to AHA treatment [[43][44][45][46]].

In countries with limited resources, as is the case of Romania, Poland, or South Africa, the experience with acquired hemophilia is scarce. Difficulties in recognition of the disease and limited national dedicated hemophilia laboratories, together with the high prices of the treatment required, are the main reasons that lead to a high mortality rate among patients. Given the restrictive nature of the literature in the field of acquired hemophilia, the experience of cases from around the world should be gathered in a database to improve the understanding of the disease and to complete the puzzle. For instance, South Africa has the largest HIV epidemic in the world and the rare association of AHA with HIV infection is therefore relatively more common and seems to predict a longer pathway to remission [57]. In Poland, AHA is currently registered in the national registry of bleeding disorders, as is the case for Romania. We present as a proof-of-concept a recent case report of a 50-year-old woman presenting with hematuria and lumbar pain who underwent ureterorenoscopy and laparotomy for ureteral stenosis, which lead to retroperitoneal bleeding. Reintervention and repeated blood products transfusion were necessary. Disseminated microinfarctions developed in the kidney requiring nephroureterectomy. Coagulation tests revealed FVIII deficiency (7%) and the presence of FVIII inhibitor (2 BU). The patient was treated with rFVIIa, aPCC, and prednisone, then discharged but later readmitted with spontaneous bleeds in extremities muscles and joints requiring rituximab, cyclophosphamide, methylprednisolone, and FVIII concentrate. Even though the bleeding stopped, there was no remission achieved with maximal FVIII activity being 12%, and the inhibitor titer increased to 13 BU. The report highlights the need to consider acquired bleeding disorders in the differential diagnosis of hematuria, even in the presence of renal pathology [58].

4. Conclusions and future directions

The lack of randomized controlled trials on AH renders the recognition, understanding, and treatment of this disease a demanding task. The delay in proper management can lead to life-threatening bleeding episodes which might lead to certain death. A high index of suspicion should be kept to diagnose AH because it often presents as a paraneoplastic syndrome, or as a surgery-associated/triggered disease (SAHA). With appropriate management AH is treatable and the patients should be further referred to specialist hemophilia centers. More reviews are needed to establish a standard of care for patients who develop AH.

4.1. Practice points

•Acquired hemophilia occurs more often than diagnosed in patients with malignancies, active infections, or autoimmune disorders.

• Although newer therapies have expanded the treatment landscape in recent years, this has also created challenges for physicians. Fast diagnosis, choosing the right drugs to use, and when to use them, can be difficult as there is no simple treatment algorithm to guide physician choices.

• Patients with AH provide a particular challenge in the ICU setting, and more work is required to identify suitable treatment options for these patients.

4.2. Research agenda

• Studies comparing different therapeutic options are needed to help define the optimal treatment strategies for different patient subgroups and create a more individualized approach.

• Trials evaluating the use of drugs with new mechanisms of action earlier in the AH setting are required.

• Efforts to identify and develop drugs with new mechanism of action.





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