Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ϳ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases. (Blood. 2011; 118(19):5302-5311) IntroductionThe blood coagulation system responds to vascular injury with local production of a clot formed of fibrin mesh and activated platelets. While this process is essential for hemostasis, dysregulated coagulation can lead to blood vessel occlusion (thrombosis), precipitating life-threatening events such as myocardial infarction, stroke and venous thromboembolism. In the classic view of blood coagulation, thrombin generation and fibrin formation can be initiated by 2 distinct mechanisms referred to as the extrinsic and intrinsic pathways. 1,2 The extrinsic pathway involves binding of plasma factor VIIa (fVIIa) to extravascular tissue factor (TF) at a site of vessel injury. 3 The first step in the intrinsic pathway requires the surface-dependent activation of plasma factor XII (fXII) to fXIIa in a process called contact activation. 4,5 Contact activation involves 2 other proteins, prekallikrein (PKK) and high molecular weight kininogen (HK). HK serves as a docking molecule for PKK on the contact surface. PKK is cleaved by fXIIa to form the protease ␣-kallikrein, which in turn cleaves fXII to generate additional fXIIa. Collectively, fXII, PKK and HK comprise the plasma contact system. FXIIa generated by contact activation can activate factor XI (fXI) to fXIa, triggering a series of proteolytic cleavage events that culminates in thrombin generation and fibrin clot formation.While the contact system can clearly trigger coagulation in vitro, it is not required for hemostasis. Humans and other animals deficient in a contact activation protein are largely asymptomatic. 4,[6][7][8] However, the contact system may play an important r...

The records of 99 dogs weighing over 20 kg with thoracolumbar disc disease were reviewed. Two types of disc disease were recognised: degenerative nuclear extrusion (n=63) and degenerative annular protrusion (n=36). Sixty-nine per cent of the affected discs were located between T12-T13 and L2-L3. Of the 63 dogs with degenerative nuclear extrusions, 35 were non-ambulatory and seven had no conscious pain perception at the time of presentation. Decompressive surgery was performed in 55 dogs, four dogs were managed non-surgically and three dogs were euthanased. A successful outcome was achieved in 49 (78 per cent) cases as assessed by the authors and in 53 (84 per cent) cases as assessed by the owners. Mean follow-up time was 11.7 months (range 1.5 to 48 months). Five dogs subsequently lost the ability to ambulate on their hindlimbs. Myelographic investigations in three of these dogs revealed a second thoracolumbar degenerative nuclear extrusion. Of the 36 dogs with degenerative annular protrusions, seven were non-ambulatory at the time of presentation. Fifteen cases had multiple protrusions. Twenty dogs were managed non-surgically, 12 surgically and four were euthanased. A successful outcome was achieved in eight (22 per cent) cases as assessed by the authors and in 19 (52 per cent) cases as assessed by the owners. Mean follow-up time was 9.2 months (range 1.5 to 30 months). The outcome of dogs with annular protrusions was significantly worse compared to the outcome of dogs with nuclear extrusions (P<0.001).

A study of 11 1 cases of cranial cruciate ligament disease, seen over a three year period has been made. Fifty-five of these dogs were under four years of age (average age 21.4 months) and most were of the larger breeds, particularly the rottweiler (25 per cent). The onset of clinical signs was sudden in 53 per cent and gradual in 47 per cent of these cases; bilateral disease was present in 31 per cent. The severity of the lameness was variable. The pathogenesis of the disease appears to involve a gradual stretching, partial rupture and eventually a complete rupture of the cranial cruciate ligament. The term cruciate disease has been used to cover this spectrum of ligament pathology and the clinical signs can appear at any stage during this ligament degeneration. Slight anterior drawer .movement can often be detected during the earlier stages of stretching and partial rupture but this can only be appreciated under general anaesthesia. Osteoarthritis is initiated during the early stages and may be well established by the time the cruciate completely tears. The predisposition to cruciate disease in these young dogs of the larger breeds is difficult to explain but may be related to inadequate exercise during puppyhood.

Pathology of the menisci was evaluated in 87 consecutive cases of cruciate disease in the dog. Lesions were recorded in 43 cases (49 per cent) and only the medial meniscus was affected. The commonest lesion was a folding of the caudal horn of the medial meniscus with its displacement between the medial femoral and tibial condyles (19 cases). Other lesions were single or multiple longitudinal tears (14 cases) in which four showed the classical ‘bucket handle’ appearance, fibrillation/tearing of the femoral surface (four cases), axial fringe tears (three cases) and transverse tears (three cases). The meniscal lesions were treated by a partial meniscectomy at the time of the cruciate surgery. Meniscectomy had no untoward effect on the postoperative recovery and overall the postoperative recovery of the dogs in this study has been superior to the author's previous cases where the menisci were not properly evaluated.

Eight dogs presented with chronic hindlimb lameness associated with cranial cruciate ligament rupture. Seven were small terriers. A caudal deformity of the proximal tibial shaft, originating at the proximal tibial physis, and an excessive caudal slope of the tibial plateau were present bilaterally in all dogs. The deformity was thought to be responsible for the cranial cruciate ligament failure and poor response to conservative management. Tibial plateau angles were in excess of 26 degrees in all dogs. The lameness was bilateral in three dogs. There was complete cranial cruciate ligament rupture in seven stifles and partial rupture in four. There were no meniscal injuries. Surgical correction resulted in a significant improvement (P<0.0001) in all dogs, with a mean follow-up of 12 months (range three to 24 months). There were no complications.