Management of the Bleeding Patient Receiving New Oral Anticoagulants: A Role for Prothrombin Complex Concentrates

Table 2

Animal and human studies using factor concentrates to reverse anticoagulant effect of dabigatran, rivaroxaban, and apixaban.

Author	Reversal agent	Test system	Coagulation test effect	Bleeding outcome effect
Dabigatran
Van Ryn et al. [16]	aPCC	Rat	aPTT unchanged	Decreased bleeding time
	rfVIIa	Rat	aPTT decreased	Decreased bleeding time
Van Ryn et al. [14]	4-Factor PCC	Rat	PT decreased, aPTT unchanged	Decreased bleeding time
	aPCC	Rat	PT decreased, aPTT unchanged, increased thrombin generation	Decreased bleeding time
	rfVIIa		PT and aPTT decreased	Decreased bleeding time
Lambourne et al. [38]	4-Factor PCC	Mouse	No effect	No effect
	rfVIIa	Mouse	aPTT decreased	No effect
	4-Factor PCC + rfVIIa	Mouse	TT and aPTT decreased	No effect
	aPCC	Mouse	No effect	No effect
Pragst et al. [39]	4-Factor PCC	Rabbit	PT decreased, aPTT unchanged	Normalized blood loss
Zhou et al. [40]	4-Factor PCC	Mouse ICH		Prevented hematoma expansion; control level mortality
	rfVIIa	Mouse ICH		Ineffective control of hematoma expansion
Marlu et al. [13]	4-Factor PCC	Human in vitro	Increased amount of thrombin generation
	rfVIIa	Human in vitro	Corrected time to thrombin generation
	aPCC	Human in vitro	Corrected time to thrombin generation
Eerenberg et al. [15]	4-Factor PCC	Human	No effect on aPTT, TT, or ECT
Khoo et al. [41]	aPCC	Human in vitro	Increased thrombin generation and corrected time to thrombin generation
Warkentin et al. [17]	rfVIIa	Human case report	Decreased aPTT and PT	Decreased blood loss
Garber et al. [18]	rfVIIa	Human case report		Worsening ICH
Truumees et al. [19]	rfVIIa	Human case report		Continued blood loss
Lillo-Le Louët et al. [20]	4-Factor PCC + rfVIIa	Human case report	PT and aPTT unchanged	Continued bleeding
	4-Factor PCC + rfVIIa	Human case report	PT and aPTT unchanged	Bleeding stopped with dialysis
Wychowski and Kouides [42]	3-Factor PCC	Human case report	TT and aPTT unchanged, PT decreased	No further bleeding
Dumkow et al. [43]	3-Factor PCC	Human case report		Clinical bleeding and hemoglobin stabilized
Rivaroxaban
Perzborn and Tinel [44]	4-factor PCC	Rat	PT decreased	Bleeding time decreased
Godier et al. [45]	4-factor PCC	Rabbit	aPTT normalized, PT decreased	No effect on blood loss
	rfVIIa	Rabbit	aPTT normalized, PT decreased	Decreased bleeding time, no effect on blood loss
Perzborn et al. [46]	4-Factor PCC	Rat	Decreased PT, normalized TAT concentration	Reduced bleeding time
	aPCC	Rat	Decreased PT	Reduced bleeding time
		Primate	Reduced PT	Normalized bleeding time
	rVIIa	Rat	Decreased PT	Reduced bleeding time
		Primate	Decreased PT	Bleeding time unchanged
Marlu et al. [13]	4-Factor PCC	Human in vitro	Increased amount of thrombin generation
	rfVIIa	Human in vitro	Corrected time to thrombin generation
	aPCC	Human in vitro	Corrected all thrombin generation parameters
Eerenberg et al. [15]	4-Factor PCC	Human in vivo	Normalized PT and thrombin generation
Dinkelaar et al. [47]	4-Factor PCC	Human in vitro	No effect on PT or time to thrombin generation Normalized amount of thrombin generation
Körber et al. [48]	4-Factor PCC	Human in vitro	No effect on aPTT, PT
	rfVIIa	Human in vitro	Decreased clotting time, no effect on aPTT, PT
Apixaban
Escolar et al. [23]	PCC	Human in vitro	Increased thrombin generation
	rfVIIa	Human in vitro	Increased thrombin generation
	aPCC	Human in vitro	Increased thrombin generation

aPCC: activated prothrombin complex concentrate; rfVIIa: recombinant factor VIIa.