In a nutshell: Explaining joint and muscle bleeding in individuals with haemophilia A and B

Abstract

(A) Formation of the platelet–fibrin haemostatic plug. Vascular injury exposes von Willebrand factor (VWF) and tissue factor (TF) to flowing blood. VWF mediates platelet adhesion, leading to platelet activation and aggregation, while TF triggers the coagulation cascade, generating thrombin that converts fibrinogen to fibrin. Thrombin also amplifies platelet activation, integrating the two arms so that platelet aggregates and a fibrin mesh combine to form a stable platelet‐fibrin haemostatic plug. (B) Anatomical correlation between bleeding phenotype and tissue factor expression. Typical bleeding sites in haemophilia A and B (intra‐articular and intramuscular) are shown relative to the tissue‐specific pattern of high tissue factor (TF) expression. Vital organs such as the brain, heart and lungs exhibit high TF expression, proposed to provide additional haemostatic protection, whereas the low TF expression in joints and skeletal muscle leaves these sites more reliant on FVIII‐ and FIX‐dependent amplification and therefore vulnerable to bleeding when these factors are deficient. Figure created with BioRender.com.

INTRODUCTION

Individuals with a deficiency of factor (F) VIII (haemophilia A) or FIX (haemophilia B) are prone to intra‐articular and intramuscular haemorrhage. ¹ , ² These two sites have low levels of tissue factor (TF) expression. TF is the receptor and cofactor for FVII/FVIIa. The TF‐FVIIa complex is the physiologic trigger of blood coagulation and is essential for haemostasis. ³ An explanation of the bleeding sites in individuals with haemophilia A or B is not widely known nor commonly taught in medical education.

FORMATION OF A HAEMOSTATIC PLUG

Coagulation is often taught in medical education as a linear pathway of sequential reactions. However, the cell‐based model of coagulation proposed that activation of coagulation is initiated by TF‐bearing cells whereas amplification occurs on the surface of activated platelets that expose negatively charged phospholipids, such as phosphatidylserine. ⁴

The TF‐VIIa complex (extrinsic tenase) activates the coagulation protease cascade by cleaving and activating both FIX and FX, which leads to the generation of a small amount of thrombin (Figure 1A,B). ³ , ⁴ , ⁵ Thrombin is the central protease of the clotting cascade and cleaves fibrinogen to soluble fibrin monomers and activates various cofactors and the transglutaminase FXIII, which crosslinks fibrin monomers (Figure 1B). Due to the rapid inactivation of the TF‐FVIIa complex by tissue factor pathway inhibitor ⁶ (Figure 1C), amplification of the coagulation cascade requires other coagulation factors, such as FVIII and FIX (Figure 1D). The FVIIIa‐FIXa complex (intrinsic tenase) activates FX that leads to the generation of high levels of thrombin (Figure 1D). Activated FXI, which is activated by either thrombin or FXIIa, can also activate FIX (Figure 1D).

FIGURE 1.

The cell‐based model of coagulation. (A) Vascular injury. Tissue factor (TF) is normally sequestered on the subendothelial vessel wall, separated from circulating factor VII (FVII). Vascular injury exposes TF to blood, allowing assembly of the TF–FVIIa complex and, ultimately, formation of a haemostatic plug. (B) Initiation. The TF–FVIIa complex (extrinsic tenase) initiates the protease cascade by activating both FIX and FX. FXa, together with its cofactor FVa, converts prothrombin (PT) to thrombin (FIIa). Thrombin cleaves fibrinogen to soluble fibrin and activates cofactors (FV, FVIII) and the transglutaminase FXIII, which crosslinks fibrin monomers. (C) Inhibition. Tissue factor pathway inhibitor (TFPI) binds FXa, and the TFPI‐FXa complex then inactivates the TF‐FVIIa complex. This rapid inhibition curtails the initiation phase, so sustained thrombin generation depends on amplification through the intrinsic pathway. (D) Amplification. The small amount of thrombin generated during initiation activates platelets and amplification factors. The FVIIIa‐FIXa complex (intrinsic tenase) activates FX, and FXa‐FVa generates a large burst of thrombin. FXI, activated by thrombin or FXIIa, further activates FIX to sustain this output. The resulting thrombin converts fibrinogen to fibrin, which FXIIIa crosslinks into a stable haemostatic plug. Figure created with BioRender.com. F, factor; PT, prothrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor. [Colour figure can be viewed at wileyonlinelibrary.com]

WHAT EXPLAINS THE BLEEDING PRESENTATIONS OF PATIENTS WITH HAEMOPHILIA A OR B?

Haemophilia A and haemophilia B are X‐linked bleeding disorders caused by deficiency of FVIII and FIX respectively. ² The most common sites for bleeding in individuals with a deficiency of FVIII or FIX are joints and skeletal muscle. ¹ , ² Although the initial cause of bleeding is not well understood, it is thought to be due to trauma. Current data suggest that episodes of intra‐articular bleeding function as self‐perpetuating cycles. ⁷ Articular haemorrhages, just like extravasated blood in other tissues, are inflammatory and cause cartilage degradation, inflammation and haemosiderin deposition. ⁷ This creates a weakened synovium that is more susceptible to microtrauma and further bleeding, continuing the cycle.

TF is expressed in around blood vessels and at body surfaces and is proposed to form a ‘haemostatic envelope’ to limit bleeding after injury to blood vessels. ⁷ In addition, TF is expressed in a tissue‐specific manner with high levels in the brain, heart, lungs, uterus and testis and low levels in skeletal muscle and joints. ³ , ⁸ , ⁹ The high TF levels in these organs are hypothesized to provide additional haemostatic protection. ⁹

The reason individuals with haemophilia A or B have intra‐articular and skeletal muscle bleeding is thought to be the low levels of TF in these tissues. ³ , ⁹ Because of the low levels of TF, these tissues are more reliant on amplification of the coagulation cascade by FVIII and FIX than tissues that express high levels of TF. This amplification is impaired in individuals with deficiencies in FVIII or FIX.

Individuals with a deficiency of FVIII or FIX can sometimes experience intracranial haemorrhage, although this is rare. ¹⁰ However, this is the most serious complication of haemophilia A or B. The brain contains high levels of TF, but this is not always sufficient to compensate for a deficiency of FVIII or FIX because the TF‐FVIIa complex is rapidly inhibited by tissue factor pathway inhibitor, and FVIII and FIX are still required for amplification of the coagulation cascade.

Another important factor that may explain the site‐specific bleeding in haemophilia B is the fact that a substantial fraction of FIX resides in an extravascular compartment reversibly bound to collagen IV within the basement membranes of blood vessels. ¹¹ This binding is mediated by the calcium‐dependent γ‐carboxyglutamic acid domain of FIX. Importantly, mutation of this domain leads to a mild haemophilic phenotype in mice. ¹² Immunohistochemical studies of tissues from human donors demonstrate abundant FIX in the perivascular regions of skeletal muscle and liver. ¹³ In addition, injection of radiolabelled FIX into mice led to a wide tissue distribution, including the liver, kidney and spleen, as well as within joints. ¹⁴ FIX infusion into mice gave a similar localization pattern. These findings indicate that FIX is preferentially localized to specific extravascular membrane compartments of blood vessels rather than uniformly distributed across all collagen 4‐containing basement membranes. These studies indicate that, in addition to the plasma pool of FIX, there is a perivascular pool of FIX that mediates haemostasis. The fact that perivascular FIX is observed in skeletal muscle and joints supports the notion that these tissues are more reliant on FIX for haemostasis than other tissues.

Acquired haemophilia A (AHA), caused by autoantibodies against FVIII, presents with a predominantly soft tissue and muscle bleeding phenotype rather than the haemarthroses characteristic of congenital haemophilia A. ¹⁵ Patients frequently present with multiple bleeding sites simultaneously, which is uncommon in congenital disease. ¹⁵ The reason for these differences is not well understood. However, several factors may explain the difference. First, AHA typically occurs in older, less mobile patients who may experience less joint microtrauma. ¹⁵ Second, the time course of disease may be too short for the self‐perpetuating cycle of synovial damage and haemarthrosis to become established. Third, subclinical joint bleeds may go unrecognized in patients who, unlike those with congenital haemophilia, are not sensitized to early intra‐articular bleeding.

CONCLUSION

We propose that the site‐specific characteristic bleeding of individuals with haemophilia A or B can be explained by understanding the regulation of the coagulation protease cascade and the tissue‐specific pattern of TF expression. The TF‐FVIIa complex initiates the coagulation cascade but is rapidly inhibited by tissue factor pathway inhibitor, whereas the FVIIIa‐FIXa complex drives amplification of the coagulation cascade. Bleeding in haemophilia A and B occurs in joints and skeletal muscle, which have low TF expression and therefore are more dependent on FVIII and FIX for generation of high levels of thrombin for haemostasis.

AUTHOR CONTRIBUTIONS

Benjamin K. Lau: Conceptualization; writing – original draft; writing – review and editing; visualization. Nigel Mackman: Writing – review and editing; conceptualization; supervision; visualization. Shantanu Srivatsa: Conceptualization; writing – original draft; visualization; writing – review and editing.

FUNDING INFORMATION

SS was supported by NIH grant T32HL007055. NM was supported by the National Institutes of Health grant R35HL155657 (N.M) and the John C. Parker professorship.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to disclose.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

Figure 1 was created using BioRender.com.

Lau BK, Srivatsa S, Mackman N. In a nutshell: Explaining joint and muscle bleeding in individuals with haemophilia A and B. Br J Haematol. 2026;209(3):915–918. 10.1111/bjh.70699

DATA AVAILABILITY STATEMENT

No original data were generated or analysed; this is a narrative review.