Musculo-skeletal problems of the hand in haemophilia

Introduction

Haemophilia is a hereditary recessive disease linked to sex, causing a coagulation disorder characterized by bleeding episodes, which can be spontaneous or as a result of minor trauma. There are two types of haemophilia: type A, due to a deficiency of factor VIII and type B, due to a deficit of factor IX. Due to their kind of inheritance, males are affected more by the disease. ¹ Based on the level of clotting factors, haemophilia is classified into mild (clotting factor level 5–40%), moderate (1–5%), and severe (< 1%).

Von Willebrand disease (VWD) is a condition considered to be related to haemophilia, affecting between 0.6% and 1.6% of the population. ^2,3 VWD is caused by a deficiency or by dysfunctional von Willebrand factor (VWF). There are three types: type I, which is the most common form (75%), and involves insufficient levels of VWF; type II in which VWF is dysfunctional; and type III, the most severe and rarest type, which combines both alterations.

Bleeding episodes induce musculo-skeletal damage through a cytotoxic effect on cartilage. Depending on the severity of the condition, bleeding may be caused by minor injury or may follow major operations or injury to the affected region. ^4,5 Haemophilic and von Willebrand patients present with 80–90% of their bleeding episodes happening in the musculo-skeletal system, especially in large synovial joints, being less frequent in small joints such as the hands. ⁶ It is somewhat striking how the hand with its multiple small joints, constant movements, and trauma escapes significant damage. ⁷ Injuries to the hand have rarely been analysed in the literature. This review aims to analyse the musculo-skeletal problems of haemophilia in the hand, with a focus on possible clinical presentations and an update on correct diagnosis and treatment strategies.

Methods

A review of the literature was performed on hand problems in haemophilia. The public search engines PubMed and the Cochrane Library were used for the search, including all available literature up to 1 December 2019. Inclusion criteria were haemophilia problems of the hand. The search strategy rendered 264 articles, of which, after reading titles and abstracts, 23 were selected and reviewed. Fig. 1 shows our search strategy.

View Full Size

Flowchart of our search strategy regarding hand problems in haemophilia.

Citation: EFORT Open Reviews 5, 6; 10.1302/2058-5241.5.190078

• Download Figure
• Download figure as PowerPoint slide

Haemophilic arthropathy in joints of the hand

Haemophilic arthropathy in the joints of the hands may be affected by spontaneous joint bleeding, with repeated haemarthrosis leading to haemophilic arthropathy, a debilitating disease with a negative impact on mobility and quality of life. Synovitis is one of the earliest complications of haemarthrosis and is characterized by synovial hypertrophy, and a high degree of neo-angiogenesis with subsequent bleeding, cartilage degeneration, and bone damage. This process perpetuates synovitis, forming a vicious circle.

The metacarpophalangeal (MCP) joints are predominantly involved (42 of 50 joints) in the hand. ⁸ Van Deukeren et al described the involvement of the different joints with bleeding in MCP joints in 52% of cases, proximal interphalangeal (PIP) joints in 48%, and distal interphalangeal (DIP) joints in 26%, the causes being mostly traumatic (77%), followed by iatrogenic (58%) and spontaneous episodes (19%). ⁹ Radiographic abnormalities are characterized by irregularity in the joint in haemophilic patients. Since more changes occur in large joints, small joints have not been primarily studied. The severity of the arthropathy increases with the age of the patient and with the number of bleeding episodes, although the correlation between these parameters is variable. The elbow joint is the most affected in the upper limb (87%), followed by the glenohumeral and wrist joints. Hand joints are uncommonly affected and rarely produce arthropathy. ¹⁰

Treatment of this condition consists of preventing joint bleeding episodes and reconstructive orthopaedic procedures ranging from synovectomy to prosthetic replacement. There is currently no disease-modifying therapy available to fill the gap between preventive measures and reconstructive procedures. Considering the pathogenic mechanisms and molecular pathways, potential targets for arthropathy therapy are iron chelators, anti-inflammatory treatment, anti-fibrinolytic, and bone-remodelling agents. These options have demonstrated beneficial effects, predominantly in a preclinical setting, but their clinical application is still a long way off. ^11,12

Primary prophylaxis is the treatment of choice to prevent bleeding episodes, but access to these programmes might be limited by cost. Intravenous infusion of deficient factors has decreased the events of muscle, articular and bony bleeding episodes. ¹³ New therapies for prophylaxis are extended plasma half-life coagulation factors. These can be given every 10–15 days, decreasing the burden of annual injections and, possibly, improving patient compliance. ¹⁴

Emicizumab is a therapeutic antibody that links activated factor IX with factor X, allowing for blood clot formation without the need for factor VIII. It has recently been approved for the prevention of bleeding episodes in haemophilic patients. It allows well-spaced dosing intervals every one or two weeks with the advantage of subcutaneous injection. ¹⁴ However, the search is ongoing to obtain curative gene transfer therapy, and stop bleeding with a single therapeutic intervention of life-long duration. ¹⁵

Haemophilia pseudotumours in the hand

Haemophilic cysts and pseudotumours are uncommon presentations of bleeding disorders such as haemophilia A, haemophilia B, and VWD, with a reported incidence among these patients of 1.14%. ¹⁶

Pseudotumours may originate in soft tissues or subperiosteal or intraosseous areas caused by recurrent bleeding. They are classified into three types according to the anatomic sites where bleeding occurs. In type I, bleeding occurs in the muscles with slow mass enlargement, developing a fibrous capsule and affecting surrounding tissues by pressure. In type II, subperiosteal bleeding occurs, and expansion of the lesion strips the periosteum, displacing soft tissue and facilitating bony erosion. Type III lesions are very infrequent and are characterized by the appearance of pseudotumours within the bone. ^17,18

In the current literature, the terms haemophilic cysts and pseudotumours have been used interchangeably. ¹⁹ According to Fernandez de Valderrama’s classification, a haemophilic cyst is an extraosseous cystic swelling confined to the muscle with no effect on the adjacent bone, whereas in pseudotumours the adjacent bone is also affected. ²⁰ Typical presentation in adult patients occurs in the proximal skeleton and is rare in small bones distally. Young patients with open epiphyseal growth plates are typically affected in the hand and these pseudotumours are characterized by faster growth when compared to other locations. ^21,22 They can develop after minor trauma or spontaneously, without correlation to the severity of the disease (factor count or orthopaedic disease). ²³

Magallón et al reported that 60.5% of hand injuries occurred in patients with haemophilia A, 9.9% in haemophilia B, 18% in VWD, and 12.1% in other coagulopathies. ²³ Other authors have reported all occurrences being in patients with haemophilia A. ¹⁶

Bleeding may produce swelling, pain, and, with repeated and continued bleeding pseudotumours may increase in size and create bone erosion that leads to fractures and infections. Additionally, when a haemophilic pseudotumour is left untreated, it may induce compression and pressure necrosis of the adjacent structures. Its more frequent location is in the long bones of the lower extremities, often resulting in soft tissue destruction and neurovascular compression. In the early stages of radiologic findings, periosteal reactions might be so minimal that soft tissue mass may be the only finding. A large soft tissue mass with areas of adjacent bone destruction can be seen, with intralesional calcification frequently observed. High-resolution computed tomography (CT) and T2-weighted magnetic resonance imaging (MRI) are useful in the evaluation of haemophilic pseudotumours. The latter has better soft tissue resolution capability, which helps to differentiate blood clots from haemophilic pseudotumours at the initial stage, and it is considered the investigative method of choice. ²⁴

A differential diagnosis must be made with several other types of lesion, including intraosseous synovial cysts, osteosarcoma, angioleiomyoma, aneurysmal bone cysts, giant cell tumours of the bone, and non-ossifying fibroma. ²⁵ Some of the most common haematologic disorders may be detected in radiographs of the hand, especially in plasma cell dyscrasias and proliferative malignant diseases. ²⁶ However, it is infrequent to see haemophilic arthropathy or cysts in developed countries.

There is a lack of consensus regarding the management of haemophilic cysts and pseudotumours. Various treatment options for this pathology have been proposed; however, because of its rarity, no standardized treatment protocol has been developed. Pseudotumours occurring in small bones, especially in younger patients, are managed with non-surgical measures using factor replacement therapy and immobilization for at least eight weeks. ²⁷ When pseudotumours are larger than 3 cm in diameter or when prior non-surgical management has failed, curettage with bone-graft packing and factor replacement therapy may be required. ^16,28

Indications for surgical excision include failure of conservative therapy, extensive lesions, soft tissue pseudotumours, imminent rupture, the presence of skin necrosis, and neurovascular complications. ²⁹ Other options for treatment include the aspiration of the lesion with fibrin glue injection, embolization of the bleeding vessel, and radiotherapy. Fibrin glue consists of two separate solutions of fibrinogen and thrombin, which, when mixed, mimic the final stages of the clotting cascade to form a fibrin clot. This clot may produce haemostasis and promote wound healing. ³⁰ Embolization is not appropriate for hand lesions due to the potential for vascular compromise. Radiotherapy is used when other methods can not control the bleeding, and it works by inducing inflammation and fibrosis of local blood vessels. Subasi et al have proposed radiotherapy as an alternative modality in haemophilic hand pseudotumours, even without factor VIII therapy, observing secondary calcification of the haemophilic pseudotumour within one month of treatment and complete healing by 2 to 3 months. ³¹ The optimal radiation dose for haemophilic pseudotumours, however, has not been defined. ³² Potential complications include stiffness and post-radiation neuropathy, which limits its use. ^33,34 Our experience of these options is very limited due to the success of haematological prophylaxis to prevent these problems.

Carpal tunnel syndrome

Haemophilia can cause haemarthrosis and haematomas, with the latter potentially resulting in compartment syndrome and nerve compression, acute carpal tunnel syndrome (CTS) being a rare complication (Fig. 2). ³⁵ Acute CTS in haemophilic patients often begins following trivial upper limb trauma. In contrast, in healthy patients, it usually follows a fracture of the distal radius. ³⁶ On clinical examination, patients may be tender over the volar aspect of the wrist, may have a positive Tinel or Phalen test, and will show neurologic impairment of the median nerve. The diagnosis requires careful clinical evaluation, as initial clinical features may be subtle. The investigation of choice for acute CTS is an MRI of the wrist to image the carpal tunnel and to exclude articular pathology. When this investigation is not available, ultrasound scans are useful to image the soft tissue mass combined with radiographs to exclude an acute fracture. Differential diagnosis must be made with fractures, dislocations, and haematoma causing compartment syndrome.

View Full Size

Clinical picture of a surgical case of carpal tunnel syndrome (CTS) release. A 51-year-old woman with pain and paresthesias of the median nerve territory of her left hand was treated with adequate replacement therapy and surgical release after progressive symptoms. An extensile volar approach was used to adequately explore the extent of the haematoma. After carpal tunnel release, evacuation of the haematoma and neurolysis of the median nerve, the patient recovered swiftly.

Citation: EFORT Open Reviews 5, 6; 10.1302/2058-5241.5.190078

• Download Figure
• Download figure as PowerPoint slide

Management includes early administration of recombinant factor VIII for 3–5 days in conjunction with elevation of the limb and immobilization. ^37,38 Close clinical observation is required to monitor the median nerve function. Urgent surgical decompression of the carpal tunnel may be needed if symptoms fail to improve, but this is a rare situation. ³⁹ The timing of surgical intervention, however, remains unclear. Cases with apparent findings of acute CTS and adequate factor replacement therapy should undergo immediate surgical decompression to obtain complete and early recovery. ⁴⁰ Similar to CTS, cubital tunnel syndrome can occur and should be handled conservatively in the majority of cases. ⁴¹ Although this pathology is rare, haemorrhage in the volar aspect of the wrist or in the anterior muscles of the forearm must always be followed to avoid potential complications such as compression neuropathies or muscular contractures. ⁴²

Pseudoaneurysms and true aneurysms

Palmar digital artery aneurysms, like all other aneurysms, are classified into two broad categories, true and false (pseudoaneurysm). In true aneurysms, normal arterial wall architecture is maintained in contrast to false or pseudoaneurysms, where the wall consists of fibrous tissue or scar. Both types of aneurysms are infrequent lesions. Despite the high incidence of hand injuries, aneurysms of the digital arteries are extremely rare. ⁴³ In our experience, pseudoaneurysms are more frequent than true aneurysms due to blunt trauma or puncture wound of the hand in haemophilic patients.

Pseudoaneurysm formation is preceded by a penetrating hand injury that breaks the arterial wall. The subsequent haematoma is organized, and then, recanalized. ^44–46 Aneurysms of the ulnar artery have also been reported for sequelae of hypothenar hammer syndrome. ⁴⁷

Aneurysms can happen at any age, even as a newborn. ⁴⁸ Clinical findings are usually a pulsating swelling in the hand associated with paresthesias and decreased sensation of the affected nerve. In 50% of cases, the mass may be pulseless, complicating the differential diagnosis from other lesions, including cysts, haematomas, foreign bodies, or granulomas. ⁴⁹

Arteriography is considered the gold standard diagnostic tool because of its ability to identify the primary lesion and assess the extent of local damage, identify distal emboli, and differentiate the aneurysm from other injuries. Furthermore, it allows the evaluation of the collateral flow to facilitate possible reconstructive procedures. ⁵⁰ Contrast-enhanced MRI angiography has high sensitivity and can be used in place of conventional arteriography in the investigation of lesions of the hand, albeit at a higher cost. ⁴³ Alternatively, ultrasonography with colour-duplex scanning is helpful for diagnosis, being the most useful non-invasive diagnostic tool.

Small aneurysms should be treated with external compression as the first line of treatment. Larger aneurysms are better treated with surgical resection and ligation of the feeding artery when distal circulation is not compromised. Surgical reconstruction with end-to-end vascular anastomosis or vein graft interposition is warranted if distal circulation is compromised. ⁴³ Percutaneous treatment using an injection of thrombin guided by Doppler ultrasound has been used safely with good results and could be an alternative treatment in haemophilic patients with pseudoaneurysms. ⁵¹

Conclusions

Most pathologies of the hand in haemophilic patients are secondary to bleeding episodes. All efforts should focus on prevention, ensuring adequate patient education, training of health personnel, and elimination of social barriers to ensure early access to adequate treatment with correct replacement factor therapy. Future research should investigate the effect of different replacement protocols or gene therapy in the incidence of haemophilia-related problems of the hand. In our experience, musculo-skeletal problems of the hand in haemophilia are rare due to the low incidence of involvement of the small joints and the improved control of the disease. A high level of clinical suspicion is necessary to promptly identify problems of the hand and ensure appropriate diagnosis and proper treatment. While surgical procedures are similar to those for non-haemophilic patients, surgical treatment is recommended to be undertaken only at institutions where there is expert haematology support to monitor factor levels correctly. Failure to do so may increase the potential of uncontrolled bleeding with potentially life-threatening complications.