Knowledge of a congenital bleeding disorder affecting male infants can be inferred from rulings in the Babylonian Talmud¹ compiled about 500 CE. A dispensation was given to forgo circumcision in brothers and cousins of affected boys who had died after the ritual was carried out (presumably from bleeding), showing that the Rabbis recognized inheritance of a bleeding tendency through carrier females. Abu al-Qasim Khalaf ibn al-Abbas Al-Zahrawi, known as Albucasis (936-1013), the great Moorish surgical writer of 10th-century Spain, wrote of a certain village where boys and men suffered excessive bleeding after minor injury. He also gave the first practical advice for treating such bleeding by means of cautery, the success of which he observed. We can now interpret this report as referring to moderately severe hemophilia with a local founder effect.

The curious word for an abnormal inherited bleeding tendency which we use today—hemophilia (literally blood lover)—was introduced by Hopff in his doctoral thesis delivered at Wurzburgin 1828.

The medical literature of the 18th and 19th centuries on hemophilia was gathered in a monumental review published in 1911 by the Francis Galton Laboratory for National Eugenics of the University of London (now abbreviated to The Galton Laboratory). The review² described clearly all the clinical features that are seen today in untreated cases of hemophilia. However, they failed to recognize the key feature of X-linked inheritance—daughters of affected males are obligate carriers of the mutant gene. The correct theoretical explanation of chromosomal sex determination and of sex-linked inheritance in mammals had only just been proposed and had evidently not come to their notice. Notably absent from the nearly 1,000 pedigrees of hemophilic families illustrated in the review was that of the most famous hemophilic family in history, namely the descendants of Queen Victoria, who was an obligate carrier on pedigree evidence (FIGURE 51.1). In addition to her British descendants, she transmitted hemophilia to three other European Royal families through dynastic marriage alliances. No antecedents of Queen Victoria had a bleeding tendency, so it is likely that she inherited a new mutation in one or other of the parental gametes, as is the case for a third of carriers of hemophilia. Three of her daughters were carriers of the hemophilic gene and her youngest son Leopold had clinically severe hemophilia. The mutant gene then made its way into the German, the Spanish, and most famously the Russian Royal families. Leopold’s daughter, the Princess Alice, was an obligate carrier and had two affected sons who died in childhood. The German affected boys also died young, but the Spanish princes with hemophilia survived into their 20s before succumbing to trauma-induced bleeding. Alexey Romanov, the Tsarevich (heir to the throne of Russia), was affected with severe hemophilia. Alexey was murdered on Lenin’s orders with his family at Yekaterinburg during the civil war following the Bolshevik revolution. Hence by 1938, there were no surviving male descendants of Queen Victoria with hemophilia. In 1952, it emerged that there are two types of hemophilia—A and B. The question then arose, whether the “Royal disease” was type A or type B. It became a long-standing historical puzzle which was finally solved almost 60 years later, by a tour de force of forensic genetics, in favor of hemophilia B,³ by genomic analysis of the Imperial family’s bones, recovered from unmarked graves near Yekaterinburg (FIGURE 51.2).

The X-linked inherited bleeding disorders, hemophilia A and B, are due respectively to mutations at the factor VIII (FVIII) locus (f8) or the FIX locus (f9), both situated on the long arm of chromosome ×X at Xq2.8 and Xq2.6, respectively. Thef8-linked condition, caused by deficient synthesis of coagulation FVIII, is known as hemophilia A, whilst the f9-linked condition, due to deficient synthesis of coagulation FIX, is called hemophilia B or Christmas disease (after one of the first described sufferers). The clinical features of the two conditions are indistinguishable, and they were not separated until complementation studies in 1952 uncovered the fact that blood from a majority of patients with X-linked hemophilia (type A) could correct the coagulation defect in blood from a minority (type B) and vice versa. FIX itself was discovered as a result of these studies, being called at first Christmas factor⁴ to distinguish it from antihemophilic factor, the name already assigned to the putative entity lacking in the blood of type A patients. Biochemically, FVIII and FIX function together as a binary enzyme (FIXa) cofactor (FVIIIa) complex whose substrate is FX.

The incidence ratio of hemophilia A to B is about 5 to 1, and both conditions are rare: hemophilia A affects 1 in 5,000 males at birth whereas hemophilia B affects only 1 in 25,000 males at birth. Contrary to the commonly held belief that carriers are unaffected, about a third of females who are heterozygous for mutations at either locus manifest mild hemophilia due to skewed ×X inactivation.

Acquired hemophilia A is a rare autoimmune disorder caused by failure of self-tolerance toward FVIII occurring in later life, with production of antibodies neutralizing the activity of the patient’s own FVIII. Hemophilia A and B are treated together in the following discussion of the pathology, clinical features, and treatment of the two disorders, only noting differences where relevant.

All clinical features of hemophilia A and B are due to deficiency of FVIIIor FIX respectively, with consequent failure to generate adequate thrombin in response to injury and hence failure to form a stable hemostatic plug at sites of vascular damage. Correction of the defect by intravenous infusion of the relevant missing factor completely normalizes thrombin generation, since all other factors required for hemostasis are present in normal amounts. Several circumstances conspire to frustrate our efforts to normalize clotting in a hemophilic person’s blood. FVIII and FIX are scarce proteins which are difficult to purify and difficult to make by genetic engineering. Hence, the cost of clinical factor concentrates is extremely high. Given a supply of factor concentrate, it still has to be introduced into the circulation by intravenous infusion. Vascular access is therefore critical for hemophilia care lifelong. Most problematic of all is the short half-life in the circulation of infused factor— 8 to 12 hours for FVIII and 15 to 20 hours for FIX. In fact, four out of five hemophiliacs worldwide have little or no access to replacement therapy at all. Treatment regimens discussed below are a compromise designed to maximize the benefit of scarce resources and minimize the dire effects of bleeding, which if left unstaunched leads to progressive damage wherever bleeding is prone to occur.

If left without effective treatment the natural history of hemophilia is progressive loss of mobility from joint and muscle bleeding and early death due to exsanguination or uncontrolled internal bleeding, most often intracranial. Prior to the advent of factor concentrates in the 1970s, the most severely affected hemophiliacs died before the age of 20. In contrast to that dire prognosis, modern comprehensive hemophilia care, supported by the resources of an economically advanced state, can normalize life span and limit or eliminate tissue damage.⁵ Adequate supplies of virus safe FVIII and FIX first became widely available in the 1990s; hence most hemophiliacs born before 1985, even in economically advanced countries, are living with the long-term effects of undertreatment in childhood and infection by hepatitis C and HIV, which were present in factor concentrates up to 1986.

Since there is no heterozygote advantage to carrying defects at the f8 or f9 loci and since the hemizygous male has severely limited reproductive fitness (absent treatment), the frequency of “hemophilic” gene defects in the population must be maintained by new mutations. Consequently and as predicted by Haldane (op. cit.), the mutations are highly diverse.

Usually genetic analysis is carried out following the measurement of blood factor level establishing the diagnosis in the affected male, but putative carriers of hemophilia A or B often have no living affected relative, due to early death. Alternatively they may be carriers of a recent mutation. To help such women with establishment of carrier status and genetic counseling, it is then necessary to sequence their f8 and/or f9 genes. Detection of a heterozygous mutation already noted in the databases associated with hemophilia, or (if not previously reported) plausibly causative of deficient/functionally defective FVIII or FIX, then confirms carrier status. The nature of the mutation can also predict the severity of the disorder. Severe gene lesions such as stop codons, large deletions, or the prevalent inversion in hemophilia A not only cause severe disease with no circulating factor but are also associated with high risk of neutralizing antibody (inhibitor) development after substitution therapy. Missense mutations on the other hand are usually associated with moderate (residual factor level 1% to <5%) or mild (residual factor > 5%) bleeding tendency.

In laboratory diagnosis of hemophilia A and B, the standard screening tests show a prolongation of activate partial thromboplastin time (APTT) with normal prothrombin time (PT). If this is the case, then specific factor assays to quantify FVIII and FIX are performed. Traditionally, residual FVIII or FIX <1% is defined as severe. However, the lower detection limit for both assays is about 1% and a residual level below 1% but above absolute zero can make some difference to bleeding frequency, that is to say—the clinical phenotype. This is notable when one compares the bleeding frequency of subjects with a null mutation against those with a missense mutation but factor level <1% who may even have no spontaneous bleeding.⁶ Although uncommon, patients with multiple defects in their hemostatic system are also found.

An assay capable of detecting antibodies to FVIII or FIX is also a mandatory part of the laboratory workup. In hereditary hemophilia A and B antibodies only develop after treatment and may do so promptly thereafter. Inhibitors may develop after many years of treatment, as recent data from the UK national database show.⁷ Thus, regular inhibitor testing is part of routine follow-up care in hemophilia.

There are two different ways of measuring FVIII activity, the one-stage clotting assay and the two-stage clotting assay. Ideally, both assays should be performed on all patients because many patients with mild hemophilia A have a much lower two-stage assay level than one-stage assay level. The clinical bleeding tendency is better predicted by the two-stage assay result. There are even a few patients who have normal one-stage assay result but clearly abnormal two-stage assay.⁸

A guide to bleeding frequency can be derived from the residual factor level in the patient’s blood⁹ (FIGURES 51.3A,B). Subjects whose residual level is <1% can attract clinical attention at birth, with bleeding complications of delivery or within a few months with spontaneous bruising, bleeding after circumcision, from primary dentition or hemarthrosis. Throughout life, such patients bleed apparently spontaneously, but also after minor trauma about once or twice a week in the most severe cases.

Patients whose residual level is 1% to <5% are said to have moderate hemophilia. Typically, they present at age 2 to 5 years with bleeding after significant trauma that has sufficiently intrigued a medical attendant to request a blood test including screening for coagulation disorders. If the residual level is over 5%, then the patient is said to have mild hemophilia. Bleeding only occurs in such cases after significant trauma or surgery. Patients with mild hemophilia are often first diagnosed in middle or late life and then only after severe trauma or major surgery brings the bleeding tendency to light. The diagnosis can
go undetected for many years; as in one extreme example noted by one of us (ET), a 90-year-old gentleman was found to have 5% FIX that came to light because he bled around the site of catheter insertion for coronary angiography.

The anatomical structures most frequently affected by hemophilic bleeding are the major load-bearing joints in the order of ankles>knees>elbow>shoulders. The hips are often spared. A target joint is one where repeated bleeding is occurring, without fully recovering between bleeds. Such joints go on to develop progressive painful, deforming, and motion-restricting arthropathy until they become fixed by reactive fibrosis. Blood within a joint capsule is highly irritant and provokes proliferative synovitis with erosion of cartilage, formation of bone cysts and deformity, and progressive fibrosis.¹⁰ The progress of such damage to joints is monitored for purposes of assessing response to treatment by standardized scales based on range of movement and function, radiology, or MRI.^11,12,13,14

Muscles develop bleeding after direct trauma or exercise or spontaneously. If the blood is confined within a muscle capsule, pressure can build up until compartment syndrome develops. This is a surgical emergency since it can lead to ischemic necrosis and contracture with loss of all function. An incision in the fascia surrounding the affected muscle combined with adequate replacement therapy is muscle saving in such circumstances, though not without risk of continued bleeding.

Bleeding into deep muscles such as the iliofemoral muscles can occur in all severity levels of hemophilia. Hip flexion, abdominal pain, and femoral nerve entrapment symptoms should lead to suspicion of this site of bleeding.

Renal tract bleeding presenting with hematuria is common and often not related to any detectable renal tract disease.

Intracerebral bleeding has been the commonest cause of death in hemophilia, even to the present.

Bruising is commonly observed in hemophilic children on the legs, trunk, and arms but is not usually a cause of concern and does not need treatment if superficial and painless.