October 2023 – Coagulation

Type O blood.

Primary hemostasis, namely platelet plug formation at sites of vascular injury, are significantly influenced by ABO group. Plasma VWF levels are ∼25% lower in healthy group O compared with healthy group non-O individuals. In addition, blood group O VWF demonstrates enhanced susceptibility to ADAMTS13 proteolysis. These effects on VWF may be mediated by the ABO(H) carbohydrate structures that are carried on both the N- and O-linked glycans of VWF and expressed on several different platelet surface glycoprotein receptors. Recent studies support the hypothesis that ABO group not only exerts major quantitative and qualitative effects on VWF, but also affect specific aspects of platelet function. 

This patient’s childhood history of severe epistaxis and easy bruising (i.e., pre-pubertal), as well as the improvement of symptoms with age can be explained by the hormonal increase associated with puberty. Increased testosterone as well as estrogen can increase the amount of von Willebrand factor production. Von Willebrand factor production is also increased in the setting of trauma and surgery, explaining why it was within normal limits peri-operatively but began to downtrend towards his baseline between 40%-50% one month after surgery. 

Type 2A vWD is characterized by defective platelet binding due to the absence of high molecular weight vWF multimers in both plasma and platelets. Type 2A vWD patients have a low vWF:RCo to vWF:Ag ratio (<0.6). 

Type 2B vWD is characterized by spontaneous and increased binding of vWF to GpIbα receptors on platelets due to dominant gain-of-function A1 domain mutations and the absence of HMW-vWF multimers in plasma. Due to spontaneous platelet binding HMW-vWF multimers in plasma are proteolyzed by ADAMTS-13. Patients have a low VWF:RCo to VWF:Ag ratio (<0.6) and an increase in ristocetin-induced platelet aggregation (RIPA) at low dose ristocetin. Thrombocytopenia can also be observed in some type 2B vWD patients under stress conditions, such as pregnancy or infection, and after DDAVP use. This patient has a vWF:RCo to vWF:Ag ratio >0.6 and normal multimers, making these two possibilities less likely.

Type 2N vWD is characterized by markedly reduced or lack of vWF affinity FVIII binding. Recessive mutations in the vWF-FVIII binding domain result in the lack of FVIII binding and a disproportionate decrease in FVIII:C level to between 0.05 and 0.30 IU/mL. Patients can be homozygous or compound heterozygous for FVIII binding mutations or be compound heterozygous a FVIII binding mutation and a vWF null allele. This patient has normal Factor VIII activity, making this possibility less likely. Type 3 vWD is characterized by the absence of plasma vWF and a consequent decrease in the FVIII level to 10%. Patients are homozygous or compound heterozygous for the vWF null mutations. The most common nonsense mutation is R1659X in exon 28. Nonsense-mediated decay of the allele-specific mRNA is thought to be the molecular mechanism of the nonsense mutations. This patient has detectable vWF antigen and activity, as well as normal Factor VIII activity, making this possibility less likely.

References

1. Ward SE, O'Sullivan JM, O'Donnell JS. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood. 2020;136(25):2864-2874. doi:10.1182/blood.2020005843
2. Berber E. The molecular genetics of von Willebrand disease. Turk J Haematol. 2012 Dec;29(4):313-24. doi:10.5505/tjh.2012.39205. Epub 2012 Dec 5. PMID: 24385719; PMCID: PMC3781629.