Paroxysmal Nocturnal Hemoglobinuria : Thromboembolism

• the ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation
• however, this is not realistic for many patients, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality.
• tendency toward thrombosis in patients with PNH is multifactorial in etiology, involving the absence of GPI-anchored complement inhibitors on the surfaces of circulating platelets, the high levels of intravascular free plasma hemoglobin with the consequent scavenging of NO, fibrinolytic defects, and the pro-inflammatory effects of C5a.
• The relative importance of each factor is not yet known but the integration between the 2 major host protection systems, coagulation and innate immunity, is obvious.

Management
Evidence for Use

• Primary prophylaxis of thromboembolism for patients with PNH has been advocated. 
• This can be prevented using inhibitors of the cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone.
• Thrombolytic agents used in the acute stage of thrombosis should be followed by full anticoagulation with warfarin or heparin (preferably LMWH).
• Patients with documented thrombosis should receive lifelong secondary prophylaxis. Most authors suggest a target international normalised ratio of 2.0 to 2.5.
• Whether this approach is safe and effective in all patients with PNH remains controversial, however.
• Unfortunately, some patients will continue to develop blot clots despite aggressive anti-coagulation agents.

Evidences against Use

• In addition, thrombocytopenia is a relative contraindication to anticoagulation and this complication is not uncommon in patients with PNH.
• In addition, there are still clear cases of thromboses occurring while patients are therapeutically anticoagulated, which is less surprising when the proposed mechanisms are considered.
• After a thrombotic event, it appears that anticoagulation alone as secondary prevention is not sufficient
• There are no studies of antiplatelet drugs, such as aspirin or clopidogrel, in PNH, but again, mechanistically, it is clear that they are unlikely to be of benefit and again there is a true risk of hemorrhage.

Recommendations

• the pros and cons of prophylactic anticoagulation needs discussion with the patient

Alternatives
Eculizumab

• Because thrombosis is the leading cause of death, the impact of eculizumab on thrombosis largely explains the improved survival seen with eculizumab therapy.
• in the past, patients with thrombosis were maintained on anticoagulation for the remainder of their life. 
• This is still recommended, although it is not clear that this is necessary in patients receiving eculizumab. 
• Eculizumab seems to markedly reduce the incidence of thrombosis in PNH

Others

• Enoxaparin, dalteparin, heparin and warfarin had also be used
• Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement.
• Prophylactic anticoagulation with warfarin or heparin derivatives has been used with variable success

Warfarin

• Not an alternative to eculizumab, but there is evidence that it reduces thrombosis risk
• The risks with warfarin anticoagulation in several studies is deemed too high as the studies were not reflective of the PNH population whom are generally younger

References:

1. http://emedicine.medscape.com/article/207468-treatment
2. http://www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/paroxysmal_nocturnal_hemoglobinuria_pnh.html
3. http://www.bloodjournal.org/content/121/25/4985?sso-checked=true
4. http://bestpractice.bmj.com
5. Technology Assessment Report no. 209. Preliminary Assessment Analysis on Eculizumab for PNH, May 2013. 
6. Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria. Cochrane Database of Systematic Reviews, 2014