Inherited Abnormalities of Coagulation

Bleeding disorders are broadly classified into primary and secondary hemostatic defects. Primary hemostatic disorders (disorders of platelets and von Willebrand factor) mainly result in mucocutaneous bleeding symptoms such as epistaxis, menorrhagia, petechiae, easy bruising, and bleeding after dental and surgical interventions. Secondary hemostatic disorders (congenital or acquired deficiencies of coagulation factors) typically manifest with delayed, deep bleeding into muscles and joints. This article provides a generalized overview of the pathophysiology, clinical manifestations, laboratory abnormalities, and molecular basis of inherited abnormalities of coagulation with a focus on hemophilia, von Willebrand disease, and rare inherited coagulation disorders.

Key points

  • Hemostasis, the arrest of bleeding at the site of vascular injury has been traditionally divided into primary and secondary hemostasis.

  • Primary hemostasis consists of vasoconstriction, platelet adhesion to the subendothelium via von Willebrand factor, platelet activation and aggregation with the eventual formation of a platelet plug.

  • Secondary hemostasis involves serine protease zymogens (coagulation factors) and their cofactors which interact sequentially to form cross-linked fibrin which helps stabilize the initial platelet plug.

  • Abnormalities of primary hemostasis classically present with mucocutaneous bleeding, whereas deficiency of coagulation factors involved in secondary hemostasis may manifest with joint and muscle bleeds.

  • Hemophilia A (HA) and hemophilia B (HB), X-linked deficiencies of factors VIII (FVIII) and IX (FIX) respectively, are associated with significant morbidity.

  • von Willebrand disease, encompassing both quantitative deficiency and qualitative defects of the von Willebrand factor, is thought to be the most common bleeding disorder in humans.

Introduction

Bleeding disorders are broadly classified into primary and secondary hemostatic defects ( Fig. 1 ). Primary hemostatic disorders (disorders of platelets and von Willebrand factor [VWF]) mainly result in mucocutaneous bleeding symptoms such as epistaxis, menorrhagia, petechiae, easy bruising, and bleeding after dental and surgical interventions. Secondary hemostatic disorders (congenital or acquired deficiencies of coagulation factors) typically manifest with delayed, deep bleeding into muscles and joints. This article provides a generalized overview of the pathophysiology, clinical manifestations, laboratory abnormalities, and molecular basis of inherited abnormalities of coagulation with a focus on hemophilia, von Willebrand disease (VWD), and rare inherited coagulation disorders (RICD).

Fig. 1
Classification of congenital bleeding disorders.

Introduction

Bleeding disorders are broadly classified into primary and secondary hemostatic defects ( Fig. 1 ). Primary hemostatic disorders (disorders of platelets and von Willebrand factor [VWF]) mainly result in mucocutaneous bleeding symptoms such as epistaxis, menorrhagia, petechiae, easy bruising, and bleeding after dental and surgical interventions. Secondary hemostatic disorders (congenital or acquired deficiencies of coagulation factors) typically manifest with delayed, deep bleeding into muscles and joints. This article provides a generalized overview of the pathophysiology, clinical manifestations, laboratory abnormalities, and molecular basis of inherited abnormalities of coagulation with a focus on hemophilia, von Willebrand disease (VWD), and rare inherited coagulation disorders (RICD).

Fig. 1
Classification of congenital bleeding disorders.

Overview of hemostasis

Hemostasis, the arrest of bleeding from a site of vascular injury, is traditionally divided into primary and secondary hemostatic responses. Primary hemostasis begins immediately after endothelial damage and consists of 4 sequential and overlapping phases: (1) vasospasm, (2) platelet adhesion to the underlying collagen mediated by VWF, (3) platelet activation, and (4) platelet aggregation. The end result of primary hemostasis is the formation of a platelet plug. Primary hemostasis is short lived; once the postinjury vasospasm abates and blood flow in the damaged vessel increases, the platelet plug may be rapidly sheared from the injured surface. Secondary hemostasis involves a series of serine protease zymogens and their cofactors, which interact sequentially on phospholipid surfaces (platelets or damaged endothelial cells) and result in the formation of covalently cross-linked fibrin, which helps stabilize and reinforce the initial platelet plug.

This sequential activation of serine protease zymogens is called the coagulation cascade. Historically, the coagulation cascade was divided into the intrinsic and extrinsic pathways, with the activated partial thromboplastin time (APTT) and prothrombin time/international normalized ratio (PT/INR) being used in clinical and laboratory settings to measure the integrity of the intrinsic and extrinsic pathways, respectively ( Fig. 2 ). Biologic advances over the past few decades have elaborated that in vivo , instead of occurring in pathways, the coagulation cascade occurs in distinct phases, namely, (1) initiation, (2) amplification, and (3) propagation. The coagulation cascade is initiated when tissue factor (TF), released from the injured endothelial cells and monocytes binds to factor VII (FVII) to form the TF-activated FVII (FVIIa) complex. The TF-FVIIa complex, in turn, activates factor X (FX) and FIX. Activated FX (FXa) combines with activated factor V (FVa) to form the FXa-FVa complex (the prothrombinase complex ). The prothrombinase complex converts small amounts of prothrombin (FII) to thrombin (FIIa) ( initiation phase ). The amount of thrombin generated in the initiation phase is inadequate (2% of the total amount required) to generate sufficient amounts of fibrin to reinforce the initial platelet plug. The primary role of this initial thrombin is to activate FV, FVIII, factor XI (FXI), and platelets through a positive feedback mechanism ( Fig. 3 ) ( amplification phase ).

Fig. 2
Schematic representation of the coagulation cascade in-vitro. APTT, activated partial thromboplastin time; HMWK, high-molecular-weight kininogen; INR, international normalized ratio; PK, prekallikrein; PT, prothrombin time, RT, reptilase time; TT, thrombin time.
( Adapted from Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults. Mayo Clin Proc 2007;82(7):866; with permission.)
Fig. 3
Schematic representation of the coagulation cascade in vivo . Vascular injury initiates the coagulation cascade, via release of tissue factor. For the sake of clarity, calcium ions and phospholipids, 2 important cofactors for most coagulation reactions, have been omitted from this image. The red box indicates the contact factors, which plays a minimal role in activation of the coagulation cascade in vivo. The red dashed lines indicate the feedback amplification loops that follow the initial generation of small amounts of thrombin (FIIa).

The amplification phase is followed by the propagation phase in which activated FIX (FIXa) binds with FVIIIa to form the FIXa-FVIIIa complex (the tenase complex ). The tenase complex activates FX, which again associates with FVa (forming more prothrombinase complex), now leading to the generation of large amounts of thrombin—the so called thrombin burst . The thrombin generated catalyzes the conversion of fibrinogen to fibrin, which is covalently cross-linked in the presence of activated factor XIII (FXIIIa) to yield a stable clot. The propagation phase occurs on the surface of activated platelets. Contact factors of the intrinsic pathway (high-molecular-weight kininogen, prekallikrein, and factor XII) are not involved in the propagation phase, thus congenital deficiencies of these factors, although significantly prolonging the APTT, are not associated with bleeding. This article focuses on the main coagulation factor deficiencies and will not discuss disorders of platelets, which are discussed in another article appearing in this issue.

Hemophilia

Introduction

HA and HB are X-linked, recessive, bleeding disorders caused by deficiency of blood coagulation factors FVIII and FIX, respectively. The incidence of HA is estimated to be 1 in 5000 males, whereas that of HB is 1 in 30,000 males. Based on the coagulation factor activity level, hemophilia is classified into severe (<0.01 IU/dL), moderate (0.01–0.05 IU/dL), and mild (0.06–0.4 IU/dL). Overall, severe hemophilia accounts for 40% or more of all hemophilia cases, although the distribution of the different severities of hemophilia varies; countries with more comprehensive national patient registries report a higher prevalence of mild hemophilia. Patients with severe hemophilia typically develop spontaneous and recurrent bleeds, most commonly into joints (hemarthrosis) and muscles, whereas those with mild-moderate hemophilia tend to experience bleeding related to trauma or surgery.

Molecular Basis and Genetics

Both FVIII and FIX circulate in blood as inactive precursors that are activated at the time of vascular injury (see Fig. 3 ). FVIII is a protein cofactor with no intrinsic enzymatic activity, whereas FIX is a serine protease zymogen with an absolute requirement of FVIII as a cofactor. On activation, FVIIIa and FIXa form the tenase complex, which activates FX. Thus, the basic biochemical abnormality in patients with hemophilia is the inability to activate FX and thereby generate thrombin and fibrin to stabilize the platelet clot. The inheritance pattern of hemophilia is elaborated in Fig. 4 .

Fig. 4
( A ) In a mating between a hemophilia carrier woman and an unaffected man, 50% of the daughters will be carriers and 50% of sons will have hemophilia. ( B ) In a mating between an unaffected woman and a man with hemophilia, no son will be affected (having inherited the Y chromosome from the father) but all daughters will be carriers (having inherited the X chromosome from the father). Note: very rarely, females may have true hemophilia secondary to consanguinity in a hemophilic family, skewed inactivation of the normal X chromosome, or loss of part or all of the normal X chromosome (Turner syndrome).

The genes for FVIII and FIX are located in the long arm of chromosome X at positions Xq28 and Xq27, respectively. The FVIII gene spans 186 kb and consists of 28 exons. The FVIII precursor protein consists of 2351 amino acids, spaced out in 6 domains: (1) three A domains (A-1, A-2, and A-3), (2) a connecting B domain, and (3) two C-terminal domains (C-1 and C-2). Intracellular proteolytic processing of FVIII involves cleavage at the Arg1689 site (at the B-A3 junction), which results in the formation of a heterodimer consisting of an N-terminal heavy chain (A-1, A-2, and partially proteolyzed B domain) bound noncovalently to a C-terminal light chain (A-3, C-1, and C-2). This heterodimeric form of FVIII circulates in blood complexed with von Willebrand factor (VWF). Activation of FVIII by thrombin involves (1) release of FVIII by VWF and (2) excision of the remnant B domain. The FIX gene is much smaller; it is 34 kb long and consists of 8 exons. FIX consists of 416 amino acids and requires posttranslational, vitamin K-dependent, γ-glutamylcarboxylation to become physiologically active.

As of November 2012 more than 2000 unique mutations in the FVIII gene have been recorded in an international database (HAMSTeRS [The Hemophilia A Mutation, Structure, Test and Resource Site]; http://hadb.org.uk/ ). The most common mutation in HA, affecting nearly 45% of patients with severe disease, is an intron 22 inversion. A similar database recording mutations for HB is accessible at http://www.umds.ac.uk/molgen/haemBdatabase . Inversion mutations are not seen in HB, and most patients (≈70%) have missense mutations. HB Leyden is a rare variant of HB that occurs secondary to point mutations in the promoter region of the FIX gene. Typically, patients with this mutation present with severe HB (FIX<0.01 IU/dL) in early childhood. However, postpuberty, increased androgen production results in increased FIX promoter activity and increased FIX production (eventually reaching ≈ 0.5 IU/dL), thereby correcting the hemophilia phenotype.

Clinical Presentation and Diagnosis

About 50% to 70% of newborns with hemophilia have a family history of the disease. Diagnosis of HA in this subcohort is usually made early in life by measuring the FVIII level on the cord blood. FIX levels, however, are physiologically low in the neonatal period (see Table 1 ), and a low FIX level in the cord blood, needs to be repeated at 6–12 months, before a diagnosis of HB can be confirmed. FIX levels increase throughout early childhood, and therefore, the ultimate classification of a patient’s HB severity may change with aging, that is, a child labeled with moderate HB in the first year of life may ultimately be labeled as having mild HB. In the remaining 30% to 50% of patients without a positive family history, the diagnosis is usually made later in life, once the neonate or toddler is worked up for bleeding symptoms. Screening laboratory tests in patients with hemophilia usually demonstrate a prolonged APTT with a normal PT/INR value (see Fig. 2 ). Diagnosis can be confirmed by demonstrating a low or absent FVIII or FIX coagulant activity. This is typically measured in platelet-poor plasma using a functional clotting assay (usually a one-stage APTT-based assay), although some laboratories may use a two-stage or chromogenic substrate assay. Of note, low FVIII and FIX activity levels do not always indicate hemophilia. A differential diagnosis of low plasma factor levels is elaborated in Table 1 .

Table 1
Differential diagnosis of low FVIII and FIX levels
Factor Condition Associated with Low Factor Level
FVIII Type 3 VWD
  • FVIII level usually ranges between 0.02 and 0.05 IU/dL

  • Associated reduction in VWF:Ag and VWF:RCo activity (see section on VWD for details)

FVIII Type 2N VWD
  • Caused by specific mutations in the VWF gene that result in reduced binding of FVIII by VWF

  • FVIII level usually range between 0.05 and 0.4 IU/dL; VWF:Ag and VWF:RCo activity are usually normal

  • Distinguished using the VWF:FVIII binding assay and/or genetic analysis

FVIII Combined deficiency of FV and FVIII
  • Very rare (1 in a million)

  • Generally causes FVIII levels in the 0.2 IU/dL range

  • Caused by mutations in genes encoding for intracellular transport protein ( LMAN1 and MCFD2 )

  • APTT and PT/INR are both prolonged

FVIII Acquired hemophilia
  • Very rare in children (0.045 in a million)

  • Associated with infection, penicillin antibiotics, and autoimmune conditions

  • Abnormal incubated mixing study

  • Bethesda assay or Nijmegen modification of Bethesda assay may be used to quantify inhibitor titer

FIX Neonatal age
  • FIX levels are low in healthy neonates

  • Low FIX levels in a newborn should be rechecked at 6–12 mo of age

FIX Acquired vitamin K deficiency
  • Liver disease, malabsorption, prolonged antibiotic use, and coumadin

  • Associated reduction in other Vitamin-K-dependent proteins (FII, FVII, FX)

FIX Congenital deficiency of Vitamin-K-dependent clotting factors
  • Mutations in GGCX or VKOR gene

  • Associated reduction in other Vitamin-K-dependent proteins (FII, FVII,FX)

Abbreviations: GGCX, γ-glutamylcarboxylase; LMAN1, lectin mannose-binding 1; MCFD2, multiple coagulation factor deficiency 2; VKOR, vitamin K epoxide reductase.

Clinical manifestations of HA and HB are identical, although there is some suggestion that HB may be milder than HA for the same level of factor activity. Bleeding is the clinical hallmark of hemophilia, but the sites and pattern of bleeding vary significantly based on disease severity and age of patients. Birth is thought to be the first hemostatic challenge for a newborn with hemophilia. In a large prospective study of 580 infants with hemophilia, enrolled in the Universal Data Collection of the Center for Disease Control and Prevention, 53% of infants with hemophilia had a bleeding episode by the age of 1 month. Bleeding post circumcision accounted for almost half (47.9%) of the bleeds in the first month of life; this was followed by head bleeds (19.4%) and bleeding from heel sticks (10.4%). Intracranial hemorrhage (ICH) remains the most serious complication of hemophilia in the immediate postnatal period and can result in severe morbidity or death. Recent studies have indicated that the rate of ICH in newborns with hemophilia (all severities) ranges from 1% to 4%, which is significantly higher than in newborns who do not have a bleeding disorder. The optimal mode of delivery for a woman known to be a hemophilia carrier has been extensively debated. However, it is clear that caesarean delivery does not completely eliminate the risk of ICH, and consequently, in most centers, the recommended mode of delivery remains an atraumatic, non–instrument-assisted vaginal delivery. In a prospective European study, assisted vaginal delivery with instrumentation was associated with a marked increased risk of head bleeds (odds ratio [OR], 8.84; 95% confidence interval [CI], 3.05–25.5), and it is generally accepted that instrumentation of any kind (forceps, vacuum extraction, or fetal scalp electrodes) should be avoided in infants born to known carriers of hemophilia. For newborns with a clinical suspicion of an ICH, factor should be administered immediately and prior to imaging confirmation. When the hemophilia subtype (HA vs HB) is not known, it may be appropriate to administer fresh frozen plasma (FFP) (10–15 mL/kg) while awaiting laboratory confirmation. It is also recommended that intramuscular vitamin K should be avoided until the diagnosis of hemophilia is excluded, and oral vitamin K may be administered in the interim or once the diagnosis of hemophilia is confirmed.

Bleeding from the oral mucous membranes becomes more common as infants with hemophilia grow older. Other sites of bleeding that become apparent by 6 to 12 months of age include bleeding into joints (hemarthrosis), muscle bleeds, and bleeding from the gastrointestinal and urinary tracts. ICH remains a serious complication of hemophilia at all ages. In a nested case-control study of more than 10,000 patients with hemophilia, older than 2 years, 2% of patients had experienced an ICH with a 20% mortality rate. High titer inhibitors (OR, 4.01; 95% CI, 2.40–6.71), prior ICH (OR, 2.62; 95% CI, 2.66–4.92), and severe hemophilia (OR, 3.25; 95% CI, 2.01–5.25) were found to be independent predictors of ICH.

Hemarthrosis is the clinical hallmark of severe hemophilia. Although all synovial joints are at potential risk, the most frequently affected are the knees, elbows, and ankles. Joint bleeds usually become apparent once the toddler starts bearing weight. The range of ages at which children experience a first joint bleed varies tremendously. In a Dutch study, the median age of first joint bleed was 1.8 years but the range was between 0.2 and 5.8 years. This marked variation in the age at which children with severe hemophilia experience their first joint bleed reflects the considerable heterogeneity that exists in the bleeding phenotype of patients with severe hemophilia. Differences in levels of physical activity, structural integrity of joints, and coinheritance of pro-thrombotic conditions, particularly Factor V Leiden mutation, have been proposed as possible explanations for this heterogeneity.

Bleeding into a joint results in synovial hypertrophy and inflammation (synovitis). A joint that undergoes repeated bleeds is referred to as a target joint. While the exact definition of a target joint is debatable, it usually refers to a joint that develops 3 or more bleeds in a period of 3 to 6 months. A target joint may eventually develop hemophilic arthropathy, characterized by loss of joint space, cystic changes within the subchondral bone, osteoporosis, and atrophy of the surrounding muscles. The final stage of hemophilic arthropathy is a deformed and dysfunctional joint, which may significantly compromise a patient’s quality of life ( Fig. 5 ).

Fig. 5
A 12-year-old boy with severe hemophilia B had received minimal treatment for hemophilia before immigrating to Canada. At presentation to our clinic, he showed significant arthropathy of his right knee. ( A ) Photograph of the legs showing valgus deformity, limb length discrepancy, and loss of normal landmarks of the right knee with diffuse muscle wasting. ( B ) Radiograph of the legs shows valgus deformity, loss of joint space, osteopenia, and deformity of the medial femoral condyle and tibial plateau. ( C ) Preoperative computed tomography shows sclerosis and irregularity of the distal femoral physis and anterolateral physeal fusion at the distal femur growth plate (architecture of the left knee is relatively preserved).
([ A ] Courtesy of Ms Pamela Hilliard, BSc (PT), Department of Rehabilitation Services, Hospital for Sick Children.)

Muscle hematomas, the second most common type of bleeding in patients with hemophilia account for 10% to 25% of all bleeds in this cohort. Bleeding into the iliopsoas muscle, a large muscle in the pelvis, is particularly concerning because patients can lose a significant volume of blood into this muscle. Inadequate or delayed treatment of muscle hematomas may result in compartment syndrome, atrophy of tendons, myositis ossificans, and rarely hemophilic pseudotumors. Pseudotumors result from recurrent hemorrhage into an enlarging, encapsulated hematoma and may lead to pressure necrosis and destruction of adjacent structures.

Clinical Management

General overview

Management of hemophilia is complex and requires a multi-disciplinary comprehensive care approach involving hematologists specialized in bleeding disorders, dedicated nurses, social workers, physiotherapists as well as the availability of dentistry, orthopedics, and psychology. It is recommended that all patients with hemophilia be followed in comprehensive hemophilia treatment centers able to provide such multi-disciplinary care. Education of patients and primary care providers about risks of bleeding and related complications is important. Lifestyle modifications including avoidance of contact and collision sports, routine dental care to reduce the risk of gingival bleeding, avoidance of platelet-impairing medications (aspirin and nonsteroidal antiinflammatory drugs), and use of MedicAlert bracelets should be encouraged. Given the risk of exposure to blood-derived products, patients should be vaccinated against hepatitis B. Vaccinations for patients with hemophilia can, and ideally should, be given subcutaneously, using the smallest gauge needle, with local pressure applied for at least 5 minutes.

Management of acute bleeds

Factor replacement

Treatment needs to be administered expeditiously in the case of acute bleeds to prevent both short-term complications and long-term disabilities. Factor replacement therapy using FVIII and FIX concentrates forms the backbone of management for patients with severe hemophilia. These concentrates may be broadly divided into 2 categories: plasma-derived and recombinant concentrates. The dose of concentrate to be administered is calculated based on the hemophilia subtype, baseline factor activity, and desired increase in the factor level. Generally, 1 U/kg of administered FVIII increases the plasma FVIII coagulant activity by 0.02 IU/dL; whereas 1 U/kg of recombinant FIX increases the plasma FIX coagulant activity by approximately 0.008 IU/dL (the expected increase is 0.01 IU/dL when using plasma-derived FIX). The half-life of FVIII is 8 to 12 hours and that of FIX is 12 to 24 hours. Factor concentrates may be administered in bolus doses or through continuous infusion. Continuous infusion of factor prevents the peaks and troughs associated with bolus dosing and may be particularly useful in surgical and postsurgical settings. A bolus dose of 50 U/kg of FVIII or FIX followed by an initial continuous infusion of 2 to 3 U/kg/h of FVIII or 4 to 8 U/kg/h of FIX is recommended with periodic measurement of factor levels to ensure that they are being maintained in the hemostatic range. For mild-moderate hemorrhage, the targeted hemostatic range is 0.3 to 0.4 IU/dL for FVIII and 0.25 to 0.3 IU/dL for FIX, whereas for severe life-threatening hemorrhages, the target range is 1 IU/dL. For details on the specific dose of factor used and duration of therapy, see article by Robertson and colleagues.

Local measures

Mild superficial bleeding symptoms in patients with mild-moderate hemophilia may be managed with local measures. Compression, use of gelatin sponge or gauge soaked in tranexamic acid may be tried for superficial wounds. Epistaxis may be managed by nasal packing and use of topical thrombin (eg, Thrombi-Gel, Evithrom) and fibrin sealant gel (Evicel).

Desmopressin

Desmopressin (1-deamino-8- d -arginine-vasopressin; DDAVP), a synthetic analog of the antidiuretic hormone, vasopressin, exerts its procoagulant effect by causing the release of stored VWF and FVIII from Weibel-Palade bodies in endothelial cells into the plasma thus increasing (doubling or tripling) the circulating levels of FVIII and VWF. Clinically meaningful response is usually seen only in patients with a baseline FVIII activity of more than 0.10 to 0.15 IU/dL. DDAVP does not increase FIX levels and therefore is not useful in patients with HB. It is important to know a priori how a patient will respond to DDAVP before using it in a clinical setting. This information is usually obtained by administering the standard dose of 0.3 μg/kg (maximum 20 μg) of DDAVP intravenously/subcutaneously or intranasally (150 μg [for children weighing <50 kg] or 300 μg [for children weighing ≥50 kg]) and monitoring the FVIII and VWF response at 1 and 4 hours (DDAVP challenge test). Younger patients (eg, <3–5 years of age) often have a suboptimal response to DDAVP, and the DDAVP challenge should be repeated in patients who were assessed as nonresponders at a young age. For patients who respond, DDAVP may be used to treat minor bleeds and for prophylaxis before dental and minor surgical procedures. Peak FVIII levels are reached within 30 to 60 minutes after intravenous injection and 90 to 120 minutes after intranasal and subcutaneous administration. Side effects of DDAVP include fluid retention and hyponatremia, and patients should be advised to limit their fluid intake for 24 hours after DDAVP administration. For the same reason, DDAVP is avoided in children younger than 2 years. The ability of DDAVP to increase FVIII and VWF levels is lost after multiple doses.

Antifibrinolytic agents

Lysine analogs, tranexamic acid (cyclokapron) and ε-aminocaproic acid (Amicar), are usually used in combination with other therapeutic modalities (FVIII or FIX concentrates or DDAVP). They are particularly useful in patients with epistaxis, gingival bleeding, and menorrhagia and may also be used for prevention of bleeding after minor surgical and dental procedures. Both agents can be used orally and intravenously. The dose of tranexamic acid is 15 to 25 mg/kg orally, taken 3 to 4 times a day (or 10 mg/kg intravenously every 8 hours). This drug is also available as a mouthwash (10 mL of a 5% solution taken 4 to 6 times a day), which if swallowed is equivalent to a dose of 500 mg. Common side effects are nausea and diarrhea, which are dose dependent. Antifibrinolytics are contraindicated in hematuria given the risk of clot formation within the renal collecting system.

Long-term management: prophylaxis versus episodic therapy

In the 1950s, Nilsson and colleagues in Malmö, Sweden, observed that patients with moderate hemophilia rarely develop chronic arthropathy and disability. They hypothesized that by prophylactically replacing FVIII/FIX concentrates on a regular basis, they could convert the phenotype of patients with severe hemophilia to a moderate one and thereby prevent recurrent hemarthrosis and arthropathy. Almost 25 years later, Professor Nilsson published data on 60 patients who had received prophylactic factor replacement for 2 to 25 years; and demonstrated that when prophylaxis was started early and administered regularly, patients with severe hemophilia had significantly reduced bleeding, excellent joint status, and were able to lead normal lives. The superiority of prophylaxis (regular administration of factor to patients with hemophilia to prevent bleeding episodes) over on-demand therapy (administration of factor only at the time of an acute bleed) was demonstrated in a landmark randomized trial published by Manco-Johnson and colleagues in 2007.

Prophylaxis is now the standard of care for patients with severe hemophilia in the developed world. Full-dose primary prophylaxis entails the administration of high doses of factor (25–40 U/kg), every other day for HA and twice a week for HB starting by 2 years of age and before the onset of joint damage. The biggest disadvantage of this regimen is the need for frequent infusions of factor starting at a very young age, which leads to a high need for central venous access devices (CVADs). Although CVADs allow the early initiation of prophylaxis and home therapy, they are associated with a substantial rate of infections and thrombosis. An alternative approach to starting very young children on full-dose prophylaxis is to instead use escalating dose/frequency prophylaxis. Such an approach starts patients on once-a-week infusions, then escalates them to twice-a-week prophylaxis, and finally moves them to full-dose prophylaxis. Some countries, notably Sweden, escalate all children quickly to full-dose prophylaxis regardless of whether these children are experiencing bleeds, whereas other groups, instead, only escalate patients if they experience what is judged to be an unacceptably high bleeding frequency (tailored prophylaxis). A head-to-head comparison between tailored prophylaxis and full-dose prophylaxis has not been done.

The Future of Hemophilia Care

Long-acting factor concentrates

The management of hemophilia is likely to change with the development of longer acting FVIII and FIX concentrates. Several companies, using different technologies (PEGylation, fusion to albumin or the Fc component of immunoglobulin), have already shown a 3- to 6-fold prolongation in the half-life of FIX. These products are still undergoing clinical trials, although preliminary data seem promising. Similar technologies are being used to develop long-acting FVIII concentrates, but so far, these technologies have only been able to result in a 1.5 to 1.7 prolongation of the half-life of FVIII.

Gene therapy

In 2011, the first successful results of gene therapy for HB were published. Six patients with severe HB (FIX<0.01 IU/dL) were treated with 3 escalating dose levels of an adenovirus-associated virus vector expressing a codon-optimized human FIX gene. A transient elevation of liver enzymes observed in 2 patients treated with the highest vector dose was rapidly cleared with a short course of steroids. Other than this there was no acute toxicity observed over 6 to 16 months of follow-up. FIX coagulant activity trough levels of 0.02 to 0.11 IU/dL were observed in all patients, and 4 of 6 patients were able to discontinue prophylaxis. Further studies evaluating the safety and long-term efficacy of gene therapy are underway.

Inhibitors in Hemophilia

Development of inhibitors is currently the most serious complication of hemophilia. Inhibitors are neutralizing allo-antibodies that develop in 30% or more of patients with HA and about 2%to 5% of patients with HB. These antibodies, which usually develop within the first 20 to 50 exposure days to factor, rapidly inactivate infused factor, rendering replacement therapy ineffective and are associated with significant morbidity. Risk factors for inhibitor development include genetic factors such as family history of inhibitor, race, underlying mutation and polymorphisms in immune regulatory genes (interleukin-10, tumor necrosis factor-α, and cytotoxic T-lymphocyte antigen-4), as well as acquired risk factors, for example, intense exposure to factor, particularly during surgery, hemorrhage, and vaccination. It is thought that these conditions act as danger signals to the immune system, resulting in upregulated immunity, and increase the risk of antibody development. The immunogenicity of recombinant versus plasma-derived factor concentrates has been a subject of intense debate. A randomized prospective study (Survey of inhibitors in plasma-product exposed toddlers [SIPPETT trial]) is currently ongoing to address this issue.

Inhibitors levels are measured using the Bethesda assay and are quantified in Bethesda units (BU; 1 BU is the amount of antibody that inactivates 50% of factor after 2 hours of incubation at 37°C). A low-titer inhibitor is defined as less than 5 BU, and a high-titer inhibitor is defined as 5 BU or more. Management of inhibitors is complex and essentially includes 2 aspects:

  • 1.

    Management and prevention of acute bleeds: acute bleeds in patients with low-titer inhibitors may be managed by giving high doses of FVIII or FIX. In patients with high-titer inhibitors, bypass agents (activated prothrombin complex concentrates [FEIBA] and/or recombinant FVIIa [NovoSeven]) may be used. In a prospective, randomized, open-label, crossover trial, both products were equally efficacious. These bypass agents can also be used in a prophylactic manner to prevent bleeding.

  • 2.

    Immune tolerance therapy: Permanent eradication of inhibitors can be achieved using immune tolerance induction (ITI). ITI entails the frequent administration of large doses of factor concentrate, and when successful, results in normalization of factor pharmacokinetics and subsequent improvement in the patient’s quality of life. ITI has been mainly studied in HA inhibitor patients where success rates of 60% to 80% have been reported. Different regimens of ITI have been reported. A recent randomized trial comparing low-dose (50 U/kg 3 times/wk) and high-dose (200 U/kg/day) ITI showed similar efficacy, although high dose was associated with quicker success and less bleeding while on ITI. Readers interested in learning details about the diagnosis and management of inhibitors are referred to the following excellent reviews.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Oct 2, 2017 | Posted by in PEDIATRICS | Comments Off on Inherited Abnormalities of Coagulation

Full access? Get Clinical Tree

Get Clinical Tree app for offline access