Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Bleeding, Blood Clot-related Events In US Tied To Acquired Hemophilia

About 30% of people hospitalized due to acquired hemophilia have a bleeding event, while 17% report a thrombotic, or blood clot-related complication, such as stroke and deep vein thrombosis, a nationwide U.S. Study finds.

Patients ages 65 years and older, and those with thrombotic events were more likely to die during a hospitalization. Also, about a third were readmitted within 30 days of being discharged, mainly due to bleeding events and infections.

"This large collection of [acquired hemophilia] admissions and readmissions on a nationwide scale has generated a valuable pool of data, helping to characterize the clinical outcomes and healthcare utilization of this otherwise rare [blood condition]," the researchers wrote. The study, "Acquired (Autoimmune) Hemophilia: Demographics, Outcomes, and Readmissions," was published in Blood Vessels, Thrombosis & Hemostasis.

While most types of hemophilia are caused by genetic mutations, acquired hemophilia has an autoimmune origin and arises when the immune system mistakenly attacks a blood clotting factor, preventing it from functioning normally. In most cases, it targets factor VIII (FVIII), the clotting protein missing or faulty in hemophilia A.

In more than half the patients, the disease is idiopathic, or has an unknown cause, while in the other half, it's associated with other conditions, including autoimmune disorders, cancer, infections, or certain medications.

Treating acquired hemophilia is focused mainly on keeping bleeds under control and suppressing the immune system to reduce the production of the self-reactive antibodies that target clotting factors.

A better look at acquired hemophilia

"Though there have been significant developments in the treatment aspects, not much literature exists on the epidemiology and outcomes of these treatments on a larger population basis," wrote researchers in the U.S. Who conducted a retrospective study using the Nationwide Readmissions Database, which contains information on hospital discharges and readmissions.

A total of 1,450 patients were admitted to the hospital for acquired hemophilia between 2016 and 2019. More than half were men (55.4%), with a median age of 73 when they were admitted. The median length of their hospital stay was seven days.

About 21% had an underlying solid tumor, while 13.5% had an autoimmune disease, and 3.9% had blood cancer. Autoimmune diseases were significantly more frequent in women (22.2% vs. 6.4%) and in those 65 years and older (15.1% vs. 8.5%). No differences in cancer prevalence were seen between gender and age groups.

Almost a third of the patients had a bleeding event. Other complications during hospitalization included heart attack (9.5%), venous thromboembolism, which is when a blood clot blocks blood flow in veins (4.4%), stroke (2.5%), brain hemorrhage (1.5%), and widespread formation of blood clots (1.2%). During their hospitalization, about a quarter of the patients received blood transfusions and 5.4% required invasive ventilation.

Overall, 101 patients (7%) died during their inpatient stay, with higher mortality rates seen in older patients (8% vs. 3%) and in those who'd had a stroke (34.4% vs. 6.3%) or venous thromboembolism (19.6% vs. 6.4%). The median time to death was nine days. The presence or absence of autoimmune conditions or cancer had no effect on mortality rates.

Of the 1,349 patients discharged, 371 (27%) were readmitted within 30 days. This occurred more frequently in those who had an underlying autoimmune condition (35.5% vs. 23.3%). Hospital readmissions lasted a median of seven days, and 10.8% of the patients died.

The most common causes for readmission were infections (30.8%), followed by bleeding (28.2%). Other reasons included heart problems (7.6%), cancer (5.7%), bone fractures (5.6%), and neurologic events (4.6%).

Median hospitalization costs were about $113,000 in first admissions and readmissions.

"These results highlight the complex challenges in managing this disease. High infection rates emphasize the toxic effects of immunosuppressive therapy, while higher bleeding rates demonstrate inadequate inhibitor clearance," the researchers wrote.

What To Know About Treatment Options For Hemophilia

Hemophilia is a serious condition that can limit the ability to avoid episodes of bleeding. Treatment includes regular infusions of proteins to replace what the body doesn't produce naturally.

Hemophilia is a genetic bleeding disorder that prevents blood from properly clotting. Severe bleeding from minor injuries or surgery can occur. Low levels or the absence of some proteins, called clotting factors, are the root cause of hemophilia.

Biological females may be carriers of hemophilia and not affected with symptoms. They can pass the condition on to their children. Hemophilia usually affects boys more than it affects girls. It does run in families, although some families have no prior history of hemophilia when it first appears.

There are a few types of hemophilia, distinguished by their causes. They have similar symptoms but are triggered by unique mutations in different genes.

Hemophilia A

A lack or decrease of clotting factor VIII (FVIII) causes hemophilia A, also called classic hemophilia. Hemophilia A is passed down through genes, but there's no family history in about one-third of cases. This is the most common type of hemophilia.

Hemophilia B

A lack or decrease of clotting factor IX (FIX) causes hemophilia B, also called Christmas disease. Hemophilia B is four times less common than hemophilia A, according to the National Hemophilia Foundation.

Hemophilia C

Reduced levels of clotting factor XI cause hemophilia C, also called factor XI deficiency. It's a rare form of hemophilia involving bleeding following trauma or surgery, including dental procedures. People with hemophilia C may bruise easily or experience nosebleeds more often than others. Biological females may have heavier periods and bleed more after giving birth.

Hemophilia B Leyden

Hemophilia B Leyden is a condition that occurs when someone experiences FIX deficiency in earlier life and the deficiency gradually improves, meaning that they may not require treatment for bleeding episodes by midlife.

The treatment of hemophilia depends on the type.

Hemophilia A treatment

Factor replacement therapy

Concentrated FVIII product, also called clotting factor, is the primary treatment for hemophilia A. This comes in two types: plasma-derived and recombinant. Recombinant factor is a synthetic product developed from DNA in a lab. Plasma-derived factor gets the name because it comes from human plasma. About 75% of people treated receive recombinant factors, according to the National Hemophilia Foundation.

Infusion through a vein in the arm or a port in the chest is the most common delivery system for clotting factors. Typically, treatment happens on a regular schedule to prevent bleeding episodes.

Non-factor replacement therapies

Non-factor replacement therapies are another way of treating hemophilia A. One treatment is emicizumab, a protein synthesized in a laboratory that replaces an activity customarily carried out by the FVIII protein. Emicizumab injected just under the skin on a preventive basis can help prevent bleeding episodes.

Desmopressin

Desmopressin acetate (DDAVP) is a synthetic version of an antidiuretic hormone that helps control bleeding. Useful for people with mild hemophilia, it stops nose, mouth, joint, and muscle bleeding or bleeding before and after surgery. DDAVP comes as an injectable and a nasal spray.

Aminocaproic acid

Aminocaproic acid keeps blood clots from breaking down. Sometimes, when taken in conjunction with clotting factor, it helps clots form and preserves them. Often suitable for dental procedures or to treat mouth or nose bleeds, aminocaproic acid comes as a tablet or liquid.

Hemophilia B treatment

Concentrated FIX

Concentrated FIX clotting factor is the primary medication used to treat hemophilia B. About 75% of people with the condition take a recombinant, or synthetic, form of the product, which is developed in a lab. The other option is a plasma-derived version of the product, which comes from human plasma.

The clotting factor is infused intravenously into the arm or through a port placed in the chest. Typically, it's given on a regular schedule to prevent bleeding.

Aminocaproic acid

Aminocaproic acid prevents blood clots from breaking down. It can be used with clotting factors to help clots form and preserve them. Available in tablet or liquid form, aminocaproic acid is often used before dental procedures or to treat mouth or nose bleeds.

Hemophilia C treatment

Aminocaproic acid and tranexamic acid

For hemophilia C, aminocaproic acid is particularly effective at stopping bleeding from mucous membranes, including bleeding of the mouth and menstruation. It prevents blood clots from dissolving or breaking down, and when used together with clotting factors, it can help clots form and prevent them from disappearing.

Additionally, tranexamic acid is also used to treat hemophilia in the short term.

Excessive menstrual bleeding might also require hormonal contraceptives.

In 2022, the Food and Drug Administration (FDA) approved a one-time, single-dose treatment for hemophilia B. Called Hemgenix (etranacogene dezaparvovec), the medication deposits a working gene for FIX clotting protein in the liver, where clotting protein originates.

Common side effects of Hemgenix included liver enzyme elevation, headache, mild infusion-related reactions, and flu-like symptoms.

Hemgenix is the most expensive medication ever approved by the FDA, costing $3.5 million per dose.

Gene therapy

Hemophilia results from a mutation to a gene that controls blood clotting. Gene therapy provides a working copy of the gene to the individual's body to prompt the body to produce its own clotting factor.

Anti-tissue factor pathway inhibitor (TFPI) or anti-TFPI

This treatment works by slowing the system that prevents the body from clotting. Anticoagulants like TFPI prevent clotting, so interrupting their work allows clotting to happen. Because anti-TFPI isn't specific to a particular clotting factor protein, it can treat hemophilia A and B.

RNA interference (RNAi) therapy targeting antithrombin

RNAi therapy focuses on an anticoagulant known as antithrombin. It encourages the development of thrombin, a coagulant that helps blood clot. RNAi therapy can treat hemophilia A and B since it doesn't rely on one clotting protein.

The FDA-approved treatment Hemgenix is the most expensive drug ever approved, costing $3.5 million per single dose. However, the drug maker, CSL Behring, thinks that's a fair price compared with the overall lifetime costs of treating hemophilia.

A 2021 study found that the cost for an adult's lifetime treatment of moderately severe to severe hemophilia B averages $22,987,483 million for preventive FIX treatment and $20,971,826 for on-demand FIX treatment.

Research from 2022 noted that the average cost of treatment in the United States is about $150,000 to $300,000 per year. This doesn't factor in indirect costs like decreased productivity or missing work or school due to bleeding or treatment.

Private health insurance may or may not cover hemophilia treatment costs, depending on the plan's guidelines. Medicare part B does cover clotting factor therapies, while part D covers prescription drugs.

Hemophilia is a bleeding disorder that's usually passed down through families. It results from a gene change that lowers the levels of certain proteins called clotting factors. There are several types of hemophilia, including A, B, C, and B Leyden.

The FDA recently approved a medication, Hemgenix, to treat hemophilia B. It's a single-dose treatment, so it may, with more research, be considered a cure. It delivers a copy of a working gene to the liver, which is then prompted to produce its own clotting factor. Hemgenix is the most expensive medication ever approved by the FDA.

Currently, the most common treatment for hemophilia is to have preventive infusions of clotting factor given several times per week. Over a lifetime, this is also an expensive treatment, so Hemgenix may be more cost-effective if it's found to work over many years.

Takeda To Discontinue Hemofil M, Recombinate For Hemophilia A

Takeda Pharmaceuticals has decided to discontinue Hemofil M (human antihemophilic factor) and Recombinate (recombinant antihemophilic factor), both of which are approved as replacement therapies to prevent and control bleeding episodes in children and adults with hemophilia A.

"This was not a decision we made lightly," Anthea Cherednichenko, Takeda's vice president and franchise head of U.S. Hematology, wrote in a letter informing patients of the company's decision to discontinue the two products globally.

The decision was made because patients are switching to newer treatments — including Takeda's own options — and not due to quality concerns, according to the company. Both Hemofil M and Recombinate remain safe and effective as described in their prescribing labels, per Takeda.

"As the treatment landscape evolves, we decided to discontinue these medicines as hemophilia patients continue to transition to alternate treatment options in the space, including those within our own hematology portfolio," Cherednichenko wrote, adding to patients, "we understand that this directly impacts you."

Hemofil M and Recombinate will be supplied until stocks run out or expire by mid-2026, depending on how many patients are still using them before switching to alternative treatments, according to the company. This was also noted in a statement from the National Bleeding Disorders Foundation, a U.S. Nonprofit advocating for patients with bleeding diseases.

The foundation encouraged all people with hemophilia to register for the patient notification system, a communication system providing information on withdrawals or recalls for therapies for bleeding disorders.

Patients can switch to Takeda's Advate, Adynovate, among other options

To help with the switch, Takeda advises patients to talk with their doctors about other treatment options. Two potential alternatives include the company's Advate (octocog alfa) and Adynovate (rurioctocog alfa pegol), marketed as Adynovi in Europe.

"We encourage you to consult with your healthcare team now to allow time to develop longer-term plans," the company wrote on a website it developed to answer to some frequently asked questions and support patients in their journey off Hemofil M or Recombinate. The site notes that, as of July 2022, Advate "the most widely used FVIII [replacement therapy] in the U.S."

Hemophilia A is caused by the lack or dysfunction of factor VIII, or FVIII, a clotting protein also known as antihemophilic factor. Without FVIII, the blood cannot clot properly. As a result, people with hemophilia A may experience heavy and longer than usual bleeding episodes, occurring either spontaneously or as a result of an injury or surgery.

Both Hemofil M and Recombinate contain a FVIII concentrate that can be used as a replacement therapy to make up for the faulty or missing clotting protein. The therapies thus help to prevent and control bleeding in hemophilia A patients. Hemofil M is pooled from human plasma, while Recombinate contains a recombinant or lab-made version of FVIII.

We are proud to offer alternative treatment options … that may meet your individual needs and are similar to Hemofil M and Recombinate.

Like Recombinate, the company's Advate and Adynovate therapies contain a recombinant version of FVIII that works in the same way as the clotting protein found naturally in the blood. Both are approved for routine prophylaxis, or preventive treatment, and for on-demand treatment of bleeding in children and adults with hemophilia A.

While both potential alternatives are given as an infusion directly into the bloodstream, in Adynovate, the recombinant protein is attached to polyethylene glycol, a molecule that makes it last longer in the blood. As a result, Adynovate requires fewer infusions than Advate when used as prophylaxis to reduce the frequency of bleeding episodes.

"For more than 70 years, we've pioneered innovations and worked tirelessly to improve the standard of care for hemophilia patients," Cherednichenko wrote in the letter to patients. "We are proud to offer alternative treatment options … that may meet your individual needs and are similar to Hemofil M and Recombinate."

Takeda also is working with healthcare professionals and national member organizations belonging to the World Federation of Hemophilia (WFH) to help with the transition, according to a WFH statement. National member organizations needing support should reach out to their WFH regional manager.

---