Sweet clover disease, cattle

The bis(hydroxycoumarin) derivative dicoumarol (45), which was first identified as the causative agent of sweet clover disease in cattle, is used as an anticoagulant in the treatment of thrombosis. Similar compounds with other linking groups have been used, and warfarin (46), which was first introduced as a rodenticide, is also of value. The hydroxycoumarins interfere with the function of vitamin K in the synthesis of prothrombin and other blood... 

Schofield first described the sweet clover disease of cattle as a defect in blood clotting [2]. It has been shown since that this disease is connected with prothrombin deficiency [403, 404]. Later, the coumarin structure was recognised as the toxic agent of spoiled sweet clover hay responsible for the anticoagulant activity [34]. The bis-hydroxycoumarin (61) (dicoumarol) as the prototype of these compounds, was isolated from clover [33, 405] and applied in therapy [406-408]. 

The aldol condensation of 4-hydroxycoumarin with fonnaldehyde provides an a,p-unsaturated carbonyl compound, which then undergoes a conjugate (1,4-) addition of a second molecule of 4-hydroxycoumarin. This reaction could be catalyzed by either trace base or trace acid the acid-catalyzed reaction is shown and discussed here. The enol portion of 4-hydroxycoumarin is the nucleophile in an aldol reaction with protonated formaldehyde. The resulting product dehydrates to provide the a,p-unsaturated carbonyl compound, which, after protonation renders it a more reactive electrophile, then reacts with another nucleophilic molecule of 4-hydroxycoumarin in a conjugate addition reaction. This product, upon loss of a proton to the aqueous solvent, leads to dicoumarol. This substance is present in moldy sweet clover. It is a blood anticoagulant and its ingestion leads to the hemorrhagic sweet clover disease that kills cattle. 

Haemorrhagic agent causing sweet clover disease in cattle vitamin K antagonist. Used as a 0.25-0.5% soln. in EtOH as turbidimetric acid-base indicator (pH range 5.4-5.7). Cryst. (cyclohexanone). Mp 288-289°. 

Coumarins are also synthesized by a variety of plant species. Medically, the most significant coumarins are dicoumarol and its derivative, warfarin. Dicoumarol was initially discovered as the active substance in mouldy sweet clover hay, which could induce haemorrhagic disease in cattle. Dicoumarol and warfarin are now used clinically as anticoagulants, as discussed in Chapter 9. 

The only major side-effect of these oral anticoagulants is prolonged bleeding, thus the dosage levels are chosen with care. Dicoumarol was first isolated from spoiled sweet clover hay, as the agent which promoted haemorrhage disease in cattle. Both dicoumarol and warfarin have also been utilized (at high doses) as rat poisons. 

Sweet clover also contains coumarin derivatives and therefore poses an increased risk of bleeding if given with warfarin. There have been no reports of an interaction between sweet clover and warfarin or hemorrhagic disease in humans. However, several cases of severe hemorrhage and death have been reported in cattle. 

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