Unexplained hemorrhagic syndrome? Consider acquired hemophilia A or B
Presumably, the pathophysiology is different from congenital hemophilia . 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 .
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 . 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 B||6. Hematological; solid tumors (malignancy) – prostate, lung, colon, stomach, pancreas, breast, kidney; as paraneoplastic syndrome|
|2. Diabetes||7. Inflammatory bowel disease or ulcerative colitis|
|3. Hepatitis||8. 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. Pregnancy||10. 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|
|Pregnancy – postpartum genital bleeding||Retroperitoneal|
|Surgery with postoperative bleeding|
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 .
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 . 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 .
Bypassing agents are concentrates of factors that bypass the acquired deficiency and have around 90% efficacy [, , ]. 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 . The dose is 70–90 μg/kg every 2–3 h until hemostasis is achieved. Afterward, the dosing interval is prolonged . 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 . The prophylactic use of bypassing agents is controversial because it can be associated with a risk of arterial and thrombotic events .
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 .
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) . 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 .
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 .
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 .
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 . 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 .
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 .
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 .
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 . 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 .
Clinical evaluation, bleeding control with stationary hemoglobin values and imaging studies are the primary mains of monitoring the response after the therapy . 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 . 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 .
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,, , , , , , , , , , , , , , , , , , , , , , ]. SAHA is reported after both minor, like tooth extraction , and major surgery on the digestive tract due to triggering inhibitors formation . 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 .
Table 4. Acquired hemophilia cases with countries of origin.
|Case with reference and country||Age/sex||Signs and symptoms at presentation||APTT at presentation (seconds)||Surgical operation||Bleeding site||APTT after hemorrhage (seconds)||Time from surgery to bleeding (days)||FVIII activity||FVIII inhibitor titer (Bethesda units)||Overall transfuion requirement||Time to dissaparance of inhibitor||Outcome/follow-up|
|82/M||hematuria; disuria||42||cystoscopy||kidney hematoma||49||1||low||elevated (NS)||–||APTT normalized after 4 days/factor VIII levels returned to normal after 2|
|stable at 6 months|
|78/F||recurrent GI bleeding,multiple ecchymoses|
over her chest and upper extremities,oral mucosal ecchymoses
|48||–||–||–||–||<1%||59.7||1PRBC||after 4 doses of Rituximab – inhibitor – > 2||stable at 6 months|
|74/M||–||–||right upper shoulder dermatofibrosarcoma and inguinal hernia repair||hematoma in the anterior soft tissues of the lower mid abdomen and a moderate to large hemoperitoneum||56.8||1||low||4.2||7 PRBC +1FFP + 1 cryoprecipitate+1 unit of platelet||APTT normalized after 10 days||–|
|94/M||TIA + spontaneous hematoma of upper arm||81.4||–||–||–||–||<0.01 UI/ml||8.2||–||–||at 36 months uneventful|
|75/M||cervical lymphadenopathies (benign follicular hyperplasia with IgG4+ lymphoplasmacytic infiltration)||72||–||–||–||–||1%||27||–||–||Remission at last follow-up (36 months from AHA diagnosis)|
|AHA relapse at 18 moths||65||–||–||–||–||2%||12||–||–|
|81/M||ecchymosis and edema of the right shin and the right and left forearms||80||Whipple’s operation for carcinoma of the ampulla of Vater||–||–||2 months (tumor relapse)||NA||–||NA||APTT normalized after 6 weeks||dischargerd after 6 weeks|
|66/M||spontaneous severe cutaneous and muscle bleeding||70||–||–||–||–||<1%||25||–||–||remission achieved on day +21|
|75/M||trunk hematoma + SARS-COV2 infection (reappearance of AHA after 9 years)||66||–||trunk hematoma||–||–||<1%||19||–||–||remission achieved on day +20|
|75/F||spontaneous bruising of the upper extremities (after levofloxacin)||–||–||spontaneous bruising of the upper extremities||–||–||low||30.4||–||–||remission achieved on day +52|
|87/F||spontaneous hematomas on the right leg and both feet since 5 weeks and spontaneous large muscular|
bleeding in the gluteal region
|87.3||–||spontaneous hematomas on the right leg and both feet since 5 weeks and spontaneous large muscular|
bleeding in the gluteal region
|–||–||1%||150||4PRBC||day +55||alive at 6 months|
|a year later – melena||73.9||–||gastrointestinal||–||–||2%||4.6||–||day +14||alive at 6 months|
|66/M||myelofibrosis evolving in acute myeloid leukemia||43.8||splenectomy + phrenic artery hemorrhage||hematoma in his pancreatic loge||52||35 days||<1%||17.3||–||day +50||remission achieved on day +50|
|77/M||compartment syndrome of left calf following a minor trauma + myeloma||119||–||compartment syndrome of left calf||–||–||2%||102||–||APTT normalized after 1 month||alive|
|65/M||ruptured aneurysmal subarachnoid hemorrhage and hydrocephalus||55||percutaneous gastrostomy||PEG insertion site||79||6 days||4%||10||PRBC||–||remission achieved on day +62|
|64/F||swelling of the left face and neck.||106||routine dental extraction of tooth||left submandibular edema||–||2 days||<0.7%||217||4FFP||–||remission achieved on day +10|
|46/M||buccal mucosal squamous cell carcinoma||31||Radical oral tumor resection||massive subcutaneous neck hemorrhage||110||1 day||4%||2||massive transfusion||inhibitor still present at 8 months – 1BU||day 35/dead from cancer relapse at 1 year|
|59/M||sudden-onset headache followed by coma and left hemiparesis; aneurysmal subarachnoid|
|22.6||surgical clipping of saccular aneurysm of the right middle cerebral artery and after 30 days cranioplasty||intracranial hematoma||51.7||6 h||27%||1.5||4FFP||inhibitor levels normal after 2 weeks and APTT normalized after 5 weeks|
|61/M||compartment syndrome of the posterior compartment||44||fasciotomy followed by seven debridements and amputation||right lower extremity posterior compartment||–||1 day||5.60%||14.6||10PRBC and 7FFP||dead after 11 weeks|
|84/M||gastric adenocarcinoma||27.5||distal gastrectomy followed by peritonitis and aspiration pneumonia||–||121||40 days||<1%||7||–||day +280||alive|
|93/F||gingival hemorrhage recession after tooth extraction followed by subdural hemorrhage from falling in hospital||70.7||tooth extraction||tooth socket followed by subdural hematoma from falling||–||8 days||9%||7||FFP||–||dead day+13|
|55/F||Pemphigus foliaceus + acute pain in the left lower limb, in the lumbosacral region|
and the left groin
|64||laparotomy for hematoma evacuation||abdominal cavity hematomas + left iliac muscle and left obturator|
|–||–||20UI/dl (low)||1.8||FFP||6 weeks||alive|
|65/M||ulcer of oral mucosa||84.8||removal of oral hematomas||two hematomas in the oral cavity from oral ulcer of mucosa||>50||<1%||165||days +35||alive|
|78/M||periampullary carcinoma||105||biposy||melena||–||–||2.50%||34||multiple transfusions||11 days||alive|
|67/M||malignant stenosis of the distal bile duct – adenocarcinoma of the distal bile duct+ swelling and large|
hematoma on his left thigh + hemoperitoneum
|92||endoscopic retrograde cholangiopancreatography with stent placement||–||–||1%||30||3PRBC + FFP + platelets||–||dead at +30 day|
|total pancreatectomy with splenectomy||hemoperitoneum with anastomotic leakage||–||–||–||55||multiple transfusions||–|
|12/F||congenital choledochal cyst||45||resection of common bile duct cyst and gallbladder, Roux-en-Y anastomosis followed by 3 laparotomies||anastomosis site||78.1||7 days||5%||–||massive transfusions||–||dead|
|18/M||choledochal cyst||45||resection of choledochal cyst and gallbladder followed by Roux-en-Y anastomosis followed by 3 laparotomies||anastomosis site||105||1 day||11.20%||16||massive transfusion||2 months||alive 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 , 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 . 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 [, , , ].
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 . 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 .
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.