Hemorrhagic diathesis – normal hemostasis. Hemophilia

01Definition and overview

Haemophilia is an inherited lack of a clotting factor: factor VIII in haemophilia A, about four cases in five, and factor IX in haemophilia B (Christmas disease). Both are X-linked, so nearly all patients are male, and both cause the same failure of secondary haemostasis: the platelet plug forms, but too little thrombin is made to bind it with fibrin. Normal haemostasis as a whole, and how the platelet plug fails, are covered with thrombocytopenia.

Disorders of the clotting factors

Severity

The factor level predicts the bleeding, though not exactly: some people with severe haemophilia bleed rarely, and some with moderate disease bleed often. Normal is 50 to 150 per cent of the average, and 1 per cent equals 1 IU/dL.

02Etiology and pathophysiology

The clotting factors

The clotting factors are plasma proteins made mostly by the liver; factor VIII comes mainly from the endothelium of the liver's sinusoids and circulates bound to von Willebrand factor (VWF), which protects it. Most are enzymes that circulate inactive and activate the next in turn; the cofactors speed their enzymes many thousand-fold.

Two models of clotting

The classic cascade describes the test tube. The prothrombin time (PT) starts clotting with tissue factor (the extrinsic pathway, factor VII), the activated partial thromboplastin time (APTT) with a contact surface (the intrinsic pathway, factors XII, XI, IX and VIII), and both end in the common pathway of factors X, V, II and fibrinogen. It explains the tests, but not why a lack of factor XII never bleeds while a lack of factor VIII or IX does. The cell-based model describes the body, here simplified:

1. 1

   Initiation

   Injury exposes cells that carry tissue factor. Tissue factor with factor VIIa activates a little factor X and IX, and Xa with Va makes a trace of thrombin, before tissue factor pathway inhibitor (TFPI) shuts this route down.
2. 2

   Amplification

   The trace of thrombin activates the platelets at the injury, frees factor VIII from VWF and activates it, and activates factors V and XI.
3. 3

   Propagation

   On the activated platelets, factor IXa with VIIIa (the tenase) makes factor Xa, and Xa with Va (the prothrombinase) makes a burst of thrombin, which turns fibrinogen into fibrin.

Haemophilia fails at propagation: initiation is normal, so a little thrombin forms, but without the tenase there is no burst, and the loose clot breaks down. The model explains the treatments: high doses of factor VIIa activate factor X on platelets without VIII or IX, and emicizumab, an antibody that holds factors IXa and X together as VIIIa does, takes over the role of factor VIII.

The brakes on clotting

Fibrinolysis clears fibrin as the vessel heals. Tissue plasminogen activator from the endothelium turns plasminogen bound to fibrin into plasmin, which cuts fibrin into fragments, among them D-dimer from cross-linked fibrin; plasminogen activator inhibitor 1 and α2-antiplasmin restrain it. Tranexamic acid stops plasminogen binding to fibrin, so it helps where fibrinolysis is brisk: the mouth, nose, uterus and gut.

Genetics

The F8 and F9 genes lie near the tip of the long arm of the X chromosome. An inversion within intron 22 of F8 causes about half of severe haemophilia A; other variants are point changes, deletions and insertions, and about a third of all cases arise from a new variant, with no family history. Large deletions and variants that make no protein carry the highest risk of inhibitors.

• An affected man passes his X to every daughter, who all carry the variant, and his Y to every son, who are all unaffected.
• A carrier woman passes it to half her sons, who are affected, and to half her daughters, who carry it.
• Random inactivation of one X in each cell (lyonisation) spreads carriers' levels widely, and about 30 per cent are below 40 per cent. Since 2021 these women are said to have haemophilia, graded as in men; carriers with normal levels who bleed are symptomatic carriers.
• Rarely, a woman has haemophilia from Turner syndrome, or as the daughter of an affected man and a carrier.

How joints are destroyed

1. 1

   Bleeding

   Blood from the vessels of the synovium fills the joint and stretches its capsule.
2. 2

   Synovitis

   Iron from the blood inflames the synovium, which thickens and grows fragile new vessels, so it bleeds again more easily: a target joint.
3. 3

   Arthropathy

   Iron and inflammation destroy the cartilage and the bone beneath, leaving a stiff, painful, deformed joint, by early adult life without prophylaxis.

03Clinical features

How it shows

Severe haemophilia usually shows in the first two years: bleeding after circumcision, bruises as a baby starts to crawl, bleeding from the mouth, then joint bleeds as he walks. Most newborns do not bleed, though a difficult delivery can cause bleeding inside the head. Mild haemophilia may go unnoticed until an extraction, an operation or an injury, sometimes in adult life, and the bleeding typically stops, then starts again hours or days later. Bleeding in childhood as a whole is covered with bleeding disorders in children.

of bleeds are into joints, mostly the knees, elbows and ankles

70–80per centof bleeds are into joints, mostly the knees, elbows and ankles

are into muscles

10–20per centare into muscles

are inside the skull or spine, the commonest fatal bleeds

5per cent or fewerare inside the skull or spine, the commonest fatal bleeds

• Haemarthrosis: tingling or warmth first, then pain, swelling, heat and a joint held bent. A target joint has had three or more spontaneous bleeds within six months.
• Muscle bleeds: an iliopsoas bleed gives pain in the groin or lower abdomen with the hip held flexed, can mimic appendicitis and can compress the femoral nerve, numbing the front of the thigh; bleeds into the forearm or calf can cause a compartment syndrome. A pseudotumour, a slowly growing encapsulated collection of blood, can erode bone.
• Life-threatening bleeds: inside the head, often after a trivial injury and sometimes hours or days later; in the throat or neck, threatening the airway; into the gut or the iliopsoas; and after any major injury.
• Other bleeds: blood in the urine, bleeding from the gums and after extractions.

04Diagnosis and management

Tests of clotting

Normal plasma restores any single missing factor to at least half, enough to correct the time, so a mix that stays long points to an inhibitor: a lupus anticoagulant, which causes clots rather than bleeding (see antiphospholipid syndrome), heparin, or an antibody against factor VIII. That antibody acts slowly, so the mix is tested again after two hours at 37 °C. The bleeding time is obsolete.

The bleeding history is scored with a tool such as the ISTH bleeding assessment tool (ISTH-BAT), abnormal at 4 or more in men, 6 or more in women and 3 or more in children. Normal screening tests do not exclude a bleeding disorder: von Willebrand disease, mild haemophilia, factor XIII deficiency, platelet function disorders and vascular disorders can all leave the PT and APTT normal.

Diagnosing haemophilia and carriers

• An isolated long APTT with a normal PT and platelet count, correcting on mixing; mild haemophilia can have a normal APTT.
• A low factor VIII or IX sets the type and severity. Both one-stage and chromogenic factor VIII assays are done, as each misses some mild haemophilia A.
• VWF tests exclude von Willebrand disease: type 2N, in which VWF cannot hold factor VIII, mimics mild haemophilia A.
• Genetic testing of the first person affected in a family finds the variant, which guides testing of relatives, prenatal diagnosis and the risk of inhibitors.
• Factor VIII is at adult levels at birth, so in a boy born to a carrier most haemophilia A can be diagnosed from cord blood; factor IX is low in every newborn, so mild haemophilia B is confirmed at 3 to 6 months.

Women at risk have a factor level and a genetic test before surgery or pregnancy, or when they bleed. A pregnant carrier can learn the baby's sex from cell-free fetal DNA in her blood, and a boy can be tested by chorionic villus sampling from about 11 weeks, or by amniocentesis late in pregnancy to plan the birth. A boy who may be affected is delivered where haemophilia care is at hand, without ventouse, mid-cavity forceps, fetal scalp electrodes or scalp blood sampling; his cord blood is tested, and intramuscular injections wait until his level is known.

Treating haemophilia

Care is led by a comprehensive care centre: haematologists, specialist nurses, a physiotherapist, a dentist, a psychologist and a specialist laboratory, with treatment at home, an emergency card and a plan for every procedure. Treatment either replaces the missing factor or rebalances clotting with a drug that is not a factor.

• Factor concentrates, plasma-derived or recombinant, are given into a vein. One unit per kg raises factor VIII by about 2 per cent and factor IX by about 1 per cent, so the dose of factor VIII is the weight in kg × the rise wanted in per cent × 0.5. Standard factor VIII has a half-life of about 12 hours, factor IX 18 to 24 hours.
• On-demand treatment stops bleeds, and prophylaxis prevents them. Prophylaxis is the standard in severe haemophilia and in moderate disease that bleeds; started before the second joint bleed and before 3 years of age, it prevents arthropathy. A trough of 1 per cent is no longer thought enough: the aim is 3 to 5 per cent or more, or no bleeds at all.

In trials, emicizumab cut treated bleeds by 87 per cent against no prophylaxis in patients with inhibitors and by 96 to 97 per cent in those without, and they had 68 per cent fewer than on their own earlier factor prophylaxis. Breakthrough bleeds and surgery still need factor VIII, or a bypassing agent if there is an inhibitor. Activated prothrombin complex concentrate at more than 100 U/kg a day for a day or longer, given with emicizumab, caused thrombotic microangiopathy and clots, so recombinant factor VIIa is preferred. All the rebalancing drugs carry some risk of thrombosis, mostly when breakthrough bleeds are treated with large doses of factor or bypassing agents.

On emicizumab, a normal APTT says nothing about haemostasis: the drug brings the APTT to normal at low concentrations and makes one-stage factor VIII assays read falsely high, so factor VIII and its inhibitor are measured with chromogenic assays that use bovine reagents.

Gene therapy delivers a working F8 or F9 gene to liver cells in an adeno-associated virus (AAV) vector, as a single infusion. Antibodies against the vector rule out valoctocogene roxaparvovec, though not etranacogene dezaparvovec; the liver enzymes often rise as immune cells attack the treated cells, needing steroids, and it cannot be given twice.

Inhibitors

About 30 per cent of people with severe haemophilia A make antibodies against infused factor VIII (inhibitors), most within the first 20 days of exposure; so do 5 to 10 per cent with mild or moderate haemophilia A and up to 5 per cent with haemophilia B, where they can come with anaphylaxis to factor IX. A bleed that does not respond to the usual dose suggests one, and children are screened regularly as treatment begins. An inhibitor below 5 Bethesda units can sometimes be overcome with more factor; stronger ones need bypassing agents, recombinant factor VIIa or activated prothrombin complex concentrate (aPCC). Immune tolerance induction, high doses of factor given regularly for months to years, clears the inhibitor in 70 to 80 per cent with haemophilia A, fewer with B, in whom it can cause nephrotic syndrome. Emicizumab now prevents bleeds in haemophilia A with inhibitors.

Desmopressin and tranexamic acid

Desmopressin, 0.3 µg/kg into a vein or under the skin, or as a nasal spray, releases factor VIII and VWF from the endothelium and raises them 3 to 6 times. It works in mild haemophilia A and most type 1 von Willebrand disease, once a test dose has shown a response, but not in haemophilia B. Repeated for more than 3 days in a row, it loses its effect; it retains water, so fluids are restricted to prevent hyponatraemia, it is not given to children under 2 years, and it is used with caution in heart and arterial disease, as it can provoke thrombosis. Tranexamic acid, 25 mg/kg by mouth 3 to 4 times a day or as a mouthwash, helps bleeding from the mouth, nose and uterus and covers extractions; it is avoided when the kidney bleeds, as clots can block the ureter.

Treating bleeds

A bleed is treated at once, at home if possible, before it is confirmed. A joint bleed also needs rest, ice and elevation, then physiotherapy as the pain settles; chronic synovitis may need synovectomy, and a destroyed joint replacement. The World Federation of Hemophilia sets these targets for factor VIII where factor is plentiful:

Targets for factor IX in serious bleeds are lower, 60 to 80 per cent at first. After a head injury, however slight, factor goes in first, to 80 to 100 per cent, and the scan follows.

Acquired haemophilia A

Acquired haemophilia A is an autoantibody against factor VIII in someone who has never bled before. About half of cases come with autoimmune disease, cancer, the months after childbirth or a drug; the rest have no cause. Bleeding is sudden and often severe, into the skin as large bruises, into muscles and soft tissue, into the gut or after procedures, but rarely into joints. The APTT is long and does not correct on mixing after incubation, factor VIII is low and the Bethesda assay measures the inhibitor; a lupus anticoagulant is excluded.

• Bleeding is stopped with recombinant factor VIIa, aPCC or recombinant porcine factor VIII (susoctocog alfa), which the antibody binds less; human factor VIII and desmopressin work only against a weak inhibitor.
• The antibody is removed with prednisolone, alone or with cyclophosphamide, or with rituximab. Remission takes a median of about 5 weeks, and about a fifth relapse.
• In a UK survey bleeding killed 9 per cent of patients, a risk that lasted until the inhibitor was gone.

Von Willebrand disease

Von Willebrand disease (VWD) is a lack or defect of VWF, which holds platelets to the injured wall and carries factor VIII. It bleeds like a platelet disorder: bruising, nosebleeds, heavy periods, and bleeding after childbirth, extractions and surgery. Joint bleeds are less common than in haemophilia but not confined to type 3: in one national cohort of moderate and severe disease about a quarter reported them, and they are likeliest where factor VIII is also low, as in type 3 and type 2N.

Type 1 is diagnosed with a VWF level below 0.30 IU/mL whatever the bleeding history, or below 0.50 IU/mL in someone who bleeds abnormally. Levels rise with stress, inflammation, pregnancy and oestrogen and are lower in blood group O, so a normal result may need repeating. Treatment is desmopressin where a trial shows it works, tranexamic acid, hormonal treatment for heavy periods, and concentrates containing VWF, plasma-derived or recombinant (in the EU since 2018), for type 3, most type 2 and major surgery.

Other acquired disorders

• Vitamin K deficiency, from malabsorption, obstructive jaundice, a poor diet with antibiotics, or in newborns not given vitamin K at birth, lengthens the PT first. Vitamin K corrects it within a day, and prothrombin complex concentrate does so at once when bleeding is serious.
• Liver disease lowers most factors, though not factor VIII and VWF, which rise, and also lowers the natural anticoagulants and the platelets, so its balance is fragile and a long PT does not measure the risk of bleeding.
• Anticoagulants are the commonest acquired cause, each with its own reversal.
• DIC consumes factors and platelets in sepsis, trauma, obstetric emergencies and cancer, notably acute promyelocytic leukaemia; its score is given with thrombocytopenia.

05Epidemiology

Haemophilia affects males of every ethnic group. National registries give a prevalence of about 17 per 100 000 males for haemophilia A, 6 of them severe, and about 4 per 100 000 for haemophilia B, 1 of them severe. At birth the rates are about 25 and 5 per 100 000 boys, roughly 1 in 4000 and 1 in 20 000; the gap, measured in high-income countries, reflects a shorter life expectancy. About 1.1 million men worldwide are expected to have haemophilia, 400 000 of them severe, far more than are diagnosed, most of the missing in poorer countries. Women with haemophilia are fewer, and often unrecognised.

Von Willebrand disease is found in up to 1 in 100 people by laboratory testing, but about 1 in 1000 has symptoms, and type 3 affects roughly 1 in a million. Acquired haemophilia A affects about 1.5 per million people a year, with a median age of 78 in a UK survey and a smaller peak after childbirth.

06Prognosis

With prophylaxis and comprehensive care, people with haemophilia in high-income countries live far longer than they did, though still a few years less than other men (6 years less in a Dutch national cohort followed to 2018); bleeding inside the head and cancer are now the commonest causes of death. Their joints depend on when prophylaxis began: those who started late live with arthropathy and chronic pain, and many need joint replacements. Plasma concentrates of the 1970s and 1980s infected many with HIV and hepatitis C, and many died; viral inactivation and recombinant products ended this, but survivors still carry its burden. Inhibitors, lack of access to factor and bleeding inside the head remain the main threats to life. How long gene therapy lasts, and its long-term effects on the liver, are still being followed. Acquired haemophilia A is often fatal in these older patients: in one registry about a third had died within a year, more often of infection under immunosuppression than of bleeding. Von Willebrand disease seldom shortens life.